The risk-score of the HER2DX genomic test (HER2DX risk-score) was first validated in an independent combined dataset of 268 patients (pts) with early-stage HER2+ breast cancer treated with neoadjuvant and adjuvant anti-HER2-based treatment (EBioMedicine 2022). Here, we report an updated survival analysis with longer follow-up, with a special focus on the value of HER2DX risk-score beyond pathological complete response (pCR).
A dataset of 268 pts with early-stage HER2+ disease obtained from a combined cohort of 3 neoadjuvant studies was used for an independent validation of the standardized HER2DX risk-score. The dataset was composed of 147 pts from Hospital Clinic, 84 pts from PAMELA trial and 37 pts from the Padova University cohort. All pts received chemotherapy and 1-year of trastuzumab; 56% of pts received dual HER2 blockade; and 9% pts with residual disease received adjuvant T-DM1. The Kaplan-Meier method and stratified Cox models were used to estimate hazard ratios (HRs) to evaluate the association between HER2DX and disease-free survival (DFS).
Median follow-up was 73.2 months (vs. 52.7 months in the prior report). HER2DX score as a continuous variable was significantly associated with DFS (HR=1.97, p=0.003) and overall survival (HR=2.23, p=0.009). According to the prespecified cut-off, the HER2DX low-risk group had longer DFS than high-risk (7-year 94.6% vs. 77.5%; HR=0.4, p=0.002). HER2DX risk-score was significantly (HR=1.90; p=0.003) associated with DFS independently of pCR status and hormone receptor status. Within pts with a pCR (n=118), the HER2DX low-risk group had longer DFS than the high-risk (5-year 96.5% vs. 88.4%; HR=0.33, p=0.178). Within pts without a pCR (n=148), the HER2DX low-risk group had longer DFS than the high-risk (5-year 95.6% vs. 85.3%; HR=0.20, p=0.004), and it was significantly (HR=2.03; p=0.006) associated with DFS independently of hormone receptor and adjuvant T-DM1.
The HER2DX risk-score determined in baseline pre-treatment core-biopsies provides prognostic information beyond pCR status in patients with early-stage HER2+ breast cancer treated with neoadjuvant and adjuvant anti-HER2 treatment.
The authors.
Has not received any funding.
O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis, Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Medical advisory: Reveal Genomics. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. L. Pare Brunet: Financial Interests, Institutional, Full or part-time Employment: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent pending: In vitro method for the prognosis of patients suffering from HER2-positive breast cancer - 905333: Reveal Genomics S.L. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, MERCK SHARP& DOHME, GSK, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp& Dohme, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. M. Marín-Aguilera: Financial Interests, Institutional, Full or part-time Employment, Product Manager: Reveal Genomics, S.L. M. Munoz: Financial Interests, Personal, Expert Testimony: Roche, Novartis; Financial Interests, Personal, Other, International conference travel grants: Roche, Pfizer, Lilly, Gilead; Financial Interests, Personal, Advisory Board: Pierre Fabre, Seagen, AstraZeneca. A. Vivancos: Financial Interests, Personal, Advisory Board: Roche, Bristol Meyers Squibb, Guardant Health, Bayer, Incyte; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Meyers Squibb, Roche, Incyte. P. Villagrasa Gonzalez: Financial Interests, Personal and Institutional, Member of the Board of Directors: Reveal Genomics; Financial Interests, Personal and Institutional, Proprietary Information: Reveal Genomics. P.F. Conte: Financial Interests, Personal, Advisory Board, advisory board for alpelisb trial: Novartis; Financial Interests, Institutional, Research Grant: Merck KGaA. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA.T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Amgen, GSK; Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Sanofi, Merck Serono, Exact Sciences, Eisai, Olema Oncology; Financial Interests, Personal, Expert Testimony: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Eli Lilly, Roche, BMS, Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, GlaxoSmithKline, Daiichi Sankyo, Nerviano; Non-Financial Interests, Member: ASCO. All other authors have declared no conflicts of interest.
In the APT and ATEMPT trials, adjuvant paclitaxel and trastuzumab (TH) and T-DM1 were found associated with excellent long-term outcomes for patients (pts) with small, node-negative HER2-positive breast cancer (HER2+ BC), respectively. HER2DX risk score was found associated with outcomes in both trials, separately.
We conducted a retrospective analysis combining pts included in the APT and ATEMPT trials with available HER2DX data. Co-primary endpoints were associations of HER2DX with relapse-free interval (RFI) and invasive disease-free survival (iDFS). The HER2DX risk-score was evaluated i) as a continuous variable (0-100), ii) using the predefined cut-off (50), and iii) using an exploratory optimal cut-off (32). The Kaplan-Meier method and stratified Cox regression models were used to evaluate the association between HER2DX and outcomes.
In total, 471 pts receiving TH (n=324) or T-DM1 (n=147) were included in the study, most having stage I (n=432, 92%) and hormone receptor-positive disease (n=335, 75%). The median follow-up was 6.7 years (10.8 and 5.8 for APT and ATEMPT, respectively). The median HER2DX risk-score was 13.9 (IQR 4.7 - 27.0), with 5.5% and 18.3% of the pts having HER2DX high-risk disease according to the predefined and optimal cut-off, respectively. HER2DX risk score as a continuous variable was associated with RFI (HR per 10-units: 1.39, 95%CI: 1.09-1.78; p=0.009) but not with iDFS (HR per 10-units: 1.18, 0.98-1.42; p=0.09). Using the predefined cut-off (50), pts with HER2DX high-risk disease had higher RFI risk (HR: 7.33, 2.29-23.47, p<0.001), but the effect on iDFS was non-significant (HR: 2.78, 0.97-7.95, p=0.057). In multivariable analysis of RFI, HER2DX remained statistically significant after adjustment for hormone receptor status and tumor size (HR: 7.89, 2.06-30.22, p=0.003). The optimal cut-off (32) distinguished pts with low-risk (7-year RFI of 98.2%; 96.7%-99.6%) from high-risk disease (7-year RFI: 88.7%; 80.4%-97.8%) [delta of 9.5%], including in multivariable analysis for RFI (HR: 6.87, 2.22-21.27, p<0.001) and iDFS (HR: 2.81, 1.26-6.23, p=0.01).
The HER2DX risk score is associated with the risk of recurrence among pts with small, node-negative HER2+ breast tumors treated with adjuvant TH or T-DM1.
The authors.
Has not received any funding.
P. Tarantino: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Lilly, Gilead. P. Villagrasa Gonzalez: Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Advisory Board: Nanostring. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. L. Pare Brunet: Financial Interests, Institutional, Full or part-time Employment: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent pending: In vitro method for the prognosis of patients suffering from HER2-positive breast cancer - 905333: Reveal Genomics S.L. A.H. Partridge: Financial Interests, Personal, Royalties, Royalties received for authorship of Breast Cancer Survivorship section: UpToDate; Non-Financial Interests, Leadership Role, co-Chair of Breast Committee: Alliance for Clinical Trials, National Cancer Institute; Non-Financial Interests, Other, Board of Directors, Member 2022-2026: ASCO. H.J. Burstein: Non-Financial Interests, Principal Investigator, Grant for clinical research: National Cancer Insti; Non-Financial Interests, Invited Speaker: Alliance for Clinical Trials in Oncology. I. Krop: Financial Interests, Personal, Advisory Board: genentech/Roche, AstraZeneca, Daiichi Sankyo, Macrogenics, Seagen; Financial Interests, Personal, Other, DSMB member: Novartis; Financial Interests, Personal, Other, DSMC member: Merck; Financial Interests, Personal, Full or part-time Employment, Spouse: PureTech, Freeline; Financial Interests, Personal, Stocks/Shares, Spouse: PureTech, Freeline; Financial Interests, Institutional, Invited Speaker: Pfizer, Macrogenics, Genentech?Roche. E.P. Winer: Financial Interests, Personal, Advisory Board: Athenex, Carrick Therapeutics, G1 Therapeutics, Genentech/Roche, Genomic Health, Gilead, GlaxoSmithKline, Jouce, Lilly, St. Lucia, Syros, Zymeworks; Non-Financial Interests, Personal, Advisory Board: Leap Therapeutics; Non-Financial Interests, Personal, Invited Speaker: ASCO. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna, Myovant, Bayer, Zetagen, Infinity Therapeutics, Umoja Biopharma; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. All other authors have declared no conflicts of interest.
HER2DX ERBB2 mRNA score captures the dynamic range of ERBB2 expression in both HER2-negative and HER2+ breast cancer (BC). In a previous study (Prat et al. EBiomedicine 2022), ERBB2 mRNA predicted clinical HER2+ status with high performance in the validation dataset (n=353; AUC=0.96). Here, we evaluated the ability of HER2DX ERBB2 mRNA to predict HER2+, HER2-low, and HER2-0 status.
Standardized HER2DX was evaluated centrally on formalin-fixed paraffin-embedded tumors from 1,149 samples with HER2+ (n=1,029) vs. HER2-negative status (n=120). We trained a new ERBB2 cutoff (by means of decision trees) to predict HER2-low (n=73) versus HER2-0 (n=47) status, and tested in an independent validation dataset of 110 HER2-negative tumors with known HER2-low (n=60) and HER2-0 (n=50) status. To quantify the diagnostic performance: area under the ROC curve (ROC AUC), global accuracy, positive (PPV) and negative predictive value (NPV) were calculated.
In the HER2+ and HER2-negative dataset (n=1,149), the ROC AUC of ERBB2 mRNA expression to predict HER2+ status was 0.98. The mean ERBB2 expression (in log base 2) in HER2+ and HER2-negative disease was 1.41 and -2.41, respectively (14.1-fold difference). Of note, 0.8% of HER2-negative cases were identified as ERBB2-positive and 9.9% of HER2+ cases were identified as ERBB2 negative. In the HER2-negative training dataset (n=120), the ROC AUC of ERBB2 mRNA expression to predict HER2-low vs. HER2-0 status was 0.80, and a new cutoff was identified with 77.5% accuracy (68.5% PPV and 84.9% NPV). In the independent validation HER2-negative dataset (n=110), the ROC AUC of ERBB2 mRNA expression was 0.77. With the new ERBB2 cutoff, the overall accuracy to predict HER2-low and HER2-0 cases was 65.5% (66.7% PPV and 64.9% NPV). Finally, the mean ERBB2 mRNA expression (in log base 2) in HER2-low and HER2-0 disease was -1.86 and -2.72, respectively (1.8-fold difference).
The standardized HER2DX ERBB2 mRNA score predicts the clinical status of HER2 (positive, low and zero) in BC.
The authors.
Has not received any funding.
G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. M. Oliveira: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo / AstraZeneca, Gilead, Pierre Fabre, Roche, Seagen, iTEOS, Relay Therapeutics; Financial Interests, Personal, Invited Speaker: Gilead, MSD, Novartis, Pfizer, Roche, Seattle Genetics, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer-Ingelheim, GSK, Roche, Seattle Genetics, Zenith Epigenetics, Gilead, Ayala Pharmaceuticals; Financial Interests, Invited Speaker: Roche; Non-Financial Interests, Invited Speaker: SOLTI Breast Cancer Research; Other, Travel Grant: Pierre Fabre, Eisai, Gilead, AstraZeneca. M.J. Vidal Losada: Financial Interests, Personal, Advisory Board: Novartis/Pfizer, Roche, Pfizer, AstraZeneca/Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis/Pfizer, Roche/Genentech, AstraZeneca/Daiichi Sankyo, Gilead Sciences; Financial Interests, Personal, Other, Travel, Accommodations, expenses: Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Gilead Sciences. M. Bellet-Ezquerra: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Lilly, Stemline-Menarini; Other, Speaker'sBureau and Travel Expenses: Pfizer; Other, Speaker's Bureau: Novartis, Lilly. J.A. Puig-Butille: Financial Interests, Personal, Invited Speaker: ThermoFisher; Financial Interests, Personal, Funding: CareDX. S. Pernas Simon: Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pfizer; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Invited Speaker: Astra-Zeneca, Novartis, Daiichi Sankyo; Non-Financial Interests, Invited Speaker: SOLTI. C. Bueno Muiño: Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, AstraZeneca, GSK; Financial Interests, Personal, Advisory Board: Pfizer. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Roche/Genentech, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly, Novartis, Roche/Genentech; Financial Interests, Institutional, Research Grant: Novartis, Roche, Puma; Non-Financial Interests, Invited Speaker: TRIO; Non-Financial Interests, Leadership Role: GEICAM. P. Tarantino: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi Sankyo. A.G. Waks: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Genentech, Macrogenics, Merck. E.A. Mittendorf: Financial Interests, Personal, Advisory Board: Merck, BioNTech; Financial Interests, Institutional, Research Grant, I have a grant from SU2C funded by Roche/Genentech that supports the conduct of a clinical trial: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Gilead provides clinical trial support to my institution for a study that I am the PI on: Gilead; Financial Interests, Personal, Invited Speaker: Roche/Genentech, BMS; Non-Financial Interests, Invited Speaker: American Society of Clinical Oncology; Non-Financial Interests, Advisory Role, I serve in an advisory role as a Komen Scholar: Komen for the Cure. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna, Myovant, Bayer, Zetagen, Infinity Therapeutics, Umoja Biopharma; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp& Dohme, GSK, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp& Dohme, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. All other authors have declared no conflicts of interest.
HER2DX is a genomic test based on the expression of 27 genes tracking 4 signatures (luminal, proliferative, immune and HER2 amplicon) that provides prognostic (HER2DX risk score) and predictive information (HER2DX pathologic complete response [pCR] score) in HER2+ early breast cancer (BC). Here, we report the initial results of the first ongoing decision impact study of HER2DX at Hospital Clinic of Barcelona.
We conducted an observational, prospective, pilot, unicentric study, since Nov/21 (ongoing), to analyze the impact of HER2DX in clinical practice in early-stage HER2+ BC. Any medical oncologist of the Breast Unit could order the test. A survey was completed by the treating physician before and after receiving the result of HER2DX. The main objective was to assess the % of change in the therapeutic plan after obtaining the HER2DX report. Secondary objectives included 1) assess changes in the physician’s confidence before and after the test and 2) analyze the association of the HER2DX pCR score with the pathological response after neoadjuvant therapy (NAT). Descriptive statistics were used.
We report the results after the inclusion of the first 89 pts (as of 2nd of Feb/23). Median age was 53 years (range 30-79) and 52% of pts were postmenopausal. Most pts had T1-2 tumors (87%), negative nodes (64%), grade 2 (56%) or 3 (41%), ductal histology (87%), hormone receptor positive (65%), median Ki67 of 35% (range 4-90%) and median tumor-infiltrating lymphocytes of 10% (range 0-90%). 78% of pts received NAT and 22% upfront surgery. A change in the treatment plan before and after the HER2DX result was observed in 49 of 87 (56%) cases. De-escalation of therapy was observed in 59% of pts (less intense chemotherapy [ChT] in 57% of them) and escalation in 41% of pts (more intense ChT in 65% of them). The confidence in the decision improved in 67% of cases. Among 56 evaluable pts treated with NAT, HER2DX pCR score was significantly associated with pCR (81% in pCR-medium/high and 32% in pCR-low; odds ratio=9.3, p=0.001), independently of the rest of variables.
In this first pilot and prospective study, HER2DX impacted clinical care in early-stage HER2+ BC.
The authors.
Has not received any funding.
O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis, Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Medical advisory: Reveal Genomics. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. M. Marín-Aguilera: Financial Interests, Institutional, Full or part-time Employment, Product Manager: Reveal Genomics, S.L. M.J. Vidal Losada: Financial Interests, Personal, Advisory Board: Novartis/Pfizer, Roche, Pfizer, AstraZeneca/Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis/Pfizer, Roche/Genentech, AstraZeneca/Daiichi Sankyo, Gilead Sciences; Financial Interests, Personal, Other, Travel, Accommodations, expenses: Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Gilead Sciences. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. J.A. Puig-Butille: Financial Interests, Personal, Invited Speaker: Thermo Fisher; Financial Interests, Personal, Funding: CareDX. L. Pare Brunet: Financial Interests, Institutional, Full or part-time Employment: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent pending: In vitro method for the prognosis of patients suffering from HER2-positive breast cancer - 905333: Reveal Genomics S.L. P. Villagrasa Gonzalez: Financial Interests, Personal, Member of the Board of Directors: Reveal Genomics; Financial Interests, Personal, Proprietary Information: Reveal Genomics. M. Munoz: Financial Interests, Personal, Expert Testimony: Roche, Novartis; Financial Interests, Personal, Other, International conference travel grants: Roche, Pfizer, Lilly, Gilead; Financial Interests, Personal, Advisory Board: Pierre Fabre, Seagen, AstraZeneca. All other authors have declared no conflicts of interest.
The prognostic value of neutrophil/lymphocyte ratio (NLR) for HER2-positive metastatic breast cancer (MBC) is not well studied. This study aims to evaluate the prognostic role of baseline NLR in HER2-positive MBC patients treated with trastuzumab/pertuzumab.
The clinical data of 780 patients from CLEOPATRA were applied from VIVLI platform, and 248 HER2-postive MBC were collected from six local hospitals. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses were used to control bias. The associations between clinicopathological factors, NLR and progression-free survival (PFS) and overall survival (OS) were analyzed by univariate and multivariate analyses.
After PSM or IPTW adjustment, the subgroups were similar. Low baseline NLR was prognostic with better PFS and OS in the TH group in raw, PSM and IPTW models. Upon IPTW, low NLR, versus high NLR, was associated with improved PFS (HR 1.35, 95% CI 1.07-1.70, P = 0.012) and OS (HR 1.47, 95% CI 1.12-1.94, P = 0.006) in the TH group. In the THP group, low baseline NLR was also correlated with better PFS, but not for OS in the three models. After IPTW, patients with low NLR were associated with better PFS (HR 1.52, 95% CI 1.20-1.93, P = 0.001) comparing that with high NLR. Multivariate analyses showed that low baseline NLR was a predictor for PFS and OS in TH group, and PFS in the THP group in the three models. In the real-world study, low baseline NLR was a predictor of better PFS among patients with trastuzumab plus docetaxel or trastuzumab plus pertuzumab plus docetaxel therapy (P = 0.025 and 0.009 respectively).
Low baseline NLR is associated with better survival outcome among HER2-positive MBC receiving docetaxel plus trastuzumab or docetaxel plus trastuzumab plus pertuzumab as first-line therapy. Re-analyses of prospective randomized studies are needed to verify the role of baseline NLR in HER2-positive MBC treated with trastuzumab/pertuzumab.
The authors.
Natural Science Foundation of Hunan Province (S2019JJKWLH0198, 2021JJ31094, 2021JJ31099) and Natural Science Foundation of Changsha City (KQ2007058).
All authors have declared no conflicts of interest.
HER2 loss on residual disease (RD) is frequent after NAT. Subtype switch has been also reported, with HER2-Enriched (HER2E) tumors converting frequently to non-HER2E. However, the association between HER2 immunohistochemistry (IHC) status and intrinsic subtype (IS) has never been described.
Between Feb/08 and Mar/22, 82 patients (pts) with HER2+ BC who underwent NAT at Hospital Clinic of Barcelona and had RD with matched IHC data were included. HER2 loss was defined as HER2 IHC 0/1+ or 2+/ISH not amplified on RD. Research-based PAM50 subtyping was performed with the nCounter platform. Associations between HER2 loss, IS dynamics, clinicopathological characteristics and event-free survival (EFS) were assessed.
At baseline, 61% (n=50) of tumors were HER2 3+ and 83% (n=68) were hormone receptor (HR) positive. All pts received NAT with trastuzumab, 98% with chemotherapy, 52% with pertuzumab; and 24% received adjuvant T-DM1. HER2 loss was identified in 46% of BC (24 IHC 0, 12 IHC 1+, 2 IHC 2+/ISH-). IS was assessed on 73 baseline and 72 RD samples (67 paired). Distribution of IS at baseline was: HER2E 42%, LumA 31%, LumB 14%, normal-like 9%, basal-like 4%; on RD was: HER2E 17%, LumA 36%, LumB 8%, normal-like 33%, basal-like 5%. ERBB2 mRNA levels significantly decreased after NAT (p=0.001). An IS switch was observed in 40% (n=27) of samples and was not associated with HER2 loss (p=0.455). However, HER2 loss was numerically more frequent among BC that switched from HER2E to non-HER2E (58%) than in BC that remained HER2E (23%) (p=0.082). In a multivariate regression analysis including baseline IHC, ERBB2 mRNA, IS, HR status, time from NAT to surgery and administration of dual HER2 blockade, only ERBB2 mRNA was significantly associated with HER2 loss (p=0.003). At a median follow up of 61.0 months, 12 EFS events were recorded. After adjusting for T-DM1 use, none of the variables assessed, including HER2 loss, was associated with EFS.
HER2 loss was associated with decrease in ERBB2 mRNA levels, was more frequent in tumors switching from HER2E to non-HER2E subtype, and was not associated with EFS. Further validation on large cohorts is warranted.
The authors.
Has not received any funding.
F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. F. Schettini: Financial Interests, Personal, Invited Speaker: Novartis, Gilead, Daiichi Sankyo; Financial Interests, Personal, Other, Travel expenses: Novartis, Gilead. M.J. Vidal Losada: Financial Interests, Personal, Advisory Board: Novartis/Pfizer, Roche, Pfizer, AstraZeneca/Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis/Pfizer, Roche/Genentech, AstraZeneca/Daiichi Sankyo, Gilead Sciences; Financial Interests, Personal, Other, Travel, Accommodations, expenses: Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Gilead Sciences. M. Munoz: Financial Interests, Personal, Expert Testimony: Roche, Novartis; Financial Interests, Personal, Other, International conference travel grants: Roche, Pfizer, Lilly, Gilead; Financial Interests, Personal, Advisory Board: Pierre Fabre, Seagen, AstraZeneca. N. Lin: Financial Interests, Institutional, Sponsor/Funding: Genentech, Pfizer, Merck, Seattle Genetics, Zion Pharmaceuticals, Olema Pharmaceuticals, AstraZeneca; Financial Interests, Personal, Other, Consulting honoraria: Puma, Seattle Genetics, Daiichi Sankyo, AstraZeneca, Denali Therapeutics, Prelude Therapeutics, Olema Pharmaceuticals, Aleta BioPharma, Affinia Therapeutics, Voyager Therapeutics, Janssen, Blueprint Medicines; Financial Interests, Personal, Stocks/Shares: Artera; Financial Interests, Personal, Other, Royalties: UpToDate. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna, Myovant, Bayer, Zetagen, Infinity Therapeutics, Umoja Biopharma; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis, Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Medical advisory: Reveal Genomics. All other authors have declared no conflicts of interest.
HER2DX is a 27-gene prognostic (risk-score) and predictive (pathological complete response [pCR]-score) assay in early-stage HER2+BC based on clinical data and the expression of 4 gene signatures (immune, proliferation, luminal differentiation and HER2 amplicon). Here we aim to further validate the ability of HER2DX to predict pCR.
Standardized HER2DX was evaluated centrally on FFPE tumor biopsies from the BionHER study, in which patients(pts) with stage I-III HER2+BC were treated with neoadjuvant THPx16weeks; tumor biopsies were obtained pre-treatment(D1) and 8 days later(D8), following the loading-dose of HP, prior to adding paclitaxel. Primary aim was to test the ability of HER2DX pCR-score to predict pCR (ypT0/isN0). Secondary objective were to test the ability of HER2DX pCR-score to predict pCR independently of hormone receptor (HR) status. HER2DX was also evaluated at D8. Logistic regression and receiver-operator curve (ROC) analysis were assessed.
HER2DX was evaluated in 49 pts of 52 (94%). cT1-2 disease represented 85% of cases (mean tumor size was 29mm), cN0 59%, and 67% were HR+. Among them, 46 of 49 (94%) pts had undergone surgery to date. The overall pCR rate was 45.6% and the rate of both pCR and ypT1miN0 was 55%. The % of HER2DX low-, medium- and high-pCR groups was 30.6%, 40.8% and 28.6%, respectively. HER2DX pCR-score (as a continuous variable [CV]) was significantly associated with pCR (odds ratio [OR]=4.25, p=0.001). The pCR rates in HER2DX pCR-high, pCR-medium and pCR-low groups were 75.6%, 40% and 13.3% (-high vs -low OR=18.33, p=0.004), respectively. The AUC ROC of HER2DX pCR score (as a CV) and pCR status was 0.813. HR status was significantly associated with pCR score (OR=0.43, p=0.008). HER2DX pCR score was significantly associated with pCR independently of HR status (OR=3.89, p=0.010), which lost its statistically significance in the presence of HER2DX pCR-score (OR=0.87), p=0.756).
The 27-gene HER2DX genomic test predicts pCR following neoadjuvant THP in HER2+ BC. Updated data, including D8 HER2DX results, will be presented at the conference.
The authors.
Reveal Genomics, S.L.
All authors have declared no conflicts of interest.
HER2DX is a 27-gene assay for early-stage HER2+ breast cancer based on clinical data and the expression of 4 signatures (immune, proliferation, luminal, and HER2). Here we evaluated the utility of HER2DX in HER2+ IBC for the first time.
Standardized HER2DX was evaluated centrally on baseline pre-treatment tumors from a prospective phase II clinical trial (NCT01796197), in which patients with HER2+ IBC were treated with neoadjuvant paclitaxel, trastuzumab and pertuzumab (THP) x 16 weeks. The primary aim of this correlative analysis was to evaluate the pCR rates (ypT0/isN0) according to HER2DX pCR-score pre-defined cutoffs (i.e., low, medium, and high). Secondary objectives were to compare the HER2DX scores and signatures in IBC vs. stage II-III HER2+ non-IBC treated with neoadjuvant THP x 12 weeks on trial (NCT03716180). Descriptive statistics were used. Means between the two groups were compared using a Student´s t-test.
HER2DX was evaluated in 23 patients with HER2+ IBC (
Study IBC non-IBC 23 80 19/21 (90.5%) 68/78 (87.2%) 23 (100%) 0 21 (91.3%) 28 (35%) 12 (52.2%) 56 (70%) 10 (43.5%) 48 (60%) 22 (95.7%; 78.1-99.9%) 39 (48.8%; 37.4-60.2%) 8 (34.8%; 16.4-57.3%) 31(38.8%; 28.1-50.3%) 11 (47.8%; 26.8-69.4%) 22 (27.5%;18.1-38.6%) 4 (17.4%; 4.9-38.8%) 27 (33.8%; 23.6-45.2%)
HER2DX pCR-high designation may be less frequent in HER2+ IBC compared to HER2+ non-IBC. Lower mRNA expression of HER2 amplicon genes, and higher tumor burden at diagnosis, might explain the differences observed in the distribution of HER2DX scores and signatures between HER2+ IBC and non-IBC.
NCT01796197.
The authors.
Reveal Genomics.
F. Lynce: Financial Interests, Personal and Institutional, Advisory Board, PI of clinical trial: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer, Merck, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Incyte, Eisai, CytomX. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. A.G. Waks: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Genentech, Macrogenics, Merck. P. Villagrasa Gonzalez: Financial Interests, Personal, Full or part-time Employment: Reveal Genomics; Financial Interests, Personal, Other, Co-Founder: Reveal Genomics. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. L. Pare Brunet: Financial Interests, Institutional, Full or part-time Employment: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent pending: In vitro method for the prognosis of patients suffering from HER2-positive breast cancer - 905333: Reveal Genomics S.L. C.M. Perou: Financial Interests, Personal, Invited Speaker: GeneCentric Therapeutics; Financial Interests, Personal, Stocks/Shares: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics; Financial Interests, Personal, Royalties, from PAM50 licensing: Bioclassifier LLC; Financial Interests, Personal, Royalties: GeneCentric Therapeutics; Non-Financial Interests, Advisory Role: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics. J. Parker: Financial Interests, Personal, Other, Advisory: Reveal Genomics, Bristol Myers Squibb; Financial Interests, Personal, Full or part-time Employment: LifeEdit Therapeutics; Financial Interests, Personal, Ownership Interest: Reveal Genomics, GeneCentric; Financial Interests, Personal, Royalties: Veracyte. A. Vivancos: Financial Interests, Personal, Advisory Board: Roche, Bristol Meyers Squibb, Guardant Health, Bayer, Incyte; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Meyers Squibb, Roche, Incyte. S. Pernas Simon: Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pfizer; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Novartis, Daiichi-Sankyo; Non-Financial Interests, Invited Speaker: SOLTI. E.P. Winer: Financial Interests, Institutional, Research Grant: Genentech/Roche; Financial Interests, Personal, Advisory Board: Athenex, Carrick Therapeutics, G1 Therapeutics, Genentech/Roche, Genomic Health, Gilead, GlaxoSmithKline, Jounce, Lilly, St Lucia, Syros, Zymeworks; Non-Financial Interests, Personal, Advisory Board, non-paid: Leap Therapeutics; Other, Personal, Leadership Role, President: ASCO. E.A. Mittendorf: Financial Interests, Personal, Advisory Board: Merck, BioNTech; Financial Interests, Institutional, Research Grant, I have a grant from SU2C funded by Roche/Genentech that supports the conduct of a clinical trial: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Gillead provides clinical trial support to my institution for a study that I am the PI on: Gillead; Financial Interests, Personal, Invited Speaker: Roche/Genentech, BMS; Non-Financial Interests, Invited Speaker: American Society of Clinical Oncology; Non-Financial Interests, Advisory Role, I serve in an advisory role as a Komen Scholar: Komen for the Cure. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna, Myovant, Bayer, Zetagen, Infinity Therapeutics, Umoja Biopharma; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. All other authors have declared no conflicts of interest.
HER2DX is a genomic test for early HER2+ breast cancer clinically available since January 2022 as a Laboratory Developed Test. Based on the expression of 27 genes (nCounter) plus tumor and nodal staging, it predicts the risk of relapse (risk-score), the probability of achieving a pathological complete response (pCR-score), and the individual levels of
Intra- and inter- labs HER2DX scores were compared by testing a set of FFPE samples previously analyzed at DLab. All scores ranged from 0 to 100 and pre-defined cut-offs were used to get HER2DX-groups. Repeatability and reproducibility were evaluated from different tissue sections, RNA, or FFPE blocks. Simulations (n=1·106) were used to calculate diagnostic values (sensitivity, specificity, positive and negative predictive values, and accuracy). Robustness was measured by evaluating the interference of non-tumor tissue and by using different RNA quantities. Differences due to the nCounter instrument, Tagset lot, and Tagset defrost cycles were also evaluated. HER2DX performance using a RNAseq platform (Illumina Exome Panel) was compared to nCounter.
Repeatability analysis within CLab in 10 samples showed a maximal standard error among the 3 scores of 0.94 (scale 0-100). Reproducibility starting from RNA was analyzed in 20 samples, and the probabilities of +/- 5 units difference in the risk-score, pCR-score, and
Analytical validation of HER2DX has proven it to be suitable for its intended purpose.
Reveal Genomics, S.L.
Reveal Genomics, S.L.
M. Marín-Aguilera: Financial Interests, Institutional, Full or part-time Employment, Product Manager: Reveal Genomics, S.L. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabre, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. J.A. Puig-Butille: Financial Interests, Personal, Invited Speaker: Thermo Fisher; Financial Interests, Personal, Funding: CareDX. A. Vivancos: Financial Interests, Personal, Advisory Board: Roche, Bristol Meyers Squibb, Guardant Health, Bayer, Incyte; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Meyers Squibb, Roche, Incyte. J. Matito: Financial Interests, Personal, Full or part-time Employment: Reveal Genomics. C.M. Perou: Financial Interests, Personal, Invited Speaker: GeneCentric Therapeutics; Financial Interests, Personal, Stocks/Shares: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics; Financial Interests, Personal, Royalties, from PAM50 licensing: Bioclassifier LLC; Financial Interests, Personal, Royalties: GeneCentric Therapeutics; Non-Financial Interests, Advisory Role: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics. P. Villagrasa Gonzalez: Financial Interests, Personal and Institutional, Member of the Board of Directors: Reveal Genomics; Financial Interests, Personal and Institutional, Proprietary Information: Reveal Genomics. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. J. Parker: Financial Interests, Personal, Other, Advisory: Reveal Genomics, Bristol Myers Squibb; Financial Interests, Personal, Full or part-time Employment: LifeEdit Therapeutics; Financial Interests, Personal, Ownership Interest: Reveal Genomics, GeneCentric; Financial Interests, Personal, Royalties: Veracyte. L. Pare Brunet: Financial Interests, Institutional, Full or part-time Employment: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent pending: In vitro method for the prognosis of patients suffering from HER2-positive breast cancer - 905333: Reveal Genomics S.L. All other authors have declared no conflicts of interest.
Recently, a HER2-targeting antibody-drug conjugates (HER2-ADC) was approved to treat HER2-low breast cancer (BC), currently defined by the immunohistochemical (IHC) HER2-expression ASCO/CAP scores of 1+ or 2+ without
We retrospectively analyzed 22 untreated BC samples with single cell RNA-sequencing and centralized HER2 IHC data. IHC staining for HER2 (Agilent, GA0485, RTU) was performed and scored according to ASCO/CAP 2018 guidelines. Single cell data were retrieved from the original publication (PMID: 33958794) and only the cancer cells (n= 31016) were retained.
We identified 1 HER2-zero (with no staining on tumor cells), 16 HER2-low (4 HER2-1+, 12 HER2-2+ FISH-negative) and 5 HER2-positive samples. The median percentage of cells expressing
Single cell data might provide more granularity into the tumor-specific expression levels of HER2. Future research is needed to investigate whether single-cell
The authors.
Has not received any funding.
H. Wildiers: Financial Interests, Institutional, Advisory Board: Roche, Lilly, AstraZeneca, Daiichi Sankyo, PSI Cro AG, KCE, MSD, MSD, E Squared Communications LLC; Financial Interests, Institutional, Invited Speaker: Eisai, AstraZeneca; Financial Interests, Institutional, Other, Consultancy fee: AbbVie, Immutep Pty; Financial Interests, Institutional, Expert Testimony: Daiichi Sankyo; Financial Interests, Institutional, Other, Consultancy: Daiichi Sankyo; Financial Interests, Institutional, Research Grant, Grant to the Leuven Breast Center to support the research database: Roche; Financial Interests, Institutional, Research Grant, Grant to institute to perform a multicentric national academic trial: Novartis; Other, Travel & accomodations: Pfizer; Other, Travel & accomodation: Roche; Other, Subscription fee: Gilead. K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Roche, Vifor Pharma, Eli Lilly, Pierre Fabre, McCann Health, Roularta, Teva, Gilead Sciences, Pfizer, Gilead, MSD; Financial Interests, Institutional, Invited Speaker: Pfizer, Roche, Novartis, Eli Lilly, Mundi Pharma, MSD, Medscape, MSD; Financial Interests, Institutional, Other, Consultancy: Roche; Financial Interests, Personal, Other, Consultancy: Gilead, Novartis, MSD, Roche; Financial Interests, Personal, Invited Speaker: Sanofi, AstraZeneca; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Institutional, Funding: Sanofi; Non-Financial Interests, Principal Investigator: EORTC 1745-ETF-BCG trial; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Invited Speaker: BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force; Non-Financial Interests, Advisory Role: Commission personalized medecine Federal Government Belgium; Non-Financial Interests, Advisory Role, External Scientific Advisor: European Medicine Agency. G. Floris: Financial Interests, Institutional, Advisory Board, paid to institution: AstraZeneca. All other authors have declared no conflicts of interest.
HER2-positive breast cancer is a heterogeneous disease, presenting tumor and microenvironment features which can impact prognosis and treatment response. Here, we aimed at better understanding the heterogeneity of this disease by performing spatial transcriptomics (ST) on HER2-positive breast cancer samples.
Spatial transcriptomics (Visium) was performed on 33 frozen HER2-positive breast cancer surgical samples, including 6 residual disease samples. H&E images of the ST slides were annotated for morphological structures at the single-cell/structure level (QuPath software). Clusters identified on integrated data (harmony R package) were characterized calculating gene expression signatures, including HER2DX gene modules, at the spot level, and by morphological annotation. Gene signatures were computed on pseudo-bulk RNA data as well.
A total of 25 integrated clusters were identified (range 15-21 in each sample). As each spot/cluster represents a mixture of different cell types, using gene expression and morphological data we defined a total of 9 tumor-enriched clusters (of which 5 sample-specific), as well as 12 clusters mainly enriched for stroma, 3 for adipose tissue, and 1 for tumor-infiltrating lymphocytes. All samples presented more than 1 tumor cluster, in various proportions. Interestingly, when comparing tumor clusters, levels of HER2DX signatures depicting HER2 amplicon, luminal phenotype, proliferation, B cell infiltration, as well as signatures related to stroma activation, signaling pathways and metabolism differed, demonstrating heterogeneity in tumor-enriched areas. Of note, within the same sample, tumor clusters with high/low levels of the HER2DX modules and other signatures could co-exist, and samples presenting signature scores above/below the cohort median at the pseudo-bulk level (also influenced by the stroma composition) showed the co-presence of tumor clusters with high/low signature levels.
Our findings highlight the heterogeneity of HER2-positive breast cancer. Spatial transcriptomics may help in refining gene expression signatures computed on bulk RNA, and these results open to further analyses aimed at better understanding the tumor microenvironment in this disease.
The authors.
Fonds de la Recherche Scientifique - FNRS (F.R.S.-FNRS); Fondation Jules Bordet; Breast Cancer Research Foundation (BCRF); Fondation contre le Cancer.
C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, Amgen, Inc., Merck & Co.; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences. All other authors have declared no conflicts of interest.
Triple-negative breast cancer (TNBC), a biologically diverse subtype of breast cancer, is associated with poor prognosis. Patients (pts) with TNBC who achieve pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have improved disease free and overall survival. We investigated whether early circulating tumor DNA (ctDNA) measurements could predict response to NAC.
ctDNA was detected in 94 serial plasma samples (n) from 37 pts (N) with TNBC (stage I=2, II=19, III=16) with a tumor-informed ctDNA assay (SignateraTM, bespoke mPCR-NGS). Pts received standard NAC; plasma was collected pre-NAC (n=30), 12 weeks after NAC initiation (mid-NAC, n=34), after NAC prior to surgery (n=15), and after surgery (n=15). Associations between ctDNA and ultrasound (US) imaging and response to NAC were evaluated. Circulating tumor cells (CTCs) were also assessed using CellSearch. pCR was defined as the absence of invasive tumor in the breast and axillary lymph nodes in surgical specimens. P values were measured using Student t-test, and correlation between variables used Pearson analysis.
At diagnosis, ctDNA was detected in 90% (27/30) of patients, of whom 76% (19/25) had early ctDNA clearance by mid-NAC. Imaging at mid-NAC showed that 95% (18/19) of cases with undetectable ctDNA had evidence of partial or complete response (PR/CR), while 1 case had progressive disease. After completion of NAC, all 19 cases had PR, CR, or stable disease. Importantly, 58% (11/19) of cases who were ctDNA-negative at their mid-NAC blood draw achieved pCR, while none of the pts with ctDNA detectable at mid-NAC (N=6) had pCR. ctDNA clearance at mid-NAC was significantly associated with pCR (P=0.0304). ctDNA dynamics early in the treatment course correlated with pCR rates (P=0.009) and tumor volume reduction based on US (P=0.008). CTCs were detected in 36% (11/30) of pts pre-NAC, 47% (16/34) mid-NAC, 40% (6/15) post-NAC, and 20% (3/15) after surgery and were not associated with pCR.
Early clearance of ctDNA at mid-treatment but not CTCs during NAC was associated with a higher rate of pCR in TNBC. Personalized ctDNA monitoring during NAC is feasible and may help predict response and guide treatment.
The authors.
The study was funded by Academic and Foundation funding, including The Wintermann Foundation, The Shiela Prenowitz Research Endowment, and the John Wayne Cancer Foundation.
E. Kalashnikova, D. Renner, A.A. Rodriguez: Financial Interests, Personal, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera. D. Tripathy: Financial Interests, Personal, Advisory Board, Serving on Steering Committee for TrialsEducational Lectures: Novartis; Financial Interests, Personal, Advisory Board, Steering Committee for and ongoing trial: Pfizer; Financial Interests, Personal, Advisory Board, Advisory council for design and interpretation of trials: GlaxoSmithKline; Financial Interests, Personal, Invited Speaker, Educational Lectures: AstraZeneca; Financial Interests, Personal, Advisory Board, To discuss and interpret clinical trial data: Immunomedics; Financial Interests, Personal, Advisory Board, Advice on clinical trial design: OncoPep; Financial Interests, Personal, Invited Speaker, Lecture on gene profiling: Exact Sciences; Financial Interests, Personal, Advisory Board, Consulting: Sermonix; Financial Interests, Personal, Advisory Board, Consultant: Personalis, Puma Biotechnology, Gilead; Financial Interests, Institutional, Research Grant, Funding for laboratory experiments on the inhibition of CXCR4 in breast cancer cells: Polyphor; Financial Interests, Institutional, Invited Speaker, Global PI on one trial and local PI on another trial: Novartis. M.C. Liu: Financial Interests, Personal, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera; Financial Interests, Institutional, Research Grant: Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, Tesaro; Financial Interests, Institutional, Advisory Board: AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, Syndax; Financial Interests, Personal, Other, Travel reimbursement: AstraZeneca, Genomic Health, Ionis. S.L. Moulder: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company. All other authors have declared no conflicts of interest.
TNBC is a heterogeneous and an aggressive disease difficult to treat due to the lack of targeted available therapies. Currently, the research of biomarkers is important to identify patients with worse response to NACT and lower disease-free survival (DFS) and overall survival (OS). The predictive and prognostic influence of cytokines levels in early TNBC is still unclear. The aim of this study is to find non-invasive biomarkers in early TNBC.
Prospective observational study was carried out in the University General Hospital of Valencia in 42 early TNBC patients treated with NACT. Blood samples were collected before NACT. 22 plasma cytokines levels were measured by multiplexed bead-based immunoassays (MILLIPLEX® HSTCMAG-28SK kit). R program was used for statistical analysis. P-value <0.05 was considered statistically significant.
Mean age: 55 years (28-77). 52.4% stage I/II and 47.6% stage III. All NACT schemes included taxanes; carboplatin was added in 17 patients. A larger tumor size was associated with higher levels of sGal-3, sMIP-3α, sMIP-1α and sIL-8 but lower levels of sITAC. Furthermore, higher levels of sTNFα and sGAL3 were correlated with node involvement. Advanced clinical stage was associated with increased levels of sGal-3 and sIL-8 but lower levels of sITAC. Increased levels of sGM-CSF were predictive of a lower response to NACT. Moreover, high levels of sGal-3 and low levels of sITAC were predictive of lower lymph node response. Survival analysis showed that larger tumours, lymph node involvement, advanced clinical stage, poorly differentiated carcinomas and non-pathological complete response after NACT, were correlated with lower DFS and OS. Moreover, patients with lower levels of sGal-3 and sIL-10 were associated with better DFS and OS
Some non-invasive biomarkers could help us to identify patients with a worse prognosis in early TNBC. Plasma levels of sMIP-3α, sGal-3, sIL-10, sIL-13 and sIL-17, among others, were correlated with worse clinical outcomes. Furthermore, higher levels of sGM-CSF and sGal-3, and lower levels of sITAC, could predict a worse response to NACT.
The authors.
The authors acknowledge grant CB16-12-00350 from CIBERONC, the AMACMA foundation, and Lopez Trigo 2017.
All authors have declared no conflicts of interest.
NACT is the standard treatment for eTNBC, yet, molecular phenotypes driving chemotherapy sensitivity are poorly understood. Whole transcriptome profiling of baseline tumor biopsies from the neoadjuvant WSG-ADAPT-TN phase II trial (NCT01815242) was performed to identify gene networks predictive and prognostic for pCR and survival.
Patients with cT1c-cT4c, cN+, centrally confirmed eTNBC were randomized to 12 weeks of nab-paclitaxel+gemcitabine (Arm A; n=182) or nab-paclitaxel+carboplatin (Arm B; n=154). The primary endpoint was pCR (ypT0/is, ypN0), secondary endpoints included survival and translational research. AmpliSeq RNA sequencing allowing simultaneous analysis of the expression of >20,000 genes was performed in 137 patients (Arm A/B: n=72/65). Differentially expressed genes were then evaluated in training (n=67) and validation (n=68) sets and two polygenic scores (PS) with a high diagnostic performance for prediction of pCR (PS:pCR) and invasive disease-free survival (PS:iDFS) were found.
49/135 (36.3%) patients had pCR; 30 iDFS events occurred during 60-month median follow-up. Genes and networks associated with immune recruitment, endogenous retroviral transcription, and viral defense were strongly associated with pCR and iDFS. PS:pCR achieved a high diagnostic accuracy (ROC AUC: 83%). In multivariate analysis (validation set) adjusted for clinical factors, pCR was associated with PS:pCR (OR 7.24; 95%CI 2.05, 25.58; p=0.002). Addition of PS:pCR to clinical factors increased ROC AUC for pCR from 0.707 to 0.887. iDFS was associated with PS:iDFS (HR 2.06; 95%CI 1.01, 4.20; p=0.046).
Polygenic scores based on immunomodulatory and anti-viral defense gene networks may have utility in predicting pCR and survival, and could represent an opportunity for selecting patients for de-escalated NACT in eTNBC. This transcriptome network analysis also identifies potential new targets for personalized medicine approaches for patients without response to chemotherapy.
NCT01815242.
West German Study Group GmbH.
Teva and Celgene funding the ADAPT TN trial.
M. Graeser: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other, Travel Support: Daiichi Sankyo. N. Harbeck: Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, Seagen; Financial Interests, Institutional, Research Grant: Eli Lilly, MSD, Novartis, Pfizer, Roche. O. Gluz: Financial Interests, Personal, Advisory Role: Celgene, Genomic Health/Exact Sciences, Eli Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Pierre Fabre, Gilead, Molecular health; Financial Interests, Personal, Expert Testimony: Genomic Health; Financial Interests, Personal, Other, travel support: Roche. U.A. Nitz: Financial Interests, Institutional, Research Grant: Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Roche, Sanofi; Financial Interests, Personal, Advisory Role: Genomic Health , Roche; Financial Interests, Personal, Expert Testimony: Genomic Health; Financial Interests, Personal, Other, travel support: Genomic Health, Pfizer , Roche; Financial Interests, Personal, Advisory Board: Roche, Seagen, Exact Sciences. S. Kuemmel: Financial Interests, Institutional, Research Grant: Roche , Novartis; Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Genomic Health/Exact Science, Lilly, MSD, Novartis, Seagen, Pfizer, pfm Medical, Roche, Somatex, Gilead; Financial Interests, Personal, Other, travel support: Roche , Daiichi Sankyo. H. Forstbauer: Financial Interests, Personal, Invited Speaker: Roche, iOMEDICO; Financial Interests, Personal, Invited Speaker, travel support: Celgene , Amgen. M. Braun: Financial Interests, Personal, Advisory Role: AstraZeneca, Exact Sciences, Novartis, Puma, Roche; Financial Interests, Personal, Invited Speaker, travel support: AstraZeneca, Celgene, Medac, Novartis, Roche, Daiichi Sankyo. C. Uleer: Financial Interests, Personal, Advisory Role: Tesaro, Novartis, Roche; Financial Interests, Institutional, Research Grant: Novartis, AstraZeneca, Tesaro, Palleos Healthcare Services GmbH, Pierre Fabre, AGO-Studiengrouppe, West German Study Group, German Breast Group; Financial Interests, Personal, Other, travel support: German Breast Group, West German Study Group, AGO-Studiengrouppe; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Novartis, Roche, PharmaMar, AstraZeneca. B. Aktas: Financial Interests, Invited Speaker, Honoraria: Pfizer, Roche Pharma, MSD, Onkowissen, Novartis, AstraZeneca, PharmaMar, Lilly, Promedicis. R. Würstlein: Financial Interests, Personal, Advisory Role, and travel support: Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Exact Sciences/Genomic Health, Gilead, GSK, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Mylan, Nanostring Technologies, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, Puma, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics/Seagen, Tesaro Bio, Teva, Veracyte , Viatris; Financial Interests, Personal, Advisory Role, and travel supportv: Carl Zeiss. H. Kreipe: Financial Interests, Personal, Invited Speaker: Roche , Novartis, Genomic Health, AstraZeneca, Lilly, Pfizer; Financial Interests, Personal, Advisory Board: Roche , Genomic Health, AstraZeneca. All other authors have declared no conflicts of interest.
Breast cancer-associated microbiome and its role in treatment efficacy are poorly understood. We aimed to study tumor-associated microbiome composition in TNBC, its dynamics upon NACT, and its correlation with TNBC outcomes.
Diagnostic biopsies and surgery samples from patients with TNBC treated with NACT were selected. A 16S rRNA subunit gene analysis was performed to describe α-diversity with Shannon Index and study taxonomic profiles at genus levels. To control for differences related to the type of sample we also analyzed diagnostic biopsies and surgical samples from patients that had surgery without NACT.
We analyzed 115 TNBC samples from: i) Diagnostic biopsies (n=87) from patients with either subsequent NACT (n=48, mean age 57) or upfront surgery (n=39, mean age 78); ii) Surgery samples (n=28) from patients with prior NACT (n=14, all unpaired; mean age 47) or upfront surgery (n=14, all paired with diagnostic biopsies; mean age 85). α-diversity was significantly lower in post-treatment surgery samples (mean 1.5) compared to pretreatment biopsy samples (mean 1.19, p=0.027), with a significant reduction of Prevotella abudance (p<0.001). Abundance of
Our results suggest that in TNBC, NACT has a significant impact in microbiome composition and some genera are correlated to outcomes. The type of sample (biopsy / surgical) must be taken into account in breast cancer-associated microbiome studies. This work provides the rationale for expanding microbiome analysis in order to find novel putative biomarkers of response to neoadjuvant therapy in early TNBC.
The authors.
European Society for Medical Oncology (ESMO) Translational Research Fellowship to Andri Papakonstantinou, Jose A. Seoane is supported by AEI RYC2019- 026576-I, “LaCaixa” Foundation LCF/PR/PR17/51120011 and Maria Butjosa by a Severo Ochoa fellowship AEI CEX2020-001024-S.”
I. Pimentel: Financial Interests, Personal, Invited Speaker: MSD, Novartis, AstraZeneca; Non-Financial Interests, Member, ASCO member: ASCO; Other, travel and accommodations expenses: Phyzer. E. Zamora: Financial Interests, Personal, Invited Speaker, Review session for medical oncologists: Eisai, Lilly; Other, Registration to ESMO Congress 2022 (virtual): Novartis; Other, Registration to: Eisai. P. Gonzalez Torres: Financial Interests, Personal, Leadership Role: Microomics. N. Carron Rodas: Financial Interests, Personal, Other: Microomics. C. Saura Manich: Financial Interests, Personal, Advisory Board: AX'Consulting, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd., Gilead, ISSECAM, Lilly, MediTech, Medical Statistics Consulting, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, Seagen, Solti, Zymeworks, Pharmalex Spain SLU; Financial Interests, Personal, Expert Testimony: AX's Consulting SARL, Boehringer Ingelheim, Bristol Meyers Squibb, INDITEX, Merck Sharp & Dohme España, Novartis, SACE Medhealth SL, Simon Kucher &Partners SL, Genentech, Innoup, Millenium, Sanofi, Seattle Genetics; Financial Interests, Personal, Other, SC: Byondis B.V., German Breast Group, Glaxo, International Breast Cancer Study Group (IBCSG), Macrogenics, Medsir, Menarini, Merus, Merus, Netherlands Cancer Institute (NKI), Queen Mary (University of London), Seagen, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, GlaxoSmithKline, Immunomedics, Innoup Farma, International Breast Cancer Study Group (IBCSG), Macrogenics, Medica Scientia Innovation Research, Menarini Ricerche, Merus, Novartis, Pfizer, Puma, Roche, Sanofi-Aventis, Seattle Genetics, SOLTI; Financial Interests, Institutional, Invited Speaker: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), SOLTI group (Academic research group in breast cancer), Geicam (Spanish Breast Cancer Research Group), American Association for Cancer Research (AACR). P.G. Nuciforo: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD Oncology, Bayer; Financial Interests, Personal, Other, Consultant: Targos Molecular Pathology GmbH. M. Oliveira: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo / AstraZeneca, Gilead, Pierre Fabre, Roche, Seagen, iTEOS, Relay Therapeutics; Financial Interests, Personal, Invited Speaker: Gilead, MSD, Novartis, Pfizer, Roche, Seattle Genetics, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer-Ingelheim, GSK, Roche, Seattle Genetics, Zenith Epigenetics, Gilead, Ayala Pharmaceuticals; Financial Interests, Invited Speaker: Roche; Non-Financial Interests, Invited Speaker: SOLTI Breast Cancer Research; Other, Travel Grant: Pierre Fabre, Eisai, Gilead, AstraZeneca. All other authors have declared no conflicts of interest.
Triple-negative breast cancer (TNBC) is a very heterogeneous disease with high metastatic recurrence risk. We showed (PMID 34535679) that TNBCs relapsing rapidly (RR) after NACT (in ≤ 12 months) are highly proliferative, immune-cold, often with large residual cancer burden (RCB) and fatal outcome. No specific biomarkers or therapeutic targets are known for this clinical category. In this study we performed spatial molecular analysis of the RR and the RCB3 TNBCs, with the aim to help improving treatment of the TNBC patients with the poorest prognosis.
We analyzed residual tumor tissue samples of TNBC patients treated by standard NACT from 01/01/2009 to 31/12/2021. The cases were classified into RR, standardly-relapsing (SR, 1-5 years post-NACT) and without recurrences (NR). The amount of tumor-infiltrating lymphocytes (TILs) was determined by optical microscopy (H&E). Tissue protein expression was spatially resolved by GeoMx® Digital Spatial Profiler (NanoString Technology).
Sixteen, 17 and 47 RR, SR and NR cases were analyzed, respectively. GeoMx analysis included 216 Region-of-Interest (ROIs) of tumor microenvironment (TME) and 207 of tumor cells (TC), with balanced (∼50/50) numbers of peripheral (P) and central (C) ROIs. Tumors and ROIs were classified into TIL-rich (LR) and TIL-poor (LP) using cut-off of 10% TILs. The RR TNBCs showed higher Ki67, cleaved caspase 9, granzyme B (GZMB), FoxP3 and fibronectin (FBNCT) in TME-P-LR ROIs but higher GADPH, TIM-3, PD-L1 and IDO in TME-P-LP ROIs. Compared to TNBC-SR, the RR had higher GZMB and CD34 in TME-P-LR ROIs. In TME-C-LR ROIs of the RRs, CD8 expression was low, as well as the one of CD45, CD3 and CD8 in TME-C-LP. The RCB3 category contained 9, 8 and 10 RR, SR and NR cases, respectively. Although most RCB3 cases were TIL-poor, the NR cases showed significantly higher expression of CD3, CD8, GZMA, CD4, CD56, CD95, LAG3, HLA-DR, BIM and BCL6 than the RR cases.
By this study we revealed several potential therapeutic targets (fibronectin, IDO, TIM-3, CD34 /angiogenesis) in the RR TNBCs. Interestingly, we also showed that some RCB3 cases have immune-activated TME and good prognosis. Spatial tissue analysis was crucial for these discoveries.
INSERM U1240, University Clermont Auvergne, Clermont-Ferrand, France.
Centre Jean Perrin.
All authors have declared no conflicts of interest.
TNBC is an aggressive breast cancer subtype that needs further molecular characterization to develop targeted therapy to improve its outcome. The ability of BCSCs to evade the immune system is one of the resistance mechanisms to chemotherapy, that remains the standard treatment. Neoadjuvant chemotherapy (NACT) could induce changes in the BCSCs subpopulation and the patients' immune response. New therapeutic strategies based on blocking this subpopulation are being evaluated.
In a retrospective study, we included 25 early TNBC patients resistant to NACT diagnosed in the Catalan Institute of Oncology (Girona, Spain) between 2010-2019. We collected 50 paired samples (pre and post NACT) from the Tumor Biobank. We determined BCSCs biomarkers (CD44+, CD24- and ALDH1) and PD-L1 by immunohistochemistry (IHQ) and TILS expression by hematoxylin-eosin stain. Clinicopathological characteristics from all patients were collected.
Mean age was 51 years old, almost 80% of tumors were ductal invasive carcinomas, 76% were grade 3 with a mean Ki-67 of 57.46%, 83% were cT2-3, 62% were node positive at baseline, 86% of patients received anthracyclines/taxanes and, at the time of data cut-off, 52% were alive, with a median follow-up of 43 months. At baseline, 46% of the tumors showed CD44 high expression, 52% showed CD24 low expression, 4% showed ALDH1 high expression, 79% were PD-L1 ≤ 1% (negative) and 60% had low expression of TILS. A statistically significant association was found between PD-L1 expression and NACT, since 52% of PD-L1-negative tumors became PD-L1 positive (> 1%) after NACT (p=0.002). No changes in BCSCs markers (CD44, CD24, ALDH1) and TILS expression were found. No association was found between high baseline BCSCs enriched subpopulation and PD-L1 changing expression after NACT.
Understanding therapeutic resistance is a major challenge in TNBC. We have observed that TNBC chemotherapy resistant tumors increase PD-L1 expression after neoadjuvant therapy. More studies are needed to evaluate the relationship between BCSCs and immunogenicity profile to develop new co-therapeutic strategies.
The authors.
Oncoswim - Fundació Oncolliga Girona.
All authors have declared no conflicts of interest.
PD-L1 test is recommended to select mTNBC patients eligible for immune checkpoint inhibitors (ICIs). Several factors may challenge this test, including: 1) different assays and platforms available, 2) different scoring systems (CPS and IC), 3) different cut-off values (CPS≥10 and IC≥1%), and 4) different indications (CPS→pembrolizumab and IC→atezolizumab). We aimed to characterize the interobserver and interassay reproducibility of PD-L1 testing in mTNBC using the currently validated CE-IVD assays for CPS and IC.
60 mTNBC samples were subjected to PD-L1 immunohistochemistry (IHC) using 22C3 pharmDx on a Dako Autostainer Link 48, and both SP263 and SP142 on a Ventana BenchMark Ultra. CPS was evaluated with both 22C3 and SP263 by 5 pathologists (certified PD-L1 trainers). In addition, IC with SP142 was assessed by 3 of the 5 pathologists, with specific expertise in breast pathology. After intraclass correlation coefficient (ICC) calculation for each assay and corresponding cut-offs (CPS≥10 and IC≥1%), the inter-rater and inter-platform agreements were measured by Fleiss’s κ (95% confidence interval, CI). Statistical analyses were performed with R (v 4.2.2) and irr (interrater reliability) package (CRAN).
Significant (p<0.001) ICC was observed with both CPS assays (22C3=0.939 (CI:0.913-0.96); SP263=0.972 (CI:0.96-0.982); combined=0.909 (CI:0.874-0.938)). Fleiss’s κ confirmed an almost perfect agreement both among pathologists and assays (22C3=0.938 (CI:0.857-1.018); κ=0.972 (CI:0.890-1.052); combined=0.907 (CI:0.869-0.945)). Perfect inter-rater agreement was reached for IC (100%). The correlation between CPS and IC scores, albeit significant, was lower (ICC=0.634 (CI:0.455-0.816); κ=0.619 (CI:0.537-0.700)).
In mTNBC, CPS can be reliably performed either by 22C3 on a Dako platform (as in the KEYNOTE studies) or SP263 on a Ventana platform. CPS and IC are not interchangeable tests in mTNBC but each test is accurate when assessed by trained pathologists using CE-IVD assays, precisely 22C3 and SP263 for CPS and SP142 for IC score.
The authors.
Has not received any funding
N. Fusco: Financial Interests, Personal, Invited Speaker: Merck Sharp & Dohme (MSD), Boehringer Ingelheim, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline (GSK), Gilead; Financial Interests, Personal and Institutional, Research Grant: Novartis. C. Criscitiello: Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Eli Lilly, Roche, Gilead; Financial Interests, Personal, Advisory Board: MSD, Seagen, AstraZeneca, Daiichi Sankyo. E. Guerini-Rocco: Financial Interests, Invited Speaker: Thermo Fisher, Novartis, AstraZeneca, Roche, Biocartis, Exact Science, GSK, Illumina. P. Graziano, M. Martini: Financial Interests, Invited Speaker: MSD. G. D'Amati: Financial Interests, Invited Speaker: MSD, Roche. All other authors have declared no conflicts of interest.
The presence of TILs is a prognostic factor in TNBC. However, the prognostic role of CD4+/CD8+ lymphocytes, as well as the intra- or peritumoral distribution remains controversial. Regarding soluble immune checkpoints, there are still very few studies and their prognostic value is unknown in early TNBC. The aim of this study is evaluate the role of TILs and also the search of non-invasive immune checkpoints markers in early TNBC.
Prospective observational study was carried out in the University General Hospital of Valencia in 42 early TNBC patients treated with neoadjuvant chemotherapy (NACT). Blood samples were collected before NACT. 17 plasma immune checkpoints were analyzed using a preconfigured panel based on Luminex xMAP®. R program was used for statistical analysis. P-value <0.05 was considered statistically significant.
Mean age: 55 years (28-77). 52.4% stage I/II and 47.6% stage III. All NACT schemes included taxanes; carboplatin was added in 17 patients. Mean TILs expression: 30.7% (1-90). Mean relationship between peri- and intratumoral lymphocytes was 68%
TILs are an important prognostic factor in patients with early TNBC, obtaining increased survival in patients with higher levels, regardless of location and lymphocyte subtype. Besides, we observe that in more advanced tumors there are higher plasmatic levels of soluble immune checkpoints, indicating decreased activity of the immune system.
The authors.
The authors acknowledge grant CB16-12-00350 from CIBERONC, the AMACMA foundation, and Lopez Trigo 2017.
All authors have declared no conflicts of interest.
The aim of this study was to investigate the correlation of
145 patients enrolled 2015-2018 in the Sweden Cancerome Analysis Network - Breast (SCAN-B) study (NCT02306096) were included. 109 had chemotherapy (>90% with sequential epirubicin + cyclophosphamide and a taxane, EC–T) according to national guidelines either as neoadjuvant (32%, NAC) or adjuvant (68%, ACT) therapy. Germline screening was performed in 54 patients with pathogenic
MSI and
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Expression of Platelet-derived growth factor-CC (PDGF-CC) is associated with the TNBC (triple-negative breast cancer) subtype. We have previously reported paracrine PDGF-CC signaling to be of importance for maintaining TNBC tumor cell phenotype.
We aimed to characterize PDGF-CC expression within the TNBC patient population by combining studies of PDGF-CC in tissue microarrays (TMAs) with matching RNA-Seq data and clinical follow-up; all variables originating from the SCAN-B (Sweden Cancerome Analysis Network – Breast) clinical study (NCT02306096). TMAs constructed of primary TNBC patient samples (N=254) were stained for PDGF-CC using the Dako PT Autostainer system. Tumor cell-specific expression of PDGF-CC intensity was scored as either absent (N=11), weak (N=86), intermediate (N=81) or strong (N=70).
Intermediate and strong PDGF-CC scores were associated with Nottingham Histological Grade 3 (p=0.001), increased Ki-67 percentage (p<0.001) and younger patient age at diagnosis (p=0.002). RNA-Seq data corresponding to tumors included in the TMAs were retrieved and Gene Set Enrichment Analysis (GSEA) was performed, comparing the TMA-derived PDGF-CC subgroups. Immune-related signatures were found to be enriched in the strong PDGF-CC subgroup vs. intermediate. Interestingly, strong PDGF-CC intensity was associated with a decreased risk of recurrence in the chemotherapy treated patient group (HR 0.28, 95% CI 0.10-0.80, p=0.017, univariate Cox regression). Finally, patient samples were assigned a PAM50 subtype and a TNBC molecular subtype (Lehmann et al 2011). Ninety-four percent of tumors in the strong PDGF-CC subgroup were classified as basal-like, whereas the corresponding number in the weak and intermediate PDGF-CC subgroups were 51% and 84%, respectively.
In conclusion, strong PDGF-CC protein expression identified basal-like TNBCs, with an increase in immune cell infiltrate shown by RNA-Seq analysis. Based on the work, a window-of-opportunity trial (NCT05722795) has been launched to examine the effect of PDGF-CC inhibition on TNBC phenotype.
Lund University.
Lund University and The Swedish Cancer Society.
A. Bosch: Financial Interests, Personal and Institutional, Advisory Board: Pfizer, Novartis; Financial Interests, Institutional, Invited Speaker: Pfizer, Roche, Lilly; Financial Interests, Personal, Member of the Board of Directors: SACRA Therapeutics. K. Pietras: Financial Interests, Personal, Stocks/Shares: Paracrine Therapeutics. All other authors have declared no conflicts of interest.
Circulating tumor DNA (ctDNA) assessment in blood is being studied as a biomarker in breast cancer. We aimed to assess the clinical value of ctDNA in patients with early breast cancer.
Systematic search of databases (PubMed, Embase, CENTRAL) up to 23/Nov/22 and conferences proceedings (ASCO, ESMO, AACR, SABCS, ESMO Breast) 2020-2022 was conducted to identify studies reporting the association of ctDNA detection with disease-free survival (DFS), and overall survival (OS) in patients with stage I-III breast cancer (PROSPERO ID: CRD42021286591). ctDNA assays were classified as tumor-informed and non-tumor informed. Timepoints of ctDNA collection were grouped as baseline (BL), after neoadjuvant therapy (End-of-NAT), and during follow-up period (FUP). Univariable (Uv) and multivariable (Mv) hazard ratios (HR) were pooled using random-effects models and reported with their 95% confidence intervals (CI).
Of 3,174 identified records, 57 studies were included in this analysis reporting data from 5,729 patients with early breast cancer. 44.5% had breast cancer stage reported (18.3%, 60.0%, and 21.5% had stages I, II, and III, respectively). We found a statistically significant association of ctDNA detection at any timepoint with worse DFS and OS (Table). Pooled HRs were numerically higher when ctDNA was detected at end-of-NAT or FUP than at BL, and for tumor-informed compared to non tumor-informed assays. ctDNA detection sensitivity and specificity for breast cancer relapse ranged from 0.31-1.0 and 0.7-1.0, respectively. The mean lead time to radiological recurrence was 10.81 months (0-58.9).
Timepoint HR (95%CI) Tumor-informed Non tumor-informed Overall BL Uv 4.2 (1.8-9.8) 2.8 (1.7-4.6) 3.0 (1.9-4.6) Mv 1.9 (1.1-3.2) 2.7 (2.0-3.8) 2.5 (1.9-3.3) End-of-NAT Uv 8.9 (5.1-15.4) 4.4 (2.6-7.2) 7.7 (4.8-12.2) Mv 9.9 (2.7-35.5) 2.7 (1.3-5.8) 5.5 (2.4-12.8) FUP Uv 16.0 (8.4-30.6) 14.0 (7.5-26.1) Mv 12.2 (2.8-53.3) 2.6 (1.1-6.3) 7.2 (2.8-6.3) BL Uv 2.6 (1.5-4.7) 2.8 (1.6-4.8) Mv 3.0 (1.4-6.4) End-of-NAT Uv 2.6 (1.0-6.4) 2.7 (1.4-5.1) Mv 12.9 (0.4-380.2) FUP Uv 22.7 (9.3-55.7) 4.0 (2.3-7.0) 9.2 (3.3-25.9) Mv 6.7 (0.2-224.4) 6.2 (3.1-12.4) 5.6 (1.5-21.8)
ctDNA detection is associated with worse DFS and OS in patients with early breast cancer, particularly when measured after treatment with tumor-informed assays. ctDNA detection has a high specificity for the diagnosis of breast cancer relapse.
Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (HUB), Institut Jules Bordet, Academic Trials Promoting Team (ATPT), Brussels, Belgium.
Has not received any funding.
G. Nader Marta: Financial Interests, Other, Travel grants to attend meetings: Roche, Bayer. E. Agostinetto: Financial Interests, Personal, Advisory Board: Eli Lilly, Sandoz, AstraZeneca; Financial Interests, Institutional, Research Grant: Gilead; Financial Interests, Personal, Other, Support for attending medical conferences: Novartis, Roche, Eli Lilly, Genetic, Instituto Gentili, Daiichi Sankyo. D. Martins Branco: Financial Interests, Personal, Advisory Board: Angelini, AstraZeneca, Janssen, Merck Sharp & Dohme, Novartis, Pfizer; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Merck Sharp & Dohme, Novartis; Financial Interests, Personal, Other, meeting/travel grant: Gilead Sciences, Ipsen, Janssen, LEO Farmacêuticos, Laboratórios Vitória, Pfizer, Roche; Financial Interests, Personal, Other, Meeting/travel grant.: Merck Sharp & Dohme, Novartis; Financial Interests, Institutional, Research Grant, Institutional funding for an observational research project.: Novartis; Financial Interests, Institutional, Research Grant, Institutional funding for an investigator-initiated clinical trial.: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Invited Speaker: Associação de Investigação e Cuidados de Suporte em Oncologia - Portuguese MASCC affiliate; Non-Financial Interests, Leadership Role, Portuguese Young Oncologists Committee Chair: November 2020 - May 2022: Sociedade Portuguesa de Oncologia; Non-Financial Interests, Leadership Role, Oncology Committee Chair: January 2020 - January 2021: Health Parliament Portugal. M. Ignatiadis: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Other, Independent monitoring committee: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: Pfizer, Roche, Natera, Inivata Inc; Non-Financial Interests, Officer: EORTC. G. Pruneri: Financial Interests, Personal, Invited Speaker: Roche, Lilly, Exact Sciences, Novartis; Financial Interests, Personal, Advisory Board: Exact Sciences, ADS Biotec; Financial Interests, Institutional, Research Grant: Roche. E. de Azambuja: Financial Interests, Personal, Advisory Board: Roche/GNE, Novartis, Seagen; Financial Interests, Personal, Invited Speaker: Zodiac, Libbs, Pierre Fabre, Lilly, Astra-Zeneca; Financial Interests, Institutional, Research Grant: Roche/GNE, AstraZeneca, GSK/Novartis, Servier; Financial Interests, Institutional, Other, Travel Grant: Roche/GNE; Financial Interests, Institutional, Invited Speaker: MSD, ABCSG, Nektar, Gilead, Immunomedics, Synthon, Odonate Therapeutics; Financial Interests, Invited Speaker, Chair of the Gilead Sciences Research Scholars Program in Solid Tumours: Gilead; Financial Interests, Invited Speaker, Aphinity, Lorelei, Impassion03: Roche; Financial Interests, Invited Speaker, AURORA: Breast International Group; Financial Interests, Invited Speaker, Olympia: Astra-Zeneca; Financial Interests, Personal, Other, Travel grant: Astra-Zeneca; Non-Financial Interests, Advisory Role, Member of the cardio-oncology council: European Society for Cardiology (ESC); Non-Financial Interests, Advisory Role, Belgium governmental institution for cancer: KCE; Non-Financial Interests, Other, Editorial board member: ESMO Open; Non-Financial Interests, Advisory Role: Anticancer Fund. S. Di Cosimo: Financial Interests, Personal, Other, Ad hoc project/protocol reviewer: MEDSIR; Financial Interests, Personal, Advisory Board, Treatment of HER2-positive breast cancer: Pier Fabre; Financial Interests, Personal, Other, Medical meeting material setup and distribution; speaker bureau.: IQVIA. All other authors have declared no conflicts of interest.
Extracellular vesicles (EVs) are lipid bilayer-delimited particles, naturally released from a cell. Initially regarded as waste products, nowadays EVs draw interest due to their role in intercellular communications. In breast cancer (BC), EVs play a role in the interplay between cancer cells and tumor microenvironment, and in the preparation of pre-metastatic niche in distant organs. Since they are present in many biofluids, EVs could have an exciting potential as liquid biopsy-derived biomarkers. Aim of this study was to assess EVs plasma levels in patients affected by early and metastatic BC using Single Molecule Array (SiMoA), a digital ELISA able to quantify low concentrations of target molecules.
SiMoA assays were developed based on a bead-immune separation of EVs followed by the direct quantification of the target on top of the magnetic beads. As target we used well know markers of EVs, i.e. CD9 and CD81, while the beads were functionalized to capture CD63, another EV-associated tetraspanin. Patients affected by early (n=56) and metastatic BC (n=44) were prospectively recruited at Istituti Clinici Scientifici Maugeri (Pavia, Italy). A control group of healthy subjects was also enrolled. For each patient a blood sample was collected and plasma was isolated for analysis.
The anti-CD63/anti-CD9 and anti-CD63/anti-CD81 SiMoA assays allowed the analysis of EVs directly in unprocessed plasma with good reproducibility performance. EVs levels were significantly higher in early BC than healthy controls by both assays. Metastatic BC, instead, showed lower levels of EVs as compared to healthy controls and early BC by both assays. By calculating the fraction of CD81-expressing EVs related to the amount of those expressing CD9 we observed that EVs from metastatic BC samples were enriched in CD81 as compared to healthy and early BC.
EVs levels measured by SiMoA increased in early BC and decreased in metastatic BC, suggesting that EVs reflect functional changes occurring during BC progression. As perspective, the identification of more specific markers will help to quantify subpopulation of EVs associated to different BC stages, improving early diagnosis and favoring timely intervention.
Prof. Fabio Corsi.
Has not received any funding.
All authors have declared no conflicts of interest.
Circulating tumor DNA (ctDNA) is promising as tumor-specific marker for progression surveillance in metastatic cancer. Our aim was to investigate the diagnostic power of ctDNA level for disease progression in metastatic breast cancer and to propose rationally selected ctDNA level thresholds with clinical validity.
This prospective single-center observational study conducted from July 1, 2019 to December 1, 2021, recruited 136 subjects with metastatic breast cancer for sequencing of their primary tumor in search of PIKC3A variants amenable for monitoring by droplet digital PCR. This interim analysis reports on 265 on-treatment samples from 19 subjects with PIK3CA variants H1047R or E545K. Subjects were sampled every 3-5 weeks with median follow-up of 85 (13-125) weeks and median of 14 (2-29) ctDNA time points per subject. The primary outcome was progression free survival. ROC analysis and logistic regression was performed to investigate the diagnostic power of quantitative ctDNA analysis and CA15-3 to predict progression within 12 weeks from each sampling time point. Likelihood ratios were used for rational selection of ctDNA result intervals.
ctDNA level (AUC: 0.856; 95% CI 0.807-0.897)) outperformed CA15-3 (AUC: 0.737; 95% CI 0.663-0.801, P<0.001) to predict progression within 12 weeks. ctDNA level below 10 mutant copies/mL were reassuring while levels above 100 copies/mL predicted 64% of progressions earlier with median (IQR) lead time of 10 (8-20) weeks versus standard of care. Logistic regression analysis indicated complementary value of ctDNA level and the presence of two consecutive rises of CA15-3, resulting in a derived risk score with AUC of 0.908 (95% CI 0.854-0.947). A risk score < 0.15 and > 0.25 achieved 93% (95%CI 87%-96%) and 82% (95% CI 71%-90%) negative and positive predictive values respectively, resulting in a clinically informative result in 89% of blood draws.
Intensive quantitative ctDNA monitoring shows clinical validity for improved surveillance of disease progression in metastatic breast cancer and has potential for risk-informed scheduling of standard clinical care.
Clinical Trial Number: B117201939334, AZ Delta General Hospital
The authors.
AstraZeneca (investigator-initiated grant, ESR-18-13805, PrecisionTrack: DNA sequencing of breast cancers for precision therapy and molecular monitoring.
All authors have declared no conflicts of interest.
High TMB has been suggested as a predictive biomarker for response to immune checkpoint blockade (ICB). Several ongoing ICB trials use liquid biopsy to identify patients (pts) with hypermutated (HMT) cancer. The prevalence of HMT breast cancer (BC) defined by LB is not well described. The aim of this study was to evaluate the frequency and genomic profile of HMT BC as assessed by LB in pts with metastatic BC (mBC).
Clinical and molecular data from pts with mBC enrolled in the STING trial (NCT04932525) was analyzed. Genomic analysis was carried out by using the FoundationOne Liquid CDx assay covering analysis of 324 genes. TMB was determined by counting all synonymous and non-synonymous variants present at 5% allele frequency or greater (after filtering). Total number is reported as mutations per megabase (mut/Mb) unit. Samples were classified as HMT BC if ≥16 mutations per megabase (mut/Mb).
From July 2020 to November 2022, 358 pts with mBC were included: 266 (74%) Luminal (Lum), 16(4%) HER2 positive (HER2+ve), and 76 (21%) with triple-negative (TN) mBC. The most common morphology was invasive ductal carcinoma (IDC) (n=304; 85%) followed by invasive lobular carcinoma (ILC) (n= 42; 12%). Pts had received a median of 3 lines of therapy at the time of LB. Median TMB in all cohort was 3 mut/Mb. The median TMB did not significantly vary according to the tumor subtype (Lum: 3 mut/Mb; HER2+ve:1 mut/Mb; TN: 4 mut/Mb (p=0.71)). HMT tumors were found in 16 pts (4.4% of the overall cohort). The majority of HMT tumors were Lum (75%; n=12). The remaining 25% (n=4) were TN. Additionally, 4.7% of ILC were HMT compared to 3.1% of IDC, but this difference in prevalence was not statistically significant (p=0.62). The most frequently altered genes in the HMT cohort were TP53, PIK3CA, NF1, ESR1, BRCA2. None of these pts presented microsatellite instability.
Hypermutated BC, measured by ctDNA, were reported in 4.4% of all pts with mBC in this cohort. These data are in agreement with the hypermutation rate described in tumor tissue in most series. Although not statistically significant, higher rate of HMT BC in metastatic ILC (4.7%) compared to metastatic IDC tumors (3.1%) was observed.
The authors.
Has not received any funding.
J.T.M.L. M Ribeiro: Financial Interests, Personal, Advisory Board: Gilead Sciences, Inc.; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: eESO. B. Pistilli: Financial Interests, Institutional, Advisory Board: AstraZeneca, Seagen, Lilly, Daiichi Sankyo, MSD; Financial Interests, Institutional, Invited Speaker: Gilead, Novartis, AstraZeneca, Gilead, Seagen, MSD, Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre, Daiichi Sankyo; Financial Interests, Personal, Other, travel support: AstraZeneca, Pierre Fabre, Msd, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Funding: Daiichi Sankyo; Non-Financial Interests, Project Lead: Unicancer. F. André: Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi; Financial Interests, Institutional, Other, advisory board: Guardant Health; Financial Interests, Institutional, Other, Advisory board: MEDIMMUNE, Gilead, Relay therapeutics; Other, Founder: Pegacsy. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Invited Speaker: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. All other authors have declared no conflicts of interest.
Gene expression signatures (GES) have emerged to predict prognosis and guide the use of adjuvant therapy in patients with hormone receptor-positive HER2-negative (HR+/HER2-) early breast cancer (eBC). However, very limited data is available in older patients, especially direct comparative information.
We tested and compared the prognostic value of four GES (Oncotype Dx Recurrence Score (RS), PAM50-based Prosigna (ROR), MammaPrint 70-gene (Prog70), and EndoPredict (EPclin)) in 3,533 operated and chemotherapy-naïve patients with pN0/pN1 HR+/HER2- eBC, according to a 70-year age cutoff, from a pooled dataset of 12,677 BC patients. The primary endpoint was Relapse-Free Survival (RFS).
Median follow-up for this analysis was 81.1 months. RFS events were recorded in 269 of the 1,167 patients ≥70 years (23%) and in 399 of the 2,366 patients <70 years (17%). Concordance tests of the four signatures did not differ between the two age groups (concordance mean of 77% and 78%, in the ≥70 and <70 groups, respectively;
We observed good prognostic performances of the four GES in patients <70, as previously described. By contrast, our results in patients ≥70 are equivocal and suggest that GES should be used with caution in this population. Further development and validation may be needed in this particular setting.
Insitut Paoli-Calmettes.
Has not received any funding.
A. De Nonneville: Non-Financial Interests, Personal, Advisory Board: Gilead, Daiichi Sankyo, Seagen, Lilly, Novartis, MSD. A. Gonçalves: Financial Interests, Institutional, Invited Speaker: Novartis, Roche, MSD, AstraZeneca, daiichy sanko. All other authors have declared no conflicts of interest.
Obesity is associated with chronic low-grade inflammation and elevated levels of circulating inflammatory biomarkers, i.e., C-reactive protein (CRP). Obesity is associated with impaired prognosis in breast cancer (BC), potentially augmented by inflammation. We hypothesize that high levels of CRP are associated with BC outcomes and that the association is more pronounced in patients with obesity.
Female patients (stage I-III) seen at Aarhus University Hospital under diagnostic work-up for BC were asked to donate blood for research (Mar. 2010 – Aug. 2020). CRP levels were measured in serum samples and divided into quartiles with the lowest quartile, Q1, as the reference. We used Cox proportional hazards regression to estimate crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI) to compare BC outcomes in CRP quartiles. Multivariate analyses were adjusted for age, menopausal status, tumor grade, stage, surgery type, systemic adjuvant treatment, radiotherapy, comorbidities, and body mass index, and stratified by estrogen receptor status.
Among the 4,190 patients who donated blood, 2,676 patients were included following exclusion of 1,514 patients with e.g. benign disease or previous cancer history. During 15,249 person-years of follow-up, 225 recurrences occurred (69 locoregional and 156 distant metastases). Patients with high CRP (Q4) had a higher risk of BC event compared with patients with low CRP (Q1) (HRadj: 1.59 (95% CI 1.13-2.24)). Among patients with normal-weight and obesity, the HRadj was 1.57 (95% CI 0.95-2.59) and 0.89 (95% CI 0.21-3.86), respectively. In overall survival analyses, Q4 was associated with inferior prognosis compared to Q1 (HRadj: 2.40 (95% CI 1.60-3.61)). In patients with normal-weight the association was evident (HRadj: 3.46 (95% CI 1.94-6.18)) whereas, in patients with obesity, CRP was not associated with OS (HRadj: 0.69 (95% CI 0.15-3.07)).
CRP levels at diagnosis seem prognostic in early BC. In patients with normal-weight, high CRP was associated with inferior disease-free and overall survival, however, in patients with obesity, CRP was not prognostic. Thus, CRP levels may help to distinguish patients with a better or worse BC prognosis among patients with normal-weight, but not obesity.
The authors.
Novo Nordisk Foundation, NEYE Foundation, The Danish Cancer Society, Fagerlund Stifelsen and the Department of Oncology Research Foundation.
All authors have declared no conflicts of interest.
We have developed a 3-protein signature blood marker (Mastocheck®) for early diagnosis of breast cancer. The purpose of this study is to improve the performance of the previously developed blood markers.
Blood from 196 breast cancer patients and 196 healthy control groups were prospectively collected.Through the development of a biomarker detectable library, PepQuant, peptides that are optimal for MS/MS detection were selected. After chemically synthesizing these selected proteins, these were quantified by multiple reaction monitoring (MRM) methods. Seven final proteins were derived by applying the PepQuant library for breast cancer biomarker discovery and verification. Machine learning algorithms was trained as protein candidates identified between breast cancer patients and healthy controls. As in previous studies, performance evaluation was conducted based on sensitivity, specificity, accuracy, false positive rate, false negative rate, positive predictive value, and negative predictive value for breast cancer diagnosis.
The sensitivity, specificity, and accuracy of Mastocheck®, were 69.4%, 83.7%, and 76.5%, respectively, which is relatively similar to that of previous studies’ results. The false positive rate(FPR) and the false negative rate(FNR) were 16.3% and 30.7%, and the positive predictive value(PPV) and negative predictive value(NPV) were 81.0% and 73.2%, respectively. During the study when 7-protein signature was combined with an artificial intelligence(AI) technique for the analysis, the sensitivity, specificity, and accuracy of diagnosis were 88.3%, 83.2%, and 85.7%, respectively, showing superior performance compared to Mastocheck®. The FPR and FNR were 16.8% and 11.7%, indicating that the FNR was improved by 20% compared to Mastecheck®. In addition, it was recognized that the PPV and NPV were also improved to 84.0% and 87.6%.
Through the collection of new prospective samples, the study confirmed that the diagnostic performance of Mastocheck® was repeatedly maintained. In addition, breast cancer diagnosis using 7-protein signatures with AI model showed that breast cancer diagnosis can be remarkably improved.
CHA Gangnam Medical Center.
Bertis. Inc.
Y. Kim: Financial Interests, Personal, Stocks/Shares: Bertis Inc. S. Kim, H. Shin, K. Ahn: Financial Interests, Personal, Member: Bertis Inc. W.S. Han: Financial Interests, Personal, Stocks/Shares: Bertis Inc; Financial Interests, Personal, Leadership Role: DCgen. D. Noh: Financial Interests, Personal, Leadership Role: Bertis Inc.
TROP2 is highly expressed in breast cancer. TROP2 antibody drug conjugates (ADCs) have shown antitumor activity in breast cancer, however the determinants of response remain controversial. Datopotamab deruxtecan (Dato-DXd) is an ADC consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. We assessed the antitumor activity in a panel of breast cancer PDXs varying in TROP2 expression.
11 PDX models that differed by TROP2 expression, generated from residual breast tumors after neoadjuvant chemotherapy were treated with Dato-DXd and Isotype control-DXd at 1 mg/kg and 10 mg/kg every 3 weeks. Antitumor activity was assessed by objective response (30% or more growth inhibition compared with baseline) and event-free survival (EFS, time to tumor doubling). Pharmacodynamic effects were assessed at 24 and 72 hours. TROP2 was overexpressed by viral transduction in cell lines derived from two different TROP2-low Dato-DXd-resistant PDXs.
Dato-DXd had dose-dependent activity. PDX models differed in sensitivity to both Isotype-Dxd and Dato-DXd, with tumor regression observed with isotype DXd in two models. Dato-DXd 10 mg/kg led to objective response in 4 (36%) models and statistically significant prolongation of EFS in 8 (73%) models. TROP2 expression was significantly higher by RNAseq and by immunohistochemistry in Dato-DXd-sensitive models. Dato-DXd led to an increase in H2AX in the 2 sensitive PDXs and not in a Dato-DXd resistant model. In Dato-DXd-sensitive models, antitumor activity was further enhanced with the combination with PARP inhibitor olaparib. In isogenic breast cancer cell lines, overexpression of TROP2 expression conferred
Dato-DXd is active in models resistant to traditional chemotherapy. Dato-DXd has TROP2 dependent and independent mediators of activity. Further study is needed into predictors of intrinsic resistance and rational combinations.
The University of Texas MD Anderson Cancer Center.
Daiichi Sankyo.
F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Tyra Biosciences, Xencor, Zymeworks, OnCusp Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Advisory Board: Silverback Therapeutics, Zentalis, Karyopharm, Biovica, Eisai; Financial Interests, Personal, Other, Consulting: Tallac Therapeutics, Lengo Therapeutics, LOXO-Oncology, Black Diamond, Infinity Pharmaceuticals, AbbVie; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis, PPD Investigator Services; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare. T. Maejima: Financial Interests, Personal, Other, Employer: Daiichi Sankyo. L.A. Byers: Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme Corp, Arrowhead, Chugai Pharmaceutical Co., AstraZeneca Pharmaceuticals, Genetech Inc, AbbVie, Jazz Pharmaceuticals, Puma Biotechnology, Amgen, Daiichi Sanyo, BeiGene; Financial Interests, Institutional, Funding, Research funding: AstraZeneca Pharmaceuticals, Amgen. D. Tripathy: Financial Interests, Personal, Advisory Board, Serving on Steering Committee for TrialsEducational Lectures: Novartis; Financial Interests, Personal, Advisory Board, Steering Committee for and ongoing trial: Pfizer; Financial Interests, Personal, Advisory Board, Advisory council for design and interpretation of trials: GlaxoSmithKline; Financial Interests, Personal, Invited Speaker, Educational Lectures: AstraZeneca; Financial Interests, Personal, Advisory Board, To discuss and interpret clinical trial data: Immunomedics; Financial Interests, Personal, Advisory Board, Advice on clinical trial design: OncoPep; Financial Interests, Personal, Invited Speaker, Lecture on gene profiling: Exact Sciences; Financial Interests, Personal, Advisory Board, Consulting: Sermonix; Financial Interests, Personal, Advisory Board, Consultant: Personalis, Puma Biotechnology, Gilead; Financial Interests, Institutional, Research Grant, Funding for laboratory experiments on the inhibition of CXCR4 in breast cancer cells: Polyphor; Financial Interests, Institutional, Invited Speaker, Global PI on one trial and local PI on another trial: Novartis. D. Okajima: Financial Interests, Personal, Other, Employer: Daiichi Sankyo, Ltd. All other authors have declared no conflicts of interest.
Hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer (BC) accounts for around 65% of all BCs. Invasive lobular and ductal carcinoma (ILC, IDC) show distinct histology and clinical presentation. In this study, our goal is to exploit morphological differences between IDC and ILC by combining artificial intelligence and spatial transcriptomics (ST) to characterize intra-tumor heterogeneity.
We analyzed 131 H&E whole slide images (WSIs) from frozen HR+, HER2- BC samples, of which 43 were ILC and 88 were IDC. Images were morphologically annotated using QuPath. We performed ST (Visium 10X Genomics®) on the ILC samples. A neural network (NN) was trained to perform histology classification from WSIs and detect the most relevant tissue regions for such classification. Gene expression data from ST were used to characterize these regions.
The NN achieved 0.95 ROC AUC in predicting histology (ILC vs IDC). Interestingly, in 36/43 ILC samples, adipose tissue had the highest relative importance in assessing the histological subtype, suggesting crucial morphological differences in adipocytes between ILC and IDC. Of note, we observed intra-sample heterogeneity in the importance levels of tumor areas, with just 13% of the overall tumor cells showing high importance in the classification. We mapped the most relevant tissue regions for histology classification to the ST spots (for ILC). Pathway enrichment analysis on differentially expressed genes (DEG) relative to these spots revealed enrichment in metabolic and adipogenesis-related pathways (padj < 0.05). When limiting the analysis on spots composed by more than 30% of tumor cells, DEG revealed enrichment in metabolic-related pathways (padj < 0.05).
Adipose tissue morphology was revealed to be a key feature in distinguishing histological subtypes in HR+, HER2- BC. Importantly, tumor cells with increased metabolism showed to be crucial in the histological classification, suggesting differences in metabolism between IDC and ILC. Further validation is needed.
The authors.
FNRS, Fondation Jules Bordet, Breast Cancer Research Foundation, Fondation contre le Cancer.
F.P. Duhoux: Financial Interests, Institutional, Advisory Board: Roche, Pfizer, AstraZeneca, Lilly, Novartis, Amgen, Daiichi Sankyo, Pierre Fabre, Gilead, Seagen, MSD; Financial Interests, Institutional, Invited Speaker: Novartis, Pfizer, MSD, Roche, MSD, Boehringer Ingelheim, Pfizer, Novartis, Lilly, AbbVie, Seagen, Gilead, AstraZeneca, Menarini, Immutep; Financial Interests, Institutional, Expert Testimony: Seagen, Novartis, MSD. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, Amgen, INC, Merck & Co; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences. All other authors have declared no conflicts of interest.
In ER+ eBC, extending AIs beyond 5 years reduces late recurrences at the price of increased skeletal events. Germline SNPs of CYP19A1 may affect aromatase activity, potentially leading to decreased AIs efficacy and toxicity. We conducted a prospective study to assess the impact of SNPs on outcomes of 886 postmenopausal patients treated with AIs.
The study included 2 cohorts of patients who were free of relapse 3-6 years from diagnosis. Patients of GIM5 cohort received 5 years letrozole after 4-6 years tamoxifen. Those of GIM4 cohort were randomized to 3-2 or 5 years letrozole after 2-3 years tamoxifen. Germline DNA was genotyped with PCR for SNPs rs4646, rs10046, rs749292, rs727479. Cumulative incidence of metastasis was analyzed in a competing risk model (CRM) with contralateral BC, second malignancy, and death without BC as competing risk. Cumulative incidence of skeletal events was analyzed in CRM with invasive BC/relapse, second malignancy, death as competing risk. Fine-Gray model was used to estimate subdistribution HR (sHR) in the CRM. Overall survival was analyzed with log-rank and Cox model.
Homozygosis of T allele (T/T) in rs10046, rs749292, and hetero and homozygosis of T allele in rs727479 (T/G + T/T) were high-risk genotypes associated with incidence of metastasis and worse OS (Table). 3 groups were identified based on number of high-risk genotypes (0, 1, >1). Genotypes-based groups identified patients with 15-year metastasis incidence of 2.5%, 8.3%, and 10.9%, respectively, and were associated with worse OS in a multivariable model (Table). Genotype-based groups were negatively associated with skeletal events (p=0.025); even after adjusting for age, BMI, smoke (p=0.028).
*cumulative incidence function
Cum. incidence of metastasis Overall survival rs10046 (T/T vs C/T + C/C) 1.57 (0.96-2.57) 0.071 1.51 (0.97-2.39) 0.070 rs749292 (T/T vs C/T + C/C) 1.83 (1.09-3.08) 0.023 1.64 (1.04-2.67) 0.050 rs727479 (T/T + T/G vs G/G) 2.62 (1.17-5.83) 0.060 2.20 (1.02-4.78) 0.040 0 high-risk genotype, N=132 1 (ref.) 0.035 1 (ref.) 0.030 1 high-risk genotype, N=524 2.54 (1.00-6.41) 2.30 (0.99-5.36) >1 high-risk genotypes, N=222 3.45 (1.32-9.04) 2.90 (1.19-7.05)
SNPs of CYP19 predict metastasis and skeletal events in patients receiving AIs, opening the opportunity to individualize therapy in ER+ BC survivors.
EudraCT 2005-001213-18.
Italy - Italian Medicines Agency.
CONSORZIO ONCOTECH, a public-private consortium funding the investigator-driven trial of the Gruppo Italiano Mammella.
B. Conte: Financial Interests, Personal, Invited Speaker: Veracyte. O. Garrone: Financial Interests, Personal, Advisory Board: Eisai, Daiichi Sankyo, AstraZeneca, Seagen, Gilead, MSD; Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Eli Lilly. S. de Placido: Financial Interests, Personal, Advisory Board: Lilly, GSK, MSD, Seagen, Daiichi Sankyo, Gilead, Eisai, Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Novartis, Pfizer, Roche. F. Schettini: Other, Personal, Sponsor/Funding, travel expenses: Novartis, Gilead; Other, Personal, Invited Speaker: Novartis, Gilead, Daiichi Sankyo. F. Montemurro: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly, Seagen, Pierre Fabre, AstraZeneca, Pfizer, MSD. C. Bighin: Other, Personal, Other, Personal fee: Novartis, Roche, Elly Lilly. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, MSD, Exact Science; Financial Interests, Personal, Research Grant, outside de submitted work: Gilead; Financial Interests, Personal, Invited Speaker: Sandoz, Libbs, Daiichi Sankyo, Takeda. L. Del Mastro: Financial Interests, Personal, Invited Speaker, Educational meeting: Novartis, Symposia, Andromeda E20, Vyvamed srl; Financial Interests, Personal, Invited Speaker, Lecture: Ipsen; Financial Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche; Financial Interests, Personal, Invited Speaker, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board, Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests, Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal, Advisory Board, Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD; Financial Interests, Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina; Financial Interests, Personal, Invited Speaker, Author for BC text: Pensiero Scientifico Editore; Financial Interests, Personal, Advisory Board, Breast cancer: Uvet; Financial Interests, Personal, Other, Author slide kits and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pfizer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL; Financial Interests, Personal, Other, Author slide kits: Forum service; Financial Interests, Personal, Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other, consultant: Kardo srl; Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl; Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca, Agendia, Gilead; Financial Interests, Personal, Other, Interview: Infomedica srl; Financial Interests, Personal, Other, Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Personal, Other, Consultancy: Eli lilly; Financial Interests, Institutional, Funding, National coordinating PI: Roche; Financial Interests, Institutional, Funding, Local PI: AstraZeneca, Roche, Eli Lilly, Daiichi Sankyo, Novella Clinical, Novartis; Non-Financial Interests, Institutional, Product Samples, Genomic Test: FoundationOne. All other authors have declared no conflicts of interest.
Megestrol-Acetate (MA) has activity after progressive disease (PD) on aromatase inhibitors, providing a disease control rate of 40% and a duration of clinical benefit of 10 months. Ligand-bound progesterone receptor modulates estrogen receptor (ER) activity and reprograms ER-regulated transcription in breast cancer (BC), leading to regression of tumour xenografts. MEGA trial [NCT03024580] aimed to evaluate modulation of steroid receptor activity in advanced BC. Here we present the clinical and preliminary translational data.
Eligible patients (pts) had metastatic ER+ HER2- BC, and were randomized to receive MA or another HT agent (AHT), Tamoxifen or Exemestane, with 10 pts planned for each arm. The primary endpoint was PFS, secondary were clinical benefit rate and OS. Tumour biopsies and blood for translational analysis (TA) were collected before day 1 of treatment and at PD. Paired samples were analysed by RNA-seq and by chromatin immunoprecipitation and sequencing (ChIPseq) for histone acetylation (H3K27-Ac).
From Aug/17 to Jan/20, a total of 20 pts were recruited and evaluable for efficacy. 16 pts evaluable for TA. No difference was observed between both arms in mPFS, MA = 121 vs AHT = 137 days (p=0.66), or mOS, MA=26 vs AHT=30 months, (p=0.35). The best clinical response at 12 weeks (w) was stable disease for MA was (50%) and AHT (58%) and the duration of response >24w for both was 25%. 10 pts in the MA arm had samples evaluable for TA. RNA-seq (n=7) analysis revealed enrichment for estrogen early and late response pathways in MA resistant samples. There was a global increase in H3K27 acetylation (n=10) at ESR1 motifs in MA resistant samples at PD, although a subgroup of pts (n=3 of 10) showed decreased H3K27Ac at these loci globally. Numerically higher median PFS and OS was observed among pts with decreased (N=3) vs increased (N=7) H3K27Ac at ESR1 motif at PD, respectively mPFS 223 (84-337) vs 137 days (46-291), (p=0.25) and mOS 30 (26-35) vs 14 (7-63) months (p=0.42).
Translational analysis find evidence of increased transcriptional activity at ER regulated genes in most resistant samples. This could indicate that MA resistant tumours will retain sensitivity to further HT, requiring future research to proof this hypothesis.
MEGA trial, NCT03024580.
Instituto Nacional de Cancer, Brazil.
Jason Carroll Lab.
All authors have declared no conflicts of interest.
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have led to a paradigm shift in the treatment of hormone receptor-positive (HR+)/HER2- advanced breast cancer (ABC). Prior data has suggested a key role of tumor immunity in CDK4/6i success. We investigate immune-mediated resistance to CDK4/6i treatment.
63 samples from 55 patients with HR+HER2- ABC treated with CDK4/6i were recruited (34 primary, 21 metastatic (M1) and 8 paired biopsies). Gene expression (GE) was assessed using NanoString Breast Cancer 360™, including intrinsic subtype (IS). Patients were stratified in good/poor responders (GR/PR), considering hormone sensitivity and progression-free survival (PFS) data from pivotal studies (GR n=38, 66.5%). Multiple t-tests comparisons were used to identify GE differences and Kaplan Meier and Cox regression models for survival.
GE comparisons between primary and M1 biopsies showed significantly higher expression of immune-related features and oestrogen receptor (ER)-signalling in primary biopsies (T.test; p-value<0.05). GE profiles between response groups were compared to identify mechanisms of resistance to CDK4/6i. Most tumors were luminal A or B (n=23, 36.5% each). The IS were not significantly associated with response (Chi-square p>0.05). High GE of tumor-immunity related signatures such as macrophages, PD-L2, inflammatory-chemokines, IDO1, and T-regs were associated with reduced efficacy of CDK4/6i (mean log2FC 0.5; p<0.05). Survival analysis in first-line CDK4/6i confirmed longer PFS within patients with luminal tumours (p=0.02). Type of M1 (visceral or non-visceral) and type of response (PR vs GR) were also associated with significantly shorter PFS and overall survival (OS) (p<0.05), remaining as independent predictors after adjustment by the standard clinico-pathological variables. High expression of macrophages signature (HR: 3.14; p=0.03) and other genes related to immunity/inflammation (CD68, CD163, CCR1 or CDC25B) were also associated with worse OS (HR 1.8-6.1; p-value<0.05).
Immune function plays a key role in tumor evolution and CDK4/6i efficacy. Further investigation of immune-tumor crosstalk and the role of immunotherapy in this setting is needed to improve CDK4/6i efficacy.
ICO Badalona.
Investigational grants: 1) ISCIII-FIS (CM20/00027 and MSII19/00012). Dates 2020- 2022; 2) ISCIII-FIS (PI17/00624 and PI21/00642). Dates: 2020-2023. Collaborations: 1) Pfizer grant (Pfizer, SA; Spain). Dates 2020-2023; 2) NanoString Translational Research Request. Dates: 13/01/2020-10/12/2022.
M.A. Bergamino: Financial Interests, Personal, Sponsor/Funding: ESAI, Novartis. E. Felip Falgas: Financial Interests, Personal, Sponsor/Funding: Novartis, Pfeizzer, Lilly, Roche. A. Ferrando Diez: Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Sponsor/Funding: MSD, Lilly, Roche, Merck. M. Romeo Marin: Financial Interests, Personal, Sponsor/Funding: GSK; Financial Interests, Personal, Research Grant: MSD, Clovis; Financial Interests, Personal, Speaker’s Bureau: AZ. A. Pous: Financial Interests, Personal, Sponsor/Funding: Lilly, Roche. M. Margeli Vila: Financial Interests, Personal, Sponsor/Funding: Novartis, Pfizer, Lilly, Gilead, PiereFabre; Financial Interests, Institutional, Research Grant: Pfizer. All other authors have declared no conflicts of interest.
CDKi have significantly improved PFS and OS in MBC HR+/HER2- patients. However, their benefit is not observed in all treated patients and currently no predictive marker has been identified. Dysregulated lipid metabolism, including alterations in fatty acid (FA) transport, uptake, and oxidation has been associated with BC outcome. The lipidome is a very sensitive measure of the lipidic phenotype and reflect its alteration. The purpose of this study is to identify lipidomic signatures with prognostic and predictive ability in patients with ER+ MBC candidate do ET + CDK 4/6i.
Thirty consecutive MBC ER+/HER2- patients were prospectively enrolled in this study. Plasma samples were collected at baseline. The lipidomic analysis was conducted following an untargeted approach, based on 1139 lipids. Analyses were performed by combining liquid chromatography and mass spectrometry. The lipidomic profile of 23 patients who achieved a PR or SD at 6 months was compared with the 7 patients who experienced disease progression or death. Moreover, a comparison was performed between patients with visceral disease (n=8) and those with bone/soft tissue disease (n=22). The differentially expressed lipids were computed by calculating the Fold Change with a p-value <0.05.
We identified 53 lipids differentially expressed: 9 were overexpressed in responding patients and 44 in those with PD/death. In the second analysis 41 differentially expressed lipids were identified according to metastatic site. By multivariate analysis 8 hypothetical biomarkers were identified in the first comparison and 6 in the second group: in responding patients higher baseline concentrations of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin and ceramides were detected, whereas those with higher levels of triacylglycerols (TG) and carnitine were more likely to have resistant disease. TG, diacylglycerols (DG) and cholesterol higher levels were found in patients with visceral compared to patients with bone/soft tissue disease.
These preliminary results suggest that lipidomic profiling might be further exploited as a possible tool to discover predictive biomarkers of response to CDKi.
The authors.
AIRC - Associazione Italiana Ricerca sul Cancro.
A. Gennari: Other, Personal, Other: Roche. All other authors have declared no conflicts of interest.
Tamoxifen is an effective drug reducing the risk of dying from breast cancer. This study aims to validate and study the feasibility of serial assessments, including therapeutic drug monitoring of tamoxifen (TAM), 4-hydroxytamoxifen (4HT) and Z-endoxifen (Z-END) by capillary blood sampling.
A prospective, single-centre study including women with stage 0-3 breast cancer receiving adjuvant tamoxifen 20 mg/day for a minimum of 2 months. Study design: Blood samples for repeated measurement of TAM, 4HT and Z-END were drawn capillary in total at 4-time points, at inclusion (baseline), and after 1, 2, and 3 weeks for each participant; and venously in total at two time-points, at inclusion (baseline), and after 3 weeks for each participant. At baseline, the capillary blood test concentrations of TAM, 4HT and Z-END were taken first by the research nurse and second by the patient. At each time, participants will be asked to leave 1 vial of capillary blood using the rhelise™ kit and 2 samples of conventional venous blood for blood and plasma. Primary Objective To validate the rhelise™ kit for monitoring TAM, 4HT and Z-END among patients who have ongoing adjuvant tamoxifen by testing for equivalence between concentrations found in the capillary sample and the venous blood sample (gold standard). Primary endpoint Blood concentrations and correlations of TAM, 4HT and Z-END at baseline and 3 weeks by capillary and venous blood sampling (whole blood/plasma). Secondary objectives To validate user acceptability and feasibility of self-testing the capillary kit by comparing the capillary blood test concentrations of TAM, 4HT and Z-END taken by the patient to the capillary sample taken by the research nurse. Secondary endpoints Capillary blood test concentrations of TAM, 4HT and Z-END were taken by the patient and the research nurse at baseline.
A capillary sampling kit was used for 40 participants. Mean TAM, 4HT and Z-END concentrations did not differ significantly in the 3 types of samples. Mean capillary TAM, 4HT and Z-END concentrations did not differ significantly between nurse and patient.
TDM of TAM using capillary blood sampling is feasible.
NCT05133674.
Elham Hedayati, Karolinska University Hospital.
Vinnova & Karolinska University Hospital, Karolinska Institutet.
S. Rehnmark, H. Randahl: Financial Interests, Personal and Institutional, Ownership Interest: Redhotdiagnostics AB. A. Lindqvist: Financial Interests, Personal and Institutional, Full or part-time Employment: Redhotdiagnostics AB. All other authors have declared no conflicts of interest.
HR+/HER2- BC is less immunogenic compared to triple-negative BC in the early setting. Lower levels of stromal tumor infiltrating lymphocytes (sTIL) are observed in BC metastases compared to the primary tumor. sTIL have not yet been investigated extensively in metastatic HR+/HER2- BC. Here, we aimed at evaluating sTIL in multiple metastatic lesions from patients with primary HR+/HER2- BC who participated in our institutional post-mortem tissue donation program UPTIDER (NCT04531696).
16 patients with HR+ (ER+ and/or PR+)/HER2- primary BC, enrolled between 01/01/2021 and 08/01/2023 were considered. sTIL were assessed according to international guidelines (PMID:28777142) and scored at the invasive margin on a total of 542 samples (481 metastatic (M) and 46 primary untreated (P)). A median of 25.5 M lesions were evaluated per patient (IQR: 20.5-38.75). M lymph nodes were only scored if there was extra nodal extension into the surrounding tissue. Central pathology evaluation was performed for histology and ER-status (EP1 clone, RTU, CE IVD). Associations between sample status (outcome: M vs P/ER+ vs ER- for M) and sTIL levels (co-variate) were assessed by logistic linear regression with data clustering by patient using the generalized estimating equation method.
A median of 4 (range:1-13, IQR:2-7) and 2 metastases (range:1-4, IQR:1-2.5) per patient had a sTIL score >5% and 10%, respectively. M sTIL scores were heterogeneous within patients (range of 16 sTIL ranges:2.34-40, median of 16 sTIL IQR’s:1.68, range of 16 sTIL IQR’s:0.34-6.34). P had higher sTIL scores compared to M (OR:0.94, 95% CI:0.89-1.00, p:0.05). 50/316 (16%) metastases lost ER expression in 12 patients with ER+ primary BC. No significant difference was detected in sTIL scores between ER+ and ER- M (OR:1.06, 95% CI:0.98-1.14, p:0.15) while higher sTIL scores were observed in NST M (n=230) compared to ILC M (n=209) (Estimate:1.1, 95% CI: -0.07-2.3, p:0.06).
This study highlights the intra-patient inter-metastasis heterogeneity in sTIL scores, differences between P and M, as well as differences according to histology in HR+/HER2- BC patients.
NCT04531696.
Laboratory for Translational Breast Cancer Research.
KU Leuven, Leuven, Belgium.
K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Roche, Vifor Pharma, Eli Lilly, Pierre Fabre, McCann Health, Roularta, Teva, Gilead Sciences, Pfizer, Gilead, MSD; Financial Interests, Institutional, Invited Speaker: Pfizer, Roche, Novartis, Eli Lilly, Mundi Pharma, MSD, Medscape, MSD; Financial Interests, Institutional, Other, Consultancy: Roche; Financial Interests, Personal, Other, Consultancy: Gilead, Novartis, MSD, Roche; Financial Interests, Personal, Invited Speaker: Sanofi, AstraZeneca; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Institutional, Funding: Sanofi; Non-Financial Interests, Principal Investigator: EORTC 1745-ETF-BCG trial; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Invited Speaker: BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force; Non-Financial Interests, Advisory Role: Commission personalized medecine Federal Government Belgium; Non-Financial Interests, Advisory Role, External Scientific Advisor: European Medicine Agency. H. Wildiers: Financial Interests, Institutional, Advisory Board: Roche, Lilly, AstraZeneca, Daiichi Sankyo, PSI Cro AG, KCE, MSD, MSD, E Squared Communications LLC; Financial Interests, Institutional, Invited Speaker: Eisai, AstraZeneca; Financial Interests, Institutional, Other, Consultancy fee: AbbVie, Immutep Pty; Financial Interests, Institutional, Expert Testimony: Daiichi Sankyo; Financial Interests, Institutional, Other, Consultancy: Daiichi Sankyo; Financial Interests, Institutional, Research Grant, Grant to the Leuven Breast Center to support the research database: Roche; Financial Interests, Institutional, Research Grant, Grant to institute to perform a multicentric national academic trial: Novartis; Other, Travel & accomodations: Pfizer; Other, Travel & accomodation: Roche; Other, Subscription fee: Gilead. G. Floris: Financial Interests, Institutional, Advisory Board: AstraZeneca. All other authors have declared no conflicts of interest.
BM can be an important cause of morbidity and mortality in breast cancer. In addition to mechanisms of endocrine therapy resistance, like ESR1 mutations, BM have other causes of resistance such as inherent resistance to systemic therapy and limited drug tissue penetration. We have shown imlunestrant has activity in ER-dependent cell lines and
ER+ breast cancer cell lines and mouse models with ESR1 wild-type or mutant tumors were treated with imlunestrant alone or with abemaciclib, alpelisib or everolimus. Effects on ER degradation, ER-mediated gene expression, cell proliferation and viability were examined
Across cell lines, imlunestrant degraded ER and decreased ER-mediated gene expression. In addition, cell proliferation and tumor growth in ESR1-wild type and mutant models was significantly inhibited by imlunestrant. Combination of imlunestrant with abemaciclib, alpelisib or everolimus further enhanced the efficacy across cell lines and
Imlunestrant, a novel potent and orally available SERD, demonstrated activity across a panel of breast cancer cell lines and decreased tumor burden in both ESR1-wild type and mutant xenograft and PDX models. Imlunestrant also demonstrated CNS penetrance and improved survival in a brain orthotopic model. Imlunestrant is being evaluated in multiple global phase III clinical trials in metastatic and early breast cancer.
Drs. Cecilia Mur and Matthew VandeKopple have equally contributed to the study.
Eli Lilly and Company.
Eli Lilly and Company.
M. VandeKopple, A. Capen, L. Huber, N. Pulliam, M. Dowless, X. Gong: Financial Interests, Personal, Full or part-time Employment: Loxo Oncology at Lilly; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. C. Mur, W. Shen, C. Marugan, M.A. Castanares, D. Garcia-Tapia, B. Mattioni, J. Bastian, J. Manro, M.J. Ortiz Ruiz, M.J. Lallena, A. De Dios: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company.
BCL2 is a key factor for the regulation of cellular apoptosis and its overexpression inhibits apoptotic cell death and activates cellular proliferation, resulting tumor progression. BCL2 are expected to be associated with an adverse prognosis in solid tumor. However, studies have reported inconsistent results and some showed even favorable features in breast cancer, which can be analyzed according to the subtype. The aim of this study is to investigate characteristics of BCL2 by subtype and to find possible confounding factor leading to conflicting results in breast cancer.
Female patients with breast cancer who completed primary treatment against breast cancer between 2003 and 2018 at Wonju Severance Hospital, Korea, were included. Clinocopathological characteristics including BCL2 expression were collected. Patients were categorized into two groups, BCL2 expression in more or less than 10% of tumor cells. Kaplan-Meier curves were generated to compare recurrence-free interval (RFI) and overall survival (OS).
The final cohort included 617 patients with a mean age of 54.79±11.2 (25-86) years. Patients did not show survival difference by BCL2 status(p=0.616). Patients showed opposite result of survival when they were divided by HER2 status. In patients with HER2-overexpressed disease, patients with high BCL2 expression showed poor prognosis with statistically significant difference(p=0.0021). This difference showed tendency in patients with ER-positive disease (p=0.297) and ER-negative disease (p=0.029). However, patients with HER2-negative disease, BCL2 overexpression showed discrepant result, better survival than patients with low BCL2 expression(p=0.009). This difference also maintained in patients with ER-positive (p=0.259) and negative disease(p=0.010).
BCL2 overexpression showed different contribution to the patients’ survival based on HER2 status. High BCL2 was poor prognostic factor in patients with HER2 overexpression, which was consistent with expected role of BCL2. However, BCL2 overexpression indicated better prognosis in patients with HER2-negative disease than who does not.
The author.
Has not received any funding.
The author has declared no conflicts of interest.
The PI3K/AKT/mTOR and MEK/MAPK pathways are suggested mechanisms of EndoR. However, single kinase inhibitors (Ki), like everolimus, only partially reverse EndoR, probably due to activation of adaptive pathways. We previously showed that combining fulvestrant (Ful) + AKT inhibitor (AKTi, Capivasertib) reversed tamoxifen resistant (TamR)
In this study we used an aggressive later generation of the transplantable ER+ MCF7/TamR xenograft model, testing the effect of the Ki alone or in combination (Ki combo: mTORi+MEKi, AKTi+MEKi) on tumor growth and signaling in the presence of Ful after short term (ST, 1 week) and long term (LT) treatment (as tumors progressed to ∼ 1000mm3 in size or at the end of the study, ∼ 130 days). Reverse phase protein array (RPPA; with 172 anti-phospho/total antibodies) was used to profile the signaling landscape of different Kis in the presence of Ful after ST (2nd study) or LT (both studies) treatment.
Lower dose AKTi and mTORi single Ki inhibited tumor growth. RPPA analysis showed on-target activity of single and Ki combo after ST and LT treatment. While MEKi, consistent with its lack of effect on tumor growth, did not show any further signaling modulation, AKTi and mTORi affected multiple signaling components. Ki combo with MEKi enhanced the effect on signaling and tumor growth, though, in the 2nd study, the effect on the latter was significant only with mTORi. Among the modulated factors in the mTORi and AKTi containing treatments, pSTAT6 was upregulated by both ST and LT treatments, possibly as an adaptive/resistant mechanism. Of note, diverse integrin and tyrosine kinases receptor members were upregulated by LT treatment with the Ki combo, potentially as escape pathways.
Our findings support the role of AKT/mTOR in EndoR BC and the clinical development of potent ER inhibitors plus AKTi to overcome it. Additional studies exploring Ki combo to counter adaptive and resistant signaling are warranted.
The authors.
AstraZeneca.
G. Morrison-Thiele: Financial Interests, Personal, Full or part-time Employment: AbbVie. A. Goldstein: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals. C. De Angelis: Financial Interests, Personal, Advisory Board: Roche, Eli Lilly, GSK, Novartis, Pfizer, AstraZeneca; Financial Interests, Institutional, Funding: Novartis. X. Fu: Financial Interests, Personal, Full or part-time Employment: Gilead. S. Cosulich: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. B. Davies: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. R. Jeselsohn: Financial Interests, Institutional, Research Grant: Pfizer, Eli Lilly; Financial Interests, Personal, Advisory Board: Carrick Therapeutics, GE Health. L. Malorni: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Seagen; Financial Interests, Personal and Institutional, Research Grant: Novartis, Pfizer. M. Rimawi: Financial Interests, Personal, Advisory Board, Consulting: Genentech, Novartis, AstraZeneca, Seagen; Financial Interests, Personal, Advisory Board, Advisory Board: Macrogenics; Financial Interests, Institutional, Research Grant: Pfizer. C.K. Osborne: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Stocks/Shares: GeneTex. R. Schiff: Financial Interests, Personal, Advisory Board: MacroGenics; Financial Interests, Institutional, Research Grant: Puma Biotechnology, Gilead Sciences; Financial Interests, Personal, Royalties: Wolters Kluwer/UpToDate; Financial Interests, Institutional, Other: PCT Patent. All other authors have declared no conflicts of interest.
Intracellular signalling pathways play a role for treatment response and outcome for patients with breast cancer (BC).
We analysed phosphorylated MAPK (pJNK, pERK, pp38) and pAkt with a commercial multiplex enzyme-linked immunosorbent assay (ELISA) (Luminex®) and M30, a marker of apoptosis, in 449 patients with primary ER-positive BC. The aim was to determine the relation between pMAPK, proliferation, apoptosis, and survival in Invasie Lobular Carcinoma (ILC) and non-Invasive Lobular Carcinoma (non-ILC).
Medium follow up was 18.9 years and ILC and non-ILC had an equal Relapse Free Survival (RFS) (p=0.68). In the whole population pAkt was the only kinase with prognostic information; patients with absent/low levels of pAkt had a worse RFS (p=0.016). A multivariate analysis showed tumour size (HR=1.8) (p=0.0016), nodal status (HR=2.8) (p<0.001) and absent/low pAkt (HR=0.69) (p=0.059) as independent prognostic factors. There was a difference between ILC and non-ILC concerning expression of estrogen receptor (ER) (p=0.033), apoptosis (p<0.001), pERK (p=0.004), pJNK (p<0.001) and pp38 (p=0.005) whilst nodal status, Progesteron Receptor (PGR), proliferation rate and pAKT were equal. ILC had a trend towards larger size, but this did not reach statistical significance (p=0.059). Proliferation was correlated to RFS in non-ILC (p<0.001) but not in ILC (p=0.94). pMAPK were not correlated to RFS when patients were split in ILC and non-ILC.
We show differences in expression of activated MAPKs in ILC and non-ILC. Despite lower proliferation and apoptosis, we could not show any correlation to survival in ILC, but this may indicate a more stem cells like behaviour. ER-positive ILC and non-ILC have similar survival, pAkt was the only kinase with prognostic information.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Gene expression profiling (GEP)-based prognostic signatures are rapidly integrated into clinical decision-making for systemic management of breast cancer patients. However, GEP remains relatively underdeveloped for loco-regional risk assessment. Yet, local-regional recurrence (LRR), especially early after surgery, is associated with poor survival.
GEP was performed on two independent luminal-like breast cancer cohorts of patients developing early (≤ 5 years after surgery) or late (>5 years) LRR and used, by training and testing approach, to build a gene signature able to intercept women at risk of developing early LRR. The GEP data of two
Analysis of the first two cohorts lead to the identification of three genes,
Our 3-gene signature represents a new exploitable tool to aid treatment choice in patients with luminal-like breast cancer at risk of developing early recurrence.
The authors.
AIRC (Italian Association for Cancer Research), Grants to MPC (AIRC IG #18425 and AIRC IG #24363) and Italian Ministry of Health, “Ricerca corrente” Funds.
All authors have declared no conflicts of interest.
The role of PI3K pathway aberrations in the clinical behavior and therapy responsiveness of hormone receptor–positive (HR+/HER2-) tumors remains controversial. Some authors suggested that mutations may be related to poor clinical outcomes, although this was reported in heterogeneous populations or only patients with early-stage disease. There is therefore a need to better understand the prognostic implications of PIK3CA mutations in advanced breast cancer (ABC). To this purpose, in this study, we analyzed patient data from a Latin-American population concerning overall survival (OS) and progression free survival (PFS).
Retrospective cohort of HR+/HER2- ABC patients, from public and private facilities in Argentina. Patients were included if PIK3CA was tested in metastatic setting. PIK3CA determination was carried out by PCR, NGS or commercially available multigenetic platforms. Kaplan-Meier method was used for survival analysis. Multivariate analysis was done with Cox regression analysis.
155 patients were analyzed (Median age 53.0, IQR 43-61.75). 39.4% (61) presented PIK3CA mutation. De novo metastatic patients covered 23.9% (37) of the sample. 74.8% (116) received CDK inhibitors added to hormone therapy (CDKi-HT) in the first-line (1L) setting. In second-line (2L) setting, 48% (48) received a combination of HT and other molecules (CDKi, Alpelisib, Everolimus), 40% (40) chemotherapy and 12% (12) HT. With a median follow-up of 42.1 months (IQR 26.9-63.8), OS analysis showed no difference according to PIK3CA status (HR 0.76. CI95% 0.40-1.47, p=0.4). 1L PFS was 23.0 months vs 22.1 months for patients with WT and PI3KCA mutated tumors, respectively (HR 0.97; CI95% 0.65-1.44; p=0.9). The observed 2L PFS was 10.6 months vs 11.1 months (HR 0.96; CI95% 0.60-1.53; p=0.9). After adjusting results by other prognostic variables, no difference was observed in survival results.
In our real-world study, no difference was observed in OS and PFS according to PIK3CA mutation presence, highlighting its lack of prognostic value. Local data from Latin America is important to uncover tumor characteristics in these populations.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Activating mutations of
We performed a retrospective and unicentric analysis of
189 samples were analyzed in 155p with HR+/HER2- BC (128 in tissue & 61 in plasma).
56 [24-91] 45(76.3%) 85(81.7%) 12(20.3%) 6(5.8%) 2(3.4%) 13(12.5%) 19(34.5%) 17(17%) 30(54.6%) 65(66%) 6(10.9%) 18(18%) 28(50%) 52(50.9%) P=0.91 28(50%) 50(49.1%) 41(74.5%) 88(85.4%) P=0.09 14(25.5%) 15(14.6%) 19(41.3%) 29(32,6%) P=0.31 27(58.7%) 60(67.4%) 10(34.5%) 21(38.2%) P=0.73 19(65.5%) 34(61.8%) 24(82.8%) 40 (72.7%) P=0.31 5(17.2%) 15(27.3%)
Mutational spectrum and clinical features in
The authors.
Has not received any funding.
C.A. Rodríguez Sanchez: Non-Financial Interests, Institutional, Advisory Role: Novartis, Lilly, Pfizer, Roche, Daiichi Sankyo, AstraZeneca, MSD, Veracyte, Gilead. All other authors have declared no conflicts of interest.
Assessment of immunohistochemical (IHC) Ki-67 expression plays a crucial role in breast cancer diagnostics for many therapy decisions. The International Ki-67 in Breast Cancer Working Group (IKWG) has recently proposed a new global scoring method on whole tissue sections to improve accuracy, involving assessment of up to four representative tumor areas with negligible, low, medium and strong proliferation levels. As precise manual assessment is time-consuming, artificial intelligence (AI) support is necessary to make this method practicable for clinical routine.
We developed an AI software for automated Ki-67 scoring according to the IKWG protocol. Seven pathologists assessed Ki-67 IHC status in 2 x 214 readings of whole-slide images (WSI) derived from 72 breast cancer specimens, four scanning hardware types and two clones. Pathologists selected representative areas manually, scored them with assistance of a CE-cleared AI software for region-of-interest (ROI) analysis and concluded global scores (weighted/unweighted). After a 2-week washout period, the same pathologists were presented with the same slides together with results by a fully automatic AI (AI-only): 1) selection of regions, 2) score and weight per region, and 3) two global scores (weighted/unweighted). Being able to adjust the AI-suggested results, pathologists concluded the two global scores (AI+path).
For weighted global scoring, interrater-agreements between a) pathologist and AI+path, b) pathologist and AI-only, and c) AI-only and AI+path were 93.9%, 92.5%, and 96.7%, respectively (for unweighted scores, 91.1%/92.1%/96.3%). With AI-assistance, pathologists scored significantly faster compared to manual scoring (median time per WSI: 229 vs. 306 sec).
Used as a diagnostics assistance tool, the presented AI system showed high agreement with pathologist scores, while reducing assessment time. Likewise, also fully automatic AI use showed high agreement with human scoring. Overall, this demonstrates that the investigated AI system is suitable to enable safe implementation of the global scoring protocol in clinical routine, ultimately leading to higher accuracy and reproducibility in Ki-67 IHC scoring.
Mindpeak GmbH.
Mindpeak GmbH.
R. Erber: Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Daiichi Sankyo , Roche, Pfizer, Eisai; Financial Interests, Personal, Expert Testimony: Mindpeak GmbH; Financial Interests, Personal, Other: Mindpeak GmbH, Diaceutics, Veracyte; Financial Interests, Personal, Research Grant: Gilead; Financial Interests, Institutional, Funding: Cepheid, Roche, Biocartis; Financial Interests, Personal and Institutional, Funding: NanoString Technologies; Financial Interests, Personal and Institutional, Other: BioNTech. P. Frey, K. Daifalla, S. Springenberg: Financial Interests, Personal, Full or part-time Employment: Mindpeak GmbH. N. Abele: Financial Interests, Personal, Other: Mindpeak GmbH; Financial Interests, Personal, Advisory Board: Mindpeak GmbH. M. Päpper, T. Lang: Financial Interests, Personal, Full or part-time Employment: Mindpeak GmbH; Financial Interests, Personal, Stocks/Shares: Mindpeak GmbH. A. Hartmann: Financial Interests, Institutional, Funding: AstraZeneca, Roche, Janssen-Cilag, NanoString Technologies, Biocartis, ZytoVision, Novartis, Cepheid, Mindpeak, Gilead, palleos healthcare, BioNTech; Financial Interests, Personal, Advisory Board: BMS, MSD, Roche, Cepheid; Financial Interests, Personal, Invited Speaker: Qiagen, Agilent, Diaceutics, Lilly, AstraZeneca, Boehringer Ingelheim, AbbVie, Janssen-Cilag, Pfizer, Ipsen. All other authors have declared no conflicts of interest.
Obesity has been associated with poor clinical outcomes and chronic systemic inflammation in patients with breast cancer (BC). Metformin has demonstrated antitumorigenic effects both in pre-clinical and clinical studies. We hypothesize that chronic inflammation may lead to immune cell dysfunction in BC that can be restored via the use of metformin.
The effect of metformin on intratumoural (IT) immune cells was evaluated in two independent peri-surgical window studies (Dundee, n=29; Oxford, n=31) using immunohistochemistry for selected immune cell markers, pre- and post-metformin. Immune cell infiltrates were digitally quantified using Definiens Architect software and correlated to clinical parameters. Descriptive and linear regression techniques were applied using STATA software. Median densities and 95% confidence intervals were reported.
In the Dundee cohort, metformin was associated with a 2.5 (1.8-3.1) fold increase in IT CD68+ macrophages, 2.7 (2.1-9.8) fold increase in IT CD8+ T-cells and 0.5 (0.4-0.6) fold decrease in regulatory T-cells (Tregs) in patients with primary BC. These findings were validated in the Oxford cohort where metformin was significantly correlated with higher density of IT CD8+ T-cells and reduced Treg density (adj P<0.05). These changes were confined to the tumour islands rather than in the stroma. Stratified analysis by BMI in both cohorts showed an increase IT CD68+ macrophages and reduction in Tregs post metformin, in patients with high BMI (adj P<0.05) whereas there was no difference in patients with healthy BMI (adj P>0.05). In the Dundee cohort, linear regression showed that metformin was significantly associated with increased IT CD8+ independently of the baseline pathological or metabolic parameters [co-efficient 7.2, 95%CI (3.2-11.2)]. In the Oxford cohort, systemic inflammation (baseline serum leptin of >17 pg/ml) was associated with lack of correlation between CD8+ and PD1+ T-cells as well as between CD16+ and CD32B+ macrophages that was restored after the administration of metformin (adj P<0.05).
Metformin is associated with changes in the IT immune cells. Further work to understand potential combination with immunotherapy is required.
The authors.
Cancer Research UK Charity, Against Breast Cancer Charity and the European Society for Clinical Nutrition and Metabolism (ESPEN).
All authors have declared no conflicts of interest.
HER2-low breast cancer is emerging as a specific subtype of breast tumor against which trastuzumab-containing antibody-drug conjugates, specifically trastuzumab-deruxtecan, are effective. However, attempts to define HER2-low breast tumors as a unique biological entity have thus far concluded that low HER2 expression does not categorize these tumors as having distinct molecular features beyond low immunohistochemical (IHC) cytoplasmic membrane expression of HER2. Our aim in this study is to characterize these tumors as separate biological entities and establish whether there are other mechanisms at play in these tumors that can be exploited as therapeutical approaches beyond trastuzumab-deruxtecan.
We have selected a cohort of patients within the large population-based SCAN-B prospective study. We included all patients diagnosed in Region Skåne between 2010 and 2014 with a follow-up of ≥ 5 years. We only included tumors with histology of invasive ductal carcinoma (IDC) to ensure homogeneity. All included cases had complete RNA-sequencing profiling. Tumors were ER positive, defined as IHC staining ≥10% of cells, HER2 negative (0-1+ by IHC or 2+ and no amplification by ISH). The HER2-low disease included all cases with HER2 IHC staining scores of 1+ or 2+ with no gene amplification, per international guidelines.
We have identified and included 1299 patients in this cohort. As with earlier described cohorts, HER2-low tumors do not show a worse prognosis regarding breast cancer event-free interval or overall survival. HER2 IHC membrane staining strength correlates with ERBB2 mRNA expression data linearly. Intriguingly, we have found a positive correlation with ERBB3 gene expression but not with other potential heterodimerization partners such as EGFR, ERBB4, and AXL.
The correlation between ERBB2 and ERBB3 mRNA expression suggests that heterodimers form to activate internal signaling in HER2-low disease. We are now specifically looking at mRNA expression patterns to elucidate if this HER2/HER3 signaling association corresponds with distinct biological entities within the HER2-low breast tumors.
The authors.
Has not received any funding.
A. Bosch: Other, Advisory Board, Participated in Advisory Board meetings: Pfizer, Novartis; Other, Institutional honoraria for consultations ans lectures: Pfizer; Other, Institutional honoraria for consultations and lectures: Roche, Lilly; Other, Member of the Board of Directors, Co-founder and board chair: SACRA therapeutics. All other authors have declared no conflicts of interest.
While many studies are addressing low ERBB2 expression in invasive breast cancer, none have dealt with DCIS. Yet DCIS is raising, patients (pts) increasingly undergo surgical and often systemic therapy to ward off recurrences, which although low are mostly invasive. Unfortunately, no markers are currently available to identify pts who will or will not relapse. With this premise, we aimed to investigate whether low ERBB2 expression is associated with distinct clinico-pathological characteristics and prognosis among pts with DCIS.
This cohort study was conducted using data from a prospectively maintained institutional database on all consecutive 7645 pts undergoing breast surgery between 2012 and 2020 at our Institute. Primary DCIS was classified by immunohistochemistry (IHC) as ERBB2-0 if IHC scored 0, ERBB2-low if IHC was 1+ or 2+; ISH was not considered as it is not routinely used in DCIS diagnostics; and ERBB2-overexpressed if IHC was 3+.
A total of 375 DCIS pts were analyzed; median age was 54 (27-88) years; primary tumor size≤ 2 cm in 59.7% of pts, grade III in 32.8%, estrogen receptor (ER) positive in 80.3%. Breast conserving surgery was performed in 70.7% of pts, adjuvant endocrine and radiotherapy in 14.40% and 38.40%, respectively; 52.54% of DCIS presented low ERBB2 expression. Differentiated grade (p<0.001), Ki67<20 (p<0.001), and ER-positive (p<0.001) were most common among ERBB2-low. The rate of ERBB2 low was as low as 6.60% and 1.52% in ER-negative (0-9%) and -intermediate (10-49%) and increased to 39.09% in ER-high (50%-95%) and 52.79 % in ER-very high (ER > 95%) tumors (p<0.001). At a median follow-up of 39 (IQR 16-65) months, the incidence for local relapse was 0.075 with no significant differences by ERBB2 expression. Among 20 evaluable relapses with paired primary and recurrent tumors, 6 presented a discordant ERBB2 status. The increase and decrease in ERBB2 expression occurred equally.
Low ERBB2 expression in DCIS is associated with features of reduced aggressiveness. Importantly, receptor conversion may happen prompting retesting in recurrent cases. The data are consistent with those observed in invasive breast cancer.
The authors.
Has not received any funding.
G. Pruneri: Other, Personal, Advisory Board: Roche, Bayer, AstraZeneca; Other, Personal, Speaker’s Bureau: Roche, Bayer, AstraZeneca. S. Di Cosimo: Other, Personal, Speaker’s Bureau: AstraZeneca; Other, Personal, Advisory Board: Pierre-Fabre; Other, Personal, Other: IQVIA, MEDSIR. All other authors have declared no conflicts of interest.
The antibody-drug conjugate (ADC) trastuzumab deruxtecan is not only efficient in
A multicentric retrospective study was performed including patients diagnosed with stage I-III ER+/HER2- pure ILC between 01/01/2000 and 12/31/2020. HER2- disease was categorized by immunohistochemistry (IHC) score into HER2 0, HER2 1+ and HER2 2+ (without amplification) following local guidelines prior to 2007 and ASCO/CAP guidelines from 2007 onwards. The association of HER2 low with clinicopathological variables was assessed using multinomial logistic regression. Univariable and multivariable survival analyses were performed to evaluate the association of HER2 low with disease-free (DFS), distant recurrence-free (DRFS) and overall survival (OS).
Data from 2098 patients with ER+/HER2- ILC were collected of which 1103 (53%) had a HER2 low tumor. Of these, 716 (34%) had an IHC score of HER2 1+ and 387 (18%) of HER2 2+. A histological grade 3 (odds ratio (OR) 1.95, p-value 0.04) and a tumor size of ≥2cm (OR 1.85, p-value <0.01) was associated with HER2 2+ vs. HER2 0. This was not seen for HER2 1+ vs. HER2 0. In multivariable analyses, HER2 1+ was associated with worse DFS (hazard ratio (HR) 1.29, p-value 0.03) and OS (HR 1.41, p-value 0.01) as compared to HER2 0. HER2 2 was significantly associated with worse OS (HR 1.45, p-value 0.04), while a trend was seen for worse DFS. No significant results were seen when comparing the HER2 categories for DRFS.
In our cohort, HER2 low was present in more than half of the early ER+HER2- ILCs. Higher HER2 IHC scores were associated with unfavorable prognostic features (higher grade and tumor size) and worse survival outcomes (DFS and OS). Studies are needed to evaluate whether patients with HER2 low ER+ pure ILC would benefit from anti-HER2 ADCs.
Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven.
This study is supported by COST (European Cooperation in Science and Technology, www.cost.eu). The study was funded by the Luxembourg Cancer Foundation (grant FC/2018/07), besides personal funds by the KU Leuven Fund Nadine de Beauffort and a Conquer Cancer – Lobular Breast Cancer Alliance Young Investigator Award for Invasive Lobular Carcinoma Research, supported by Lobular Breast Cancer Alliance. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the American Society of Clinical Oncology® or Conquer Cancer®, or Lobular Breast Cancer Alliance.
M.M. Karsten: Financial Interests, Personal, Invited Speaker: Roche, Gilead, Sysmex. G. Nader Marta: Financial Interests, Personal, Other, Travel: Roche, Bayer. H. Wildiers: Financial Interests, Institutional, Advisory Board: Roche, Lilly, AstraZeneca, Daiichi Sankyo, PSI Cro AG, KCE, MSD, MSD, E Squared Communications LLC; Financial Interests, Institutional, Invited Speaker: Eisai, AstraZeneca; Financial Interests, Institutional, Other, Consultancy fee: AbbVie, Immutep Pty; Financial Interests, Institutional, Expert Testimony: Daiichi Sankyo; Financial Interests, Institutional, Other, Consultancy: Daiichi Sankyo; Financial Interests, Institutional, Research Grant, Grant to the Leuven Breast Center to support the research database: Roche; Financial Interests, Institutional, Research Grant, Grant to institute to perform a multicentric national academic trial: Novartis; Other, Travel & accomodations: Pfizer; Other, Travel & accomodation: Roche; Other, Subscription fee: Gilead. C. Desmedt: Financial Interests, Personal, Invited Speaker: Lilly. All other authors have declared no conflicts of interest.
HER2-low is a novel breast cancer entity, however the ability of proper discrimination between HER2 negative and low is still matter of debate. This study investigates whether HER2 gene expression determined by ODX can differentiate between HER2 negative and low at IHC.
Retrospective cohort analysis on 229 patients with early BC tested with ODX after surgery in Humanitas Cancer Center between Jan 2020 and Jan 2023. We gathered well-known clinicopathological data, in particular HER2 by IHC, categorized as 0, 1+, and 2+ with negative fluorescent in situ hybridization (FISH). Difference between HER2 gene expression and HER IHC were tested with Wilcoxon test.
In our cohort, 53.3% were HER2 0, 29.7% HER2 1+, and 17.0% HER2 2+. Clinical characteristics were similar in the three groups, including age and menopausal status without any statistical difference. The median recurrence score (RS) was 21 [IQR: 15-29], 20 (IQR: 15-31), and 21 (IQR: 15.5-28), respectively, for HER2 0, HER2 1+, and HER2 2+. RS > 25 was found in 42.6% of HER2 0 and 55.6% of HER2 2+ patients in the node-negative cohort, with no statistically significant difference (p = 0.618). In all patients, the median HER2 gene expression was 9.20 [IQR: 8.70- 9.60]. HER2 gene expression increased with the higher HER2 score at IHC with broad overlapping in three groups [HER2 0: median 8.90 (IQR 8.5 – 9.28); HER2 1+: median 9.40 (IQR 8.90 – 9.72); HER2 2+: median 9.50 (IQR 9.30 – 10.0)].
HER2 gene expression and HER2 IHC by nodal status
HER2 IHC Node negative 0 1+ 2+ p 54 29 18 23 (42.6) 14 (48.3) 10 (55.6) 0.61 24.00 [17.25, 31.75] 24.00 [17.00, 33.00] 27.50 [20.25, 33.50] 0.87 8.90 [8.50, 9.28] 9.20 [8.70, 9.70] 9.50 [9.20, 9.78] 0.001 Node positive 68 39 21 18 (26.5) 8 (20.5) 4 (19.0) 0.68 17.00 [13.75, 26.25] 17.00 [14.00, 24.00] 17.00 [13.00, 24.00] 0.88 8.90 [8.60, 9.22] 9.50 [9.15, 9.90] 9.60 [9.40, 10.10] <0.001
HER2 gene expression was found to be increased by greater HER2 IHC but with significant overlap. This raises the possibility that subgroups with varying degrees of expression exist in all IHC categories which may be considered as a potential target for antibody-drug conjugates.
The authors.
Has not received any funding.
A. Zambelli: Non-Financial Interests, Personal, Invited Speaker, personal fees and non-financial support: Exact Science. All other authors have declared no conflicts of interest.
Trastuzumab deruxtecan (Enhertu®) has shown significant anti-tumour efficacy against HER2-low-expressing metastatic breast cancer (mBC) and has received approval in the US and Europe in this setting. Identification of patients with the potential to respond to the therapy relies on assessment of HER2 protein expression at a low level, a category not considered clinically significant previously. We report on a study examining testing proficiency in this area.
UK NEQAS ICC & ISH recruited 45 laboratories from its participants that regularly undertake clinical BC testing. They were provided with BC tissues in which HER2 expression levels had been established independently in two reference laboratories, both using the approved immunohistochemical (IHC) assay (4B5, Ventana) according to manufacturer’s instructions. Expression levels were consistently shown to be: 1+ on tumour A; variably 1+ or 0 on tumour B; 0 on tumour C; and 2+ on tumour D. Laboratories were asked to demonstrate HER2 by IHC and then interpret the staining.
39 (86.7%) laboratories used an approved assay (4B5, Ventana), the remaining 6 (13.3%) employed a variety of primary antibodies in laboratory developed tests (LDTs). Overall, 22 (56.4%) of those using the 4B5 assay achieved results concordant with the expected reference levels in all 4 tumours when they were assessed by an expert panel; none (0.0%) of the laboratories using an LDT achieved the expected levels of staining. Interpretive performance was assessed for each of the 4 BC samples: 14 (41.2%) were concordant with the reference score on tumour A; 17 (47.2%) on tumour B; 30 (83.3%) on tumour C; and 23 (63.9%) on tumour D. The combined technical and interpretative performance assessment showed: 8 (38.1%) laboratories achieved the expected staining levels and interpretation on tumour A; 17 (47.2%) on tumour B; 30 (83.3%) on tumour C; and 15 (41.7%) on tumour D.
The study indicates that in the HER2-low expression range, BC samples when tested for HER2 expression in clinical laboratories produce scores showing poor agreement (<50%) with those obtained using a well-validated assay interpreted by experts.
External Quality Assessment Services for Cancer Diagnostics CIC.
AstraZeneca UK LTD.
S. Parry: Financial Interests, Institutional, Other, Joint project: Diaceutics; Financial Interests, Personal, Advisory Board: AbbVie. A. Shaaban: Financial Interests, Personal, Advisory Board: AstraZeneca, Diaceutics; Financial Interests, Personal, Invited Speaker: Ventana Roche, Exact Science, Prosigna. A. Dodson: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Other, Lead joint project: Diaceutics. All other authors have declared no conflicts of interest.
HER2-low represents ∼65% of HR+/HER2-negative(-) BC; there is conflicting evidence regarding the potential association with higher pathologic complete response (pCR) and differential prognosis compared to HR+/HER2 0. Moreover, molecular changes induced by NAT have not been studied so far.
Patients with HR+/HER2- BC treated with NAT at our institution between 2014-2018 were analyzed. Gene expression was assessed using nCounter. Associations with pCR, event-free survival (EFS) and overall survival (OS) were assessed with logistic and Cox regressions. Paired and unpaired SAM analyses for differential gene expression were performed. Significance was set at p≤0.05 and false discovery rate (FDR)≤5%.
Overall, 186 patients were included, 52.2% treated with neoadjuvant chemotherapy (NACT) and 47.8% with endocrine therapy (NET); 62.9% were HER2-low and 37.1% were HER2 0, with no difference in main clinicopathological features and neo/adjuvant treatments administered. Luminal A+B were the most frequent intrinsic subtypes (IS) (84.6%). The pCR rate was 10.1%, similar between HER2-low and HER2 0 (p=0.704). At baseline, HER2-low vs. HER2 0 showed upregulation of ESR1, ERBB2 and GRB7 (FDR<5%). NAT induced a significant reduction of progesterone receptor (p<0.001) and Ki67 (p<0.001), but not TILs (p=0.994), regardless of HER2 status. An upregulation of Basal-like-related genes, CD8A, PDCD1 and CD274, with a downregulation of CD4, Luminal- and proliferation-related genes (FDR<5%) were observed in both cohorts, with no significant post-NAT differences, except for already differentially expressed genes at baseline. A switch towards less aggressive IS (p<0.001; Luminal A+Normal-like increase from 51.8% to 94.7%) and lower risk of relapse (ROR) score (p<0.001; ROR-low increase from 22.9% to 78.8%), was observed regardless of HER2 status. There were no differences in EFS (p=0.335) and OS (p=0.627) based on HER2 status.
HER2-low status in HR+ BC was not predictive of pCR nor prognostic. Tailored neo/adjuvant approaches based on pathologic/molecular downstaging merit exploration, but differential strategies based on HER2-low status are not encouraged.
The authors.
European Society for Medical Oncology (ESMO Fellowship - Translational to Francesco Schettini) and AstraZeneca Spain.
F. Schettini: Financial Interests, Personal, Invited Speaker: Novartis, Daiichy Sankyo, Gilead; Financial Interests, Personal, Other, Travel expenses: Novartis. O. Martínez-Sáez: Financial Interests, Personal, Other, travel expenses: Roche and Reveal Genomics; Financial Interests, Personal, Invited Speaker: Eisai and Novartis; Financial Interests, Personal, Other, consulting fees: Roche and Reveal Genomics. M.J. Vidal Losada: Financial Interests, Personal, Advisory Board: Roche, Novartis, Daiichi Sankyo|AstraZeneca, Gilead, Eisai; Financial Interests, Personal, Other, Meeting and&or travel expenses: Roche, Novartis, Daiichi Sankyo |AstraZeneca , Gilead; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Daiichi Sankyo|AstraZeneca. A. Prat: Financial Interests, Personal, Advisory Board: Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardan Health, Peptomyc and Lilly; Financial Interests, Personal, Invited Speaker: Roche, Pfizer, Novartis, Amgen, BMS, Nanostring Technologies and Daiichi Sankyo; Financial Interests, Institutional, Funding: Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, Medica Scientia inno. Research, SL, Celgene, Astellas and Pfizer; Financial Interests, Personal, Member of the Board of Directors: Reveal Genomics. All other authors have declared no conflicts of interest.
The variation and heterogeneity of conventional immunohistochemistry (IHC) or in situ hybridization (ISH) techniques for measuring HER2 has long been pointed out, and the method of testing for HER2 has been discussed for the selection of appropriate treatment. Therefore, we compared HER2 expression in RT-PCR using OncotypeDX have correlation with conventional IHC, and evaluated HER2 expression in RT-PCR as a prognostic factor in HER2-negative early breast cancer.
ER+/HER2- patients who underwent breast cancer surgery between 2004 and 2016 and underwent OncotypeDX testing were included. Data from 632 patients were collected and analyzed by retrospective chart review at 9 centers to determine if there was a correlation between HER2 expression by IHC and RT-PCR. HER2 expression was classified as negative, HER2-low, and positive when HER2 mRNA levels were ≤ 9.1, 9.2-11.4, and11.5≤, respectively, based on the median mRNA level in HER2 negative in IHC. Survival curves were estimated using the Kaplan-Meier method with a log-rank test between the three groups.
The median age of the 632 patients was 51 years. Of the 632 patients, 311(49.2%) were pStage I, the 309 (48.9%) were pStage II, and 11(1.7%) were pStage III. 127 (20%) patients received postoperative chemotherapy, and 54 (8.5%) patients had relapse. HER2 IHC rates were HER2 0: 166 (26.3%), 1+: 304 (48.1%), and 2+: 162 (25.6%). There was a weak correlation between the IHC and RT-PCR methods for HER2 expression (Spearman rank correlation
In the analysis of HER2 expression, there was a weak correlation between IHC and RT-PCR mRNA expression levels; in the HER2-negative population, RT-PCR mRNA expression of HER2 was not a prognostic factor in early breast cancer.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Early stage breast cancers (BC) are treated the same whether they are HER2 Negative (Neg), which stain 0 for HER2 by immunohistochemistry (IHC), or HER2 Low, which stain 1+ by IHC or 2+ with a negative result for HER2 amplification by fluorescence in-situ hybridization (FISH). Recent studies show metastatic HER2 Low patients can benefit from HER2 targeted therapy. Our study aims to describe the prevalence, pathological, and clinical aspects of HER2 Low compared to HER2 Neg in high risk early stage BC patients within a community practice setting in the United States. High risk early stage BC was defined as BC of stages I-III treated with neoadjuvant or adjuvant chemotherapy.
This retrospective study analyzed 1,106 patients, excluding patients with HER2-positive or metastatic disease. 136 of the 440 HER2 Low patients and 128 of the 365 HER2 Neg patients received chemotherapy and were included. Patients had diagnosis dates between January 1st, 2015 and December 31st, 2021. Categorical and continuous analyses (two-proportion Z test) were performed to study differences between HER2 Low and HER2 Neg patients at time of diagnosis in age, BMI, menopausal status, smoking status, histology, grade, and surgery.
51% of the 264 included patients were HER2 Low and 49% HER2 Neg. 85% of HER2 Low and 83% of HER2 Neg (p=.69) were ductal in histology. Most HER2 Low patients were grade 2 (65%), whereas most HER2 Neg patients were grade 3 (46%). HR+ status was found in 99% of HER2 Low and 71% of HER2 Neg. Mean BMI was 30.6 for HER2 Low and 29.5 for HER2 Neg. HER2 Low (98%) and HER2 Neg (88%) were mainly postmenopausal (p=.58). The majority of HER2 Low (51%) and HER2 Neg (47%) had never smoked (p=.98). Lumpectomies were most common in HER2 Low (51%) and HER2 Neg (49%) (p=.81).
Our study demonstrates that there are both distinguishable and similar aspects between HER2 Low and HER2 Neg patients. A predominant ductal histology and post-menopausal status between both groups was revealed. Differences included a higher prevalence of grade 2 histology and black women affected with HER2 Low tumors. These groups should be studied further in a more diverse patient population with long-term follow up data looking at overall and progression free survival.
1. Hannah Barger, Comprehensive Hematology Oncology: Park Street 2. Rebecca Nashed, Comprehensive Hematology Oncology: Park Street 3. Dylan Schlyer, Comprehensive Hematology Oncology: Park Street 4. Ankur Verma, Comprehensive Hematology Oncology: Park Street 5. Dr. Neeharika Srivastava Makani MD, Comprehensive Hematology Oncology: Park Street.
Dr. Neeharika Srivastava Makani MD.
Has not received any funding.
All authors have declared no conflicts of interest.
The excisional rings of the T cell receptor rearrangement (TREC) and the κ-deletion element (KREC) are extrachromosomal DNA structures formed during V(D)J-recombination. A decrease in the number of TREC and KREC below age-related values may be a manifestation of immunodeficiency conditions, which can be caused by oncological and hematological diseases.
Objective: To study the change in the amount of TREC and KREC in breast cancer. Methods. For the study, blood was taken from patients with malignant neoplasms in the main group and group of healthy women of various ages. Of these 35 healthy individuals and 77 patients with breast cancer. Median age 54 years (Q1-Q3: 36-81 years). Quantification of TREC and KREC was performed by real-time PCR using the IMMUNO-BIT reagent kit (ABV-test LLC) in accordance with the instructions for the kit. DNA extraction from whole blood was performed using the AmpliPrime RIBO-prep reagent kit (NextBio LLC).
According to our study, in healthy individuals, the TREC level is 75.6/105 PBMC (Q1-Q3: 19.2-135.3), the KREC level is 317.3/105 (Q1-Q3: 118.1-565.9). Whereas in patients with breast cancer, the level of TREC is 4.4/105 PBMC (Q1-Q3: 0.9-17.3), the level of KREC is 101.3/105 (Q1-Q3: 29.3-339.28). When comparing the TREC and KREC indicators in different groups, statistically significant differences were established (p<0.001, p=0.006). The levels of TREC and KREC in the healthy population were significantly higher than among patients with cancer (median TREC were 75.6 and 4.4, median KREC 317.3 and 101.3, respectively).
The data obtained demonstrate significant changes in T- and B-cell lymphopoiesis in patients with breast cancer. Quantitative determination of TREC and KREC makes it possible to assess the state of the T- and B-cell link of the immune system in patients with malignant neoplasms.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Invasive lobular carcinoma (ILC) is the second most common histological breast cancer (BC) subtype. Little is known regarding the tumor microenvironment (TME) that characterizes ILC. In this work, we aimed to study TME and uncover tumor and stroma cells interactions with potential clinical implication in ILC using spatial transcriptomics (ST).
We performed ST (Visium 10X Genomics®) on frozen tumor samples from 43 primary HR+, HER2- ILC patients. Nine samples were from patients who experienced disease relapse. Morphological annotation of the H&E slides relative to the ST samples was performed using QuPath software. METABRIC (HR+, HER2- ILC samples, n = 122) was used as external validation cohort.
Intriguingly, morphological annotations revealed a greater co-localization at the spot level between adipocytes and cancer cells in samples from patients with relapse (p = 0.04). This area was enriched in metabolism-related pathways (padj < 0.05). To assess the prognostic implication of this co-localization, we derived a 27 gene signature by performing differential gene expression analysis between patients with vs without relapse considering the ST spots laying on the tumor-adipocytes contact area. Interestingly, our adipocytes-related signature was significantly associated with poor survival in ILC patients in METABRIC. Of note, no correlation was found between the adipocytes-related and proliferation-related signatures (including genomic grade index – GGI), which were also found to be prognostic in ILC. By combining the adipocytes-related signature with the GGI, we built a robust prognostic index that outperformed the other prognostic-related signatures (computed with genefu R package) both at the univariable (HR = 1.8, p = 3.4x10-4) and at the multivariable analysis (HR 1.7, p = 0.0016) in predicting relapse free survival.
To our knowledge, the adipocytes-related signature is the first prognostic signature in ILC not related to proliferation, highlighting an important implication of adipocytes in the biology of ILC. The strong prognostic power of the integrated predictor has the potential to improve prognostication in ILC. Further validation is needed.
The authors.
FNRS, Fondation Jules Bordet, Breast Cancer Research Foundation, Fondation contre le Cancer.
F.P. Duhoux: Financial Interests, Institutional, Advisory Board: Roche, Pfizer, AstraZeneca, Lilly, Novartis, Amgen, Daiichi Sankyo, Pierre Fabre, Gilead, Seagen, MSD; Financial Interests, Institutional, Invited Speaker: Novartis, Pfizer, MSD, Roche, MSD, Boehringer Ingelheim, Pfizer, Novartis, Lilly, AbbVie, Seagen, Gilead, AstraZeneca, Menarini, Immutep; Financial Interests, Institutional, Expert Testimony: Seagen, Novartis, MSD. C. Sotiriou: Financial Interests, Institutional, Advisory Board: Astellas, Vertex, Seattle Genetics, AMGEN, INC, Merck & Co; Financial Interests, Personal, Advisory Board: Cepheid, Puma; Financial Interests, Personal, Invited Speaker: Eisai, Prime oncology, Teva; Financial Interests, Institutional, Other, Travel: Roche; Financial Interests, Institutional, Other, Internal speaker: Genentech; Financial Interests, Personal, Other, Regional speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Exact Sciences. All other authors have declared no conflicts of interest.
Clinical trials are exploring the possibility of active surveillance for low-risk ductal carcinoma in situ (DCIS) and atypical ductal hyperplasia (ADH). However, interobserver variability in grading DCIS exists. We aim to train and evaluate a deep learning model (Deep DCIS) on breast biopsy with ADH/DCIS to improve the risk stratification of these precursor lesions.
Patients diagnosed with ADH or DCIS by breast biopsy and who received wide excision within six months were included (n=592 and 112 for primary and independent validation cohorts). Two pathologists independently evaluated nuclear grade, comedonecrosis, and focus suspicious for microinvasion and annotated patch-level labels by consensus. Estrogen receptor immunostain and apocrine features were also assessed. Clinical features (e.g., biopsy method, lesion size, BIRADS classification of ultrasound and mammogram) were collected. The model adopted Inception-V3 with a train-valid-test split and Adam optimization. The outputs of Deep DCIS comprised five parameters: total patches, lesion extent, Deep Grade, Deep Necrosis, and Deep Stroma. These parameters were combined with clinical information and hormone status to predict upstaging to invasive breast carcinoma.
Deep Grade strongly correlated with the pathologists' grading on both slide- and patient-level labels. All five parameters from Deep DCIS were associated with upstaging to invasive carcinoma. Deep DCIS successfully predicted upstaging with an area under the curve (AUC) of 0.81 and an accuracy (acc) of 0.75, outperforming pathologists' evaluation (AUC 0.71 and 0.69; acc 0.67 and 0.65 from two pathologists). The prediction improved after combining Deep DCIS with clinical factors and hormone status (AUC 0.87; acc 0.79). This combined model retained its predictive power in the subgroup of ADH and low-/intermediate-grade DCIS (AUC 0.81; acc 0.76). The independent validation cohort confirmed the model's performance (AUC 0.82; acc 0.72).
The deep learning model refines histological evaluation of ADH and DCIS on breast biopsy and improves prediction of upstaging to invasive carcinoma on wide excision, which may help guide treatment planning in future clinical studies.
Chung-yen Huang.
Has not received any funding.
All authors have declared no conflicts of interest.
Gene expression signatures (GES) have emerged to predict prognosis and guide the use of adjuvant chemotherapy (CT) in patients with hormone receptor-positive HER2-negative (HR+/HER2-) early breast cancer (eBC). However, the predictive value of the currently available GES to novel anti-cancer drugs used, such as CDK4/6 inhibitors and PARP inhibitors, remains unknown.
We applied four commercially available prognostic GES (Oncotype Dx Recurrence Score (RS), PAM50-based Prosigna (ROR), MammaPrint 70-gene (Prog70), and EndoPredict (EPclin)) to 5,391 HR+/HER2- eBC patients with pN0 or pN1 disease. We then assessed in each genomic risk category several multigene signatures predicting sensitivity/vulnerability to endocrine therapy (ET; E2F4), CDK4/6 inhibitors (E2Fregulon & RBsig), PARP inhibitors (HRD), and chemotherapy (CT; DLDA30) at individual patient’s level.
Vulnerability signatures consistently (p<0.001, Fisher’s exact test) identified genomic high-risk patients as more vulnerable to CT and PARP inhibition, but less sensitive to ET and CDK4/6 inhibition (Table). Oppositely, genomic low-risk patients were predicted as strongly vulnerable to ET and CDK4/6 inhibition, but less sensitive to CT and PARP inhibition. For example, the ROR-P “high-risk” patients included more patients predicted as sensitive to CT and PARP inhibitors than the ROR-P “low-risk” patients (17%
Prediction ROR-P RS EPclin Prog70 Low/int high low high low high low high 96% 83% 99% 78% 99% 84% 100% 86% 4% 17% 1% 22% 1% 16% 0% 14% 12% 78% 26% 62% 15% 58% 5% 57% 88% 22% 74% 38% 85% 42% 95% 43% 10% 80% 25% 64% 12% 59% 3% 58% 90% 20% 75% 36% 88% 41% 97% 42% 12% 80% 27% 62% 17% 58% 6% 57% 88% 20% 73% 38% 83% 42% 94% 43% 97% 83% 96% 84% 98% 87% 98% 87% 3% 17% 4% 16% 2% 13% 2% 13%
Our analysis provides the first vulnerability prediction frame of genomic risk patients assessed by routinely used GES. This underlines the need of caution in interpreting the results of active clinical trials recruiting patients according to genomic risk for the assessment of novel anti-cancer drugs in HR+/HER2- eBC such as NATALEE trial.
Institut Paoli-Calmettes.
Has not received any funding.
A. De Nonneville: Non-Financial Interests, Advisory Board: Gilead, Daiichi Sankyo, Seagen, Lilly, Novartis. A. Gonçalves: Financial Interests, Institutional, Invited Speaker: Novartis, Roche, MSD, AstraZeneca, Daiichi Sankyo. All other authors have declared no conflicts of interest.
To differentiate prognostic groups in patients with ER+HER2neg breast cancer (BC) Ki67 thresholds of 14% and 20% have been defined. However, most clinical research has been driven by outcomes of invasive carcinoma of no special type, with ILC underrepresented. Previous studies suggested a 4% Ki67 cut-off to distinguish prognostic groups in the ILC population
Retrospective study including early-stage BC patients (pts) with ER+HER2neg pure ILC diagnosed from 2010 to 2015 at 2 sites (Vall d’Hebron University Hospital and Institut Català d’Oncologia-Hospitalet) and with tumor sample available. Local and central Ki67 values from surgical specimen (or initial biopsy for neoadjuvant treated-pts) were obtained. The primary endpoint were disease free-survival (DFS) and overall survival (OS). The log-rank statistic was used to select the optimal Ki67 cut-off.
Overall, 275 pts were identified, median age: 61 years, postmenopausal (71.4%), stage I-II (73.4%), progesterone receptor (PgR) (78%), histology grade 1-2 (92.7%) and 34.5% receiving adjuvant chemotherapy. The median Ki67 values with local (n=257) and central (n=164) assessment were 12% and 13%, respectively (correlation= 0.63). Several factors such as pT, stage, PgR, and grade were associated with DFS and OS in the univariable analysis. Local Ki67 as a continuous variable was not associated with DFS (p=0.75), but showed a trend for association with OS (p=0.06). With local Ki67 values, cut-off from 10% to 24% showed similar results (using 10% as a cut-off, OS HR: 1.82, 95%CI 1.10-3.01, p=0.02). Central Ki67 as a continuous variable was not statistically associated with DFS (p=0.09) or OS (p=0.33). However, the optimal cut-off was identified at 10% allowing to separate two groups with different prognostic (Ki67% 10% vs <10%, HR: 2.37, 1.09-5.19, p=0.03).
In our series of ILC median Ki67 was around 12%, with moderate concordance between local and central assessments. Lower Ki67 cut-off (10%) than those reported in overall population may better distinguish prognostic groups in ILC pts.
Vall d'Hebron Institute of Oncology (VHIO).
Has not received any funding.
M. Bellet-Ezquerra: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Lilly, Stemline-Menarini; Other, Speaker'sBureau and Travel Expenses: Pfizer; Other, Speaker's Bureau: Novartis, Lilly. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. E. Zamora: Financial Interests, Personal, Invited Speaker, Review session for medical oncologists: Eisai, Lilly; Other, Registration to ESMO Congress 2022 (virtual): Novartis; Other, Registration to: Eisai. C. Saura Manich: Financial Interests, Personal, Advisory Board: AX'Consulting, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd., Gilead, ISSECAM, Lilly, MediTech, Medical Statistics Consulting, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, Seagen, Solti, Zymeworks, Pharmalex Spain SLU; Financial Interests, Personal, Expert Testimony: AX's Consulting SARL, Boehringer Ingelheim, Bristol Meyers Squibb, INDITEX, Merck Sharp & Dohme España, Novartis, SACE Medhealth SL, Simon Kucher &Partners SL, Genentech, Innoup, Millenium, Sanofi, Seattle Genetics; Financial Interests, Personal, Other, SC: Byondis B.V., German Breast Group, Glaxo, International Breast Cancer Study Group (IBCSG), Macrogenics, Medsir, Menarini, Merus, Merus, Netherlands Cancer Institute (NKI), Queen Mary (University of London), Seagen, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, Glaxosmithkline, Immunomedics, Innoup Farma, International Breast Cancer Study Group (IBCSG), Macrogenics, Medica Scientia Innovation Research, Menarini Ricerche, Merus, Novartis, Pfizer, Puma, Roche, Sanofi-Aventis, Seattle Genetics, SOLTI; Financial Interests, Institutional, Invited Speaker: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), SOLTI group (Academic research group in breast cancer), Geicam (Spanish Breast Cancer Research Group), American Association for Cancer Research (AACR). S. Pernas Simon: Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pfizer; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Invited Speaker: Astra-Zeneca, Novartis, Daiichi Sankyo; Non-Financial Interests, Invited Speaker: SOLTI. P.G. Nuciforo: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD Oncology, Bayer; Financial Interests, Personal, Other, Consultant: Targos Molecular Pathology GmbH. All other authors have declared no conflicts of interest.
In MINDACT trial, 4 risk categories (RC) by clinical (c) and genomic (g) breast cancer (BC) risk were defined. The study showed that the cHigh/gLow group without chemotherapy (CT) had a 94.8 % (CI 95% 92.9-96-2) 5-year Distant Metastases Free Survival (DMFS), so meeting the trial primary objective. Recently, a MP g group with excellent prognosis, named ultralow (gUL), has been described (15% in MINDACT). However, few data exist regarding the distribution of these 4 MINDACT RC and the proportion of gUL in the invasive lobular carcinoma (ILC) population. Moreover, association of Ki67 values and MP RC is rarely studied, both in general population and, particulary, in ILC pts. We aimed to address all these questions by comparing our series of invasive carcinoma of non-special type (NST) and ILC pts in whom MP was performed.
Pts with ER+/PgR±/HER2- early BC diagnosed from 2012 to 2020 in our institution and with MP data were reviewed. Clinical risk was defined as in the MINDACT trial; genomic risk defined by MP score (UL score: 0.355 to 1.00).
152 pts were identified. NST: 85%, ILC: 15%. Median age NST/ICL: 54/59 years. Histological grade (HG) 1/2/3 (NST vs ILC) 19%/73%/8% and 18%/82%/0%, respectively. UL (g) risk: 17 (13.2%) in NST, 3 (13%) in ILC. The distribution of RC is summarized in the table [UL and Low-non-Ultralow (LNUL) combined for small numbers in ILC]. Median Ki67 value by (g) RC (gLow vs High) in the NST group were 12 and 20: (p<0.001). Of note, in ILC pts median Ki67 was 15 for both MP (g) RC (p=0.77).
Overall (n=151) NST (n=129) CLI (n=22) 61 (40.4) 51 (39.5) 10 (45.5) 39 (25.8) 36 (27.9) 3 (13.6) 36 (23.8) 28 (21.7) 8 (36.3) 15 (9.9) 14 (10.8%) 1 (4.5)
Our results suggest a trend for lower genomic RC in ILC population compared to NST pts. As expected, median Ki67 values correlated with MP genomic categories in overall population and in NST but, intriguingly, not in ILC pts. The small number of pts in this latter group limits results. Further data in wider populations are needed to establish the true association of Ki67 with MP categories in ILC population.
The authors.
Has not received any funding.
E. Zamora: Financial Interests, Personal, Invited Speaker, Review session for medical oncologists: Eisai, Lilly; Other, Registration to ESMO Congress 2022 (virtual): Novartis; Other, Registration to: Eisai. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. C. Saura Manich: Financial Interests, Personal, Advisory Board: AX'Consulting, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd., Gilead, ISSECAM, Lilly, MediTech, Medical Statistics Consulting, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, Seagen, Solti, Zymeworks, Pharmalex Spain SLU; Financial Interests, Personal, Expert Testimony: AX's Consulting SARL, Boehringer Ingelheim, Bristol Meyers Squibb, INDITEX, Merck Sharp & Dohme España, Novartis, SACE Medhealth SL, Simon Kucher &Partners SL, Genentech, Innoup, Millenium, Sanofi, Seattle Genetics; Financial Interests, Personal, Other, SC: Byondis B.V., German Breast Group, Glaxo, International Breast Cancer Study Group (IBCSG), Macrogenics, Medsir, Menarini, Merus, Merus, Netherlands Cancer Institute (NKI), Queen Mary (University of London), Seagen, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, Glaxosmithkline, Immunomedics, Innoup Farma, International Breast Cancer Study Group (IBCSG), Macrogenics, Medica Scientia Innovation Research, Menarini Ricerche, Merus, Novartis, Pfizer, Puma, Roche, Sanofi-Aventis, Seattle Genetics, SOLTI; Financial Interests, Institutional, Invited Speaker: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), SOLTI group (Academic research group in breast cancer), Geicam (Spanish Breast Cancer Research Group), American Association for Cancer Research (AACR). M. Bellet-Ezquerra: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Lilly, Stemline-Menarini; Other, Speaker'sBureau and Travel Expenses: Pfizer; Other, Speaker's Bureau: Novartis, Lilly. All other authors have declared no conflicts of interest.
Ki67 index, a prognostic biomarker in early breast cancer (eBC), is being used as an endpoint in neoadjuvant endocrine therapy (NET) clinical trials. We aim to describe baseline characteristics associated with Ki67 drop (Ki67d) after NET in patients (pts) with HR+/HER2- eBC.
We did a systematic search of PubMed, Embase, CENTRAL, and conference proceedings (ASCO, ESMO, ESMO Breast, and SABCS) up to 28 June 2022, to identify studies reporting Ki67d after NET in pts with HR+/HER2- eBC (PROSPERO ID: CRD42022333735). Here we report data from studies assessing the association of baseline characteristics with Ki67d after NET.
56 studies tested the association of 45 different baseline characteristics with Ki67d after NET (Table). For clinical variables, most studies reported higher Ki67d after NET in postmenopausal pts. Conversely, one study using telapristone acetate showed Ki67d only in premenopausal pts. Higher body mass index (BMI) was reported to be associated with Ki67d, in one of the studies together with metformin. For pathological factors, Ki67d was associated with higher baseline estrogen receptor (ER) and progesterone receptor (PR) expression. Regarding genomic determinants, we mostly found higher Ki67d in pts with favorable intrinsic subtypes (luminal A vs luminal B, or luminal vs non-luminal). Two studies showed more pronounced Ki67d in pts with luminal B tumors (vs luminal A). Higher Ki67d was reported when pictilisib or enzalutamide were added to NET in luminal B or luminal A tumors, respectively. PIK3CA exon 9 mutation was associated with lower Ki67d. The effect of this mutation was reverted in these studies by the addition of targeted therapy to NET (pictilisib, everolimus, or lapatinib). Summary of the six most assessed baseline characteristics, two per category
Category Characteristics assessed Most assessed characteristics Studies Statistically significant association (N, studies) (N) (two per category) (N) Higher Ki67 Lower Ki67 None (p>0.05) 9 6 1 2 5 0 3 14 10 0 4 12 0 6 22 11 2 5 6 0 3
We summarize baseline characteristics associated with Ki67d after NET in pts with eBC. These characteristics are important to inform clinical trial design and pts selection in clinical practice.
Université Libre de Bruxelles (ULB), Hôpital Universitaire de Bruxelles (HUB), Institut Jules Bordet, Academic Trials Promoting Team (ATPT), Brussels, Belgium.
Research Grant - Fonds de Barsy-Laffut from Université Libre de Bruxelles (ULB).
D. Martins Branco: Financial Interests, Personal, Advisory Board: Angelini, AstraZeneca, Janssen, Merck Sharp & Dohme, Novartis, Pfizer; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Merck Sharp & Dohme, Novartis; Financial Interests, Personal, Other, meeting/travel grant: Gilead Sciences, Ipsen, Janssen, LEO Farmacêuticos, Laboratórios Vitória, Pfizer, Roche; Financial Interests, Personal, Other, Meeting/travel grant.: Merck Sharp & Dohme, Novartis; Financial Interests, Institutional, Research Grant, Institutional funding for an observational research project.: Novartis; Financial Interests, Institutional, Research Grant, Institutional funding for an investigator-initiated clinical trial.: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Invited Speaker: Associação de Investigação e Cuidados de Suporte em Oncologia - Portuguese MASCC affiliate; Non-Financial Interests, Leadership Role, Portuguese Young Oncologists Committee Chair: November 2020 - May 2022: Sociedade Portuguesa de Oncologia; Non-Financial Interests, Leadership Role, Oncology Committee Chair: January 2020 - January 2021: Health Parliament Portugal. C. Molinelli: Financial Interests, Personal, Invited Speaker: Novartis, Lilly; Financial Interests, Personal, Other, travel grant: Novartis, Gilead. G. Nader Marta: Financial Interests, Personal, Other, meeting/travel grant: Roche, Bayer. R.F. Salgado: Financial Interests, Personal, Advisory Board: Roche, BMS, Exact Sciences; Financial Interests, Personal, Funding, Roche funded personally the assessment of immune-markers in a research study. This was in 2019.: Roche; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Funding: Puma Biotechnology. P.G. Aftimos: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Macrogenics, Roche, Novartis, Amcure, Servier, G1 Therapeutics, Radius, Deloitte, Menarini, Gilead, Novartis, Eisai, Lilly; Financial Interests, Personal, Invited Speaker: Synthon, Amgen; Financial Interests, Institutional, Research Grant: Roche. E. de Azambuja: Financial Interests, Personal, Advisory Board: Roche/GNE, Novartis, Seagen; Financial Interests, Personal, Invited Speaker: Zodiac, Libbs, Pierre Fabre, Lilly, Astra-Zeneca; Financial Interests, Institutional, Research Grant: Roche/GNE, AstraZeneca, GSK/Novartis, Servier; Financial Interests, Institutional, Other, Travel Grant: Roche/GNE; Financial Interests, Institutional, Invited Speaker: MSD, ABCSG, Nektar, Gilead, Immunomedics, Synthon, Odonate Therapeutics; Financial Interests, Invited Speaker, Chair of the Gilead Sciences Research Scholars Program in Solid Tumours: Gilead; Financial Interests, Invited Speaker, Aphinity, Lorelei, Impassion03: Roche; Financial Interests, Invited Speaker, AURORA: Breast International Group; Financial Interests, Invited Speaker, Olympia: Astra-Zeneca; Financial Interests, Personal, Other, Travel grant: Astra-Zeneca; Non-Financial Interests, Advisory Role, Member of the cardio-oncology council: European Society for Cardiology (ESC); Non-Financial Interests, Advisory Role, Belgium governmental institution for cancer: KCE; Non-Financial Interests, Other, Editorial board member: ESMO Open; Non-Financial Interests, Advisory Role: Anticancer Fund. All other authors have declared no conflicts of interest.
Digistain is a mid-infrared imaging technology that assesses aneuploidy by measuring the nuclear-to-cytoplasmic chemical ratio in the cellular content of tissues to generate the Digistain Index (DI). The Digistain Prognostic Score (DPS) has been developed by incorporating DI with pathological features. The ability of DPS to predict clinical outcomes in patients with HR-positive HER2-negative primary breast cancer was investigated as a means to guide adjuvant chemotherapy.
Infrared spectrometry was performed on existing tissue microarrays to determine the DI and DPS of 801 patients with HR-positive HER2-negative primary breast cancer with ≤3 positive lymph nodes who had received systemic endocrine therapy only. AUC for ROC curves were used to assess the ability of DPS to predict 5- and 10-year progression-free survival (PFS), recurrence and overall survival (OS) in the total population and in 3 subgroups: no positive lymph nodes, premenopausal (based on age <45 years) and postmenopausal (>60 years).
DPS was highly accurate for prediction of risk in the total population and by subgroup. In the total population, AUC for PFS and recurrence were the same, 0.81 and 0.75 at 5 and 10 years, respectively, and 0.77 and 0.69 for OS at 5 and 10 years, respectively. In the 3 subgroups, AUC values were similar for all outcomes ranging from 0.67 to 0.76 and 0.59 to 0.74 for 5 and 10 years, respectively. Across the total population and subgroups, negative predictive values were high for all outcomes, ranging from 0.96 to 0.99 at 5 years and 0.84 to 0.95 at 10 years. Across the total population, hazard ratios for PFS, recurrence and OS for low- vs. high-risk classification were significant (1.80, 1.83 and 2.49, respectively; P<0.001). DPS also showed significant (P<0.05) risk prognostication for PFS and recurrence in the lymph node-negative group, and for recurrence and OS in postmenopausal women.
DPS showed high accuracy and predictive performance across the total population and different subgroups, and was able to stratify patients into low or high risk. DPS warrants further development considering its rapid turnaround times, low cost and potential for widespread use.
Chris Phillips.
The National Institute of Health Research UK.
All authors have declared no conflicts of interest.
Recent studies have shown that the tumor microenvironment can shape the response to immune-modulating therapies. Anthracyclines are a major chemotherapy regimen for breast cancer that induce immunogenic cell death. We hypothesized that patients with “immune hot” tumors may benefit from anthracyclines more than patients with “immune cold” tumors.
As one of the largest breast cancer studies using the GeoMx digital spatial profiling, we tested this hypothesis by profiling 35 biomarkers on 536 cases obtained from the Canadian Cancer Trials Group MA.5 phase III clinical trial. In this trial, node-positive breast cancer patients were randomized to receive either a cyclophosphamide-based (cyclophosphamide-methotrexate-fluorouracil (CMF)) or anthracycline-containing adjuvant chemotherapy (cyclophosphamide-epirubicin-fluorouracil (CEF)). Tissue microarray sections were stained with barcoded antibodies to obtain digitally quantified biomarker counts.
Unsupervised hierarchical clustering revealed two patient clusters: immune infiltrated and ignored. Following a pre-specified statistical plan crafted to meet ReMARK (REporting recommendations for tumor MARKer prognostic studies) guidelines, we did not observe significant results for the primary hypotheses: Immune cluster assignment did not predict an improved 10-year relapse-free survival or overall survival for patients receiving CEF compared to CMF in the full cohort. However, some of our secondary hypotheses revealed a significant predictive value for immune cluster assignment and stromal tumor infiltrating lymphocytes assessed on hematoxylin and eosin (H&E)-stained sides for CEF benefit over CMF in the human epidermal growth factor receptor 2 (HER2)-enriched subset. As an exploratory analysis, supervised clustering of immune biomarkers suggested that low levels of TIM-3 and high levels of HLA-DR and PD-L1 were associated with an extra benefit from CEF compared with CMF.
While novel multiplexing techniques provide a detailed insight into the tumor microenvironment, conventional H&E staining acts as a powerful tool to assess the value of immune microenvironment in predicting benefits from immunogenic chemotherapies.
The authors.
Our study is funded by the Canadian Cancer Society, grant number 705463; Canada Foundation for Innovation / John R. Evans Leaders Fund in collaboration with the UBC Department of Pathology and Laboratory Medicine British Columbia Knowledge Development Fund (BCKDF). First author is supported by BC Cancer Rising Star Award and by IOP travel award.
Z. Kos: Financial Interests, Institutional, Advisory Role, not related to this project: AstraZeneca Canada, Eli Lilly Canada. T.O. Nielsen: Financial Interests, Institutional, Proprietary Information, Licensed to Veracyte technologies through Bioclassifier LLC.: Prosigna. All other authors have declared no conflicts of interest.
HER-2/neu expression is observed in 15-20% of all breast cancers and is clinically relevant due to the several anti-HER2 treatment modalities. HER-2/neu status is assessed and quantified using immunohistochemistry (IHC). Although well-standardized in clinical practice, it is still subject to interobserver variability. Automating HER-2/neu scoring can improve accuracy, efficiency, consistency, and cost-effectiveness while reducing the pathologist's burden.
A total of 7,395 patch images were extracted automatically using a custom-built python application from 50 IHC-stained whole slide images (WSIs) from the HER2 challenge dataset of Warwick University. 1000×1000 pixels patches were created from the regions of interest of 20x zoomed WS image. All the patches were annotated to 0, 1+, 2+, and 3+ scores (i.e., classes) by two experts using an in-house built python application. Patches containing multiple classes or without any tumor tissues were not considered. Finally, a total of 6,488 patches (0: 1108, 1+: 276, 2+: 1442, 3+: 3662) were selected for five-fold subject-wise cross-validation after discarding 856 non-tumor patches and 51 multi-class patches. Three state-of-the-art deep learning models (GoogleNet, Densenet201, and Vit-base-r50) were validated to automatically classify the patches into four classes (0, 1+, 2+, and 3+).
Among the three investigated models, the Vit-base-r50 model showed the best performance with overall accuracy, precision, and sensitivity of 90.02%, 90.11% and 90.09%, respectively. It achieved a sensitivity of 97.64%, 75.07%, 84.19% and 85.75%, while the second-best model (Densenet201) achieved a sensitivity of 95.51%, 75.79%, 78.54% and 76.86% for 0, 1+, 2+, and 3+ classes, respectively.
The proposed deep learning-based approach for automatic detection and assessment of HER-2/neu expression in breast cancer shows promising results. This procedure can offer a cost and time-effective alternative to producing clinically relevant results and may help pathologists in a proper assessment of HER-2/neu expression.
Dr. Semir Vranic.
Has not received any funding.
All authors have declared no conflicts of interest.
Knowledge of population specific BRCA1/2 founder mutations provides a valuable and cost-effective genetic testing strategy. Twenty-three recurrent BRCA1 mutations have been identified previously in 100 Pakistani breast and/or ovarian cancer families. These accounted for 72.5% of all BRCA1 mutations identified.
In this study, we investigated whether these mutations (identified in >2 unrelated patients) have a common ancestral origin and estimated the ages of these mutations. Haplotype analyses were performed in 188 individuals (100 index patients, 88 relatives) from Pakistani breast/ovarian cancer families, all harboring one of the 23 recurrent BRCA1 mutations, and 90 healthy controls. Six microsatellite markers (D17S800, D17S1801, D17S855, D17S1322, D17S1323, and D17S951) were analyzed. Mutation ages were estimated using DMLE+2.3 software.
An identical haplotype of different length was found in families harboring the same BRCA1 mutation and suggested founder effects for all 23 mutations. Sixteen founder mutations were ethnicity-specific: 15 occurred in families of Punjabi background and one in a family of Pathan background. The remaining seven mutations occurred in families with two ethnic backgrounds. All BRCA1 founder mutations were estimated to have arisen approximately 147 to 159 generations ago. Our findings suggest founder effects for all 23 recurrent BRCA1 mutations.
Our findings suggest founder effects for all 23 recurrent BRCA1 mutations. This knowledge allows the design and development of a cost effective local genetic testing strategy in Pakistan.
The authors.
Foundation or academic group WITHOUT funding from a pharma, biotech, or other commercial company.
All authors have declared no conflicts of interest.
ILC represents ∼15% of all breast cancers (BC). Clinical, histological and molecular differences between ILC and BC of non-special type support the idea of ILC as a separate entity. Unfortunately, evidence on treatment efficacy for ILC is often lacking. We aimed to map out the lack of documentation and representation of patients with ILC in clinical drug trials (CT), trials investigating gene expression profiles (GEPs) and molecular screening programs (MS).
Phase III and IV CT for novel BC treatments were identified on clinicaltrials.gov and Pubmed by use of keywords linked to treatment strategies, GEPs and MS and ‘breast cancer’. CT were included if a manuscript was available on 15.01.2023. Inclusion and exclusion criteria were reviewed to see if patients with ILC or non-measurable disease were excluded. Documentation of ILC was assessed and if reported, percentage of ILC, central pathology for ILC and ILC subgroup analyses were evaluated.
In total, 80 CT were included of which 14 were neoadjuvant, 11 adjuvant and 55 metastatic. One CT restricted inclusion to patients with NST. Non-measurable disease was an exclusion criterium in 20% of the CT (14.3% neoadjuvant and 25.2% metastatic) and non-measurable disease with the exception of bone-only disease was excluded in 30.9% of the metastatic CT. Inclusion of patients with ILC was documented in 11/80 CT (13.8%: 35.7% neoadjuvant, 9.1% adjuvant, 9.1% metastatic). Inclusion rates varied between 2.0 and 16.3%. Only 2/11 CT had specific sub-analyses on ILC and no CT reported central pathology for ILC. The initial manuscript of 6/7 of the GEPs and 1/3 of the MS was lacking ILC information. Secondary retrospective analyses for ILC are available for 5/6 remaining GEPs.
ILC is greatly overlooked in the majority of CT with poor representation, documentation and lack of specific sub-analyses. Eligibility criteria and definitions of treatment response do not reflect the unique biology and clinical course of ILC. Thus, conclusions about efficacy with respect to ILC cannot accurately be drawn. It is critical that these gaps in inclusion and study of ILC are closed. ILC deserves much more attention from both clinical investigators and pharmaceutical industries.
The authors.
This study is supported by COST (European Cooperation in Science and Technology, www.cost.eu), besides personal funds by the KU Leuven Fund Nadine de Beauffort and a Conquer Cancer – Lobular Breast Cancer Alliance Young Investigator Award for Invasive Lobular Carcinoma Research, supported by Lobular Breast Cancer Alliance. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the American Society of Clinical Oncology® or Conquer Cancer®, or Lobular Breast Cancer Alliance.
All authors have declared no conflicts of interest.
Breast cancer (BC), is a heterogeneous disease, divided into molecular subtypes based on gene expression and clinical outcomes. MABC is a poorly diagnosed subtype, characterized by estrogen (ER), progesterone receptor (PR) negativity, and HER-2-amplification in most cases; yet it overexpresses androgen receptor (AR) and activates its pathway. Its improper diagnosis demands the adoption of complementary tools to refine classification; miRNA, key players in regulating cell behavior, AR, and tumorigenic processes of BC hold promise in defining and studying the behavior of MABC.
539 breast cancer microarray data were downloaded from The Cancer Genome Atlas (TCGA-BRCA). Cases with available miRNA data were retained and classified using citbcmst R package (PMID: 30289602). Differential expression analysis identified deregulated miRNAs using DEseq2. A validation set of 131 ER-neg samples was constituted and MABC tumors were characterized apart of triple-negative (TN)BC by the previously described molecular signature (AR, FOXA1 and AR-related genes, PMID: 23663520) on fresh tissue sections. Using miRCURY LNATM miRNA PCR assay, miRNA profiling was done for a panel of 6 differentially expressed miRNAs. Finally, expression of
TCGA data analysis indicated MABC as a separate entity based on gene signature. MiRNA-seq data analysis depicted a set of 6 significantly deregulated miRNA with absolute value of log2 fold change> 1 and P-adjusted value <0.05 between MABC and TNBC
MABC has a unique signature of miRNA compared to TNBC. The identified miRNAs regulate a set of genes implicated in tumorigenic processes and can potentially serve as biomarkers to effectively diagnose, prognose and treat MABC
The authors.
The Medical Practice Plan (MPP) at the American University of Beirut, and CEDRE from the French Government.
All authors have declared no conflicts of interest.
Recent evidence support that the immune system has both positive and negative effects on tumorigenesis. Systemic inflammation has been linked to aggressive tumor growth, metastasis, and drug resistance in breast cancer (BC) patients. Therefore, serum cytokines (SC) may represent an exciting biomarker in the monitoring of BC pathogenesis.
Pretreatment serum from 204 BC patients (23% Luminal A, 23.6% Luminal B/HER2-, 22.5% Luminal B/HER2+, 10.3% HER2-enriched, and 20.6% Triple-Negative/Basal-like -TNBL-) and 50 healthy donors was collected. Measurement of 62 SC was performed using LEGENDplex immunoassay. Fluorescence intensity was quantified by flow cytometry. The results were correlated with age, tumor size and grade, vascular invasion, necrosis, phenotype, tumor-infiltrating lymphocytes, lymph node status, and Ki67. Statistical analysis was done by Student’s t-test and Mann–Whitney U test.
BC patients showed higher levels of SCF, MIP3α, EPO and 4-1BB but lower levels of IL-2RA, IL-8, IL-12p40, IL-18, IL-23, IL-27, PDGF-AA, Galectin 9, PDGF-BB, B7.2, MIP1β and PD1, compared to the healthy group. Furthermore, IL-23, IL-27, and EPO correlated with younger age (p≤0.041), in contrast to Galectin 9, MCP1, IL-2RA, and MIP1β (p≤0.003). IL-12p40 and IFNγ were elevated in cases with grade I tumors (p≤0.05) and, in addition to IL-11 and IL-27 in low Ki67 tumors (p≤0.030). Moreover, IL-12p40 and IL-23 were associated with positive lymph nodes (p≤0.031). In Luminal tumors, we detected high IL-12p40, IL-15, IL-23, IL-27, and IFNγ (p≤0.048). However, only PDGF-BB was seen in non-Luminal tumor patients (p=0.040). IL-12p40, IL-18, IL-23, IL-27, SCF, and EPO were mainly higher in Luminal A, while PDGF-AA in Luminal B/HER2-. Likewise, MIP1β, MIP3α, and EPO were elevated in Luminal B/HER2+ serum, whereas Galectin9, PDGF-BB, IL-2RA, B7.2, SCF, 4-1BB, and PD1 were found in TNBL, with no specific profile for HER2-enriched.
Our results showed specific serum profiles of SC among BC phenotypes. Moreover, IL-12p40 and IL-23 were correlated with lymph node involvement in Luminal tumors, especially in Luminal A.
The authors.
Grant (SEAP-Proyecto Semilla; Expt. 200042); Biobank HGUA (21-154) and HUB-ICO-IDIBELL (PT17/0015/0024).
All authors have declared no conflicts of interest.
We recently reported that high cancer cell protein levels of PD-L2 in patients (pts) with treatment-naïve estrogen receptor-positive breast cancer (ER+ BC), was an independent predictor of shorter progression-free survival in two distinct cohort of pts (1). These findings suggest that PD-L2 may help improve BC pt selection for PD-1 inhibitors. We therefore initiated efforts to determine baseline expression patterns of PD-L1 and PD-L2 in BC.
PD-L1 and PD-L2 protein levels in cancer cells and tumor-infiltrating immune cells were prospectively analyzed by immunohistochemistry (IHC) using validated antibodies in diagnostic core biopsies of 28 consecutive pts diagnosed with localized or locoregional ER+/HER2- BC or TNBC. Percent positivity of PD-L1 and PD-L2 in cancer cells and immune cells was determined by a breast pathologist.
PD-L1 and PD-L2 expression patterns in BC differed in several ways. First, PD-L1-positivity in immune cells was higher than in cancer cells (median=5.0% vs. 0.05%; p=0.002), whereas PD-L2-positivity was higher in cancer vs. immune cells (median=20% vs. 5.0%; p=0.001). Second, there was no significant correlation between PD-L1 and PD-L2 expression, neither across all cases (N=28), nor within ER+ (N=20) or TNBC (N=8) cases. Third, PD-L1 positivity in cancer cells and immune cells were positively correlated in TNBC (
PD-L1 and PD-L2 proteins show divergent expression and are not correlated in BC. Discordant PD-L2 and PD-L1 expression may be more common in ER+ BC than in TNBC. This progress justifies efforts to explore PD-L2 as a complementary marker to PD-L1 for improved prediction of responses to PD-1 inhibitors, which may also benefit pts with aggressive ER+ BC. Reference: 1.JCO Precis Oncol 7:e2100498, 2023.
Tumor specimens from diagnostic core biopsies from our ongoing phase II clinical trial (NCT04243616) of neoadjuvant chemotherapy and PD-1 inhibitor (cemiplimab; Regeneron Pharmaceuticals Inc) were used for these analyses
The authors.
National Center for Advancing Translational Sciences, National Institutes of Health Awards KL2TR001438.
L.N. Chaudhary: Other, Personal, Advisory Board: Puma Biotechnology, Seattle Genetics, Gilead Sciences, AstraZeneca, Novartis; Other, Institutional, Research Grant: Regeneron Pharmaceuticals. All other authors have declared no conflicts of interest.
Breast cancer (BC) mostly occurs in women over 50 years old, however, around 5% of cases are very young women (BCVY) (age ≤35) being associated to poorer prognosis and shorter survival. Age-associated differences in BC remain poorly studied. Understanding biological differences in BCVY may lead to better therapeutic options for these patients. This work aimed to identify molecular differences between breast tumors from BCVY and old women (BCO).
The formalin-fixed samples of a retrospective cohort (
The BCVY cohort included 12 (55%) luminal, and 10 (45%) non-luminal BCs, while the BCO cohort was 17 (63%) luminal and 10 (37%) non-luminal patients. Principal Components Analysis of mRNA-seq data revealed a higher heterogeneity among BCVY. Age-related gene expression differences were confirmed (40 and 13 genes down- and up-regulated [fold change ± 2]). BCVY presented higher chromosomal instability (CIN70,
Our study provides novel findings on the impact of aging on transcriptional landscape in BC. We found age-related gene expression changes not only in cancer cells but also in the tumor microenvironment. These data suggest that luminal BCVY could be more endocrine-resistant and aggressive than BCO. Therefore, this work highlights age as an important factor to be considered in clinical practice.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Electronic patient-reported outcomes (ePRO) have shown the potential to improve clinical practice for cancer patients. The collection of ePRO via smartphone apps is becoming more wide-spread. Such data, comprising of symptom and diary entries, could conceivably be utilised to predict the occurrence of unplanned hospitalisation events via machine learning algorithms.
226 cancer patients (mainly breast cancer) using the consilium care ePRO app under systemic therapy. A diary entry is associated with an “unplanned visit” flag if such a visit or a hospitalization of the patient occurred on or within 3 days. We assume that on these days, an alarm raised to the patient or her/his physician would have been helpful.
Out of 16,670 entries, only 166 (1%) were flagged. To implement an early warning system, we trained a rule-based ML algorithm to predict critical situations, which we made more sensitive to the few flagged entries by applying cost-sensitive classification, assigning a 10-fold higher cost to missing a critical situation as compared to a false alarm. Rules are using are based on the strengths of symptoms captured by the patients, their perceived wellbeing, drugs they were taking, as well as keywords derived from free-text notes of patients and from their diagnosis; e.g. one of our rules suggests that an unplanned visit is likely to occur if a patient reports pain on a level of 38 or more and a wellbeing of 60 or less (both out of 100) and uses the word “today” in his/her notes of the given day. We intentionally used algorithms that are potentially inferior in prediction quality to modern deep learning approaches, but have the advantage of being not only human-interpretable, but even directly “human-modifiable” so that we can incorporate medical expertise into the machine-learned model at a later stage. We discovered a set of 55 rules which, as a whole, were able to correctly predict 47 of the 166 critical situations (28.3% recall), while raising 267 false alarms (15.2% precision).
Preliminary analysis of this study suggests that ML based prediction models trained on ePRO data can predict unplanned hospitalisation events within cancer patients.
NCT03578731.
We would like to thank Prof. Hansfriedrich Witschel, Dr. WEmanuele Laurenzi, Stephan Juengling from Fachhochschule Nordwestschweiz for ML analysis,and Yannickl Kadvani for reading the manuscript.
mobile Health AG, Zurich.
Grant from the Foundation Swiss Tumor Institute, a Swiss Research Organzation.
A. Trojan: Financial Interests, Personal, Ownership Interest: mobile Health AG. All other authors have declared no conflicts of interest.
CDK4/6i plus endocrine therapy is standard of care for patients with hormone receptor-positive/human epidermal growth factor receptor-negative advanced or metastatic breast cancer; however, patients frequently develop resistance to therapy. Identifying biomarkers that are associated with CDK4/6i resistance or response is key to selecting the most appropriate patients for treatment and could be used to develop novel agents or combination therapies. The aim of this study was to comprehensively describe the CDK4/6i biomarker landscape to guide future research.
We used a combination of bioinformatics and AI techniques to examine and collate putative biomarkers. Data were mined from Uniprot to identify proteins related to CDK4/6. Biomarkers used in clinical trials were mined from the PharmaProjects database. Protein interaction networks were generated using Signor, STRING, and Bioplex 3.0. To explore relevant publications, we performed a Geneshot analysis and used the output to conduct an enrichment analysis using the MSigDB database. To find non-protein biomarkers such as non-coding RNA species or molecular signatures, we used deep learning text analytics to interrogate more than 50 million documents across several platforms including PubMed, medRxiv, and bioRxiv. Results were prioritized by manual curation and target tractability analysis.
Bioinformatic database analyses identified 876 genes with known Uniprot functions potentially related to CDK4/6i response in breast cancer. Additionally, genes identified by Geneshot were contained within 42 oncogenic gene sets; 5 of these gene sets contained > 60 of the identified genes, with the most significant dysregulated pathways being TBK1, Rb, PDGF, SNF5, cyclin D1, Raf, and p53. Following target tractability analysis and literature review, we prioritized ∼20 promising candidates, including
The compendium developed using our multi-approach, AI-assisted review of existing knowledge of the CDK4/6i biomarker landscape will be central in supporting next generation research and drug development for breast cancer.
Editorial support, conducted in accordance with Good Publication Practice (GPP3) and the International Committee of Medical Journal Editors (ICMJE) guidelines, was provided by Oxford PharmaGenesis, Inc., Newtown, PA with funding provided by Pfizer Inc.
Pfizer Inc.
Pfizer Inc., USA.
K. Wager: Financial Interests, Personal, Writing Engagements, are employees of Oxford PharmaGenesis, Inc. who was funded by Pfizer Inc. to conduct the study.: Oxford PharmaGenesis. Y. Wang: Financial Interests, Personal, Stocks/Shares, are employees and stockholders of Pfizer Inc.: Pfizer Inc. A. Liew: Financial Interests, Personal, Writing Engagements, are employees of Oxford PharmaGenesis, Inc. who was funded by Pfizer Inc. to conduct the study.: Oxford PharmaGenesis. D. Campbell: Financial Interests, Personal, Stocks/Shares, are employees and stockholders of Pfizer Inc.: Pfizer Inc. L.M. Fettig: Financial Interests, Personal, Writing Engagements, are employees of Oxford PharmaGenesis, Inc. who was funded by Pfizer Inc. to conduct the study.: Oxford PharmaGenesis. F. Liu: Financial Interests, Personal, Stocks/Shares, are employees and stockholders of Pfizer Inc.: Pfizer Inc. J. Martini: Financial Interests, Personal, Stocks/Shares, are employees and stockholders of Pfizer Inc.: Pfizer Inc. N. Ziaee: Financial Interests, Personal, Stocks/Shares, are employees and stockholders of Pfizer Inc.: Pfizer Inc. Y. Liu: Financial Interests, Personal, Stocks/Shares, are employees and stockholders of Pfizer Inc.: Pfizer Inc.
Immunotherapy (IO) has been recently introduced in triple-negative breast cancer (TNBC) therapeutic algorithm, however no predictive biomarkers beyond PDL-1 expression demonstrated utility in clinical practice. BRCA mutations account for 15-20% of TNBC, with a positive association with platinum response and an inflammatory background on tumor tissue. Preclinical evidences demonstrated a lack of T-cell activation in BRCA-mutant (BRCAm) tumors due to an HLA machinery defects, but no subgroup effects were observed in IO pivotal trials evaluating chemotherapy-IO combinations.
We retrospectively evaluated the effect of germline BRCA mutations in consecutive BC patients underwent any-line IO-only treatment in phase I/II trials at Fondazione IRCCS Istituto Nazionale dei Tumori in Milan. Only mutations evaluated as pathogenic after genetic counselling were considered. IO treatment included PD(L)1, LAG3 and ICOS inhibitors, single agents or in combination. Statistical analysis were performed with RStudio software v2022.07.0.
Of 39 pts treated with IO from June 2016 to September 2022, 22 had available germline BRCA status. 4 pts exhibited mutations in
In our small retrospective cohort, the presence of a pathogenic mutation in
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
Has not received any funding.
M. Di Nicola: Non-Financial Interests, Institutional, Principal Investigator: AMGEN, BMS, Novartis, Roche, Sanofi, Incyte, Beigene, Genentech, Merck. F.G.M. De Braud: Financial Interests, Personal, Advisory Board: Ignyta, BMS, Daiichi Sankyo, Pfizer, Incyte, Roche; Financial Interests, Personal, Invited Speaker: MSD, Bayer, ACCMED, Merck; Non-Financial Interests, Institutional, Principal Investigator: Novartis, Celgene, Tesaro. All other authors have declared no conflicts of interest.
Tertiary lymphoid structures (TLS) are ectopic lymphoid organs that arise in nonlymphoid tissue sites of chronic inflammation including tumours. The presence of TLS, has been associated with increased tumour antigen presentation and improved cytokine-mediated signalling activity against tumour cells. Due to this, TLS have been associated with favourable outcomes in a number of cancer types. There is limited data regarding the prevalence and prognostic implication of TLS in hormone positive, HER2-negative (ER+/HER2-) breast cancer.
Formalin-fixed paraffin embedded blocks from a cohort of 429 patients with early stage hormone positive/ HER2-negative breast cancer were used to construct a TMA with three x 1 mm cores per patient. Multiplex chromogenic immunohistochemistry staining was performed to stain for CD3+ T cells, CD20+ B cells and DCLamp + dendritic cells. Digital image analysis was performed using Qupath open source software.
On the basis of staining with the TLS panel, samples could broadly be divided into three categories; immune cold with minimal immune infiltrate, T-cell only infiltrate and TLS defined by the presence of CD20+ B cells. TLS were seen in 14% (n=60) of patient samples which was similar to the rate of patients with a significant T-cell only immune infiltrate which was also 14% (n=60). The majority of samples had no infiltrate, comprising of 72% (n=312) of the cohort. The median CD3+ cells/mm2 in the entire cohort was 295mm2. When divided into these categories, there was no statistically significant difference in disease free survival (p value= 0.39) although there was a trend towards worse disease free survival in those with a high T-cell only infiltrate.
In contrast to other breast cancer subtypes, tumour infiltrating lymphocytes in ER+/HER2- breast cancer may be a poor prognositc feature. However this may be dependant on the subpopulation of immune infiltrate, with TLS presence perhaps differing from T-cell only infiltrate. Further research with larger cohorts would be required to investigate this further.
The authors.
Royal College of Surgeons Ireland (University) StAR MD programme.
All authors have declared no conflicts of interest.
Dose-dense sequential (dds) chemotherapy has tremendously changed the clinical outcome of patients with early breast cancer (BC). To investigate the impact of dose intensity (DI) in the adjuvant setting of BC, this observational trial (HE 10/10) was conducted assessing the long-term survival outcome, safety and toxicity of a now widely used chemotherapeutic regimen consisting of 4 cycles of cyclophosphamide and epirubicin q2 weeks, followed by 4 cycles of docetaxel q3 weeks. In addition, the prognostic significance of tumor infiltrating lymphocytes (TILs) and infiltrating CD8+ lymphocytes were also evaluated in the same cohort.
Totally, 1,054 patients were prospectively enrolled in the current study with 1,024 patients being eligible, while adequate tissue was available for 659 of them. TILs, CD8+ lymphocytes in intratumoral areas in contact with malignant cells (iCD8), CD8+ lymphocytes in tumor stroma (sCD8) as well as the total number of CD8+ lymphocytes within the tumor area (total CD8) were assessed by immunohistochemistry.
Within a median follow-up of 125.18 months, a total of 200 disease-free survival (DFS) events (19.5%) were reported. The median DFS and overall survival (OS) had not been reached yet at the time of data cut-off for the analysis, while the 10-year DFS and OS rates were 78.4% (95% CI 75.0-81.5) and 81.7% (95% CI 79.0-84.1), respectively. The studied regimen was well tolerated with 94.7% of the patients completing the full course of adjuvant chemotherapy (8 cycles), while the rest of them discontinued the treatment, mainly due to non-fatal reasons. Only a very small percentage of patients faced clinically significant myelotoxicity. Interestingly, higher CD8+ T cells in the tumor microenvironment were associated with an improved long-term survival outcome.
In conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well as the prognostic significance of infiltrating CD8+ lymphocytes in BC patients with early stage disease.
ACTRN12616001043426.
Hellenic Cooperative Oncology Group (HeCOG).
Hellenic Society of Medical Oncology (HeSMO), Hellenic Cooperative Ongology Group (HE10/10).
F.D. Dimitrakopoulos: Financial Interests, Personal, Research Grant: Merck Sharp & Dohme; Financial Interests, Personal, Other, Travel: Roche, MSD. D.G. Pectasides: Financial Interests, Personal, Advisory Role: Roche, MSD, Astellas; Financial Interests, Personal, Other, Honoraria: Roche, MSD, Astellas. A. Koutras: Financial Interests, Personal, Advisory Board: Pierre Fabre, AstraZeneca, Gilead, Pfizer, Genesis, MSD, BMS; Financial Interests, Personal, Invited Speaker: Sanofi, Gilead; Financial Interests, Personal, Other, TRAVEL, ACCOMMODATIONS: Rafarm, Lilly, Ipsen, Gilead, Pfizer; Financial Interests, Institutional, Funding: Lilly, Pfizer, Merck; Financial Interests, Institutional, Research Grant: AstraZeneca, Pierre Fabre, BMS, DEMO, FARAN, Amgen, Roche, Ipsen, GALENICA, WIN MEDICA. F. Zagouri: Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi, Eli Lilly, Merck, MSD, Genesis-Pharma, Roche; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Daiichi, Eli Lilly, Merck, MSD, Genesis-Pharma, Roche. H. Gogas: Financial Interests, Personal, Advisory Board: MSD, BMS, PIERRE FABRE; Financial Interests, Personal, Invited Speaker: MSD, BMS, NOVARTIS, PIERRE FABRE, SANOFI; Financial Interests, Invited Speaker: AMGEN, REPLIMMUNE; Financial Interests, Institutional, Invited Speaker: AMGEN, MSD, BMS, REPLIMMUNE, IOVANCE; Financial Interests, Institutional, Research Grant: BMS, PFIZER. G. Fountzilas: Financial Interests, Personal, Advisory Board: Pfizer, Novartis; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Novartis; Financial Interests, Personal, Stocks/Shares: Genprex, Daiichi Sankyo , RFL Holdings, FORMYCON. All other authors have declared no conflicts of interest.
Trop-2 is a transmembrane glycoprotein calcium signal transducer expressed in human epithelial cells and its increased expression has been linked with tumor growth and poorer prognosis in a variety of solid epithelial tumors. Trop-2 has been extensively evaluated in metastatic breast cancer with scarce data in earlier settings of the disease.
Cross-sectional study evaluating TROP-2 protein expression by immunohistochemistry (IHC) in patients with non-metastatic luminal breast. After the initial slide preparation process, the optimal antibody dilution for IHC of 1:100 was used (Trop-2 Antibody (B-9): sc-376746; Santa Cruz Biotechnology Inc., Dallas, TX, USA). The following categorization was used for readings for tumor cells: H-Score 0-<100 low, H-Score 100-200 intermediate and H-Score >200-300 high. Statistical analysis of the study was be performed using SPSS version 20.0 (IBM Germany). The expression profile of the Trop-2 biomarker was described by percentage and absolute frequency, respecting the scores for determining high, intermediate and low expression. Comparison of the markers described above with clinicopathological parameters was performed using Fisher's exact test. A value of P≤ 0.05 was considered statistically significant.
Eighty-four patients were included in the study. The median age was 57, 70% of tumors were non special type ductal invasive carcinoma, 75% were T2, 47.6% were node negative and Trop-2 is highly expressed in 56% and medium expressed in 38% of patients. Trop-2 expression was correlated with well known clinical and pathological prognostic factors such as age (p=0.319), histological subtype (p=0.290), grade (p=0.806), Ki67 (p=0.940), tumor size (p=0.505), nodal status (p=0.505), lymphovascular invasion (p=0.519), tumor subtype (p=1.00), pathological staging (p=0.594) and prognostic staging (p=0.978). No evidence of association among Trop-2 biomarker and clinicopathological factors was found.
Trop-2 is a constitutional biomarker in Early Luminal Breast Cancer expressed independently of other characteristics and probably could be a target for personalized medicine in this clinical setting.
Prof. MD,PhD Marcia Silveira Graudenz.
The Hospital de Clinicas de Porto Alegre (HCPA).
All authors have declared no conflicts of interest.
Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and no amplification of the human epidermal growth factors 2 (HER2) receptor. ATP-binding cassette superfamily G member 2 (ABCG2) is a transport protein that functions to eliminate xenobiotics in ATP dependent manner. The genetic variations might alter the gene expression, substrate specificity, and xenobiotics elimination function which ultimately affect the susceptibility of individuals towards cancer. The aim of this study is to investigate the association of
Genomic DNA was extracted from blood samples of 75 TNBC patients and 100 normal controls. The genotyping was performed by using the PCR-RFLP method and the genotype pattern was grouped into three, which are homozygous wildtype, heterozygous and homozygous variant. The genotype, allele, and haplotype frequencies with TNBC and pathological variables were calculated by using the independent χ2 test whereas the level of association was evaluated by deriving odds ratio (OR) with 95% confidence intervals (CI) using binary logistic regression analysis.
The
In conclusion,
Ahmad Aizat Abdul Aziz.
This study was supported by Universiti Sains Malaysia Short Term Grant (304/PPSP/6315508).
All authors have declared no conflicts of interest.
Current guidelines do not recommend retesting biological parameters on breast cancer (BC) surgical specimens (SS) after an initial tumor biopsy (TB).
We retrospectively gathered data from the TB and SS of 193 BC specimens collected in the Pathology Department of the Policlinico “G. Rodolico - S. Marco” in Catania between 2012 and 2022. Patients receiving neoadjuvant treatment were excluded. Differences between TB and SS in estrogen receptor (ER), progesterone receptor (PR) and Ki67 were tested using paired t-test, while changes in HER2 immunohistochemistry (IHC) score, tumor grade and intrinsic subtypes (according to IHC values) were evaluated with the Wilcoxon rank-sum test.
Mean ER and PR expression were 88% and 55% in TB and 89% and 59% in SS. Mean Ki67 value was 15% in TB and 16% in SS. HER2 IHC score was 0 in 119 TB vs 140 SS, 1+ in 31 TB vs 26 SS, 2+ in 41 TB vs 21 SS and 3+ in 2 TB vs 6 SS. Tumor grading was 1 in 41 TB vs 36 SS, 2 in 128 TB vs 112 SS and 3 in 24 TB vs 45 SS. PR and HER2 expression were significantly lower in SS compared to TB (p 0.008 and 0.007, respectively), while tumor grade was significantly higher in resected samples (p 0.0004). No differences emerged between TB and SS in terms of ER expression and Ki67. After surgery, intrinsic variants changed in 41 (21.2%) tumors. 25/61 luminal B-like BC were reclassified: 22 as luminal A-like and 3 as triple-positive cancers (p 0.0004). 15/119 luminal A-like cases were also reclassified: 13 in luminal B-like and 2 in triple-positive malignancies (p 0.0001). 1/7 triple-positive BC in the TB failed to confirm HER2-positivity in the SS. No changes occurred among HER2-enriched and triple-negative BC.
We detected a significant variability in PR, HER2 and tumor grading between TB and SS, while ER and Ki67 showed no significant differences. Moreover, a relevant proportion of tumors were reclassified in different variants after surgery, with the greatest variability observed among luminal B-like tumors. While our findings require confirmation in a larger cohort, initial results indicate that reassessing biological parameters on SS after an initial TB may have meaningful prognostic and therapeutic value.
The authors.
Has not received any funding.
G.M. Vecchio: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo. F. Martorana: Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Lilly, Istituto Gentili; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Other, Travel grant: Roche; Financial Interests, Personal, Invited Speaker, Travel grant: Gilead. P. Vigneri: Financial Interests, Personal, Invited Speaker: AstraZeneca, Lilly, Gilead, GSK, Istituto Gentili, Novartis, Teva, Pfizer; Financial Interests, Personal, Research Grant: Pfizer, Novartis. All other authors have declared no conflicts of interest.
Breast cancer (BC) is the first cancer in terms of frequency and mortality in women. The aim of this retrospective study is to identify the role of exosome microRNAs (Exo-miRNAs) as possible early biomarkers for identifying patients with higher risk of developing the disease and to personalize their screening programmes. For this purpose, Exo-miRNAs derived from cyst fluid of women affected by Gross Cyst Disease of the Breast (GCDB - a benign disease of the mammary gland associated with a 2-4-fold increase in the risk of developing BC) have been analysed.
Cyst fluids have been selected among samples from 600 patients diagnosed with GCDB between 1985 and 1993, some of whom developed BC during follow-up. Exo-miRNAs were extracted from 400 μl of cyst fluid using the exoRNeasy midi kit (Qiagen). Quality control was assessed by Bioanalyser (Agilent) and Qubit™ using the microRNA Assay Kit (Thermo Fisher Scientific). Exo-miRNome profiles were investigated by microarray on Agilent platform using an optimised protocol (labelling and hybridization on SurePrint Human miR Microarrays 8×60 K and image acquisition using the G2565CA scanner).
A total of 46 samples (23 cases and 23 controls, paired on the bases of clinical and pathological variables) have been analysed. The analysis allowed to identify 10 Exo-miRNAs slightly modulated between cases and controls, and 7 Exo-miRNAs in the Type 1 cyst, that are correlated with a higher risk of developing BC. A single variable logistic regression model on the most expressed Exo-miRNAs detected, pointed out 3 Exo-miRs (miR-6076, miR-3660, miR-6879-5p), whose expression was negatively associated to the development of BC (raw p-value <0.05). A risk score combining the 3 Exo-miRNAs by multivariable logistic regression modelling showed an optimal accuracy (AUC = 0.8, 95%, [CI] 0.6703-0.9282).
These data, to be validated in further 72 samples equally divided between cases and controls, show that Exo-miRNAs are promising minimally invasive biomarkers of BC risk. In order to transfer these data to the clinic, the Exo-miR signature will be tested on plasma of patients with BC enrolled in a prospective study.
Protocol EsomiR- Supported by Compagnia San Paolo ROL ID 32134.
Prof. Lucia Del Mastro.
Fondazione Compagnia di San Paolo, ID ROL: 32134.
All authors have declared no conflicts of interest.
Salivary gland–like tumors represent 2% of primary breast carcinomas. They are histologically triple negative (-ve for ER, PR, and HER2). Salivary and mammary gland tumors show morphological similarities, and it is evident the same neoplasms can arise at both sites but differ in the incidence and clinical behavior according to the primary site. There are numerous studies describing salivary gland tumors but few studies have described this rare subtype of the breast. So the aim of this study was to describe the clinicopathological features of salivary gland tumor of the breast and chemotherapy as a treatment modality.
We used Surveillance, Epidemiology and End Results (SEER) software to extract the data of 808 patients diagnosed with microscopically confirmed salivary gland tumor of the breast from 2000-2019. We divided them into two subgroups according to the chemotherapy received. We extracted the demographic and clinicopathologic data including: age, race, year of diagnosis, stage, grade, histological subtypes and surgery. We used SPSS version 23 for data analysis. Kaplan-Meier curve, Log-rank test for survival analysis.
Age-standardized relative 5-year survival was 97.1% and cause-specific 5-year survival was 93.5%. The group who had no chemotherapy had survival benefit of only 11% compared to those who received chemotherapy (98.0% and 87.0%, respectively;
Salivary gland tumor of the breast has good overall survival. Chemotherapy is the gold standard for triple-negative breast cancer, either primary or combined regimens. However, there was no significant improvement in survival for salivary gland tumor of the breast. These results discourage the use of chemotherapy in this subtype to avoid unnecessary complications.
The author.
Has not received any funding.
Although microbiome involvement in the development of breast cancer is well known, there have been few cases using the microbiome in the primary treatment of patients with breast cancer. Using prebiotics in patients with breast cancer, so improving the microbiome and serum tests of patients was confirmed.
Additional prebiotics were used to treat patients diagnosed with breast cancer histologically for 12 weeks for after surgery, chemotherapy, and radiation treatment. The primary endpoint was an improvement in the microbiome via changing blood glucose and blood lipid tests, which are known risk factors for breast cancer, in serum tests performed after treatment. Serum, stool, and urine tests were performed before ingestion of prebiotics and in the same manner after ingestion. The microbiome was analyzed in serum, feces, fecal extracellular vesicles, and urine.
Of the 60 patients screened, 18 were enrolled according to the exclusion criteria. After taking prebiotics in patients with breast cancer, 9 patients took them completely, excluding patients who could not take the prebiotics to the end or those who stopped due to side effects. These patients showed improvement in ANC (absolute neutrophil count), fasting glucose level, and LDL (low-density lipoprotein) cholesterol. Most side effects were mild and were mainly gastrointestinal symptoms such as constipation or indigestion. The microbiome that showed changes after prebiotics administration differed in feces, extracellular vesicles in feces, urine, and serum, but the bacteria that showed the most changes were
Oral administration of prebiotics is thought to reduce the risk of recurrence by improving risk factors in patients whose breast cancer has resolved after standard treatment surgery, chemotherapy, and radiotherapy. The observed side effects of prebiotics (gastrointestinal symptoms) are not severe but should be improved. If these are improved, prebiotics can be used additionally for the treatment of patients with breast cancer.
CRIS number, PRE20230213-007.
The authors.
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2021R1A2C1014094).
All authors have declared no conflicts of interest.
Phyllodes tumours (PT), comprising <1% of breast tumours, are rare fibroepithelial lesions ranging from benign to malignant. Although their excision is generally recommended, there is still no consensus on optimal PT management. This study thus aimed to better delineate the course and management of PT through our 15-year experience at a breast surgery unit.
This was a retrospective single-center study of patients with histologically proven PT from 2005-2021. Data regarding demographics, presentation, investigations, management, and follow-up were extracted, and were statistically analysed using R.
101 cases were identified, comprising 79 benign, 15 borderline and 7 malignant PT. Mean age was 39.7±17.0 years, and patients with malignant PT were significantly older (p=0.039). All patients presented with masses, 52.5% affecting the left breast. On triple assessment, higher clinical scores (p=0.008) and biopsy scores (p<0.001) were associated with malignancy, however ultrasound and mammogram scores were not. Biopsy histology was available for 98.9% of patients, of which 35.6% did not suspect PT on initial biopsy as they were predominantly believed to be fibroadenomas (84.4%). 93.1% underwent wide local excision (WLE), and 6.9% underwent mastectomies. The nearest excision margin was stated in 37.2% after WLE; however, only 5.7% were above the recommended 1cm, and 40.4% had positive margins. Mean margins were highest in malignant PT (p=0.054). Subsequently, 43.6% underwent margin excision, and 2 patients with malignant PT underwent mastectomy. Mean follow-up period was 29.4±35.2 months, with significantly longer FU in malignant PT (p<0.001). Recurrence rate was 12.9% overall, comprising 12 benign PT cases recurring as 8 benign, 2 borderline and 2 malignant PT, as well as 1 borderline PT recurrence. Survival was 92.4%, with no record of metastases.
Although rare and variable in disease course, comprehensive guidelines are needed in managing PT. In particular, further research is warranted into optimal excision margins and follow-up given the difficulty differentiating between benign fibroadenoma and early PT, and the risk of upgrading PT on recurrence.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Male breast cancer (MBC) is rare and comprises < 1% of breast cancers. The incidence of MBC has increased by 40% from 1975 to 2015. It is projected that 2800 new cases of invasive MBCs will be discovered in the US in 2023, and 530 men will die from it. We examined the demographics of MBC and assessed the racial differences influencing survival.
We performed a retrospective cohort study of the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed with primary MBC between 2000 and 2019 in the United States. Patient demographics, tumor characteristics, and treatments were analyzed by descriptive statistics. Cox proportional hazards regression analysis was performed to identify the factors influencing survival, followed by subgroup analysis by Caucasian (WH) and African American (AA) race.
A total of 8373 patients had MBC. AA had 1111 (13.26%) and WH had 6817 (81.41%) MBC cases. AA had a median age of diagnoses of 69 vs WH of 63 years. AA (22.4%) men with MBC had a higher mortality rate (HR 1.44) than WH (16.8%). Older patients were found to be at increased risk of mortality in AA (HR 1.07) and WH (HR 1.17). Tumor size <20 mm halved the risk of death in WH (HR 0.56), it did not have any significance in AA. Regional lymph node involvement increased the risk of death in AA and WH (HR 4.79 vs 4.05). Poorly differentiated tumors had worse outcomes in WH than AA (HR 2.11 vs. 1.8). ER/PR + status was protective for both races. Mortality was higher in AA men residing in rural areas (HR 1.47) and lower for AA men in urban cities. Marriage improved outcomes for both AA (HR 0.63) and WH (HR 0.61). Surgery alone had better outcomes, AA (HR 0.21) and WH (HR 0.14) than chemotherapy or radiation. Median income was of no significance on survival in either race.
Overall, there is a significant difference in incidence and factors influencing survival for male breast cancer between Caucasians and African Americans. Despite the markedly lower incidence of MBC in the AA population, they have poorer outcomes overall. Further studies are required to determine the specific reasons for the disparity in their survival.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Male breast cancer constitutes <1% of breast cancer and is a relatively unexplored area. Guidelines on this entity are by and large extrapolated from female breast data. Survival in male breast cancer is not clearly elucidated and more data is required to better understand this disease.
We retrospectively analyzed the data of 192 patients with male breast cancer registered at our institute from 2010 to 2020. For the purpose of this study all patients were staged as per the 8th edition AJCC recommendations. Statistical analysis was done using SPSS version 28.0.
Of the 20,277 new patients of breast cancer registered between 2010 and 2020, 0.94% (192) were males. The median age at presentation was 58.0 years (23-82). Commonest presenting symptom was breast lump accounting for 85.9%. Invasive ductal carcinoma NOS was seen in 84.9%. Stage I, II, III and IV accounted for 4.7%, 31.3%,33.3% and 27.1% respectively. ER, PR, HER2 positivity was noted in 72.4%, 64.6% and 13.5% respectively. Fifty one percent had upfront surgery followed by adjuvant chemotherapy while neoadjuvant chemotherapy was required in 8.9%. Chemotherapy regimen given was as per institutional protocol. Survival data of 152 patients was analyzed. At a median follow up of 25 months the EFS was 100%, 78%, 67.3%, 78.3% and the estimated median EFS was not reached,139, 48 & 24 months in stage I, II, III and IV respectively. The Overall survival (OS) was 100%, 96.1%, 91.8% & 78.3% for Stage I, II, III and IV respectively and the median OS was not reached. Median EFS (estimated) was 96 and 48 months for node negative and positive patients respectively.
This is one of the largest series of male breast cancers reported to date. Due to paucity of quality evidence the outcomes and survival remain suboptimal in comparison to their female counterparts. This difference is more evident in middle and low-income countries pertaining to factors like social stigma and lack of awareness. Current study provides useful information regarding the demography, natural history, treatment response and survival outcomes of male breast cancers.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer outcome, drug response and adverse effects vary significantly among races in the USA, with Black women being the most disproportionately burdened. However, recent reports are pointing out a significant underrepresentation of minorities, especially Black and Hispanic, in American clinical trials. Among breast cancer trials leading to FDA drug approval, race was reported in 66.67% and 75.70% White, 15.52% Asian, 3.73% Hispanic and 2.10% Black patients were enrolled. There is no such analysis though about the situation in Europe. The aim of this study is to assess the representation of racial and ethnic minorities in the population enrolled in clinical trials for breast cancer pharmacological treatments in Europe.
PubMed and ClinicalTrials databases were systematically reviewed for clinical trials on drug efficacy for breast cancer. Phase II and III clinical trials conducted exclusively in Europe with at least 250 participants and results published within 2010-2022 were included in this study. Descriptive statistics were applied.
Ninety-seven clinical trials with a total of 113,045 patients were included. Patient race or ethnicity was reported in the patient demographics of only 10 (10.31%) articles. The lack of racial background data or ethnic diversity in their trial was acknowledged by three additional authors (3.1%). There were no substantial differences in race reporting trends depending on study phase (2/14 of phase II trials and 8/80 phase III trials). Among the 12,179 (10.77%) patients with available race data, 92.65% of patients were White/Caucasian, 1.08% were Asian and 0.88% Black. 3.20% identified as Hispanic/Latino (partially overlapping with the White population). Additionally, Europe’s largest ethnic minority, the Roma, is not mentioned in any of the included studies.
Despite the proven correlation of race with breast cancer outcome, this study reports a concerningly low Black and Asian patient enrolment in European breast cancer trials compared to reports from corresponding analyses in the United States. These observations highlight the need for stricter guidelines for race and ethnicity reporting and inclusion in cancer clinical trials to match the diversity of the European population.
Faculty of Medicine, School of Health Sciences, University of Thessaly.
Has not received any funding.
All authors have declared no conflicts of interest.
Clinical trials are essential for enhancing cancer care and providing the best possible treatment for patients with cancer. HIs, comprising 18.9% of the US population, but only 4% of clinical trial patients. Effective doctor-patient communication is fundamental in establishing a functional doctor-patient relationship, and is vital in delivering high-quality health care. In this study, we question whether physician-patient language concordance affects clinical trial enrollment.
The study evaluated 233 patients with breast cancer who consented to experimental clinical trials from 2008-2022 in a private practice in Houston, Texas. All trials had approved translations in English and Spanish. We used logistic regression to model the probability of treatment, adjusting for cancer type, gender, race, ethnicity, and language.
Of the 233 patients with breast cancer, 191(82%) were enrolled in a clinical trial, and 96% had providers who spoke the same language. 42 patients were not enrolled, with 95% of patients speaking the same language as their provider. There were 209 (90%) English-speaking, 22 (9%) Spanish-speaking, and 2 (1%) Arabic-speaking patients. Of the Spanish speakers enrolled, 72% had language concordance with their provider. The ethnicity was evaluated, resulting in 72 (31%) patients being Hispanic, 55 (24%) African American, 94 (40%) Caucasian, 7 (3%) Asian, 4 (2%) Middle Eastern and 1 (0.4%) American Indian. The study found that only 6 (3%) patients withdrew consent. After evaluating the results, there was no statistically significant association of physician-patient language concordance with enrollment rate (p=0.776). There was no difference in consent withdrawal (p=0.626), gender (p=0.344) or ethnicity (p=0.13).
Our study found no significant difference in breast cancer patients' enrollment in clinical trials when there is language concordance between physician and patient. The medical workforce's efforts to use translators and translated versions of informed consents, surveys or outcome assessments, when available, seem sufficient for our patients to collect the information required to agree to continue enrollment.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
The proportion of patients with breast cancer (BC) who are overweight or obese has been increasing. Obesity is associated with worse prognosis and with differential response to several anti-cancer therapies. However, we still lack knowledge about potential differential efficacy of most drugs according to BMI. Here, we aimed to investigate how BMI is documented in recent clinical drug trials (CTs), in trials investigating gene expression profiles (GEPs) and molecular screening programs (MS).
A search of Pubmed and ClinicalTrials.gov was performed using medical subject heading terms and words related to the treatments (CDK4/6 inhibitors, antibody drug conjugates, oral selective estrogen receptor degrader, PARP inhibitors, tyrosine kinase inhibitors, mTOR inhibitors, immune checkpoint inhibitors, PIK3CA inhibitors and others). The considered GEPs were: OncotypeDx, Mammaprint, EPClin, Prosigna, BreastCancerIndex, and OncoMasTR. Only phase III and IV CTs with a full manuscript available on 15/01/2023 were included. Documentation of BMI category was assessed and if reported, it was checked if subgroup analyses were performed. We also searched for other measures of adiposity.
In total, 80 CTs were included. Of the 23 evaluated drugs, 19 (82.6%) are given as a fixed dose independent of patient weight. Maximum or minimum BMI was not an exclusion criterium in any of the CTs. Distribution of patients according to BMI was mentioned in the original manuscript of one CT. Initially, this was also the only trial were a subgroup analysis was performed. No other measures of adiposity were mentioned in any of the CTs. Additional retrospective analyses on the impact of BMI were performed in 5 CTs. The initial manuscript of all GEPs and MS was lacking information regarding patient’s BMI but was retrospectively evaluated for 3/6 (50%) GEPs.
This study emphasizes that most drugs are given at fixed dose and the gap in knowledge we have on the efficacy of the novel anti-cancer treatments and the use of GEP and MS according to patient adiposity. As the prevalence of obesity is increasing worldwide, the evaluation of body composition is needed to increase knowledge on optimal use of drugs in clinical practice.
The authors.
Has not received any funding.
K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Roche, Vifor Pharma, Eli Lilly, Pierre Fabre, McCann Health, Roularta, Teva, Gilead Sciences, Pfizer, Gilead, MSD; Financial Interests, Institutional, Invited Speaker: Pfizer, Roche, Novartis, Eli Lilly, Mundi Pharma, MSD, Medscape, MSD; Financial Interests, Institutional, Other, Consultancy: Roche; Financial Interests, Personal, Other, Consultancy: Gilead, Novartis, MSD, Roche; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker: Sanofi, AstraZeneca; Financial Interests, Institutional, Funding: Sanofi; Non-Financial Interests, Principal Investigator: EORTC 1745-ETF-BCG trial; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Invited Speaker: BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force; Non-Financial Interests, Advisory Role: Commission personalized medecine Federal Government Belgium; Non-Financial Interests, Advisory Role, External Scientific Advisor: European Medicine Agency. H. Wildiers: Financial Interests, Institutional, Advisory Board: Roche, Lilly, AstraZeneca, Daiichi Sankyo, PSI Cro AG, KCE, MSD, MSD, E Squared Communications LLC; Financial Interests, Institutional, Invited Speaker: Eisai, AstraZeneca; Financial Interests, Institutional, Other, Consultancy fee: AbbVie, Immutep Pty; Financial Interests, Institutional, Expert Testimony: Daiichi Sankyo; Financial Interests, Institutional, Other, Consultancy: Daiichi Sankyo; Financial Interests, Institutional, Research Grant, Grant to the Leuven Breast Center to support the research database: Roche; Financial Interests, Institutional, Research Grant, Grant to institute to perform a multicentric national academic trial: Novartis; Other, Travel & accomodations: Pfizer; Other, Travel & accomodation: Roche; Other, Subscription fee: Gilead. All other authors have declared no conflicts of interest.
The management of breast cancer (BC) is rapidly developing with important new data being presented and published. This micro-learning CME series shared clinical cases highlighting the recent latest advances in early & metastatic BC. Learners were evaluated on their knowledge of the latest data, competence in the management of adverse events and confidence in their ability to identify appropriate treatment options for patients.
The outcomes of 6 short medical educational (CME) chapters (video with accompanying slides) were evaluated. The educational impact was assessed with a repeated pairs design, participants were questioned pre-education and post-education (knowledge/competence & confidence). The questions and the outcomes data were divided into 8 topics, 2 covering ER+ breast cancer; 1 on gBRCA mutated early BC; 3 on HER2+ (after 1L) and 2 on HER2-Low metastatic breast cancer. Data were collected from 29th August to 9th December 2022. Statistical significance was assessed using McNemar’s test (P < .05 level).
A total of 3,202 HCPs participated in these activities, of whom 439 were oncologists and 409 were obstetrics/gynaecology physicians. Significant overall improvements were observed in the knowledge and competence of Oncologists and Ob/Gyns as shown below:
Oncologists (% of correct responses) % improvement & P-value Ob/Gyns (% of correct responses) % improvement & P-value Pre-education 50% 75% 25% 69% Post-education 71% 41% KEY OUTCOMES ER+ BC Pre 37%; Post 66% 78%↑ Pre 16%; Post 34% 113%↑ gBRCA EBC Pre 60%; Post 86% 43%↑ Pre 38%; Post 55% 45%↑ HER2+ AEs Pre 78%; Post 96% 23%↑ Pre 41%; Post 68% 66%↑ Diagnosing HER2 Low BC Pre 38%; Post 38% 0% Pre 14%; Post 14% 0%
This micro CME educational program demonstrated a statistically significant improvement in knowledge/competence and confidence for all HCPs who completed the assessments. Outcomes by chapter showed a positive impact for each activity except the HER2-Low disease case. With recent developments in the identification and treatment of HER2-Low BC, this data underlines the need for ongoing education to help HCPs understand this important BC population.
Web MD Global / Medscape Education.
Medscape Global Education using an independent educational grant from AstraZeneca.
All authors have declared no conflicts of interest.
In the phase II PHranceSCa study (NCT03674112), 85% of patients preferred the fixed-dose combination of pertuzumab (P) and trastuzumab (H) for subcutaneous injection (PH FDC SC) over PH infused intravenously (IV) as adjuvant treatment for HER2-positive early breast cancer, with no new safety signals with PH FDC SC. We present efficacy and safety data after continuation of treatment and follow-up.
Patients with locally advanced, inflammatory, or early breast cancer who had completed neoadjuvant PH + chemotherapy and surgery were randomised 1:1 to 3 cycles of PH FDC SC (600 mg P/600 mg H in 10 mL) followed by 3 cycles of PH IV (P 420 mg; H 6 mg/kg) or 3 cycles of PH IV followed by 3 cycles of PH FDC SC. If needed, loading doses were P 1200 mg /H 600 mg in 15 mL for PH FDC SC and P 840 mg/H 8 mg/kg for PH IV. After the crossover period, patients continued treatment by their preferred method (continuation period, up to 18 cycles total). Efficacy (invasive disease-free survival [IDFS]) and overall survival (OS), safety and quality of life (EORTC QLQ-C30) were assessed after 3 years.
159/160 patients were treated in the continuation period (138 PH FDC SC, 21 PH IV, median 8 cycles for both) and 148 completed follow-up. The table shows safety in the continuation period. Most adverse events (AEs), including all cardiac AEs (n = 2) and anaphylaxis/hypersensitivity (n = 2), were grades 1/2. No grade 4/5 AEs occurred. There were six IDFS events (3.8%: 3-year IDFS 97.4%, 95% confidence interval [CI] = 94.9, 99.9) and two deaths (1.3%: 3-year OS 98.7%, 95% CI = 96.9, 100.0). Mean changes from baseline in EORTC QLQ-C30 were generally minimal.
PH FDC SC was well tolerated, with safety consistent with that of PH IV (except injection-site reactions) and no grade ≥3 anaphylaxis/hypersensitivity or new safety signals in the continuation period. Efficacy data are immature but show high IDFS and OS rates at 3 years.
For the latest information on IDFS data, please consult the Poster.
Patients, n (%) Any AE 92 (66.7) 14 (66.7) Grade 3–5 AE 7 (5.1) 2 (9.5) Serious AE 4 (2.9) 0 Cardiac AE 1 (0.7) 1 (4.8) Anaphylaxis/hypersensitivity 2 (1.4) 0 Administration-related reaction 16 (11.6) 1 (4.8) Local injection-site reaction 13 (9.4) 0 Systemic injection reaction 2 (1.4) 0 Systemic infusion reaction 0 1 (4.8) AE leading to interruption or dose reduction 8 (5.8) 1 (4.8) AE leading to treatment discontinuation 0 1 (4.8)
NCT03674112.
Support for third-party writing assistance for this abstract, furnished by John Carron, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland.
F. Hoffmann-La Roche Ltd.
F. Hoffmann-La Roche Ltd.
J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie, Agendia, Amgen, Aptitude Health, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Ondonate, Pfizer, Puma, Prime Oncology, Roche, Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre Pharmaceuticals, Samsung Bioepis, Sanofi. S.P. Sousa: Financial Interests, Invited Speaker: Roche, Novartis, Pfizer, MSD Oncology, AstraZeneca, Merck, GSK, Gillead. J. Cruz Jurado: Financial Interests, Personal, Advisory Board: PharmaMar, Roche, Lilly, Pfyzer, Novartis, Gilead, AstraZeneca, Daiichi, Seagen, GSK, Bayer; Financial Interests, Personal, Invited Speaker: PharmaMar, Roche, Lilly, Pfyzer, Novartis, Eisai, Gilead, AstraZeneca, Daiichi, Seagen, Esteve, Roche. L.J. Fallowfield: Financial Interests, Personal, Invited Speaker, Genomic Health Nurses ForumMAY 2019/ DEC 2019: Genomic Health; Financial Interests, Personal, Invited Speaker, MAR 2021. Understanding the quality of survival in metastatic breast cancerOCT 2020. Novartis Virtual Summit: Novartis; Financial Interests, Personal, Advisory Board, Lilly Oncology Breast Cancer European Advisory BoardAPR 2019: Lilly; Financial Interests, Personal, Invited Speaker, NOV 2019. PrIME Masterclass in NET Neuroendocrine Tumours: prIME A Medscape Oncology Company; Financial Interests, Personal, Invited Speaker, SEP 2020. Chair national Pfizer virtual meeting: Pfizer; Financial Interests, Personal, Invited Speaker, OCT 2020. CATCH Collaborate and address treatment challenges in haemophilia Workshop Talk: Patient Engagement: Sobi; Financial Interests, Personal, Invited Speaker, SEP 2020. Communicating Risk - Virtual Consultations MSD speaker meeting: MSD; Financial Interests, Personal, Invited Speaker, OCT 2020. Financial Toxicity In Oncology From Worldwide To Italy: 3P SOLUTION; Financial Interests, Personal, Invited Speaker, NOV 19. Prosigna Event: Communicating risk to patients incorporating aspects of the recent Prosigna videos.: Veracyte; Financial Interests, Personal, Invited Speaker, SEP 2021. Step Ahead - 4th Biennial Breast Cancer Summit AZ: AstraZeneca; Financial Interests, Personal, Advisory Board: Voluntis; Financial Interests, Institutional, Funding, PI: Veracyte; Financial Interests, Institutional, Research Grant, PI: Eli Lilly, Roche, Bristol Myers Squibb. P. Auvinen: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd. C. Pulido: Non-Financial Interests, Funding, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. A.S. Cvetanovic: Financial Interests, Invited Speaker, Speaker honoraria: Roche, Novartis, Pfizer, MSD Oncology, AstraZeneca, Merck. S.T. Wilks: Non-Financial Interests, Funding, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. L.A. Ribeiro: Financial Interests, Personal, Advisory Board: Novartis Farma. M. Burotto: Financial Interests, Other, Consulting fees: F. Hoffmann-La Roche Ltd., Genentech , Bristol Myers Squibb, MSD Oncology, Novartis, AstraZeneca; Financial Interests, Speaker’s Bureau: F.Hoffmann-La Roche Ltd., Genentech, MSD Oncology, Bristol Myers Squib, AstraZeneca. T. Boulet: Financial Interests, Personal, Full or part-time Employment, Employee from Parexel which is contracted by F.Hoffmann – La Roche Ltd. for statistical services in the conduct of the study: Parexel. V. Revelant: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd. N. Theron: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research funding: Support for third-party editing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. P. Trask: Financial Interests, Personal, Full or part-time Employment, Employed by Genentech and hold stock in Roche.: F. Hoffmann-La Roche Ltd. L.A. Wahyudi: Non-Financial Interests, Funding, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. Z. Machackova: Financial Interests, Stocks/Shares: F. Hoffmann-La Roche Ltd. L. Stamatovic: Financial Interests, Personal, Invited Speaker: AstraZeneca, F. Hoffmann-La Roche Ltd., Novartis, Pfizer, MSD , Eli Lilly; Non-Financial Interests, Personal, Funding, Research Funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd.
Neratinib was approved as an extended adjuvant therapy by FDA in 2017 for patients (pts) with HER2+ eBC and by the EMA in 2018 for pts with HER2+ HR+ eBC who completed adjuvant trastuzumab-based therapy within the prior 1 year (EU Label) based on the phase III ExteNET trial. The present study objective was to investigate neratinib effectiveness and tolerability in real-world clinical practice.
Patients with stage I–III HER2+ eBC who started extended adjuvant neratinib at US Oncology Network centres from 15 July 2017 to 30 June 2020 were retrospectively identified and followed to last visit, death or study end. Demographic/clinical data, effectiveness and tolerability outcomes were extracted from electronic medical records and assessed descriptively.
Of 240 patients, 166 pts (69.2%) had HER2+ / HR+ eBC and had completed adjuvant trastuzumab-based treatment within 1 year of initiating extended adjuvant neratinib (EU Label). The median age was 50 years. 72% (n=120) of patients presented stage ≥ II. 106 pts received neoadjuvant therapy (96.2% pertuzumab) and of those, 49 patients (46.2%) achieved a pathological complete response (pCR). 72 (43.4%) and 3 (1.8%) pts received prior adjuvant pertuzumab or T-DM1, respectively. 81.3% initiated neratinib at full dose and 12.6% had dose escalation. 38% of patients required dose adjustments since treatment start. Median neratinib treatment duration was 11.6 months. Six pts had invasive relapses (5 distant, 1 locoregional) over a median of 26.9 months of follow-up. The 12- and 24-month iDFS rates were 97.5% and 96.0%, respectively. 90.4% of patients experienced any-grade diarrhea during treatment, which was the main AE leading to treatment discontinuation. Patients who received anti-diarrheal prophylaxis (66.9%) had a longer median time to discontinuation than patients who did not receive prophylaxis (11.8 and 6.8 mo, respectively).
Based on these US community oncology data, the real-world effectiveness of neratinib in patients with HER2+ HR+ eBC ≤ 1 year after completing current adjuvant trastuzumab based therapies is consistent with that observed in the ExteNET study with no new safety findings.
Catherine Rees provided editorial assistance in the development of this abstract on behalf of Springer Healthcare Communications. This medical writing assistance was funded by Pierre Fabre.
Pierre Fabre Medicament.
Pierre Fabre.
D.I. Lüftner: Financial Interests, Personal, Invited Speaker: Roche, Pierre Fabre, Daiichi Sankyo, Gilead; Financial Interests, Personal, Advisory Role: Roche, Pierre Fabre, Daiichi Sankyo, Gilead. J. O'Shaughnessy: Financial Interests, Advisory Role: AbbVie Inc., Agendia, Aptitude Health, AstraZeneca, Athenex, Bayer, Bristol Myers Squibb, Caris, Carrick Therapeutics, Celgene Corporation, Daiichi Sankyo , Eisai, Exact Sciences, G1 Therapeutics , Genentech, Gilead Sciences, Immunomedics, Lilly, Merck, Novartis, Ontada, Pfizer, Pharmacyclics, Pierre Fabre Pharmaceuticals, Puma Biotechnology, Prime Oncology, Roche, Samsung Bioepis, Sanofi, Seagen, Theralink, Synthon. A. Zkik, O. Dialla, M. Brignone, M. Zivanov: Financial Interests, Personal, Full or part-time Employment: Pierre Fabre. J. Andersen: Financial Interests, Personal, Speaker’s Bureau: Puma, AstraZeneca, DSI, Exact Sciences, Gilead, Seagen; Financial Interests, Personal, Advisory Board: AstraZeneca, Athenex, Novartis, Merck, Biotheranostics.
This exploratory biomarker analysis aimed to identify prognostic gene sets in the. T-DM1 and H arms of the phase III KATHERINE study (NCT01772472).
RNA sequencing was performed on post-NAT surgical samples. Genes and pathways associated with prognosis were identified using DGE, comparing pts with invasive disease-free survival (iDFS) events with censored pts at a 3-year cut-off, and gene set enrichment analysis (GSEA), using Hallmark, KEGG, xCell, and selected signatures. NMF was used to identify transcriptional subgroups; their association with iDFS was assessed by Cox regression. Association analyses were adjusted for tumour content (TC) and stratification factors.
Eight hundred and fifteen samples were included in the analysis. GSEA showed that cell cycle, oxidative phosphorylation and DNA repair gene sets were associated with poor prognosis in both arms; in the H arm, metabolism-related signatures were associated with poor prognosis while immune signatures were associated with good prognosis; and in the T-DM1 arm, apoptosis and epithelial mesenchymal (EM) transition (EMT) gene sets and fibroblast, stroma and endothelial cell scores were associated with good prognosis. Trends were seen for poor prognosis with malignant-specific EM signatures in both arms. NMF clusters are described in the table.
Cluster, % prevalence Gene and signature expression, TC and association with prognosis iDFS hazard ratio, CL1, 24.0% Cell cycle and DNA repair-related genes. High TC, higher 0.42 (0.24, 0.75) CL2, 8.3% Metabolism signatures and keratinisation-related genes 0.58 (0.16, 2.19) CL3, 40.6% Focal adhesion, TGFβ, Wnt β catenin, EMT and extracellular matrix-related genes. Low TC, best prognosis 0.25 (0.11, 0.57) CL4, 18.5% Oestrogen- and cilium assembly-related genes. High TC, highest 0.49 (0.22, 1.08) CL5, 8.5% Immune-related genes 0.65 (0.18, 2.38)
Both DGE and NMF approaches identified cell cycle pathway-related and DNA repair genes as associated with poor prognosis in both arms. Stromal genes and high stromal content were associated with good prognosis. The advantage of T-DM1 over H was seen across all NMF clusters.
NCT01772472, January 21, 2013.
Support for third-party writing assistance for this abstract, furnished by Brian Law, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland.
F. Hoffmann-La Roche Ltd.
F. Hoffmann-La Roche Ltd.
C. Denkert: Financial Interests, Personal, Stocks/Shares: Sividon Diagnostics; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, MSD Oncology; Financial Interests, Personal, Other: Novartis, F. Hoffmann-La Roche Ltd., AstraZeneca, Merck, Molecular Health; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. M. Nowicka: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. M. Basik: Financial Interests, Personal, Other, Honoraria: Roche Canada; Financial Interests, Personal, Funding, Research funding: LabCorp, Pfizer; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. G. Lewis: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. P.A. Fasching: Financial Interests, Personal, Other, Honoraria: Agendia, AstraZeneca, Daiichi Sankyo, Eisai, Gilead Sciences, Hexal, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, F. Hoffmann-La Roche Ltd., Seattle Genetics; Financial Interests, Personal, Advisory Role: Agendia, AstraZeneca, Daiichi Sankyo, Eisai, Gilead Sciences, Hexal, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, F. Hoffmann-La Roche Ltd., Seattle Genetics; Financial Interests, Personal, Funding, Research funding: F. Hoffmann-La Roche Ltd.; Financial Interests, Institutional, Other, Honoraria: BioNTech, Cepheid; Financial Interests, Institutional, Funding, Research funding: BioNTech, Cepheid, Novartis; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. P. Lucas: Financial Interests, Personal, Other, Honoraria (spouse): Schrodinger, Inc.; Financial Interests, Personal, Stocks/Shares: Amgen; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. D. Eiger: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. C.E. Geyer: Financial Interests, Personal, Funding, Research funding: Genentech Inc., F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Other, Honoraria: Athenex, Exact Sciences; Financial Interests, Personal, Other, Travel, accommodation, expenses: AbbVie, Daiichi Sankyo, Genentech Inc., F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. S. Loibl: Financial Interests, Institutional, Funding, Research funding: AbbVie, AstraZeneca, Celgene, Daiichi Sankyo, Gilead Sciences, Novartis, Pfizer, F. Hoffmann-La Roche Ltd.; Financial Interests, Institutional, Speaker’s Bureau: AstraZeneca, Daiichi Sankyo Europe GmbH, Medscape, Novartis, Pfizer, Pierre Fabre, F. Hoffmann-La Roche Ltd., Samsung; Financial Interests, Institutional, Advisory Role: AbbVie, Amgen, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Celgene, Daiichi Sankyo, EirGenix, GlaxoSmithKline, Immunomedics, Lilly, Medscape, Merck KGaA, Novartis, Pfizer, Pierre Fabre, Puma Biotechnology, F. Hoffmann-La Roche Ltd., Seattle Genetic; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. S. de Haas: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd. C. Lambertini: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance from F. Hoffmann-La Roche Ltd.: F. Hoffmann-La Roche Ltd.
The phase III KATHERINE trial showed that trastuzumab emtansine (T-DM1) significantly improved invasive disease-free survival (iDFS) compared to trastuzumab in the adjuvant treatment of patients with residual invasive human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC), who received neoadjuvant therapy containing taxanes and trastuzumab. This study evaluated the cost-effectiveness of adjuvant T-DM1 versus trastuzumab for patients in Singapore with HER2+ EBC after neoadjuvant therapy.
A six-state Markov model (iDFS, non-metastatic recurrence, remission, first-line metastatic, subsequent line metastatic, death) was developed from the Singapore healthcare system perspective, with a 35-year time horizon. Clinical inputs and utilities were derived from KATHERINE (iDFS) and from published literature (other health states). Direct costs were obtained from government sources and published literature. Model outputs were: costs; life-years (Lys); quality-adjusted Lys (QALYs); incremental cost-effectiveness ratios (ICERs). Sensitivity/scenario analyses explored uncertainties.
The base case projected increased costs by S$64,458, improved outcomes by 1.726 Lys and 1.661 QALYs, and an ICER of S$38,818/QALY. A higher proportion of patients on T-DM1 remained in iDFS at 10 years compared to patients on trastuzumab (76% versus 63%). Assuming a longer time horizon or T-DM1 treatment effect reduced the ICER. In deterministic sensitivity analyses, the ICER was most sensitive to: metastatic recurrence proportion; maximum cure proportion; time horizon. Probabilistic sensitivity analyses showed T-DM1 had a 96.5% probability of being cost-effective at a willingness-to-pay threshold of S$75,000/QALY.
Compared to trastuzumab, patients with HER2+ EBC receiving T-DM1 in the adjuvant setting spent longer in iDFS, contributing to cost-offsets driven by avoidance of care costs in the metastatic health states together with improved patient outcomes. The resulting ICER suggests cost-effectiveness of adjuvant T-DM1 in the Singapore setting.
Roche Singapore Pte Ltd.
Roche Singapore Pte Ltd.
E.H. Lim: Financial Interests, Personal and Institutional, Advisory Board: Roche Singapore Pte Ltd., Novartis, DKSH, Eisai, Eli Lilly. A. Lim: Financial Interests, Institutional, Advisory Role: a. Roche Singapore Pte Ltd. J.S. Khara: Financial Interests, Personal, Full or part-time Employment: Roche Singapore Pte Ltd.; Financial Interests, Personal, Stocks/Shares: Roche Singapore Pte Ltd. J. Cheong: Financial Interests, Personal, Full or part-time Employment: Roche Singapore Pte Ltd.; Financial Interests, Personal, Stocks/Shares: Roche Singapore Pte Ltd. J. Fong: Financial Interests, Personal, Full or part-time Employment: Roche Singapore Pte Ltd.; Financial Interests, Personal, Stocks/Shares: Roche Singapore Pte Ltd. S. Sivanesan: Financial Interests, Personal, Full or part-time Employment: Roche Singapore Pte Ltd.; Financial Interests, Personal, Stocks/Shares: Roche Singapore Pte Ltd. M. Griffiths: Financial Interests, Institutional, Advisory Role: Roche Singapore Pte Ltd. E. New: Financial Interests, Institutional, Advisory Role: Roche Singapore Pte Ltd. S.C. Lee: Financial Interests, Personal and Institutional, Research Grant: Pfizer, Eisai, Taiho, ACT Genomics, Karyopharm, Epizyme, Adagene, MSD; Financial Interests, Personal and Institutional, Advisory Board: Pfizer, Eisai, ACT Genomics, Novartis, AstraZeneca, Eli Lilly, MSD, Roche Singapore Pte Ltd., Daiichi Sankyo; Financial Interests, Personal and Institutional, Invited Speaker: Pfizer, Eisai, ACT Genomics, Novartis, AstraZeneca, Eli Lilly, MSD, Roche Singapore Pte Ltd.
Despite its crucial role in guiding clinical choices and trial eligibility for patients (pts) with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (BC), the endocrine sensitive (ES) or primary (1ER)/secondary (2ER) resistant classification is largely based on expert opinion and no proper evidence exists to support its possible prognostic and clinical impact.
This analysis included individual pts-level data from 4 adjuvant phase III randomized trials by MIG and GIM study groups. The impact of ER/ES classification on overall survival (mOS, defined as time between date of distant relapse and death) was assessed in both univariate and multivariate Cox proportional hazards models.
Between November 1992 and July 2012, 6612 pts with HR+/HER2- BC were randomized in 4 trials. Median follow-up was 9.1 years (IQR 5.6-15.0). In the whole cohort, the estimated hazard of recurrence raised constantly during the first 15 years from diagnosis, being more pronounced during the first 2 years and less after year 7. Among 493 pts with a distant relapse as first recurrence, 72 (14.6%), 207 (42.0%) and 214 (43.4%) were classified as having 1ER, 2ER and ES, respectively. Pts with 1ER were significantly more likely to be younger, to have N2/N3 nodal status, grade 3 tumors and to develop visceral metastases. Site of first distant relapse was significantly different between the 3 groups. In pts with 1ER, 2ER and ES breast cancer, median mOS was 27.2, 38.4 and 43.2 months, respectively (p=0.05). As compared to pts with ES disease, a significantly higher risk of death was observed in those with 1ER (adjusted [a] HR 1.57; 95% CI 1.08-2.28) and 2ER (aHR 1.25; 95% CI 0.94-1.67).
This large analysis with long-term follow-up provides evidence on the prognostic and clinical impact of the currently adopted ER/ES classification in pts with HR+/HER2- advanced BC. This classification may be considered a valid tool to guide clinical decision-making and to design future trials in the metastatic setting.
GIM (Gruppo Italiano Mammella).
Has not received any funding.
M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Takeda, Sandoz, Ipsen, Libbs, Knight, Daiichi Sankyo, Lilly, Pfizer, Novartis, Roche; Financial Interests, Personal, Other, Travel grant to attend ASCO 2022: Gilead; Financial Interests, Institutional, Invited Speaker, 2-year research grant paid to my Institution: Gilead. G. Bisagni: Financial Interests, Advisory Board: PharmaMar, GSK. S. de Placido: Financial Interests, Invited Speaker: Novartis, Roche, Celgene, Bristol Myers Squibb, AstraZeneca, Pfizer, Lilly, Eisai, Seagen, Daiichi Sankyo, Clovis, GSK, MSD, Gilead, Exact Sciences. A. Fabi: Financial Interests, Invited Speaker: Roche, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, Seagen, MSD, Eli Lilly, Pierre Fabre, Epionpharma , Eisai. A. Michelotti: Financial Interests, Invited Speaker: Seagen, Gilead, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Eisai, Lilly, Istituto Gentili. M. Mansutti: Financial Interests, Invited Speaker: Roche, Novartis, Lilly, Pfizer, MSD, Gilead, Seagen, AstraZeneca, Gentili. A. Russo: Financial Interests, Invited Speaker: Brystol, Pfizer, Bayer, Kyowa Kirin, Ambrosetti, MSD, Roche Diagnostic. F. Montemurro: Financial Interests, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Seagen, MSD, Eli Lilly, Pierre Fabre, Novartis. A. Frassoldati: Financial Interests, Invited Speaker: Roche, AstraZeneca, Lilly, Novartis, Seagen, Daiichi Sankyo, Gilead. A. Turletti: Financial Interests, Invited Speaker: Novartis, Pfizer, Lilly, Roche. S. Tamberi: Financial Interests, Invited Speaker: Incyte MSD, Roche, Merck, AstraZeneca. E. de Azambuja: Financial Interests, Personal, Advisory Board: Roche/GNE, Novartis, Seagen; Financial Interests, Personal, Invited Speaker: Zodiac, Libbs, Pierre Fabre, Lilly, Astra-Zeneca; Financial Interests, Institutional, Research Grant: Roche/GNE, AstraZeneca, GSK/Novartis, Servier; Financial Interests, Institutional, Other, Travel Grant: Roche/GNE; Financial Interests, Institutional, Invited Speaker: MSD, ABCSG, Nektar, Gilead, Immunomedics, Synthon, Odonate Therapeutics; Financial Interests, Invited Speaker, Chair of the Gilead Sciences Research Scholars Program in Solid Tumours: Gilead; Financial Interests, Invited Speaker, Aphinity, Lorelei, Impassion03: Roche; Financial Interests, Invited Speaker, AURORA: Breast International Group; Financial Interests, Invited Speaker, Olympia: Astra-Zeneca; Financial Interests, Personal, Other, Travel grant: Astra-Zeneca; Non-Financial Interests, Advisory Role, Member of the cardio-oncology council: European Society for Cardiology (ESC); Non-Financial Interests, Advisory Role, Belgium governmental institution for cancer: KCE; Non-Financial Interests, Other, Editorial board member: ESMO Open; Non-Financial Interests, Advisory Role: Anticancer Fund. L. Del Mastro: Financial Interests, Personal, Invited Speaker, Educational meeting: Novartis, Symposia, Andromeda E20, Vyvamed srl; Financial Interests, Personal, Invited Speaker, Lecture: Ipsen; Financial Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche; Financial Interests, Personal, Invited Speaker, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board, Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests, Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal, Advisory Board, Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD; Financial Interests, Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina; Financial Interests, Personal, Invited Speaker, Author for BC text: Pensiero Scientifico Editore; Financial Interests, Personal, Advisory Board, Breast cancer: Uvet; Financial Interests, Personal, Other, Author slide kits and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pfizer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL; Financial Interests, Personal, Other, Author slide kits: Forum service; Financial Interests, Personal, Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other, consultant: Kardo srl; Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl; Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca, Agendia, Gilead; Financial Interests, Personal, Other, Interview: Infomedica srl; Financial Interests, Personal, Other, Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Personal, Other, Consultancy: Eli lilly; Financial Interests, Institutional, Funding, National coordinating PI: Roche; Financial Interests, Institutional, Funding, Local PI: AstraZeneca, Roche, Eli Lilly, Daiichi Sankyo, Novella Clinical, Novartis; Non-Financial Interests, Institutional, Product Samples, Genomic Test: FoundationOne. All other authors have declared no conflicts of interest.
The HER2DX risk-score has been validated across several studies in patients (pts) with early-stage HER2+ breast cancer, including the 1st release of the SCAN-B cohort (n=378; EBioMedicine 2022). Here, we report the result of the HER2DX risk-score in the latest release of the SCAN-B HER2+ cohort, which includes a larger sample size, longer follow-up and treatment information.
The clinical and RNAseq data from the SCAN-B dataset was obtained from GEO (GSE81538). Among 6600 pts, 819 had HER2+ breast cancer and 757 pts had research-based HER2DX risk-score and survival outcomes. The HER2DX risk-score was evaluated i) as a continuous variable and ii) using predefined cut-offs. The primary endpoint for this study was overall survival (OS). The Kaplan-Meier method and Cox models were used to estimate survival outcomes.
Median follow-up was 7.5 years (n=757). Most pts received chemotherapy (85.1%) and trastuzumab (79.1%), most tumours were T1-T2 (97.1%) and hormone receptor-positive (71.5%). HER2DX risk-score was associated with OS as a continuous variable (OS HR per 10-units increment=1.39, 95%CI 1.27-1.5; p<0.001) and using the predefined risk groups (cut-off=50; OS HR=2.91, 1.95-4.34; p<0.001). HER2DX risk-score remained associated with OS after adjustment by clinical variables and treatment regimen (multivariable analysis, Table). Among HER2+ T1N0 tumours (n=297), HER2DX high-risk had an inferior OS than low-risk (cut-off=50 [5.0% high-risk]; 7-years OS 68.9% vs 93.0%, p=0.02)) and using cut-off=32 ([24.6% high-risk]; 7-years OS 80.0% vs 94.9%, p=0.002). Similar results were obtained in other survival endpoints.
HR (95% CI) p-value 1.41 (1.17 - 1.69) 1.46 (1.24 - 1.72) T1 Ref - T2 0.73 (0.42 - 1.28) 0.28 T3-T4 0.98 (0.17 - 5.51) 0.98 N0 Ref - N1 0.42 (0.22 - 0.81) N2 0.63 (0.27 - 1.47) 0.28 Negative Ref Positive 0.16 (0.05 - 0.47) 1-2 Ref - 3 1.21 (0.79 - 1.87) 0.38 Negative Ref - Positive 9.66 (3.23 - 28.9) 1.02 (0.99 - 1.04) 0.09 None Ref - CT/Endocrine trt (or both) 0.83 (0.42 - 1.65) 0.59 Trastuzumab + CT 0.45 (0.23 - 0.89) Trastuzumab + CT 0.20 (0.09 - 0.42)
In patients with early-stage HER2+ breast cancer, HER2DX risk-score provides prognostic information beyond clinical-pathological variables, including treatment regimen with or without trastuzumab.
The authors.
Has not received any funding.
T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. L. Pare Brunet: Financial Interests, Institutional, Full or part-time Employment: Reveal Genomics S.L.; Financial Interests, Institutional, Other, Patent pending: In vitro method for the prognosis of patients suffering from HER2-positive breast cancer - 905333: Reveal Genomics S.L. O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis, Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Medical advisory: Reveal Genomics. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, MERCK SHARP& DOHME, GSK, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, MERCK SHARP& DOHME, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca. E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau. Educational activities: Roche; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Roche, Lilly, Novartis, Pfizer, Daiichi Sankyo, MSD; Financial Interests, Personal, Invited Speaker, Symposia and Education: Lilly; Financial Interests, Personal, Invited Speaker, Educational activities: Pfizer; Financial Interests, Personal, Advisory Board, Non-permanent advisor, Travel accommodation: AstraZeneca; Financial Interests, Personal, Other, Advisory Board: Gilead; Financial Interests, Personal, Other, Advisory Board, Invited speaker: Seagen; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Invited Speaker, Non-profit organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientific Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Roche/Genentech, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly, Novartis, Roche/Genentech; Financial Interests, Institutional, Research Grant: Novartis, Roche, Puma; Non-Financial Interests, Invited Speaker: TRIO; Non-Financial Interests, Leadership Role: GEICAM. P.F. Conte: Financial Interests, Personal, Advisory Board, advisory board for alpelisb trial: Novartis; Financial Interests, Institutional, Research Grant: merch Kga. L.A. Carey: Financial Interests, Personal, Royalties, immediate family member-royalty-sharing agreement, investorship interest in licensed IP to startup company, Falcon Therapeutics, that is designing neural stem cell-based therapy for glioblastoma multiforme.: Falcon Therapeutics; Financial Interests, Institutional, Funding, research funding: Syndax, Immunomedics, Novartis, Nanostring Technologies, AbbVie, Seattle Genetics, Veracyte; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: sanofi, Novartis, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, AstraZeneca/ Daiichi Sankyo, Apitude Health, Exact Sciences. N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Seagen, Medscape, Art Tempi, Onkowissen, Gilead, Sanofi, Exact Sciences; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Roche, Sandoz-Hexal, Seagen, Aptitude Health, Gilead, Sanofi; Financial Interests, Personal, Other, Husband: WSG (Husband); Financial Interests, Personal, Ownership Interest: West German Study Group; Financial Interests, Institutional, Funding: AstraZeneca, BMS, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, TRIO, Roche, Palleos, Seagen, WSG; Non-Financial Interests, Member, Member German AGO Breast Guideline Committee: AGO Breast Committee; Non-Financial Interests, Member, Breast Cancer Educational Programs: ESO/ESCO; Other, Founding Editor: BreastCare Journal. M. Marín-Aguilera: Financial Interests, Institutional, Full or part-time Employment, Product Manager: Reveal Genomics, S.L. A. Vivancos: Financial Interests, Personal, Advisory Board: Roche, Bristol Meyers Squibb, Guardant Health, Bayer, Incyte; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Meyers Squibb, Roche, Incyte. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Invited Speaker, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Invited Speaker, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Officer, ESMO Clinical Practice Guidelines Chair: ESMO. P. Villagrasa Gonzalez: Financial Interests, Full or part-time Employment: Reveal Genomics. J. Parker: Financial Interests, Personal, Other, Advisory: Reveal Genomics, Bristol Myers Squibb; Financial Interests, Personal, Full or part-time Employment: LifeEdit Therapeutics; Financial Interests, Personal, Ownership Interest: Reveal Genomics, GeneCentric; Financial Interests, Personal, Royalties: Veracyte. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna, Myovant, Bayer, Zetagen, Infinity Therapeutics, Umoja Biopharma; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. C.M. Perou: Financial Interests, Personal, Invited Speaker: GeneCentric Therapeutics; Financial Interests, Personal, Stocks/Shares: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics; Financial Interests, Personal, Royalties, from PAM50 licensing: Bioclassifier LLC; Financial Interests, Personal, Royalties: GeneCentric Therapeutics; Non-Financial Interests, Advisory Role: GeneCentric Therapeutics, Bioclassifier LLC, Reveal Genomics. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. All other authors have declared no conflicts of interest.
EMIT1 is a national, observational single-arm trial designed to assess the value of the Prosigna PAM50/ROR test as a routine diagnostic tool, examining its impact on adjuvant treatment (tx) decisions vs standard histopathology, clinical outcomes, long-term side effects and cost-effectiveness. Here we present the impact of Prosigna on tx decisions.
Patients (pts) with HR+/HER2- pT1-T2 pN0 early breast cancer (EBC) were included. Prosigna test and standard histopathology assessments were performed on all tumors. Clinicians’ tx decisions were recorded
Of 2203 patients included (2019-2022), 2174 tumors had conclusive Prosigna result; 62% were Lum A, 36% Lum B, 1% HER2 enriched and 1% Basal-like. The ROR score was ≤40 in 49% of tumors, 41-60 in 31% and >60 in 20%. Based on national guidelines for risk profile assessment, the pre-Prosigna tx decisions were: no systemic tx (NT) in 27% of pts (low risk), endocrine tx only (ET) in 38% (intermediate risk) and chemotherapy (CT) followed by ET (CT-ET) in 35% (higher risk). Post-Prosigna tx decisions were 25%, 51% and 24%, respectively. Adjuvant tx changed in 29% of pts, including 21% change in CT use. For pts assigned to CT pre-Prosigna, 45% were de-escalated to ET post-Prosigna. For pts allocated to ET, 12% were escalated to CT-ET and 8% de-escalated to NT. For pts allocated to NT, 18% were escalated to ET/CT-ET. For pts with pT1c-2 G2 and intermediate Ki67 (0.5-1.5x hospitals own median Ki67), the pre-Prosigna tx decision varied widely across hospitals (i.e. use of CT <5–51%). Post-Prosigna, the variability in CT use was markedly reduced (8–24%). Overall, the correlation between Ki67 and ROR score was moderate (r=0.66) with large variation between hospitals (r=0.49-0.83/R2=0.24-0.68). The median ROR score increased by increasing grade, but the ROR score-ranges were wide (for G1 0-79, G2 0-90, G3 16-94).
The Prosigna-test result changed adjuvant tx decisions in all EBC clinical risk groups, markedly decreased the CT use for pts with higher clinical risk and reduced treatment decision discrepancies between hospitals.
NCT03904173. Oct 29, 2018.
Oslo University Hospital.
Norwegian Cancer Society, Pink Ribbon and Clinical therapy research in the specialist health services, Norway. Test discount from Nanostring/Veracyte.
E.S. Blix: Non-Financial Interests, Institutional, Advisory Role: AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis. S.X. Raj: Financial Interests, Institutional, Invited Speaker, Lecture Honoraria: Pfizer, AstraZeneca, Novartis. H.P. Eikesdal: Financial Interests, Institutional, Invited Speaker, Honoraria: Amgen, Bristol Myers Squibb, Dagens Medisin, HAI Interaktiv AS; Financial Interests, Institutional, Invited Speaker, Honoraria + Travel/accomaodation expences: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Honoraria and Advisory Role: Novartis; Financial Interests, Institutional, Invited Speaker, Honoraria and Advisory Role and Expert Testemony: Pfizer; Financial Interests, Institutional, Invited Speaker, Honoraria and Advisory Role +Travel/Accomodation expences: Pierre Fabre; Non-Financial Interests, Institutional, Advisory Role: Aptitude Health, Daiichi Sankyo, Eli Lilly, medac, MSD, Roche. B. Gilje: Financial Interests, Institutional, Advisory Board, Honoraria: Eli Lilly, Gilead, Daiichi Sankyo, Roche, Pierre Fabre. All other authors have declared no conflicts of interest.
Clinical studies confirm that obesity is a key risk factor for recurrence in postmenopausal women with estrogen receptor (ER)-positive breast cancer. Concerning evidence suggests that women with obesity do not obtain similar protection from aromatase inhibitors (AI) as healthy-weight women.
We examined a cohort of postmenopausal women diagnosed with stage I-III ER+ breast cancer from 1998-2016, treated with AIs in the adjuvant setting. The study was conducted using data from the Danish Breast Cancer Group and information on height and weight was supplemented with data from the Danish Anesthesiology database. Body mass index (BMI) was classified as I) healthy-weight (18.5-24.9 kg/m2), II) overweight (25-29.9 kg/m2), III) obesity (30-34.9 kg/m2), and IV) severe obesity (≥ 35 kg/m2) using the World Health Organization guidelines. Follow-up began six months after breast cancer surgery and continued to the first event of recurrence, contralateral breast cancer, another malignancy, death, emigration, end of clinical follow-up, or 25th September 2018. We used Cox regression to estimate crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI). The model was adjusted for patient, tumor and treatment characteristics.
From the original 44,449 eligible patients, we enrolled patients who were postmenopausal, had ER-positive breast cancer, were treated with AIs, and had information on BMI (N=13,261). There were 442 recurrences over 37,668 person-years of follow-up among patients with healthy-weight, 339 recurrences in 27,061 person-years among patients with overweight, 165 recurrences in 11,843 person-years in patients with obesity and 82 recurrences in 5,234 person-years in patients with severe obesity. Multivariable analyses revealed increased recurrence hazards associated with overweight (HR: 1.09 [95% CI: 0.95-1.26]), obesity (HR: 1.22 [95% CI: 1.02-1.46]) and severe obesity (HR: 1.42 [95% CI: 1.12-1.80]), compared with healthy-weight.
Obesity was associated with an increased risk of breast cancer recurrence among postmenopausal ER+ early-stage breast cancer patients treated with AIs.
The authors.
Jeppe Juhl Memorial Foundation, Health Research Foundation of Central Denmark Region, Institute of Cancer Research Aarhus, Danish Cancer Research Foundation, Wørzner Memorial Foundation, Eva and Henry Frænkels Memorial Foundation, Astrid Thaysens Grant for Medical Research, Helga og Peter Kornings Grant, Aarhus University & Danish Cancer Society.
All authors have declared no conflicts of interest.
This study determines the proportion of patients with high-risk hormone receptor-positive human epidermal growth factor receptor-2-negative (HR+/HER2-) breast cancer (BC) within the total cohort of patients with non-metastatic HR+/HER2- BC and compares their systemic treatments and survival rates with those of patients with low- and intermediate-risk HR+/HER2- BC and triple-negative (TN) BC.
All women (≥18 years) diagnosed with non-metastatic invasive HR+/HER2- BC or TNBC in the Netherlands between 2011 and 2019 were identified from the Netherlands Cancer Registry. Patients with HR+/HER2- BC were classified as low-, intermediate-, or high-risk, based on the number of positive lymph nodes, tumour size, and histological grade. Overall survival (OS) was evaluated using Kaplan-Meier survival analyses. Relative survival (RS) was estimated with the Pohar Perme method and defined as the ratio between OS and the expected survival of the Dutch population, using data from Statistics Netherlands. Survival data were available up to January 31, 2022.
This study included 86,522 patients with HR+/HER2- BC. Of these, 51% had low-risk, 32% had intermediate-risk, and 13% had high-risk disease. In 4% of patients, the risk profile could not be defined. Endocrine therapy and chemotherapy use increased with an increasing risk classification: from 38% and 7% in low-risk, and 90% and 47% in intermediate-risk patients to 94% and 73% in high-risk patients. The 10-year OS and RS (95% confidence interval) were 84.2% (83.6-84.7) and 97.7% (96.8-98.4) in low-risk, 75.4% (74.5-76.2) and 92.4% (90.9-93.6) in intermediate-risk, and 64.4% (63.0-65.7) and 72.6% (70.8-74.3) in high-risk patients. The 10-year OS and RS of 12,448 patients with TNBC were 70.5% (69.4-71.6) and 78.3% (76.7-79.8), respectively.
This study shows that 13% of patients with non-metastatic HR+/HER2- BC had high-risk disease. Although the majority of these patients received endocrine therapy and chemotherapy, the 10-year OS and RS rates were low and even worse than those of patients with TNBC. These data indicate an unmet medical need for modification of systemic treatment in this subgroup of patients.
MUMC+.
Eli Lilly.
S.W.M. Lammers: Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Funding: AstraZeneca. M. Meegdes: Financial Interests, Institutional, Research Grant: Eli Lilly, Novartis BV, Roche, Pfizer, Gilead. I.J.H. Vriens: Financial Interests, Institutional, Research Grant: Eli Lilly, Pfizer; Financial Interests, Institutional, Funding: AstraZeneca. T.J.A. van Nijnatten: Financial Interests, Personal, Invited Speaker: GE Healthcare, Bayer Healthcare. V.C.G. Tjan-Heijnen: Financial Interests, Personal and Institutional, Research Grant: Eli Lilly, Novartis, AstraZeneca; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche, Pfizer, Daiichi Sankyo, Gilead; Financial Interests, Personal, Advisory Role: AstraZeneca, Novartis, Eli Lilly; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Eli Lilly. S.M.E. Geurts: Financial Interests, Institutional, Research Grant: Eli Lilly, Roche, Pfizer, Novartis, Daiichi Sankyo, Gilead; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca. All other authors have declared no conflicts of interest.
HER2 is overexpressed/amplified in 10-15% of eBC, which is associated with worst outcomes. Recent findings suggest that patients' perception of risk and fear of relapse may affect their health behavior and ability to participate in decision making during treatment (tx). The aim of this survey is to better understand their perceptions, attitudes, and behaviors regarding the risk of relapse in HER2+ eBC.
Direct-to-patient online survey was conducted in 6 European countries according to a standardized protocol, transmitted by a patient association and patient panel. Eligible participants were women aged ≥18 years with early-stage (stages I-III) or metastatic (stage IV) HER2+ breast cancer resulting from relapse of an initial diagnosis of eBC. Soft quotas were applied to ensure the representativity of sample size. Here we present the results of the survey in France.
Of the 108 participants, 72.2% were between 40 and 65 years of age. 88.9% had eBC, 62.1% had been diagnosed with HER2+ eBC for >2 years, and 64.8% were undergoing tx. Patients reported alopecia, fatigue and nausea-vomiting as the first rank of most difficult tx-related side effects to manage. The main concern regarding tx was fear of dying (25.9%), risk of relapse (25.0%) followed by the risk of tx failure (13.9%). 21.3% of patients said they had fully discussed risk of relapse with their doctor, while 31.5% had not. 97.3% wanted to be involved in their tx decision, 41.7% completely and 55.6% partially. Among women with eBC, >50% were worried about the risk of relapse. To reduce this risk, they were willing to exercise more (86.5%), change their eating habits (74.0%) or undergo surgery/additional tx (52.1%). 68.5% of all participants were willing to take additional tx if it would reduce their risk of relapse by up to 49%.
The responses collected in France suggest that HER2+ eBC cancer has a significant psychological impact on the surveyed women. Patients want to be involved in the decision-making process but one-third report lack of information about their risk of relapse. They are willing to take additional measures including additional treatment to reduce their risk of relapse. The global survey is ongoing.
Pierre Fabre.
Pierre Fabre.
O. Tredan: Financial Interests, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Pfizer, Lilly, AstraZeneca, MSD Oncology, Daiichi Sankyo Europe GmbH, Eisai Europe, Sandoz-Novartis, Seattle Genetics, Pierre Fabre; Financial Interests, Institutional, Research Grant: Roche, Bristol Myers Squibb, MSD Oncology, AstraZeneca, Novartis, Bayer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche, Novartis, Pfizer, Lilly, AstraZeneca, MSD Oncology. S. Matos: Financial Interests, Personal, Full or part-time Employment: Pierre Fabre. A. Zkik: Financial Interests, Personal, Full or part-time Employment: Pierre Fabre. L. Gueroult-Accolas: Financial Interests, Advisory Role: AstraZeneca, BMS, Daiichi Sankyo, Lilly, Pierre Fabre, Pfizer, Novartis, Roche, Seagen, Vifor; Financial Interests, Other, Travel/Accommodation/Expenses: Cours St Paul, Congrès Parkours, Pierre Fabre, Pfizer, Vifor, Seagen; Financial Interests, Invited Speaker, Travel, Accommodations, Expenses: Exact Sciences.
Abemaciclib (oral CDK4 and 6 inhibitor) plus endocrine therapy (ET) as adjuvant treatment demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in Chinese patients (pts) with Hormone Receptor (HR+)-positive and human epidermal growth factor 2 (HER2)-negative high risk early breast cancer (EBC). This combination therapy provided sustained clinical benefits at the pre-planned overall survival interim analysis (OS IA2). Here we present the results of the subset of Chinese patients from monarchE at OS IA2.
The overall study design was previously reported. Pts were randomized 1:1 to receive Abemaciclib + ET or ET alone. Eligible pts with ≥4 positive nodes, or 1-3 nodes and Grade 3 disease and/or tumor size ≥5 cm were included in Cohort 1 (C1); pts with 1-3 nodes and central Ki-67 ≥20% who did not meet entry criteria for C1 were included in Cohort 2 (C2). Analyses were conducted in Chinese pts enrolled from Mainland China, Hong Kong, and Taiwan in the intent-to-treat (ITT) population (501 pts), consisting of C1 (440 pts) and C2 (61 pts).
At the time of data cutoff (July 1, 2022), all Chinese pts were off treatment with median follow-up of around 41 months. Sustained benefits of IDFS (HR=0.563, 95%CI: 0.343-0.923) and DRFS (HR=0.586, 95%CI: 0.341-1.006) were observed in Chinese pts in the ITT, with clinically meaningful improvement in the 4-year IDFS rates (88.5% vs 79.6%) and DRFS rates (90.0% vs 82.4%). In C1, the HR for IDFS was 0.582 (95%CI: 0.351-0.965) and DRFS was 0.610 (95%CI: 0.350-1.063), and a consistent benefit of abemaciclib was observed regardless of Ki-67 index. There were limited events of deaths in Chinese pts (abemaciclib plus ET vs ET: 6 [2.3%] vs 5 [2.1%]). No new safety signals were observed in Chinese pts.
Consistent with reported results for the overall ITT population, abemaciclib combined with ET demonstrated clinically meaningful and sustained IDFS and DRFS benefits among Chinese pts with HR+, HER2-, high risk EBC and continued separation of the IDFS and DRFS curves. The OS data remain immature and follow-up is ongoing.
NCT03155997.
Eli Lilly and Company.
Eli Lilly and Company.
L. Yang, C. Qian: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company. All other authors have declared no conflicts of interest.
T-DM1 is standard treatment in patients (pts) with HER2-positive breast cancer with residual disease after neoadjuvant therapy. The GIM26-TRASTHER study of the Gruppo Italiano Mammella (GIM) study group collects data from the Italian compassionate use program that anticipated drug reimbursement.
Inclusion criteria mirrored the Katherine trial. We registered adverse events (AEs) that were considered to be certainly/probably/possibly related to T-DM1 as per investigators’ judgement. We used descriptive analysis for data presentation.
202 pts were included in 18 centers between Sep 2021 and Dec 2022. Median age was 52 years (IQR 45-59), 30% of the pts (n=61) were premenopausal and 56% (n=113) had at least 1 comorbidity (main: thyroid disorders 13%, hypertension 13%, dyslipidemia 4.5%). Smoking status was available for 156 pts, and 39 (25%) were current or former smokers. As neoadjuvant therapy, 85 % of the pts (n=169) received anthracycline plus taxane chemotherapy and 25 % (n=50) dual anti-HER2 blockade. Overall, 320 T-DM1-related AEs of any grade were registered in 105 pts (52%). G3 AEs were observed in 11 pts (5.4%), while there were no G4-G5 AEs. Most prevalent AEs of any grade were transaminases increase (19.8%), thrombocytopenia (15.3%), nausea and vomiting (13.3%), fatigue (10.9%), myalgia and arthralgia (7.4%), peripheral neuropathy (6.4%) and neutropenia (5%). For 42 out of 202 pts (20.8%), T-DM1 was reduced in dose, delayed or discontinued due to toxicity. Pts experiencing any grade AEs were older (54 vs 51, p=0.046), more frequently current or former smokers (34% vs 16.6%, p=0.034), and were less exposed to anthracyclines (79% vs 92%, p=0.012) as compared to those with no AEs. No impact of menopausal status, pre-existing comorbidities and type of neoadjuvant anti-HER2 therapy was observed.
In this multicentric Italian study, no new safety concerns of adjuvant T-DM1 were observed. Toxicity seems to be mostly linked by patient’s characteristics, underlying the importance of evaluating safety profile of anticancer drugs in a real-world setting in less selected pts. Further analyses, including survival outcomes, are ongoing.
GIM (Gruppo Italiano Mammella).
Roche.
F. Poggio: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Pfizer; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other: Daiichi Sankyo, Gilead. M. Tagliamento: Financial Interests, Personal, Other, travel grants: Roche, Bristol Myers Squibb; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Writing Engagements: Novartis, MSD, Amgen. M. De Laurentiis: Financial Interests, Personal, Advisory Board: Roche, Eli Lilly, Novartis, AstraZeneca, Seattle Genetics, Gilead, Ipsen, Takeda; Financial Interests, Personal, Research Grant: Puma Biotechnology, Macrogenics, Bristol Myers Squibb. A. Gennari: Financial Interests, Personal, Invited Speaker: Eisai, Novartis, Roche, Eli Lilly, Daiichi Sankyo, Gilead. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, Novartis, Eli Lilly, AstraZeneca, Gilead, MSD, Exact Science, Seattle Genetics; Financial Interests, Personal, Speaker’s Bureau: Takeda, Knight Terapeutics, Ipsen, Sandoz, Libbs; Financial Interests, Institutional, Research Grant: Gilead. L. Del Mastro: Financial Interests, Personal, Invited Speaker, Educational meeting: Novartis, Symposia, Andromeda E20, Vyvamed srl; Financial Interests, Personal, Invited Speaker, Lecture: Ipsen; Financial Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche; Financial Interests, Personal, Invited Speaker, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board, Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests, Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal, Advisory Board, Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD; Financial Interests, Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina; Financial Interests, Personal, Invited Speaker, Author for BC text: Pensiero Scientifico Editore; Financial Interests, Personal, Advisory Board, Breast cancer: Uvet; Financial Interests, Personal, Other, Author slide kits and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pfizer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL; Financial Interests, Personal, Other, Author slide kits: Forum service; Financial Interests, Personal, Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other, consultant: Kardo srl; Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl; Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca, Agendia, Gilead; Financial Interests, Personal, Other, Interview: Infomedica srl; Financial Interests, Personal, Other, Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Personal, Other, Consultancy: Eli lilly; Financial Interests, Institutional, Funding, National coordinating PI: Roche; Financial Interests, Institutional, Funding, Local PI: AstraZeneca, Roche, Eli Lilly, Daiichi Sankyo, Novella Clinical, Novartis; Non-Financial Interests, Institutional, Product Samples, Genomic Test: FoundationOne. All other authors have declared no conflicts of interest.
The majority of breast cancers occur in women over the age of 65, but older breast cancer patients are largely underrepresented in clinical trials. We investigated the effect of adding capecitabine to adjuvant treatment with ibandronate in elderly breast cancer patients.
The multicenter phase III ICE trial enrolled women ≥65 years with early node-positive/high-risk node-negative breast cancer and a Charlson Comorbidity Index (CCI) ≤2. Patients were randomized to capecitabine 2000 mg/m2 day 1-14 q3w for 6 cycles plus ibandronate (50 mg p.o. daily or alternatively 6 mg i.v. q4w) or ibandronate alone for 2 years. We present here an update on long-term follow-up for the secondary endpoint of overall survival (OS).
1358 (96.4%) from 1409 randomized patients started treatment. 564 (83.4%) completed 6 cycles of capecitabine. 513 (77.7%) and 516 (78.8%) completed ibandronate in the capecitabine/ibandronate and ibandronate arm, respectively. Median age was 71 (range 64-88) years, 1099 (81%) were hormone receptor (HR)-positive, 705 (51.9%) node-negative, 794 (58.5
The adjuvant combination of capecitabine and ibandronate did not show significantly better OS than ibandronate alone in elderly breast cancer patients.
Trial Registration: NCT 00196856.
The authors.
Roche and AstraZeneca.
E. Stickeler: Financial Interests, Institutional, Other, Consulting Fees: AstraZeneca, MSD, Roche, Gilead; Financial Interests, Institutional, Speaker’s Bureau: Roche, MSD, Gilead, Novartis, Seagen, PierreFabre, Onkowissen; Financial Interests, Institutional, Other, Travel support: Novartis, MSD; Financial Interests, Institutional, Advisory Board: iOMEDICO, AstraZeneca. J. Huober: Financial Interests, Institutional, Research Grant: Novartis, Lilly; Financial Interests, Personal, Other, Consulting Fees: Lilly, Novartis, Roche, Pfizer, Hexal, AstraZeneco, MSD, Celgene, AbbVie, Daiichi; Financial Interests, Personal, Other, Cinsulting Fees: Gilead; Financial Interests, Personal, Speaker’s Bureau: Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene, Eisai, AbbVie, Seagen, Gilead, Daiichi; Financial Interests, Personal, Other, Travel support: Roche, Pfizer, Novartis, Celgene, Daiichi, Gilead. C. Jackisch: Financial Interests, Personal, Speaker’s Bureau: Roche, Novartis; Financial Interests, Personal, Other, Travel support: Roche. V. Nekljudova: Financial Interests, Institutional, Research Grant: AbbVie, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche; Non-Financial Interests, Institutional, Other: Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, Seagen; Other, Institutional, Other, EP14153692.0: Patent; Other, Institutional, Other, EP21152186.9: Patent; Other, Institutional, Other, EP15702464.7: Patent; Other, Institutional, Other, EP19808852.8: Patent; Other, Institutional, Royalties: VM Scope GmbH; Other, Institutional, Full or part-time Employment: GBG GmbH. S. Loibl: Financial Interests, Institutional, Advisory Board, Member: Amgen, AstraZeneca, BMS, Celgene, EirGenix, GSK, Lilly, Pierre Fabre, Roche, Seagen, AbbVie, Sanofi, Gilead, Merck, Novartis, Relay Therapeutics; Financial Interests, Institutional, Invited Speaker: AstraZeneca, DSI, Novartis, Pfizer, Roche, Gilead, Seagen; Financial Interests, Institutional, Advisory Board: DSI, Pfizer, Olema; Financial Interests, Personal, Invited Speaker: Medscape; Financial Interests, Personal, Full or part-time Employment, CEO: GBG Forschungs GmbH; Financial Interests, Institutional, Invited Speaker, Ki67: VM Scope GmbH; Financial Interests, Institutional, Research Grant: AstraZeneca, Celgene, Novartis, Immunomedics/Gilead, Pfizer, Roche, Daiichi Sankyo; Financial Interests, Institutional, Funding: AbbVie, Molecular Health; Financial Interests, Personal, Other, PIPenelope/Padma: Pfizer; Financial Interests, Personal, Other, SC PALOMA3: Pfizer; Financial Interests, Personal, Other, SC SOLAR1: Novartis; Financial Interests, Personal, Other, SC ASCENT: Immunomedics/Gilead; Financial Interests, Personal, Other, SC HERCLIMB: Seagen; Financial Interests, Personal, Other, SC Katherine: Roche; Financial Interests, Personal, Other, SC Capitello; EC Cambria 1: AstraZeneca; Financial Interests, Personal, Other, SC Inavo: Roche; Financial Interests, Personal, Other, SC Destiny B05; SC Destiny B09: Daiichi Sankyo; Non-Financial Interests, Principal Investigator, After publication of primary endpoint: PI Aphinity; Non-Financial Interests, Advisory Role, Group in Germany responsible for breast cancer guidelines: AGO Kommission Mamma; Non-Financial Interests, Member, German Gynaecological Oncology society: AGO; Non-Financial Interests, Member, German Cancer Society: DKG; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member, Member guideline committee; past chair in ESMO Breast: ESMO; Other, EP14153692.0No financial interest, Institutional: Patent; Other, EP21152186.9No financial interest, institutional: Patent; Other, EP15702464.7No financial interest, institutional: Patent; Other, EP19808852.8 No financial interest, Institutional: Patent. All other authors have declared no conflicts of interest.
Patient-centred care can improve disease-related outcomes and quality-of-life (QoL), but studies gauging patient preferences in early breast cancer (eBC) are limited. This study aimed at identifying preferences of patients (pts) with high-risk hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) eBC related to adjuvant endocrine treatment (ET) characteristics.
Women with HR+/HER2- eBC with high-risk of relapse (defined by (neo)adjuvant chemotherapy pre-treatment) who were prescribed ET and diagnosed between 2009-2021 were recruited in Germany. Patient-relevant attributes for ET were identified by a stepwise multimodal approach [desk research, qualitative interviews (20 pts, 5 caregivers, and 12 physicians), quantitative survey (85 pts: 79 on ET, 6 planned), and cross-functional review]. A conjoint matrix was developed consisting of one attribute for ET goal (30% reduced risk of relapse), 4 attributes for QoL, and 5 attributes for side effects (Table), forming the basis of a subsequent adaptive choice-based conjoint survey.
In the quantitative study, pts aged 49.4 years (mean) were included; among which 69.4% were still working. Relative assessment of ET attributes against each other revealed that achieving ET goal had the highest relevance, while avoiding side effects and maintaining QoL were less relevant. Most pts rated side effect avoidance, particularly diarrhoea, arthralgia, and nausea as the least relevant criterion for ET decision. Overall, 34.6% of pts have considered stopping ET while 6.4% have taken ≥ 1 break due to side effects.
ET goal attainment (30% reduced risk of relapse) was of greatest relative relevance to pts while side effect avoidance and QoL maintenance were less relevant highlighting the impact of relapse risk reduction on ET decisions in high-risk eBC. ET attributes employed in the conjoint analysis
ET attribute Factors Risk of tumour recurring in some way ET goal Physical fitness and agility QoL Mental/emotional stability QoL Maintaining ability to work QoL Participation in family life & leisure QoL Diarrhea Side effects Fatigue Side effects Arthralgia Side effects Loss of hair Side effects Nausea Side effects
Dr. Catherine Sirafim, an employee of Eli Lilly and Company, provided editorial assistance for this abstract.
Eli Lilly and Company.
Eli Lilly and Company.
A. Wöckel: Financial Interests, Personal, Other, Consulting honorarium: Amgen, AstraZeneca, Celgene, Eisai, Lilly, Novartis, Pfizer, Roche, Tesaro, Sirtex, MSD, Genomic Health, Pierre Fabre, Clovis, Organon, Seagen, Exact Sciences, Gilead, Dajiichi Sanko; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Celgene, Eisai, Lilly, Novartis, Pfizer, Roche, Tesaro, Sirtex, MSD, Genomic Health, Pierre Fabre, Clovis, Organon, Seagen, Exact Sciences, Gilead, Dajiichi Sanko; Financial Interests, Personal, Other, Support for advanced trainings: Amgen, AstraZeneca, Celgene, Eisai, Lilly, Novartis, Pfizer, Roche, Tesaro, Sirtex, MSD, Genomic Health, Pierre Fabre, Clovis, Organon, Seagen, Exact Sciences, Gilead, Dajiichi Sanko. T. Park-Simon: Financial Interests, Personal and Institutional, Invited Speaker: Roche, GSK, AstraZeneca, Pfizer, Lilly, Daiichi-Synkyo, Seagen, Gilead, Eisai, MSD; Financial Interests, Personal and Institutional, Advisory Board: Roche, GSK, AstraZeneca, Pfizer, Lilly, Daiichi-Synkyo, Seagen, Gilead, Eisai, MSD; Financial Interests, Personal and Institutional, Principal Investigator: Roche, GSK, AstraZeneca, Pfizer, Lilly, Daiichi-Synkyo, Seagen, Gilead, Eisai, MSD. A. Korfel, K. Raab, H. Silberzahn: Financial Interests, Personal, Full or part-time Employment: Eli Lilly; Financial Interests, Personal, Stocks/Shares: Eli Lilly. H. Tesch: Financial Interests, Personal and Institutional, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer, Seagan, Daiichi, GSK, Exact Science, Vifor, Lilly, AstraZeneca, MSD; Financial Interests, Personal, Ownership Interest: VISION MED GmbH, Care and Coach GmbH, CHOP GmbH; Financial Interests, Personal, Funding: Lilly; Non-Financial Interests, Personal, Member: DGHO, ESMO, ASCO, Deutsche Gesellschaft für Senologie; Financial Interests, Personal, Other, Travel Expenses: GSK, Pfizer; Non-Financial Interests, Personal, Other, Travel Expenses: Deutsche Gesellschaft für Senologie.
Goserelin 10.8 mg 3-monthly depot demonstrated non-inferior to 3.6 mg monthly depot in randomized clinical trials. This first retrospective, observational, non-inferiority, real-world study compared effectiveness of goserelin 10.8 mg 3-monthly depot to 3.6 mg monthly depot in breast cancer (BC) patients.
Data were extracted from electronic records of pre- and perimenopausal BC patients who received the first dose of goserelin between January 2015 to December 2022 at Sun Yat-sen University Cancer Center, China. The primary endpoint was non-inferiority analysis of proportion of patients with serum estradiol (E2) suppression. Secondary endpoints included overall survival (OS), disease-free survival (DFS) for early BC, progression-free survival (PFS) for advanced BC. Propensity score matching (PSM) was used to balance baseline characteristics considering age, prior chemotherapy, and BMI as covariates with caliper of -25%.
In total, 240 (goserelin 10.8 mg, n = 143; goserelin 3.6 mg, n = 97) HR+ BC patients with E2 tests were included. Post PSM, 96 patients in each group were considered for the primary analysis. E2 suppression rate was 98.96% in goserelin 10.8 mg and 92.71% in goserelin 3.6 mg with a RD of 0.065 (95%CI: 0.021, 0.135;
Goserelin 10.8 mg was non-inferior to goserelin 3.6 mg in peri- and premenopausal BC patients in terms of E2 suppression.
The authors.
This research was supported by National Natural Science Foundation of China (No.81974444, Xinhua Xie; No.82203569, Hao Wu).
All authors have declared no conflicts of interest.
The prognosis of hormone receptor (HR)-positive early breast cancer (eBC) may vary according to different factors. Human Epidermal Growth Factor Receptor-2 (HER2) is one of them. HER2-low population, defined as HER2 1+ or 2+ with negative fluorescent in situ hybridization (FISH), seems to have a different prognosis than the HER2-0. We aimed to explore the impact of HER2-negative status on the risk of recurrence according to PAM50 score.
We conducted a retrospective monocentric study including all eBC patients eligible for PAM50 test, according to local recommendations. We collected for each patient tumor characteristics, PAM50 score, results of risk of recurrence (ROR) at 10 years and the HER2 subtype. The primary endpoint of this study was to evaluate correlation between HER2 status (from score 0 to 2+ with negative FISH) and PAM50 score. Correlation between HER2 score, considered as ordinal, and both the PAM50 score and the PAM50 ROR was estimated by the Pearson coefficient.
From October 2016 to September 2021, we included 282 patients with median age of 58 years. One-hundred ninety eight patients (70%) had HER2 score 0, 42 (15%) had score 1+ and 42 (15%) score 2+. There was no significant difference between each HER2 subgroup, except for higher estrogen and progesterone receptors discordance and higher median age for the HER2 2+ subpopulation. PAM50 score was significantly different between the 3 subgroups of HER2, with median PAM50 score of 47 [range: 1-89] for HER2 0, 50 [15-78] for HER2 1+ and 54 [8-85] for HER2 2+ (p=0.038). PAM50 ROR at 10 years significantly differs between HER2 subgroups, with 0.11 [0.02-0.39] for HER2 0, and respectively 0.14 [0.03-0.28] and 0.14 [0.04-0.44] for HER2 1+ and HER2 2+ (p = 0.013) (without significant intrinsic difference between HER2 low subgroups). PAM50 score and risk of recurrence both increased with HER2 score (Pearson r=0.15, p=0.01, and r=0.18, p=0.002, respectively).
This study suggests a correlation between HER2 status and PAM50 score. Further investigations are needed to better describe HER2-low population with larger and prospective studies.
The authors.
Has not received any funding.
G. Emile: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Novartis, Roche. A. Da Silva: Non-Financial Interests, Invited Speaker: Leopharma, Novartis. All other authors have declared no conflicts of interest.
Endocrine therapy (ET) for 5 years substantially reduces recurrence rates and increases survival in patients with estrogen-receptor (ER)–positive breast cancer. Recently, large-scale clinical data have shown further benefit of extended ET up to 10 years instead of stopping at 5 years. We evaluated demographic and clinical factors associated with late recurrence after 5-year completion of ET.
This retrospective analysis used medical records of 1, 058 ER-positive breast cancer patients who underwent curative operation and completed 5 years of scheduled endocrine therapy with no recurrence in 5 years in two institutions between 2001 and 2014. We assessed the associations of demographic and clinical-pathological factors with patients’ outcomes.
The mean follow-up period was 13.2 years (ranging from 5.6 to 23.3 years). All type of recurrence rate was 12.5% and distant metastasis was observed in 69 (6.5%) patients after 5 years of ET. The distant recurrence was related with the original TN status (p<0.001) and the kind of ET regimen (tamoxifen (TMX) versus aromatase inhibitors, p=0.038). Distant recurrence-free survival showed statistically significant difference according to original TN stage (p<0.001) and tumor grade (p=0.017) in Kaplan-Meier analysis. Tumor diameter over than 2cm and metastasis in axillary lymph nodes were significantly related with poor outcomes in Cox regression analyses (tumor size HR 3.770, 95%CI:1.993-7.130, p<0.001 and LN metastasis HR 2.105, 95%CI:1.201-3.691, p<0.001).
After 5 years of adjuvant ET, TN stages and tumor grade predicted late relapse and survival from breast cancer. Risk factors reported herein may provide insights to optimize decision making regarding extended ET.
Eun-Shin Lee.
Has not received any funding.
All authors have declared no conflicts of interest.
Estimating the risk of late distant recurrence (DR) is an important goal for the management of hormone receptor-positive (HR+) early breast cancer (EBC) patients (pts) after 5 years of endocrine treatment (ET) without recurrence. The Clinical Treatment Score post–5 years (CTS5) tool was developed to estimate residual risk of Distant Recurrence (DR) after 5 years of ET (Dowsett 2018). CTS5 is a continuous score based on 4 clinical variables (number of positive nodes, tumor size, grade, and age) which distributes HR+/human epidermal growth factor receptor-negative (HER2-) EBC pts in 3 risk of DR groups depending on the score (low-risk: <3.13, intermediate-risk: 3.13-3.86 and high-risk: > 3.86).
We performed a retrospective analysis of 5739 HR+/HER2- EBC pts to validate the CTS5 score as prognostic tool of late relapse, beyond 5 years. They were selected from El Álamo IV registry with pts diagnosed between 2002 and 2005 (N=3061) and 4 adjuvant GEICAM studies (9805, 9906, 2003-02 and 2003-10; N=2678) carried out from 1996 and 2006. Pts had to be distant recurrence free at 5 years from ET initiation.
CTS5 classified 43.9% as low-risk, 32.2% as intermediate-risk and 23.9% as high-risk. A significant difference in DR was seen among the three groups, HR intermediate-risk vs low, 2.55 (95% CI, 1.85 to 3.52) and HR high-risk vs low, 5.77 (95% CI, 4.28 to 7.78). The continuous CTS5 (range: 1.2 - 6.06) was significantly prognostic (HR, 2.31; 95% CI, 2.05 to 2.61). DR percentage expected and observed by subgroups are described in the table.
The CTS5 was able to classify Spanish patients according to different risk of late DR, independently of menopausal status, ET duration or CT treatment. However, the model seems to overestimate the number of events particularly in the high-risk group. This overestimation was more pronounced among patients treated with ET for less than 60 months or those not receiving CT.
GEICAM Spanish Breast Cancer Group.
Has not received any funding.
S. Lopez-Tarruella Cobo: Financial Interests, Advisory Role: AstraZeneca, Novartis, Roche, Pfizer, Pierre Fabre, Lilly, Seagen, Daiichi Sankyo Europe GmbH, Gilead Sciences,MSD, GlaxoSmithkline, Veracyte; Financial Interests, Other, Travel, Accommodation, Expenses: AstraZeneca, Pfizer, Gilead Sciences. M. Martin Jimenez: Financial Interests, Personal, Advisory Role: AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology, and Pfizer; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Amgen, Roche/Genentech, Novartis, Daiichi Sankyo, and Pfizer; Financial Interests, Personal, Other, Contracted research fees: Roche, Novartis, and PUMA. S. Servitja Tormo: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, AstraZeneca, MSD, Genomic health; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: AstraZeneca, Roche, Eisai. B. Bermejo: Financial Interests, Personal, Advisory Role: MSD, Roche, Pierre Fabre, Novartis, AstraZeneca, Seagen; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Roche, MSD, Palex, Eisai, Daiichi Sankyo, AstraZeneca, Seagen. A. Anton Torres: Financial Interests, Personal, Advisory Role: Gilead, Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: Seagen, Eli Lilly and AstraZeneca-Daiichi Sankyo; Financial Interests, Personal, Expert Testimony: Pfizer. A.L. Guerrero Zotano: Financial Interests, Personal, Advisory Role: Pfizer, AstraZeneca, Pierre Fabre, Novartis, Exact Science; Financial Interests, Personal, Research Grant: Lilly; Financial Interests, Personal, Other, Travel, accommodation, expenses: Pfizer, Novartis, Gilead. M. Munoz: Financial Interests, Personal, Advisory Role: Pierre Fabre, Seagen; Financial Interests, Personal, Speaker’s Bureau: Novartis, Roche, Eisai; Financial Interests, Personal, Other, Travel, accommodation, expenses: Roche, Pfizer, Lilly. P. Martinez del Prado: Financial Interests, Personal, Advisory Role: Lilly, Sanofi, Leo Pharma; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Daiichi Sankyo, Leo-Pharma; Financial Interests, Personal, Other, Travel, accommodation, expenses: AstraZeneca, Lilly, Roche, Pfizer, Daiichi Sankyo, Leo Pharma. I. Alvarez Lopez: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Novartis, Roche, Gilead; Financial Interests, Personal, Research Grant: AstraZeneca, Pfizer, Novartis, Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other, Meetting travel and inscription expenses: Pfizer, Roche, Eisai, Eli Lilly. A. Rodríguez-Lescure: Financial Interests, Personal, Advisory Role: Roche, Pfizer, Novartis, Lilly, MSD, AstraZeneca.; Financial Interests, Personal, Speaker’s Bureau: Roche, Pfizer, Novartis, Lilly, A-Z, MSD, Merck. All other authors have declared no conflicts of interest.
In the MINDACT trial, 4 risk categories (RC) by clinical (c) and genomic (g) risks were defined. In cHigh/gLow risk patients (pts) with no adjuvant chemotherapy (CT), 8y-Distant Metastases Free Survival (DMFS) was 89.4 % [95% CI 86.2-91.5]. MP also identified a third subgroup of gUL pts (score 0.355 – 1.0, 15% in MINDACT), with an excellent prognosis and no benefit from extended endocrine therapy (EET). We aimed to study: DFS/ DMFS by the 6 RC resulting from combining the 2 (c) categories with the 3 (g) groups; the timing of recurrences; and the putative benefit of EET for each genomic group.
All ER+/HER2- BC pts with MP data diagnosed between 2012-2017 at Vall d'Hebron University Hospital were selected. cLow risk was defined as in MINDACT trial. To study the benefit of EET, a landmark analysis at 5y from ET initiation was conducted.
140 pts were identified. Baseline features: 47.8% premenopausal; stage I/II: 74%/26%; histological grade 1/2/3: 19.6%/74.9%/6.5%. cLow/cHigh: 67%/33%; gUL/gLow-Non-Ultralow (LNUL)/gHigh: 11.4%/53.6%/35%. PgR and Ki67 tended to correlate with MP g risks, but only the IHC-subtype reached statistically significance. Systemic adjuvant treatments [N/%]: ET 138/98.5%; ovarian function suppression for premenopausal pts 23/35%; CT: 45/32%; EET: 49/35.8%. After 8y-median FU, 15 DFS events and 11 DMFS were observed. DMFS in cHigh/gLow (UL+LNUL) without CT was 90.6% [81.1%; 100%]. DFS/DMFS rates by each c/g category are depicted in the table. Only 4 DMFS events occurred after 5 years, precluding to explore EET role by RC
cLow-gUL cLow-gLNUL cLow-gHigh cHigh-gUL cHigh-gLNUL cHigh-gHigh 13 (9.4) 45 (32) 35 (25) 3 (2.2) 30 (22) 13 (9.4) 100 91 84.8 100 90 76.9 - 83.2-99.8 71.6-100 - 79.9-100 57.1-100 100 95.5 89.1 100 90 84.6 - 89.6-100 77.7-100 - 79.9-100 67.1-100 90.6% (CI 95% 81.1-100) 89.4% (CI 95% 86.2-91.5)
In our series, DMFS rate in cHigh-gLow pts without CT was similar to that reported in MINDACT trial. In line with prior reports, gUL pts had excellent survival, while cHigh-gHigh group showed significantly poorer outcome. Albeit limited by small sample size, classification in 6 RCs instead of 4 seems useful to redefine prognosis. Additional FU is warranted to determine the EET benefit in each RC.
The authors.
Has not received any funding.
E. Zamora: Financial Interests, Personal, Invited Speaker, Review session for medical oncologists: Eisai, Lilly; Other, Registration to ESMO Congress 2022 (virtual): Novartis; Other, Registration to: Eisai. I. Pimentel: Financial Interests, Personal, Invited Speaker: MSD, Novartis, AstraZeneca; Non-Financial Interests, Member, ASCO member: ASCO; Other, travel and accommodations expenses: Phyzer. M. Cruellas Lapena: Financial Interests, Institutional, Invited Speaker: ROCHE. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. M. Oliveira: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo / AstraZeneca, Gilead, Pierre Fabre, Roche, Seagen, iTEOS, Relay Therapeutics; Financial Interests, Personal, Invited Speaker: Gilead, MSD, Novartis, Pfizer, Roche, Seattle Genetics, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer-Ingelheim, GSK, Roche, Seattle Genetics, Zenith Epigenetics, Gilead, Ayala Pharmaceuticals; Financial Interests, Invited Speaker: Roche; Non-Financial Interests, Invited Speaker: SOLTI Breast Cancer Research; Other, Travel Grant: Pierre Fabre, Eisai, Gilead, AstraZeneca. C. Saura Manich: Financial Interests, Personal, Advisory Board: AX'Consulting, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd., Gilead, ISSECAM, Lilly, MediTech, Medical Statistics Consulting, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, Seagen, Solti, Zymeworks, Pharmalex Spain SLU; Financial Interests, Personal, Expert Testimony: AX's Consulting SARL, Boehringer Ingelheim, Bristol Meyers Squibb, INDITEX, Merck Sharp & Dohme España, Novartis, SACE Medhealth SL, Simon Kucher &Partners SL, Genentech, Innoup, Millenium, Sanofi, Seattle Genetics; Financial Interests, Personal, Other, SC: Byondis B.V., German Breast Group, Glaxo, International Breast Cancer Study Group (IBCSG), Macrogenics, Medsir, Menarini, Merus, Merus, Netherlands Cancer Institute (NKI), Queen Mary (University of London), Seagen, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, Glaxosmithkline, Immunomedics, Innoup Farma, International Breast Cancer Study Group (IBCSG), Macrogenics, Medica Scientia Innovation Research, Menarini Ricerche, Merus, Novartis, Pfizer, Puma, Roche, Sanofi-Aventis, Seattle Genetics, SOLTI; Financial Interests, Institutional, Invited Speaker: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), SOLTI group (Academic research group in breast cancer), Geicam (Spanish Breast Cancer Research Group), American Association for Cancer Research (AACR). M. Bellet-Ezquerra: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Lilly, Stemline-Menarini; Other, Speaker's Bureau and Travel Expenses: Pfizer; Other, Speaker's Bureau: Novartis, Lilly. All other authors have declared no conflicts of interest.
In oncologic monotherapy, SC compared to intravenous (IV) route brings advantages like patients’ (Pts) and healthcare professionals (HCP) preference and improved healthcare efficiency, thanks to reductions of both time and use of resources.
During adjuvant dual blockade for HER2 EBC, trained observers measured time used in various treatment activities for 3 cycles (2nd to 4th) of pertuzumab (Perjeta or P) IV and trastuzumab (Herceptin® or H) IV or SC (Group A: P-IV+H-IV; Group B: P-IV+H-SC) and later for subsequent 3 cycles (5th to 7th) of PH FDC SC (Phesgo). The objectives were to assess time saved by Pts and HCP and what resources were used with PH FDC SC versus P-IV+H-IV or P-IV+H-SC.
In 10 Spanish centres, 34 women were randomised (n=17 in Groups A and B). Per cycle, PH FDC SC saved 71% and 63% of Pts time in treatment room (-119 and -87 min, both p<0.0001) and 75% and 69% in chair (-121 and -90 min, both p<0.0001) compared with P-IV+H-IV and P-IV+H-SC, respectively. Active HCP time was reduced by 49% and 48% (-22.9 and -23.0 min, both p<0.0001), including preparation (-6.05 min p<0.0001 and -2.05 min p=0.1112) and administration (-16.9 min p=0.0006 and -20.8 min p<0.0001). Active times were reduced both for pharmacists (-2.10 min p=0.0185 and -1.46 min p=0.0488) and nurses (-18.3 min p=0.0004 and -20.0 min p<0.0001). PH FDC SC reduced use of consumables and avoided drug waste. Safety data up to cycle 7 (in 2025 ends 3-year follow-up) reported 20 Pts with 38 adverse events related to study treatments (only 2 Grade 3: diarrhoea and a serious [SAE] drug hypersensitivity).
PH FDC SC significantly saved Pts and HCP times and reduced use of healthcare resources. In dual therapies, the advantages of the SC route are added to those of fixed dose combination, versus administering drugs separately. Preliminary safety data indicated that the study treatments were overall well tolerated. Together with previous findings showing comparable efficacy and safety profiles and Pts preference of PH FDC SC versus P-IV+H-IV in (neo)adjuvant settings, these results encourage the use of PH FDC SC for dual blockade treatments.
EudraCT 2020-004241-36.
Medical writing services were provided by María Dolores Julián from Linical and supported by Roche Farma S.A.
Roche Farma S.A.
Roche Farma S.A.
S. González-Santiago: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, GSK, Pierre Fabre; Financial Interests, Personal, Advisory Role: Lilly, Seagen, AstraZeneca; Financial Interests, Personal, Other, Travel: Clovis, Pfizer. E. López-Miranda: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Roche, Novartis; Financial Interests, Personal, Speaker’s Bureau: Roche, Novartis, Eisai, AstraZeneca; Financial Interests, Personal, Other, Travel: Roche, Novartis. S. Escrivá-De-Romaní: Financial Interests, Personal, Advisory Board: Roche, Daiichi Sankyo/AstraZeneca, Seagen; Financial Interests, Personal, Invited Speaker: Roche, Daiichi Sankyo/AstraZeneca, Pfizer; Financial Interests, Institutional, Invited Speaker: Roche, Synthon, Byondis, Lilly, MedSIR. B. Jiménez-Rodríguez: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Lilly, Roche; Financial Interests, Personal, Advisory Role: Esteve; Financial Interests, Personal, Other, Travel: Daiichi Sankyo, Gilead, Roche. S. Antolín-Novoa: Financial Interests, Personal, Invited Speaker: Roche, Daiichi Sankio, Pierre Fabre, Lilly, Pfizer; Financial Interests, Personal, Advisory Role: Roche, Daiichi Sankio, Pierre Fabre, Lilly, Pfizer. L.A. Fernández-Morales: Financial Interests, Personal, Advisory Role: Novartis, Pfizer; Financial Interests, Personal, Principal Investigator: Roche, Novartis, Gilead Sciences; Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, MSD, BMS, Pierre-Fabre. E. Galve-Calvo: Financial Interests, Personal, Advisory Board: Pfizer, Daiichi Sankyo, AstraZeneca, Gilead; Financial Interests, Personal, Expert Testimony: Pfizer, Novartis, Roche, Pierre Fabre, Eisai, Daiichi Sankyo, AstraZeneca, Gilead; Financial Interests, Personal, Invited Speaker: Pfizer, Daiichi Sankyo, AstraZeneca, Gilead; Other, Travel acomodation: Pfizer. I. Arroyo-Rivera: Financial Interests, Personal, Full or part-time Employment: Roche Farma S.A. C. García-Bernáldez: Financial Interests, Personal, Full or part-time Employment: Roche Farma S.A. J. Lagunar-Ruiz: Financial Interests, Personal, Full or part-time Employment: Roche Farma S.A. J. Gavilá-Gregori: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Lilly, Roche, AstraZeneca, MSD; Financial Interests, Personal, Advisory Role: Novartis, Seagen, Roche, AstraZeneca, MSD. All other authors have declared no conflicts of interest.
A significant increase in breast cancer (BC) rates has been observed among pre-menopausal woman. Considering the higher number of patients (pts) who have not completed their family planning and impact of age on fertility, fertility preservation (FP) is proving to be a major challenge. Gemme Dormienti Onlus (GD) is an italian association that helps pts by promoting a valid model of FP counselling. Our aim was to identify age influence on ovarian function (OF) and FP in BC pts.
We analyzed 100 BC pts referred to GD. Pts were stratified by age in 3 groups: group 1 (G1) 18-29 years (y) (N= 15), group 2 (G2) 30-35 y (N=39), group 3 (G3) 36-39 y (N=46). All pts underwent basal laboratory and instrumental tests. FP options were gonadotropin-releasing hormone agonists (GnRHa) and/or cryopreservation of oocyte and/or cryopreservation of ovarian tissue (OTC).
Basal follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH) and 17 beta-estradiol (E2) variations were affected by woman age in all groups [FSH (mU/ml): G1=3.6 (2.8-9.1), G2= 5.6 (1.5-12.4); G3= 5.9 (1.8-12.2); p= 0.323], [AMH (ng/ml): G1=6.0 (2.4-9.4); G2= 2.9 (1.0-7.6); G3= 4.0 (1.0-8.1); p= 0.099], [E2 (pg/ml): G1=89.0 (58.0-133.0), G2= 72.5 (11.0-511.3), G3= 50.8 (10.0-314.3), p=0.248]. Age-associated changes in antral follicular count (AFC) and endometrial thickness (ET) were clearly evident [Left-right AFC: G1=7.0 ± 3.1, 7.0 ± 5.3; G2= 4.0 ± 3.1, 4.0 ± 2.5; G3= 3.5 ± 2.5, 3.0 ± 4.2; p=<0.001, p=0.022], [ET (mm): G1=11.0 ± 2.9; G2= 9.0 ± 3.1; G3= 6.5 ± 3.0; p= 0.022]. All pts underwent GnRHa treatment, 30 pts oocyte cryopreservation (G1=40%, G2= 36.8%, G3=21.7%; p= 0.219); 18 OTC (G1=46.7%, G2=13.2%, G3=13%; p=0.008), 5 both techniques (G1=26.6%, G3=2.1). Lack of time (G2=15.8%; G3=12.9%), contraindications (G1=66.7%; G2= 47.4%; G3= 51.6%) and patient choice (G1=33.3%; G2= 36.8%; G3= 35.5%) were the main reasons for not starting FP. We observed 6 post-therapies pregnancies: 2 spontaneous in the G3 and 4 induced, 1 in G2 from OTC and 3 in G3 from oocyte cryopreservation.
Our data showed that FP counseling is a crucial need for BC premenopausal pts to express and realize the desire of pregnancy and improve a better quality of life.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Data are needed to improve the current understanding of the epidemiology and clinical management of high-risk early stage HER2- BC patients.
This study was a retrospective longitudinal cohort study using real-world, population-level data from Alberta, Canada. All individuals newly diagnosed with high-risk, stage II/III HER2- BC in Alberta, Canada between 2013-2019 were included. Data on treatment, laboratory results and pathology findings were collected through electronic health records and administrative databases. High-risk BC was defined as receipt of adjuvant systemic therapy within 120 days of surgery as well as the presence of the following characteristics: 1) For triple-negative BC (TNBC): tumor 2+ cm (AJCC T2 or greater) or axillary lymph node (LN) involvement; 2) For hormone-receptor positive (HR+/HER2-): four or more positive LNs. Treatment eras were separated into pre/post 2016. Overall survival (OS) was defined as the date of diagnosis to death from any cause or last known contact.
The annual cumulative incidence of early-stage, high-risk, HER2- BC ranged from 6% to 9%. Individuals with TNBC were more likely to be younger, have grade 3 histology, stage II BC, and receive systemic therapy at a community centre (p < 0.05) when compared with HR+/HER2- BC. Germline BRCA testing was not widely conducted in this patient population, with an estimated 14% of patients diagnosed in 2010-2017 being tested at some point post-diagnosis. Neoadjuvant systemic therapy was given to 37% of patients with high-risk BC. The 5-year OS from initiation of adjuvant systemic therapy (for patients who received adjuvant systemic therapy) or date of surgery (for patients who did not receive adjuvant systemic therapy) was 77% (95% CI: 75 to 79). OS was significantly worse among patients who were older, had grade 3 histology, stage III BC, or had LN involvement (p < 0.05). OS among patients with TNBC between 2016-2019 who initiated adjuvant capecitabine was markedly worse than that of the overall cohort (2-year OS: 70% vs. 89%).
Outcomes analyses in this population suggest a continued unmet clinical need. Additional analyses into the indications for use of systemic therapies are underway.
AstraZeneca.
AstraZeneca.
S. Shokar: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. D. Granados: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. A. Parackal-Rochard: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. All other authors have declared no conflicts of interest.
Neratinib is an oral, irreversible tyrosine kinase inhibitor of HER1, HER2 and HER4. In China, neratinib was approved in 2020 in the extended adjuvant treatment for HER2+ EBC adult patients who completed prior adjuvant trastuzumab-based therapy. Neratinib is currently the only approved anti-HER2 extended adjuvant therapy for HER2+ EBC. The ExteNET phase III trial, that included patients after adjuvant trastuzumab, has provided concrete efficacy evidence of neratinib in the extended adjuvant setting, but the adjuvant treatment landscape has changed since. Diarrhoea was the most common grade 3 adverse event observed without mandated antidiarrheal prophylaxis (39,8 %). With the evolving landscape of adjuvant treatments, there is a great need to identify real-world treatment patterns of neratinib in HER2+ EBC, its use in clinical practice, its effectiveness and safety data in patients in China.
This is a multi-center, open-label, single-arm, non-interventional study in patients with HER2+ EBC in China. 500 patients in 30 centers who completed adjuvant trastuzumab based treatment and scheduled to receive 1-year of extended adjuvant neratinib will be included. Patients will undergo 12 months of extended adjuvant neratinib treatment and 12 months follow-up. Due to its observational nature, treatment decisions will be independent of the registration to the study. The primary objective aims to describe the real-world treatment patterns with neratinib among HER2+ early-stage breast cancer patients. Primary endpoints are patterns of adjuvant treatment, including patient demographics, characteristics, and different prior adjuvant treatments; and patterns of neratinib use as extended adjuvant treatment. Secondary endpoints include incidence, type, severity, and action taken of all grades of AE of special interest. Exploratory endpoints are characterization of recurrence patterns and assessment of self-reported HRQoL. As of 10 Jan 2023, 49 patients have been enrolled from 14 initiated sites.
NCT05491057.
Medical writing support was provided by Buffy Li, Beijing MetHealth Technology Co., Ltd.
Pierre Fabre Medicament.
Pierre Fabre Medicament.
H. Zhen: Financial Interests, Institutional, Full or part-time Employment: Pierre Fabre Medicament. All other authors have declared no conflicts of interest.
During the past years, clinical routine has shifted away from relying solely on clinicopathologic factors toward increasing use of multigene expression assays in guiding treatment decisions regarding adjuvant chemotherapy (CT) for hormone receptor-positive, HER2-negative early breast cancer (EBC) with 0 to 3 positive lymph nodes. In the case of a low genomic risk, there is a strong consensus in favor of pure endocrine therapy (ET) for postmenopausal patients regardless of the clinical risk (data from the PlanB-, ADAPT-, RxPonder-, TailorX- and MINDACT-studies). However, there is uncertainty regarding the optimal therapy for pre- and perimenopausal patients with a similar clinical/genomic risk profile. Since the observed benefit of CT in this patient group may be partly attributable to CT-induced ovarian function suppression (OFS), some of these patients could be spared CT by adding OFS to endocrine therapy. The West German Study Group (WSG) initiated the PROOFS-registry to create a real-world database and to obtain clarity how to optimally treat these patients.
PROOFS (NCT pending) is an observational, non-interventional registry aiming at the long-term follow up of pre- or perimenopausal patients with luminal EBC with intermediate to high clinical risk for recurrence and low genomic risk measured by MammaPrint®. Study participants will receive standard-of-care treatment at physicians´ discretion and according to clinical routine, which may include CT neoadjuvant or adjuvant + ET, ET + OFS in premenopausal, or ET +/- OFS in perimenopausal women. The registry aims to give insights in the real-world use of OFS and to confirm an excellent outcome in patients treated by ET +/- OFS alone. In addition, quality of life is captured (QLQ BR23 and QLQ-C30). The study is open for recruitment of 1470 patients (approximately 20% receiving CT and 80% receiving ET +/- OFS) at up to 100 centers in Germany.
Westdeutsche Studiengruppe GmbH.
Agendia N.V., Amsterdam.
O. Gluz: Financial Interests, Personal, Advisory Board: Roche, Lilly, Amgen, Novartis, Pierre Fabre, MSD, Celgene, Pfizer, Gilead, Molecular Health, Seagen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Exact Science; Financial Interests, Institutional, Invited Speaker: Roche; Non-Financial Interests, Leadership Role: West German Study Group; Non-Financial Interests, Personal, Proprietary Information: West German Study Group. M. Graeser: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other: Daiichi Sankyo, AstraZeneca. U.A. Nitz: Financial Interests, Personal, Advisory Role: Agendia;, Amgen;, Celgene;, Genomic Health, NanoString Technologies, Novartis pharma, fizer Pharmaceuticals;, Roche/Genentech, Teva; Financial Interests, Institutional, Sponsor/Funding: Agendia, Amgen, Celgene, Roche, Sanofi. N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Seagen, Medscape, Art Tempi, Onkowissen, Gilead, Sanofi, Exact Sciences; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Roche, Sandoz-Hexal, Seagen, Aptitude Health, Gilead, Sanofi; Financial Interests, Personal, Other, Husband: WSG (Husband); Financial Interests, Personal, Ownership Interest: West German Study Group; Financial Interests, Institutional, Funding: AstraZeneca, BMS, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, TRIO, Roche, Palleos, Seagen, WSG; Non-Financial Interests, Member, Member German AGO Breast Guideline Committee: AGO Breast Committee; Non-Financial Interests, Member, Breast Cancer Educational Programs: ESO/ESCO; Other, Founding Editor: BreastCare Journal. S. Kuemmel: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Lilly, MSD, Novartis, Seagen, Pfizer, Roche, Somatex, Gilead, Sanofi; Financial Interests, Personal, Invited Speaker: ExactScience, pfm medical, MSD, Lilly, Gilead, Roche, Sanofi, Daiichi Sankyo; Financial Interests, Personal, Ownership Interest, Minority Ownership: WSG Study Group; Financial Interests, Personal and Institutional, Invited Speaker: Roche, Novartis; Financial Interests, Institutional, Invited Speaker: Roche, Novartis, Lilly, Somatex, AstraZeneca, MSD. R. Wuerstlein: Financial Interests, Personal, Funding: Agendia, Amgen, Aristo, AstraZeneca, Boehringer Ingelheim, Carl Zeiss, Celgene, Daiichi Sankyo, Eisai, Exact Sciences, Genomic Health, Gilead, GSK, Hexal, Lilly, Medstrom Medical Medical, MSD, Mundipharma, Mylan, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, Puma Bio, Riemser, Roche, Sandoz/Hexal, Sanofi Genentech, Seagen, Tesaro Bio, Teva, Veracyte, Viatris; Financial Interests, Personal, Other: Westdeutsche Studiengruppe GmbH. All other authors have declared no conflicts of interest.
Adjuvant Endocrine Therapy (AET) is the cornerstone treatment of localized hormone-receptor-positive (HR+) breast cancer, with demonstrated benefits on overall survival (30-40% relative decrease in mortality) but also on the risk of local and contralateral relapse (43-50% relative decrease). While the relative benefit of 5 years of ET is identical for small tumors as compared to larger ones, the absolute benefit is much lower, and the risk-benefit ratio becomes questionable given the frequent and impactful side effects of ET which are associated with non-adherence. If recent trials tested longer durations as compared to 5 years for high-risk cancers, older trials have tested shorter durations. Five years appeared at that time as the gold standard because of optimal benefit-risk ratios of tamoxifen among rather high-risk patients. However, shorter treatments of 2-3 years were already associated with substantial benefits. The purpose of this study is to demonstrate that AET limited to 2 years of aromatase inhibitor (AI) in postmenopausal women at very low risk of recurrence as determined with a MammaPrint/BluePrint Ultra Low Risk test result can ensure very high survival without metastatic relapse and allows a reduction of side effects and a better quality of life.
LESS is a prospective, national, multicenter, single-arm, interventional, non-threshold crossing phase II study evaluating a therapeutic de-escalation that limits adjuvant ET to 2 years of AI. Approximately 696 post-menopausal patients with an invasive unilateral, HR+, HER2-negative, without indication of adjuvant chemotherapy and genomically-assessed MammaPrint/BluePrint Ultra Low risk luminal A breast cancer tumors, will be enrolled. LESS will include 2 sub cohorts: the majority of patients with Grade 2, pT1c-2, pN0/N1mic tumors, and up to 80 patients ≥65 years with Grade 1, pT1, pN0 and Ki67 ⩽ 10% tumors. The primary endpoint is distant metastasis free survival defined as the time from date of registration to date of 1st event of distant recurrence, death, or 2d primary non-breast invasive cancer. The 1st patient was included in Oct 2022, initiating the 2-year inclusion period.
NCT05297617.
Unicancer.
Agendia.
E. Deluche: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, FRESENIUS-KABI, Lilly; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Other, scientific events: Lilly, GSK; Financial Interests, Personal, Other, funding for conference travel: AstraZeneca-Daiichi, Roche, AMGEN. S. Michiels: Financial Interests, Personal, Other, Statistical advice: Roche; Financial Interests, Personal, Other, DSMB member: Sensorion, Servier, Biophytis, Yuhan, IQVIA, Kedrion. C. Bailleux: Other, Travel, accommodations, expenses: AstraZeneca; Financial Interests, Advisory Role: Seagen, Novartis, AstraZeneca. T. Bachelot: Financial Interests, Personal, Advisory Board: Roche, Novartis, AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Novartis, Roche, AstraZeneca, Seagen, Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca. I.V. Vaz Luis: Financial Interests, Institutional, Invited Speaker: Amgen, Pfizer/Edimark, Pfizer/Edimark, AstraZeneca; Financial Interests, Institutional, Advisory Board, Consulting/ AB: Novartis; Financial Interests, Institutional, Expert Testimony: Sandoz; Financial Interests, Institutional, Funding: Resilience; Non-Financial Interests, Member, Member of WG: ASCO. F. André: Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi; Financial Interests, Institutional, Other, advisory board: Guardant Health; Financial Interests, Institutional, Other, Advisory board: MEDIMMUNE, Gilead, Relay therapeutics; Other, Founder: Pegacsy. All other authors have declared no conflicts of interest.
GP2 is a biologic nine amino acid peptide of the HER2/
This phase III trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up. Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. The patient population is defined by these key eligibility criteria: 1) HER2/neu positive and HLA-A*02 and 2) Residual disease or High risk pCR (Stage III at presentation) post neo-adjuvant therapy. The trial objectives are to: 1) Determine if GP2 therapy increases IBCFS, 2) Assess the safety profile of GP2, and 3) Monitor immunologic responses to treatment and assess relationship to efficacy and safety. The study has been initiated in the US with plans to open in Europe.
NCT05232916.
Greenwich LifeSciences, Inc.
Greenwich LifeSciences, Inc.
S. Patel: Financial Interests, Personal, Ownership Interest: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Stocks/Shares: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Member of the Board of Directors: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Officer: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Full or part-time Employment: Greenwich LifeSciences, Inc. J. Thompson: Financial Interests, Personal, Ownership Interest: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Stocks/Shares: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Officer: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Full or part-time Employment: Greenwich LifeSciences, Inc. M. Patel: Financial Interests, Personal, Ownership Interest: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Stocks/Shares: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Full or part-time Employment: Greenwich LifeSciences, Inc. F.J. Daugherty: Financial Interests, Personal, Ownership Interest: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Stocks/Shares: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Member of the Board of Directors: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Officer: Greenwich LifeSciences, Inc.; Financial Interests, Personal, Full or part-time Employment: Greenwich LifeSciences, Inc. M. Rimawi: Other, Personal, Speaker’s Bureau: Daiichi Sankyo, Genentech, Macrogenics; Other, Personal, Other, Contracted Research: F. Hoffmann-La Roche Ltd., Pfizer; Other, Personal, Speaker’s Bureau, Greenwich LifeSciences: Seattle Genetics; Other, Personal, Principal Investigator: Greenwich LifeSciences, Inc.
In IMpassion050 (NCT03726879), adding atezolizumab (A) to neoadjuvant chemotherapy (CT) and pertuzumab–trastuzumab (PH) did not increase pathological complete response (pCR) vs placebo (Pl), CT and PH in patients (pts) with high-risk, HER2-positive (+) early breast cancer (EBC) in either the intention-to-treat or PD-L1+ populations. Additional BM data are warranted to better inform future immunotherapeutic strategies in HER2+ BC. We report exploratory analyses of the relationship between BMs with pCR, and their dynamics.
Overall, 454 pts with centrally confirmed HER2+, node+ EBC were randomly assigned to 8 cycles of A and CT with 4 cycles of PH, followed by A plus PH until completion of 1 year of treatment after surgery, or Pl, CT and PH followed by Pl plus PH. Pre-specified HER2, hormone receptor (HR), PD-L1 and
BM characteristics were well balanced between arms: 89% of tumours were HER2 immunohistochemistry (IHC) 3+; 51%, HR+ (capping at 50%); 48%, PD-L1+; 28%,
OR 95% CI p-value N=411 Treatment effect (reference: Pl arm) A arm 1.00 0.65, 1.54 0.9972 HER2 IHC 2+/3+ staining pattern (reference: focal/heterogeneous) Homogeneous (≥80% staining) 2.51 1.46, 4.31 0.0009 ≥4 1.94 1.18, 3.20 0.0091 HR status (reference: oestrogen and/or progesterone receptor+) Oestrogen and progesterone receptor-negative 2.41 1.55, 3.76 0.0001 PD-L1 status (reference: tumour-infiltrating immune cells [IC] 0) IC 1/2/3 1.61 1.04, 2.49 0.0321 No mutation detected 1.72 1.07, 2.77 0.0264
There was no differential treatment effect detected with the addition of A to CT and PH according to BMs analysed. HER2 IHC staining pattern, gene ratio, and HR, PD-L1 and
NCT03726879.
Support for third-party editing assistance for this abstract, furnished by Daniel Clyde, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd., Basel, Switzerland.
F. Hoffmann-La Roche Ltd.
F. Hoffmann-La Roche Ltd.
H.A. Zhang: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Funding, Research funding: Roche. C. Lambertini: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd. D. Eiger: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd. C.H. Barrios: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: MedSIR, Tummi; Financial Interests, Personal, Other, Honoraria: Novartis, Roche/Genentech, Pfizer, GlaxoSmithKline, Sanofi, Boehringer Ingelheim, Eisai, MSD, Lilly, Bayer, AstraZeneca, Zodiac Pharma; Financial Interests, Personal, Other, Travel, accommodations, expenses: Roche/Genentech, Novartis, Pfizer, BMS Brazil, AstraZeneca, MSD Oncology, Lilly; Financial Interests, Institutional, Funding, Research funding: Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, AbbVie, Astellas Pharma, Biomarin, Bristol Myers Squibb, Daiichi Sankyo, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Exelixis, ImClone Systems, LEO Pharma, Millennium, Janssen, Clinica Atlantis, INC Research, Halozyme, Covance, Celgene, inVentiv Health, Shanghai Henlius Biotech, Polyphor, PharmaMar; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim, Roche/Genentech, Novartis, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Libbs, MSD Oncology, United Medical, Lilly. N. Niikura: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Other, Honoraria: Chugai Pharma, AstraZeneca, Eisai, Novartis, Daiichi Sankyo/UCB Japan, Eli Lilly Japan, MSD, Pfizer Japan, Taiho Pharmaceutical, Kyowa Kirin; Financial Interests, Personal, Funding, Research funding: Chugai Pharma, Nihon Medi-Physics, Daiichi Sankyo, Eisai, Pfizer, Nippon Kayaku, Kyowa Kirin, Takeda, Eli Lilly Japan, Taiho Pharmaceutical, Boehringer Ingelheim, Puma Biotechnology, Mochida Pharmaceutical Co. Ltd. M. Jarzab: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Other, Honoraria: Roche, Novartis, Pfizer; Financial Interests, Personal, Advisory Role: Pfizer, Novartis, Lilly, Roche; Financial Interests, Personal, Speaker’s Bureau: Exact Sciences, Roche, Novartis, Pfizer; Financial Interests, Personal, Funding, Research funding: Roche; Financial Interests, Personal, Other, Travel, accommodations, expenses: Pfizer, Lilly, Roche, Novartis. Y. Chang: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Funding, Research funding: Roche. S.L. Huggins-Puhalla: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Advisory Role: AbbVie, Roche/Genentech; Financial Interests, Institutional, Funding, Research funding: AbbVie, Pfizer, AstraZeneca. M. Curran: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Other, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd. S. Sarkar: Financial Interests, Personal, Full or part-time Employment, Employee: Parexel (F. Hoffmann-La Roche Ltd. external business partner).: Parexel; Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd. E. Restuccia: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd. J. Huober: Non-Financial Interests, Personal, Funding, Research funding: Support for third-party writing assistance: F. Hoffmann-La Roche Ltd.; Financial Interests, Institutional, Research Grant: Novartis, Lilly; Financial Interests, Personal, Other, Consulting fees: Lilly, Novartis, Roche, Pfizer, Hexal, AstraZeneca, MSD, Celgene, AbbVie, Daiichi, Gilead; Financial Interests, Personal, Other, Honoraria: Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene; Eisai, AbbVie, Seagen, Gilead, Daiichi; Financial Interests, Personal, Other, Travel: Roche, Pfizer, Novartis, Celgene, Daiichi, Gilead.
Neoadjuvant therapy combining immunotherapy (IO) and chemotherapy (CT) is the standard of care in early-stage triple-negative breast cancer (ESTNBC), following the results of the KEYNOTE-522. However, overall survival (OS) gain is uncertain so far. This study aims to evaluate long-term outcomes of neoadjuvant IO plus CT for ESTNBC.
We conducted a systematic review using PubMed, Embase, and Cochrane databases until February 13th, 2023. Randomized phase II or III trials evaluating neoadjuvant IO plus CT versus CT alone for ESTNBC were selected. A meta-analysis of extracted individual patient (pt) data (eIPD) was performed to evaluate event-free survival (EFS) and OS outcomes. Individual pt data was reconstructed from reported Kaplan-Meier plots through WebPlotDigitizer and the R package IPDfromKM and further combined. In addition, we conducted a trial-level meta-analysis using fixed and random effects models. Comparisons were made with Cox regression.
The literature search resulted in 107 items, and 4 trials with EFS or OS data available were included (Keynote 522, IMpassion 031, I-SPY 2 and GeparNuevo). 1456 patients were included in EFS analysis (900 in IO arm versus 556 in control arm) and 1348 patients in OS analysis (872 versus 476 patients, respectively). The addition of neoadjuvant IO to CT was associated with better EFS and OS in eIPD analysis (Table). Median OS and EFS were not achieved. The trial-level meta-analysis yielded similar results (fixed effects model: HR 0.66, 95%CI 0.48-0.90; random effects model: 0.57, 95% CI 0.33-1.01).
eIPD meta-analysis IO arm Control arm HR 95% CI P
This meta-analysis suggests that the addition of IO to neoadjuvant CT in ESTNBC provides a significant improvement in EFS (absolut gain of 11% in 4 years) and a possible OS benefit (significant in the eIPD and in the trial-level fixed effects model meta-analysis). Longer follow-up with mature OS data are awaited to confirm these results.
The authors.
Has not received any funding.
L. Testa: Financial Interests, Personal, Advisory Role: Lilly, Novartis, MSD, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Other, Educational Support: Pfizer, Lilly, Zodiac, AstraZeneca; Financial Interests, Personal, Invited Speaker: Novartis, Roche, Pfizer, Zodiac, Lilly, MSD, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Other, Institutional Research Funding: Novartis. R. Colombo Bonadio: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Nestle, AstraZeneca, Ache, Nestle; Financial Interests, Personal, Other, Financial support for educational programs and symposia: AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Other, Research grant: Novartis, AstraZeneca. All other authors have declared no conflicts of interest.
TROP-2 is involved in regulating cancer growth and invasion in different tumour types. It is also a potent therapeutic target, being addressed by antibody drug conjugates (ADC). This study evaluates the impact of TROP-2 on breast cancer prognosis in high-risk, node-positive BC of the German adjuvant intergroup node-positive (GAIN) cohort.
Tissue microarrays (TMAs) were generated from FFPE-pre-therapeutic surgical resection tissue (n = 1358). Immunohistochemical staining was performed with human TROP-2 antibody SP295. Membranous and cytoplasmic expression of TROP-2 in invasive tumor cells was assessed. The Cutoff Finder web application was used for identification of the best cutoff point according to disease-free survival (DFS) and overall survival (OS). For n = 996 patients, data on hormone receptor (HR), HER2 and Ki67 status were available. The association of membranous (m)TROP-2 and cytoplasmic (c)TROP-2 expression with molecular intrinsic subgroups, TNM stages, age, proliferation and HR status were evaluated.
For 1186 TMA spots valid TROP-2 evaluation was available. The Cutoff Finder identified 70 % as best cutoff for cTROP-2 expression. cTROP-2 ≤ 70 % was significantly associated with better grading (p < 0.001). In multivariate Cox regression analysis, cTROP-2 ≤ 70% was associated with improved DFS in HR+/HER2- (p = 0.006) and luminal A-like tumors (p = 0.013). For mTROP-2, a product score (IRS) of grouped percentage and staining intensity showed better DFS and OS for IRS > 3 (also identified by Cutoff Finder) in HER2+/HRany and HER2+/HR+ patients (uni-/multivariate). Detailed data incl. molecular subtypes will be presented.
TROP-2 is commonly expressed in breast cancer with its cellular localization differentially affecting survival. The results are relevant for biomarker strategies for future therapeutic concepts. In the SASCIA trial investigating Sacituzumab TROP-2 is prospectively assessed.
NCT01690702.
The authors.
Roche.
P. Jank: Other, Personal, Stocks/Shares: Myriad Genetics. W. Janni: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Gilead; Financial Interests, Personal, Full or part-time Employment: Universitätsklinikum Ulm; Financial Interests, Institutional, Invited Speaker: Novartis, GSK, Sanofi, Amgen, Roche, Lilly; Non-Financial Interests, Leadership Role: Chair of AGO Breast Council. P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Sanofi Aventis; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Lilly, Seagen, Gilead; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BionTech, Cepheid; Non-Financial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v. F. Marmé: Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK/Tesaro, Clovis, Pfizer, Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Novartis, Roche, Gilead/immunomedics, EISAI, PharmaMar, GenomicHealth, Myriad, Seagen; Financial Interests, Institutional, Invited Speaker: Seagen, Daiichi Sankyo, GSK, AstraZeneca, Roche, AstraZeneca, Novartis, Roche, Eisai, Gilead/Immunomedics, MSD, German Breast Group, AGO Research GmbH, Vaccibody, GSK; Financial Interests, Institutional, Advisory Board: Roche, Immunicom; Financial Interests, Institutional, Funding: AstraZeneca, Lilly, Seagen. M. Schmidt: Financial Interests, Institutional, Research Grant: AtraZeneca, BioNTech, Eisai, GBG, Genentech, Novartis, Pantarhei Bioscience, Pfizer, PierreFabre, Roche; Financial Interests, Personal, Other, Consulting fees: AstraZeneca, BioNTech, Eisai, Daichi-Sankyo, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, Seagen; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Novartis, Pfizer, Roche, Segaen; Financial Interests, Personal, Other, Travel support: Pfizer, Roche; Financial Interests, Personal, Other, Patent: EP 2951317 B1, EP 2390370 B1; Financial Interests, Personal, Advisory Board: AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, Seagen. V. Mueller: Financial Interests, Institutional, Research Grant, Speaker Honoraria: Amgen, AstraZeneca, Daiichi Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Teva, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, Pierre Fabre, Medscape; Financial Interests, Institutional, Other, Consultancy Honoraria: Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Sanofi, Seagen, Gilead, Pierre Fabre; Financial Interests, Institutional, Other, Travel Support: Roche, Pfizer, Daiichi Sankyo, Gilead. M. Untch: Financial Interests, Institutional, Other, Supportfor present Abstract: Amgen; Financial Interests, Institutional, Funding, Support for Present Abstract: Roche; Financial Interests, Institutional, Other, Consulting fees: Amgen, AbbVie, Sanofi-Aventis, Pfizer, Agendia, Daiichi, AstraZeneca, Seagen, Gilead, Genzyme, MSD, Lilly, Stemline; Financial Interests, Institutional, Speaker’s Bureau: AstraZeneca, Lilly, Baxter, Pfizer, Gilead, Myriad, Pierre Fabre. C. Schem: Financial Interests, Personal, Advisory Board: Roche, Novartis, Lilly, AstraZeneca, Daichi Sanyo; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, Gilead. V. Nekljudova: Financial Interests, Institutional, Full or part-time Employment: GBG; Financial Interests, Institutional, Research Grant: AbbVie, AstraZeneca, BMS, Daichi-Sankyo, Gilead, Novartis, Pfizer, Roche, Seagen; Non-Financial Interests, Institutional, Writing Engagements: Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, Seagen; Other, Institutional, Other, EP14153692.0: Patent; Other, Institutional, Other, EP21152186.9: Patent; Other, Institutional, Other, EP15702464.7: Patent; Other, Institutional, Other, EP19808852.8: Patent; Other, Institutional, Royalties: VM Scope GmbH. S. Loibl: Financial Interests, Institutional, Advisory Board, Member: Amgen, AstraZeneca, BMS, Celgene, EirGenix, GSK, Lilly, Pierre Fabre, Roche, Seagen, AbbVie, Sanofi, Gilead, Merck, Novartis, Relay Therapeutics; Financial Interests, Institutional, Invited Speaker: AstraZeneca, DSI, Novartis, Pfizer, Roche, Gilead, Seagen; Financial Interests, Institutional, Advisory Board: DSI, Pfizer, Olema; Financial Interests, Personal, Invited Speaker: Medscape; Financial Interests, Personal, Full or part-time Employment, CEO: GBG Forschungs GmbH; Financial Interests, Institutional, Invited Speaker, Ki67: VM Scope GmbH; Financial Interests, Institutional, Research Grant: AstraZeneca, Celgene, Novartis, Immunomedics/Gilead, Pfizer, Roche, Daiichi Sankyo; Financial Interests, Institutional, Funding: AbbVie, Molecular Health; Financial Interests, Personal, Other, PIPenelope/Padma: Pfizer; Financial Interests, Personal, Other, SC PALOMA3: Pfizer; Financial Interests, Personal, Other, SC SOLAR1: Novartis; Financial Interests, Personal, Other, SC ASCENT: Immunomedics/Gilead; Financial Interests, Personal, Other, SC HERCLIMB: Seagen; Financial Interests, Personal, Other, SC Katherine: Roche; Financial Interests, Personal, Other, SC Capitello; EC Cambria 1: AstraZeneca; Financial Interests, Personal, Other, SC Inavo: Roche; Financial Interests, Personal, Other, SC Destiny B05; SC Destiny B09: Daiichi Sankyo; Non-Financial Interests, Principal Investigator, After publication of primary endpoint: PI Aphinity; Non-Financial Interests, Advisory Role, Group in Germany responsible for breast cancer guidelines: AGO Kommission Mamma; Non-Financial Interests, Member, German Gynaecological Oncology society: AGO; Non-Financial Interests, Member, German Cancer Society: DKG; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member, Member guideline committee; past chair in ESMO Breast: ESMO; Other, EP14153692.0No financial interest, Institutional: Patent; Other, EP21152186.9No financial interest, institutional: Patent; Other, EP15702464.7No financial interest, institutional: Patent; Other, EP19808852.8 No financial interest, Institutional: Patent. C. Denkert: Financial Interests, Personal, Advisory Board: MSD Oncology, Daiichi Sankyo, Molecular Health, AstraZeneca, Roche, Lilly; Financial Interests, Personal, Invited Speaker: AstraZeneca, VmScope digital pathology software; Financial Interests, Institutional, Research Grant: Roche, Myriad, German Breast Group. All other authors have declared no conflicts of interest.
Studies evaluating adjuvant CDK4/6i provided contradictory results thus far and further characterization of the biological effect of CDK4/6i in residual disease (RD) after neoadjuvant chemotherapy (NAC) is needed. Here we report the primary analysis of the PROMETEO II trial.
Patients (pts) with HR+/HER2- BC and RD after completing anthracycline/taxane-based NAC were included. RD was confirmed with an ultrasound showing a tumor diameter ≥ 10 mm and a core-biopsy detecting the presence of invasive tumor with Ki67% ≥ 5% by local IHC. Before surgery (SUR), patients received palbociclib 125mg for 21 days and letrozole until SUR. The primary endpoint was complete cell cycle arrest (CCCA) rate determined by Ki67 ≤2.7%, centrally assessed, at SUR. Secondary endpoints include residual cancer burden (RCB) and safety. Tumor samples collected at 3 timepoints (before NAC, during screening (SCR) period and at SUR) were mandatory to assess gene expression, sTILs and PD-L1 IHC (SP142).
22 pts were enrolled: median age 56y (41-69), 45% premenopausal and histologic grade 2/3 63%. The rate of CCCA at SUR was 59% (Table). Between SCR and SUR, Ki67% decreased by a geometric mean change of 44.2%. One patient achieved RCB-I. Intrinsic subtype changes at SUR occurred in 58% of cases, mostly (38.1%) Luminal A/B converting to Normal-like. After palbociclib, immune genes were induced and proliferation genes were suppressed (FDR<5%). Interestingly, immune genes were upregulated in tumors with CCCA after palbociclib compared to tumors with non-CCCA. 9 patients (41%) experienced grade 3 AEs (all neutropenia). Biomarkers according with the 3 timepoints by central assessment
PRE_NAC SCR SUR CCCA, n(%) 1 (4) 6 (27) 13(59) Mean %ki67 22.5 7.2 4.2 sTILs, median (r) 2.5 (<1-35) 2.5 (0-40) 4 (1-20) PDL1+, n(%) NA 0 3 (14) IgG high group, n(%) 2 (9) 7 (32) 13 (59)
In chemo-resistant residual disease in pts with HR+/HER2- BC, palbociclib induce a potent anti-proliferative effect. A direct relationship between immune infiltration and anti-proliferative response exists, where immune infiltration is increased in residual tumors with CCCA.
EudraCT 2019-001275-36, NCT04130152 First posted: October 17, 2019.
SOLTI.
Sponsor: SOLTI Cancer Research Group. This study was funded by Pfizer.
S. Pernas Simon: Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pfizer; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Invited Speaker: Astra-Zeneca, Novartis, Daiichi Sankyo; Non-Financial Interests, Invited Speaker: SOLTI. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau. Educational activities: Roche; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Roche, Lilly, Novartis, Pfizer, Daiichi Sankyo, MSD; Financial Interests, Personal, Invited Speaker, Symposia and Education: Lilly; Financial Interests, Personal, Invited Speaker, Educational activities: Pfizer; Financial Interests, Personal, Advisory Board, Non-permanent advisor, Travel accommodation: AstraZeneca; Financial Interests, Personal, Other, Advisory Board: Gilead; Financial Interests, Personal, Other, Advisory Board, Invited speaker: Seagen; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Invited Speaker, Non-profit organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientific Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. All other authors have declared no conflicts of interest.
Conflicting results have been reported on the impact of HER2-low expression on the efficacy of CDK4/6 inhibitors in hormone receptor-positive (HR+) metastatic breast cancer. No data are yet available in the neoadjuvant setting. We investigated the efficacy of letrozole-palbociclib (LETPAL) combination as neoadjuvant treatment according to HER2 expression in an exploratory analysis of the NeoPAL study (UCBG104, NCT02400567).
NeoPAL was a randomised, parallel, non-comparative phase II study which assigned pts with HR+ HER2-, Prosigna®-defined luminal B or A and node-positive, stage II-III breast cancer to LETPAL or chemotherapy. Primary endpoint was residual cancer burden (RCB 0-I rate). Secondary endpoints included clinical response, proliferation-based markers, and safety. HER2 low status was centrally reviewed according to the ASCO/CAP guidelines.
40/53 patients treated in the LETPAL arm were evaluable for this substudy: HER2-low (n=20), HER2-0 (n=20). Luminal B molecular subtype was predominant in both groups (95% and 80% respectively) with a baseline high risk Prosigna® ROR score in 88.9% and 82.6% of patients, respectively. After 4 months of LETPAL, RCB 0-I was observed in one patient of each group and pathological complete response rates were 2.5% and 0% in the HER2-low and HER2-0 subgroups respectively. A 0-I PEPI score was observed in 4 patients in each group. Interestingly, the HER2 status switched (either way) in 7 out of 28 analysable matched samples (25%). LETPAL induced a decrease in the ROR score at surgery in a similar proportion in both groups: 68.4% and 60.0% of tumors switched from high or intermediate risk to low risk in the HER2-low and HER2-zero groups, respectively. All exploratory p values were >0.1. Strikingly similar results were observed in the chemotherapy arm.
Neoadjuvant palbociclib activity in combination with letrozole does not seem to be influenced by the tumor’s HER2 status (low versus zero).
NCT02400567.
Unicancer.
Has not received any funding.
J. Frenel: Financial Interests, Personal, Advisory Board: Pfizer, Novocure, Pierre Fabre, Eisai, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: GSK, Amgen; Financial Interests, Institutional, Advisory Board: Exact Science, Lilly, Daiichi Sankyo, AstraZeneca, Clovis Oncology; Financial Interests, Institutional, Invited Speaker: Novartis, MSD; Financial Interests, Invited Speaker: AstraZeneca, Seagen, MSD, Daiichi; Non-Financial Interests, Principal Investigator: Novartis, Lilly, AstraZeneca, Pfizer, Daiichi, MSD. A. Vincent-Salomon: Financial Interests, Personal, Invited Speaker, Lectures honorarium: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Ibex, Roche; Financial Interests, Personal, Invited Speaker: MSD, Roche; Financial Interests, Personal, Stocks/Shares: Ibex; Financial Interests, Institutional, Research Grant: AstraZeneca, Ibex; Financial Interests, Institutional, Funding: Owkin. P. Heudel: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Novartis, Seagen, Lilly; Financial Interests, Institutional, Invited Speaker: AstraZeneca. F.P. Duhoux: Financial Interests, Institutional, Advisory Board: Roche, Pfizer, AstraZeneca, Lilly, Novartis, Amgen, Daiichi Sankyo, Pierre Fabre, Gilead, Seagen, MSD; Financial Interests, Institutional, Invited Speaker: Novartis, Pfizer, MSD, Roche, MSD, Boehringer Ingelheim, Pfizer, Novartis, Lilly, AbbVie, Seagen, Gilead, AstraZeneca, Menarini, Immutep; Financial Interests, Institutional, Expert Testimony: Seagen, Novartis, MSD. G. Emile: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Novartis, Roche. F. Dalenc: Non-Financial Interests, Principal Investigator: Roche, AstraZeneca, Gilead, Novartis. J. Ferrero: Financial Interests, Personal, Advisory Board: Pfizer, Exact sciences, Novartis; Financial Interests, Personal, Invited Speaker: Lilly. S. Delaloge: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Pierre Fabre, Orion, Sanofi, Rappta, Cellectis, Isis/servier; Financial Interests, Institutional, Invited Speaker: Exact Sciences, Pfizer, Seagen, Lilly, AstraZeneca, MSD, Roche Genentech, BMS, Puma, AstraZeneca, Orion, Sanofi, Pfizer; Financial Interests, Institutional, Advisory Board, ad board: Besins Healthcare; Financial Interests, Institutional, Invited Speaker, ESMO symposium: Gilead; Financial Interests, Institutional, Advisory Board, scientific board: Elsan; Financial Interests, Institutional, Funding: GE; Financial Interests, Institutional, Invited Speaker, clinical research funding to my institution: Taiho; Non-Financial Interests, Invited Speaker, Société Française de Sénologie et Pathologie Mammaire: SFSPM; Non-Financial Interests, Principal Investigator, H2020 funding: European Commission. P.H. Cottu: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer, Lilly; Financial Interests, Personal, Expert Testimony: Roche; Financial Interests, Institutional, Invited Speaker: Daiichi, Lilly, Gilead; Financial Interests, Institutional, Funding: Novartis. All other authors have declared no conflicts of interest.
Outcome of patients (pts) w/ stage I node neg HER2+ treated w/ wkly paclitaxel x 12 doses and trastuzumab x 1yr is excellent (10yr RFS 96%). Therefore, trials to de-escalate chemo and use targeted therapy alone are underway. Zanidatamab is a novel, humanized, bispecific, immunoglobulin G isotype 1-like, monoclonal antibody directed against the juxtamembrane extracellular domain (ECD4) and the dimerization domain (ECD2) of HER2. This results in HER2 clustering that modulates signaling and leads to immune activation. Zanidatamab demonstrated antitumor activity in heavily pre-treated HER2+ metastatic BC with acceptable safety profile. We
Pts w/ 1-3cm, clinically node neg HER2+ BC were enrolled in this investigator-initiated clinical trial. Pts had HER2+ BC: HER2 3+ by IHC or IHC 2+ and ISH +. Pts received 2-wkly zani x6 prior to surgery. Pts with ER+ tumors also received neoadjuvant endocrine therapy: postmenopausal pts received letrozole 2.5mg daily, and premenopausal pts received tamoxifen 20mg daily or GNRH and letrozole 2.5mg on treating physician preference. The primary objective was to evaluate efficacy as determined by pathologic complete response (pCR). Secondary objectives included pathologic response by residual cancer burden (RCB), radiological response, and safety profile of zanidatamab.
Eleven pts w/ HER2+ BC were enrolled. Median age was 61yrs old (range 30-72). Median tumor size was 2.2cm (range 1-3cm). Four pts were pre-menopausal. Six pts had tumors >2cm tumors. Three received tamoxifen and 3 letrozole. All pts completed 6 cycles of zanidatamab and had Sx. Four (36%) had pCR, 3 RCB1 (28%) and 4 RCB2 (36%). This met the success criterion of Simon’s design (>=3/17 pts with pCR) of targeting a 25% pCR rate against a 5% null rate. Treatment was tolerated well. There were no grade 3 or 4 toxicities. One pt had minor infusion-related reaction and grade 2 acne, and 1 grade 2 diarrhea.
Neoadjuvant zanidatamab for 3 months showed significant efficacy, (pCR/RCB-1 64%) w/ acceptable safety profile in pts w/ stage I node neg HER2+ BC. The trial is ongoing and has been modified to increase treatment duration to 5mths (10 cycles).
The authors.
Zymeworks Inc.
All authors have declared no conflicts of interest.
Analysis of ctDNA offers a minimal-invasive approach for monitoring treatment response in pts with breast cancer (BC). Serial ctDNA testing during neoadjuvant therapy (NAT) may provide early indicators of resistance and disease progression.
Plasma samples (n=178) collected from 34 pts with eBC (stage II-III) were prospectively analyzed using a personalized, tumor-informed ctDNA assay (SignateraTM bespoke mPCR-NGS). All pts received standard of care NAT (anthracycline, taxane). Longitudinal blood samples were collected at the time of diagnosis (baseline), followed by on treatment (every 3 weeks) with a median of 6 samples (1-10). ctDNA status and dynamics were correlated with clinicopathological features.
At baseline, ctDNA was detected in 85% (29/34) of pts. ctDNA-positivity was observed in 95% (18/19)of pts with triple-negative breast cancer and in 73% (11/15) pts with HER2+ disease at baseline. ctDNA was detectable in 78% (18/23) of pts with T1-2 disease and 100% (11/11) of pts with T3-4 disease. At baseline, 75% (15/20) of low-/intermediate-grade disease had detectable ctDNA; all cases with high-grade disease were ctDNA positive (14/14), irrespective of nodal status. Of the 19 with surgical outcomes, 9 pts with longitudinal samples achieved pathologic complete response (pCR). While all 9 pts were ctDNA positive at baseline, 67% (6/9) became ctDNA negative after the first cycle of treatment. Among those with residual disease (pT1c-T3), 50% (2/4) remained ctDNA positive after the first cycle of therapy. Interestingly, one pt with inflammatory BC failed to clear ctDNA despite achieving pCR and remained ctDNA positive after definitive surgery. Based on unfavorable ctDNA dynamics and high-risk disease the pt was initiated on ado-trastuzumab adjuvant therapy. Association between ctDNA dynamics and pt clinical outcome will be presented.
This study demonstrates the feasibility of ctDNA detection in pts with eBC treated with NAT. ctDNA monitoring during NAT can facilitate real-time assessment of treatment response and resistance and predict pCR.
NCT05333874.
The authors.
Natera supported us with patient testing for ctDNA. Funding was institutional funding-through Rutgers Cancer Institute if New Jersey.
M. George: Financial Interests, Institutional, Funding: Incyte, Oncolytics; Financial Interests, Personal, Advisory Board: Seattle Genetics, OBI Pharma. E. Kalashnikova: Financial Interests, Personal, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera. R. Watters: Financial Interests, Personal, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera. A.A. Rodriguez: Financial Interests, Personal, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera. S. Ganesan: Financial Interests, Personal, Advisory Board: Merck, Roche, Foundation Medicine, Ipsen, Foghorn Therapeutics, SilaGene, EQRx, Kayothera; Financial Interests, Institutional, Funding: M2GEN, Gandeeva; Other, Spouse employed: Merck. D. Toppmeyer: Financial Interests, Personal, Other, Spouse employed: Merck. M.C. Liu: Financial Interests, Personal, Full or part-time Employment: Natera; Financial Interests, Personal, Stocks/Shares: Natera; Financial Interests, Institutional, Research Grant: Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, Tesaro; Financial Interests, Institutional, Advisory Board: AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, Syndax; Financial Interests, Institutional, Other, Travel reimbursement: AstraZeneca, Genomic Health, Ionis. All other authors have declared no conflicts of interest.
MammaPrint (MP) and BluePrint (BP) signatures have been validated in the adjuvant setting to identify patients for which adjuvant chemotherapy (CT) could be spare. Neoadjuvant Chemotherapy (NCT) is a common approach for patients (pts) with clinically high-risk Early Breast Cancer (EBC). Other options include neoadjuvant endocrine therapy (NET) or primary surgery particularly for those patients with low-risk luminal tumors. In the DETERMIND study, we explore whether pre-operative use of MP/BP may help clinicians to reinforce the best treatment strategy for clinically high-risk patients.
DETERMIND is a prospective, open-label, multicenter study, assessing the utility of the MP/BP signature on the decision-making process of optimal therapy for patients with operable clinically high-risk HR+/HER2- EBC, stage II-IIIA (up to N1) and recommendation for NCT. A total of 165 pts have been included in 11 centers. Patient data will be collected at inclusion (baseline), and at the time of MP/BP results and at 1- and 3-years follow-up.
This initial analysis includes the first 99 pts: Median age was 57 years (range 31-85), 94% were stage II, and 51% cN1. By MP/BP, 37 pts (37%) were classified as Luminal A, 58 (59%) as Luminal-B, and 4 cases presented as non-Luminal phenotype (3 Basal, 1 HER2). In line with MP/BP results, 44 pts did not receive NCT. In the MP/BP Luminal A group, 35 pts (95%) did not receive NCT, and for 19 pts it was replaced by NET. Patients with MP High-Risk received NCT in 53 cases (85%). The confidence on the final treatment decision by physicians and patients was significantly increased by the MP/BP result.
In clinical high-risk HR+/HER2- EBC pts with criteria for NCT there is a high prevalence (35%) of MP/BP Luminal A, who were able to de-escalate NCT. MP/BP also further supported decision to administered NCT in the majority (85%) of patients with MP High Risk. Our findings support the utility of MP/BP in high clinical risk HR+/HER2- EBC to guide neoadjuvant therapy decision and provide further information and confidence to clinicians and patients for shared-decision making.
FISABIO.
Agendia N.V.
A. Llombart Cussac: Financial Interests, Institutional, Project Lead: Agendia; Financial Interests, Personal, Expert Testimony: Agendia; Financial Interests, Personal, Invited Speaker: Agendia. All other authors have declared no conflicts of interest.
Pathological complete response (pCR) is a surrogate biomarker of survival in Human Epidermal Growth Factor Receptor 2-positive (HER2+) breast cancer (BC) and more likely to occur in hormonal receptor (HR) negative (-). In the early efficacy and safety analysis of the ZoNAnTax trial, 4 cycles of doxorubicin/cyclophosphamide with ZOL, followed by 4 cycles of docetaxel with trastuzumab and ZOL prior to surgery induced similar pCR rates in HR positive (+) 40% and HR- 44%, and were well tolerated. The translational analysis demonstrated the mechanistic behind the clinical results, including the crosstalk between the WNT, HER2 and estrogen pathways with the mevalonate pathway and the modulation by ZOL being relevant to the treatment response in HR+/HER2+BC. Here we present the 5-years (5y) disease-free survival (DFS) and overall survival (OS) for the entire study sample according to pCR status and stratified by HR.
Kaplan-Meier Survival curves were estimated, and the Log-rank statistical test was performed to evaluate the hypothesis of survival differences between groups according to pCR status at 5% level of significance.
From 71 HER2+ BC patients with stage IIA-IIIB, 58 were eligible for efficacy analysis. Overall DFS rate was 79.3%, for patients achieving pCR was 83.3% versus (vs) non-pCR 76.5% (p=0.57), and for HR+ was 81% vs HR- 75% (p=0.58). DFS according to pCR status stratified by HR for HR- achieving pCR was 71.4% vs non-pCR 71.8% (p=0.72) and for HR+ achieving pCR was 88.2% vs non-pCR 76% (p=0.32). Overall OS rate was 86.2%, for patients achieving pCR was 95.8% vs non-pCR 79.4% (p=0.08), and for HR+ was 85.7% vs HR- 87.5% (p=0.91). OS according to pCR status stratified by HR for HR- achieving pCR was 100% vs non-pCR 77.8% (p=0.23) and for HR+ achieving pCR was 94.1% vs non-pCR 80% (p=0.20).
Taken together with the safety and early efficacy, the long-term benefit of the ZoNAnTax regimen demonstrating DFS and OS rates as high as reported by pivotal studies that contained Pertuzumab in the same setting, suggests that adding ZOL as a repositioning drug to the NT of HER2+ BC should be considered.
NCT01472146.
Instituto Nacional de Cancer Hospital do Cancer III - INCA Rio de Janeiro, Brazil, 20560-120.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer patients undergoing PET/CT scans for neoadjuvant systemic therapy may have non-breast cancer (BC) related finding. The aim of this study is to describe the incidence, additional work-up and possible impact of these findings.
We included BC patients who underwent a PET/CT scan in our institute between 2011-2019 prior to neoadjuvant systemic therapy. An additional finding was defined as a non-physiologic abnormal lesion only depicted by PET/CT. Patients with a BC-related or no additional finding were excluded. For the remaining patients with a non-BC related additional finding, we retrospectively gathered information on the additional work-up and the clinical consequences.
Of the 1337 patients included, 561 had additional findings on PET-CT, of whom 258 had a non-BC related additional finding. Further work-up was conducted in 202 patients (78%), including 282 examinations during initial work-up. In these 202 patients the non-BC related findings were detected in the endocrine region (26%), gastro-intestinal region (16%), lungs (15%), bones (14%), distant lymph nodes (11%), urogenital region (11%), liver (10%) and other (5%). In the end, 17 (8%) of the 202 patients were diagnosed with malignant and 138 patients (68%) with benign lesions. Only 8 patients (4%) had an additional non-BC related finding that was considered a more prognosis-determining diagnosis than their breast cancer disease. Malignant and prognosis-determining non-BC related additional findings mostly occurred in the endocrine, gastro-intestinal and urogenital region.
PET/CT scans used for dissemination imaging in breast cancer patients detect a high number of non-BC related additional findings, with the majority being clinically irrelevant and causing a relatively large amount of unnecessary additional work-up. Additional non-BC related findings in the endocrine, gastro-intestinal and urogenital region have a higher change of being malignant. Clinicians should be aware of potential non-BC related PET/CT findings and carefully consider the clinical implications.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
We aimed to reveal the prognostic value of the inflammatory-nutritional prognostic score (INPS), a new scoring system using immune-nutritional markers, in breast cancer with NACT.
Patients who were treated in Dokuz Eylul University Department of Medical Oncology and diagnosed breast cancer with NACT were included in this study retrospectively.We selected the most valuable biomarkers (Alb, Alb/ALP Ratio (AAR), ALBI, CRP, CRP/Alb Ratio,HALP, LDH, MLR, NLR, PLR, PNI, SII) to develop INPS by the least absolute shrinkage and selection operator (LASSO) Cox regression model. A prognostic nomogram incorporating INPS and other independent clinicopathological factors was developed based on the stepwise multivariate Cox regression method. The retained features with nonzero coefficients were used to establish a novel INPS. The selected four biomarkers were used to construct the novel INPS for our patients.Survival curves by INPS status were generated using the Kaplan-Meier method with logrank tests.
Median follow-up time of 98 patients was 22.1 months(95% CI= 2.2-149.3) and DFS was 24.0 months (95%CI= 4.8-128.0 ). While 13.3% (n=13) of the patients relapsed, also 7.1% (n=7) died. The 98 patients were randomly divided into the train (n = 65) and test (n = 33) sets in a 2:1 ratio. Using the LASSO Cox regression model, four inflammatory-nutritional biomarkers with nonzero coefficients, namely, AAR, ALBI, LDH, and CRP, of the 14 parameters were selected.The optimum cut-off value was determined for these four markers according to DFS, and the groups were divided into low and high according to these cut-off values for INPS. Kaplan-Meier curves in both the train and test sets showed significant differences in the survival probabilities of the low INPS and high INPS groups. A prognostic nomogram including INPS and other independent clinicopathological factors was developed.
In breast cancer patients receiving NACT, it has been shown for the first time in the literature that INPS, created with immune-nutritional markers, can be used as a prognostic tool on DFS in this patient group.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
The role of HER2 status as possible predictor of pathological complete response (pCR) and disease-free survival (DFS) in Luminal-HER2-negative EBC patients undergoing NACT is currently unclear. In this regard, a retrospective analysis evaluating the correlation between HER2 status (low vs score 0) and pCR/DFS was conducted.
Data of EBC patients undergoing NACT and surgery were collected. HER2 low breast cancer (BC) was defined as IHC score of 1+ or 2+ with negative FISH. Concordance of HER2 status at biopsy and residual disease (RD) was analyzed. Logistic regression model and Cox proportional hazard model were adopted to investigate the putative independent role of HER2 status and outcomes of interest (pCR, CPS-EG and DFS).
566 patients were included: 340 (60%) were HER2 low and 226 (40%) were HER2 0; 294 (61%) and 186 (39%) of non-pCR patients had HER2 low and HER2 0 expression on biopsy, respectively. 281 (63%) had HER2 low expression on RD. The HER2 discordance rate was 35% (158/452), with 17% (78/452) converting from HER2 0 to HER2 low and 17% (76/452) from HER2 low to HER2 0. The concordance rate of HER2 low BCs between pre- and post-NACT was significantly higher than that of HER2 0 BCs (71% vs 55%,
Among Luminal-HER2-negative EBCs, our results do not support a clear predictive and prognostic effect of HER2 status, although a trend of worse pCR and better survival for HER2 low BCs cannot be ruled out.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer is the fourth leading cause of disability and death among all cancer types around the world. Cancer-associated inflammation is a key characteristic of tumor microenvironment which could be responsible for mechanism and pathogenesis of tumor aggregation and progression. In the present study, we sought to evaluate the prognostic value of Systemic Inflammation Response Index (SIRI) and Systemic Immune-Inflammation Index (SII) for a cohort of patients with locally advanced breast cancer receiving neoadjuvant chemotherapy (NACT).
Patients were included if they had confirmed diagnosis of locally advanced breast cancer by core needle biopsy. All patients underwent NACT prior to complete or partial excisional surgery of the breast tumor. The optimal cut-off values for inflammatory markers (i.e., SII, and SIRI) were evaluated by the receiver operating characteristic curve (ROC) analyses. The independent prognostic value of these indices was assessed by the cox proportional hazards regression model.
A total of 112 patients were included. The median follow-up time was 22 months. According to the ROC curve, the optimal cut-off value for SIRI and SII that predict disease-free survival (DFS) was 0.95 and 582 x 109/L, respectively. Higher SIRI and SII were associated with lower rate of pathologic complete response (pCR) (p<0.01) and higher rate of recurrence (p<0.01). In univariate analysis, the level of SIRI and SII negatively impacted DFS as follows: not reached vs 16.1 months (HR 14.83, 95%CI 3.26-67.44) and not reached vs 16.5 months (HR 20.08, 95%CI 2.62-53.78), respectively. No such effect was evident on overall survival (OS). HER2 status and platelet-lymphocyte ratio (PLR) were also independently correlated with DFS while none could significantly predict OS.
In this study, we established SIRI and SII as novel and easily accessible prognostic factors for cancer progression and response to therapy. These results can offer potential therapeutic benefit with cut-off values to be standardized further.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
In this study, we have compared the clinicopathologic characteristics of HER2-low breast cancer to HER2-zero and HER2-positive breast cancer, including response to neoadjuvant chemotherapy and prognosis.
Patients who underwent neoadjuvant chemotherapy between 2008 and 2018 at Asan Medical Center were included in this study. HER2-low was defined as immunohistochemistry (IHC) 1+ or IHC2+/in-situ hybridization negative and HER2-zero was defined as IHC 0.
A total of 1667 breast cancer patients who had neoadjuvant chemotherapy were included in this study. Among them 474 (28.4%) patients had a HER2-low tumor, 677 (40.6%) patients with a HER2-zero tumor and 516 (31.0%) patients with a HER2-positive tumor. The proportion of HER2-low tumors was higher in hormone receptor (HR)-positive patients compared to triple-negative breast cancer (TNBC) patients (49.5% vs 28.9%, respectively). HER2-low tumors had a significantly lower pCR rate compared to HER2-zero tumors (11% vs 15.4%, p=0.04). pCR rate was also significantly lower in HER2-low tumors compared to patients with HER2-positive tumors who were not treated with neoadjuvant HER2-targeted therapy (11% vs 17.4%, p=0.008). However, pCR rates did not differ according to HER2 status in HR-positive subgroups or TNBC subgroups. Patients with HER2-low tumors had significantly longer survival compared to patients with HER2-zero tumors (5-year RFS 78.8% vs 73.3%, log-rank test p=0.017; 5-year OS 90.8% vs 84.0%, log-rank test p=0.005). Survival differences were seen in patients with TNBC tumors (5-year RFS 73.5% vs 64.8%, log-rank test p=0.034), but not in patients with HR-positive tumors (5-year RFS 80.8% vs 81.5%, log-rank test p=0.87). Survival difference according to HER2-low status was only identified in TNBC patients with non-pCR, whereas no difference was noticed in TNBC patients with pCR (5-year RFS: low/pCR 92.7%, zero/pCR 90.0%, low/non-pCR 68.6%, zero/non-pCR 56.7%; log-rank test p<0.001).
HER2-low tumors have a distinct biology presenting with lower pCR but longer survival rate compared to patients with HER2-zero tumors. These results suggest a need for better understanding of the biology of HER2-low tumors and the refinement of future therapeutic strategies.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
The role of concurrent neoadjuvant endocrine therapy with chemotherapy in HR+HER2- breast cancer remains controversial. This systematic review and meta-analysis was conducted to better assess the efficacy and safety of this strategy in patients with HR+HER2- breast cancer.
The trials in which patients with HR+HER2- breast cancer were randomly assigned to receive neoadjuvant chemotherapy alone or with concurrent endocrine therapy were eligible for inclusion. Prime endpoint was the pathological complete response (pCR) rate. Clinical response (complete clinical response: CR, partial response: PR) and safety were secondary endpoints. A random effects model was used to perform statistical analyses.
A total of 695 patients from five trials were included. PCR rate was 10.34% in concurrent endocrine group and 7.78% in control group (OR=1.40, 95%CI 0.71-2.75, P=0.33). CR rate was 15.65% in concurrent endocrine group and 10.20% in control group (OR=1.66, 95%CI 0.99-2.79, P=0.05). ORR (CR+PR) was significantly higher in concurrent endocrine group than in control group ( 79.42%(274/345) vs. 69.97%(240/343) , OR=1.69, 95%CI 1.19-2.42, P=0.004) and the meta-analysis approach showed no heterogeneity(I2=0%, P=0.54) . Concurrent tamoxifen with chemotherapy could potentially increase the occurrence of adverse events while aromatase inhibitors (AIs) would not.
Our findings provide evidence for the efficacy and safety of concurrent neoadjuvant endocrine therapy (AIs) with chemotherapy as an available option to achieve a higher clinical response rate for HR+HER2- breast cancer patients compared with chemotherapy alone with low toxicity.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
The efficacy of neoadjuvant chemotherapy (NAC), as measured by the pathological complete response (pCR), varies between molecular subtypes in breast cancer (BC). Oestrogen receptor (ER)-positive, human epidermal growth factor 2 receptor (HER2)-negative patients tend to have lower pCR rates. The transcription of the progesterone receptor (PR) is dependent on the ER therefore PR negativity may suggest an erroneous oestrogen signalling pathway rendering resistance to endocrine therapy. PR- tumours tend to be more aggressive but more chemosensitive. This study aimed to determine if PR status, no longer routinely tested in ER+ BC in the UK, can identify which ER+/HER2- patients will achieve pCR. This would enable more appropriate selection of patients for NAC.
Patients undergoing NAC at the Royal Victoria Infirmary, Newcastle, between 2013 and 2021 were identified and their clinicopathological features were collated in a retrospective dataset. PR status was ascertained with standard immunohistochemistry. The PR score was correlated with the pCR rate. Overall survival (OS) and disease-free survival (DFS) were calculated against pCR.
244 patients were included in the analysis (78 triple-negative BC (TNBC); 25 ER+/HER2-; 141 HER2+). In the ER+/HER2- group, PR- patients achieved higher rates of pCR compared to PR+ patients (31% and 9%; χ2; p=0.327). The pCR rate in the ER+/HER2-/PR- group was not statistically different to that of TNBC (31% and 29%; Fisher’s exact test; p=1.000). In the ER+/HER2+ group, PR- patients achieved higher rates of pCR than PR+ patients (23% and 4%; χ2; p=0.090). The breast pCR rate in the ER+/HER2+ group was statistically different (52% and 24%; χ2; p = 0.015) when comparing PR- and PR+ patients. Oncological outcomes of patients that achieved pCR were significantly improved (DFS p = 0.005; OS p = 0.032).
PR- patients achieved higher rates of pCR in both ER+/HER2- and ER+/HER2+ subtypes. ER+/HER2-/PR- tumours may behave more like TNBCs than hormone-positive BCs and require more aggressive chemotherapeutic strategies. PR status has value in determining which ER+ patients might benefit from NAC with improved oncological outcomes.
Newcastle University.
Roche.
H.J. Cain: Financial Interests, Personal, Advisory Board, Honorarium for speaking, research grant, support with travel: Roche Medical; Financial Interests, Personal, Invited Speaker, Ad board, research grant: Exact Health; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker, Ad board: Baxter; Financial Interests, Personal, Advisory Board, Honorarium for speaking: Lilly, Merck&Co (MSD), AstraZeneca; Financial Interests, Personal, Advisory Board: Veracyte. All other authors have declared no conflicts of interest.
Pembrolizumab is now part of a neoadjuvant (NA) regimen for patients (pts) with triple-negative breast cancer (TNBC) that results in a higher pathologic complete response (pCR) rate compared to chemotherapy alone (Keynote 522). However, real-world experience will reveal the true tolerability of the regimen. This retrospective review at a single tertiary care center aims to evaluate side effects (SEs), treatment changes/interruptions, urgent care (UC), ER visits, and hospitalizations in pts who received NA Keynote 522 (pembro) compared to chemotherapy alone (chemo), and to compare to the results of the phase III Keynote 522 trial.
229 patient charts were reviewed. Included pts had stage II/III TNBC and received NA pembro from 2/2020 - 8/2022 or NA chemo from 7/2017 - 1/2020. Demographics, blood test results, # of UC, ER visits, and hospitalizations during treatment were collected. Provider notes and plans were reviewed for SEs and changes or interruptions during treatment. Data were analyzed using SPSS Statistics. Chi-square tests were performed on categorical variables.
There were 28 and 45 patients in the pembro and chemo groups, respectively. Age, race, ethnicity, & surgery type were similar between groups. Pts in the pembro group had more advanced stage at diagnosis (p = 0.003). pCR rate was higher in the pembro group (53.6% vs 35.6%). Neutropenia, rash, infusion reaction, thyroid abnormalities, and grade 3 LFT elevations were more common in the pembro group (p = <0.001, <0.001, 0.01, <0.001 and 0.025). Pts in the pembro group had more treatment interruptions (67.9% vs 13.3%, p < 0.001), changes due to SEs (57.1% vs 11.1%, p < 0.001), and ER and UC visits (p = 0.012 and p <0.001). More frequent SEs were observed in the pembro group compared to the Keynote 522 trial pembro arm (anemia (96.4% vs 55.1%), neutropenia (71.4% vs 46.7%), fatigue (89.3% vs. 41.1%), & neuropathy (57.1% vs 19.7%)).
In this study, the Keynote 522 regimen was more poorly tolerated compared to chemo alone with increased SEs and treatment changes/interruptions. While the pCR rate was higher, potential SEs and treatment changes/interruptions must be considered when selecting appropriate pts for treatment.
The authors.
Departmental funding from the Department of Oncology at Rush University Medical Center.
R. Rao: Financial Interests, Personal, Advisory Role: Novartis, Puma Biotechnology, Genentech/Roche, Seattle Genetics, Immunomedics. All other authors have declared no conflicts of interest.
Globally, triple-negative breast cancer (TNBC) is responsible for approximately 15% of all invasive Breast cancer and some retrospective studies have suggested a more advanced presentation and poorer treatment outcome in the Middle East and North African Arab countries. Nevertheless, there is complete lack of prospective reliable data on this topic. The TRIPOLI study aims to bridge this information gap.
Tripoli is an ongoing prospective multinational disease registry including newly diagnosed patients with TNBC from 17 institutions within 9 Arab countries. Herewith, we present Interim Analysis-2, including 590 patients with early TNBC (eTNBC). This report focuses on the treatment patterns and pathology outcomes for patients who received neoadjuvant chemotherapy (NAC).
Of the 590 patients with eTNBC that were included within TRIPOLI, 535 (90,6%) were stage II and III. 421 patients (71.5%) had a tumor size ≤ 5cm and majority of patients were grade 3 invasive ductal carcinomas. Only 213 (39,8%) were offered NAC and proceeded for surgery. Among those, 115 (54%) had tumor size ≤ 5cm and 139 (65%) had node+ disease. 163 (76%) received a combination of AC+T (Adriamycin/Cyclophosphamide + Taxane) while carboplatin was added in 43 (20%) patients. No patient received immune checkpoint inhibitors (ICIs). 70 (32,8%) patients achieved a pathological complete response (pCR). The pCR rate was 39,1% in patients who presented with stage II and 26,6% in those with stage III. Multivariate analysis of tumor size, histological subtype, grade ,lymph node involvement and addition of Carboplatin did not reveal any significant association with the pCR status. Among the 143 non-pCR patients, 45 (31.7%) received Capecitabine as adjuvant chemotherapy after surgery.
Baseline characteristics in patients treated in neoadjuvant setting differ in Middle East real-life practice from international clinical trials with more advanced tumors and less utilization of NAC during the study period. pCR rate achieved in this study is lower than what has been recently reported by more effective therapies including ICIs.
The authors.
MSD Sharp & Dohme.
H.A. Azim: Financial Interests, Personal, Research Grant: Pfizer, MSD, ASZ; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Novartis, MSD, ASZ, Lilly, BMS, Roche, EVA Pharma; Financial Interests, Personal, Advisory Board: Pfizer, Novartis, MSD, ASZ, Lilly, BMS, Roche, EVA Pharma; Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, MSD, ASZ, Lilly, BMS, Roche, EVA Pharma. All other authors have declared no conflicts of interest.
Young age and pathogenic germline
The study included retrospective real-world data of young women with breast cancer before the age of 40 undergoing neoadjuvant chemotherapy. All patients were diagnosed between 2008-2019 and presented at Charité – Universitaetsmedizin Berlin. Patients with missing germline testing, pathogenic germline variants in
A total of 143 cases were included in the analysis, of which 62 (43.4%) achieved pCR. gBRCA1m was most prevalent in triple-negative patients (38/79) and less prevalent in HR+/Her2- (10/33) and Her2+ patients (2/31). Patients with gBRCA1m achieved pCR more often than patients with gBRCA1wt (58.0% vs. 35.5%). This was associated with a crude odds ratio of 2.51 (95% CI 1.24-5.08, p=0.010). The associated increase of the pCR-rate varied across clinical subtypes. gBRCA1m was associated with a significant increase of the pCR-rate in patients with HR+/Her2- subtype (60.0% vs. 8.7%, p=0.002) and a not significant increase in triple-negative patients (60.5% vs. 39.0%, p=0.056). Among Her2+ patients, both gBRCA1m patients did not achieve pCR and gBRCA1wt patients had a pCR rate of 51.7%.
Triple-negative and especially HR+/Her2- breast cancer in young women might be more chemosensitive if associated with a pathogenic germline variant in
DRKS00021459.
Charité-Universitaetsmedizin Berlin, Department of Gynecology with Breast Centre, AG Karsten-Speiser.
Has not received any funding.
J. Blohmer: Financial Interests, Personal and Institutional, Other, honoraria, AdBoard, training event funding: AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Seagen; Financial Interests, Personal and Institutional, Other, training event funding: BD, SonoScape, Somatex. D. Speiser: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca. M.M. Karsten: Financial Interests, Personal, Invited Speaker: Roche, Gilead, Sysmex. All other authors have declared no conflicts of interest.
Pertuzumab (P) has been approved in neoadjuvant setting for HER2-positive early breast cancer patients (pts) in association with Trastuzumab (T) and chemotherapy. Diverse studies support this treatment. The pathologic complete response (pCR) showed achieve percentages from 45.8 % to 66.6% depending on chemotherapy combination.
This is a retrospective and multicentric study. We have collected all HER2-positive early breast cancer pts treated with P in neoadjuvant setting in our hospitals between 2015 and 2018. The effect of adding P on pCR was analyzed, as well as other predictive factors of response using logistic regression analyses. Kaplan Meier analysis has been used for survival analysis.
A total of 310 pts met the selection criteria. The median age was 51 years (22-88 years), 54,5% were premenopausal. 4 pts were stage I, 204 pts stage II, 101 pts were stage III. The majority of the patient received anthracyclines and taxanes with P and T regimen (77,1%), 16,5% received carboplatin-docetaxel-P-T combination and 6,5% received taxane-P-T. 307 pts were analysed for response. pCR was seen in 62,2 % of the pts, dividing by hormonal receptor (HR) status, pCR was 53,8% in HR-positive and 71,1% in HR-negative. Treatment was well tolerated with only 14.8 % G3-4 adverse events related to chemotherapy and 1.9% related to antiHER2 therapy. Different adjuvant treatments patterns were seen between hospitals. After a follow-up of 7,5 years, 43 pts (13,9%) had a distant relapse, 16 of them (37,2%) had achieved a previous pCR. 38,5% had CNS recurrence and 61,5% non-CNS recurrence. In multivariate analysis non-pCR pts have 3.9 relative risk of experience disease relapse event (p 0.0001; 1.84-8.88), and patients with stage III at diagnosis have 4.3 relative risk (p 0.00004; 2.15-8.75). Disease free-survival (DFS) rates at 7.5 years is 86.4 %. After separating between pCR outcomes, results were statistical significative (p < 0.0001) with DFS rates of 89.4% in pCR pts and 70.6% in non-pCR pts.
In our knowledge, this is the first real-world study that shows survival results for adding Pertuzumab in the neoadjuvant setting of HER2-positive breast cancer patients. Our results are consistent with those previously published.
The authors.
Has not received any funding.
A. Falcon Gonzalez: Non-Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo, Roche, Novartis, Seagen, Pfizer, Eisai; Non-Financial Interests, Personal, Advisory Board: Medtronic, Pfizer, Seagen. J. Cruz Jurado: Financial Interests, Personal, Advisory Board: PharmaMar, Roche, Lilly, Pfizer, Novartis, Gilead, AstraZeneca, Daiichi, Seagen, GSK, Bayer; Financial Interests, Personal, Invited Speaker: PharmaMar, Roche, Lilly, Pfizer, Novartis, Eisai, Gilead, AstraZeneca, Daiichi, Seagen, Esteve, Roche. All other authors have declared no conflicts of interest.
It remains inconclusive whether germline
We reviewed a total of 442 breast cancer patients who underwent g
We detected pathogenic
In this analysis, patients with g
Eun-Shin Lee.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer (BC) has emerged as a commonest cancer in India. There is a shift of transition from axillary lymph node dissection (ALND) to sentinel lymph node biopsy (SLNB). Recently SLNB is emerging as an option following neoadjuvant chemotherapy (NACT). To formulate policies for ALN management, we present our experience of the pattern of ALN involvement among Indian BC patients and also to assess the scope of SLNB among LABC patients.
This study is conducted in a tertiary care center, North India. A prospective breast cancer computerized data base was created and data captured from 1992 to 2020. A total of 4186 ALNDs done were analyzed and 1998 ALNDs were done in LABC patients.
Mean age was 48.5years. Stage-wise distribution where ALND was done is 5.16% in stage I, 41.92% in stage II, 47.73% in stage III and 4.06% in stage IV. Pathologic node positivity was seen in 55.75% patients and node negativity in 44.24% patients. Among 1998 LABC patients analyzed, 47.49% patients received NACT and 52.5% patients had upfront surgery. Among patients who received NACT, pathologic node positivity was seen in 59.95% patients and 40.04% had pathologic complete response (pCR) in nodes. This shows NACT improves node-negative status. Among NACT group, 53.78% patients were node negative with cN0, 39.74% patients with cN1, 35.22% patients with cN2 and 38.46% patients with cN3.
This study is one of the largest ALND series in LMIC. Overall lymph node positivity rates among Indian breast cancer patients are high due to heavy nodal burden disease at presentation. Results indicate that de-escalation of axilla from ALND to SLNB is feasible in approximately 40% undergoing NACT.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Some recent evidence has suggested that HER2-low breast cancers (BC) are distinct entities. The prognostic impact of low expression of HER-2 are not yet well defined, and inconsistent results were reported. This study aims to evaluate the impact of low HER-2 status on the response to neoadjuvant chemotherapy (NACT).
We retrospectively analyzed HER2-negative BC patients treated with NACT from 2017 to 2022 in a single academic center. HER-2 low status was defined by IHC +1 or +2 ISH non-amplified, and HER2-zero was defined by IHC 0. The primary objective was to compare pathological complete response (pCR) rates between HER2-low and HER2-zero populations.
101 patients were identified. 70 (69.3%) patients had hormone receptor (HR) positivity, and 31 (30.7%) patients had TNBC. Overall 70 (69.3%) patients were HER2-zero and 31 (30.7%) patients were HER2-low. Among HR-positive patients, 25 (35.7%) were HER2-low, while only 6 (19.3%) patients were her2 low in TNBC group,There were no significant differences in median age, Ki67 score, histology, menopausal status, histologic grade, or T stage between the HER2-zero and HER2-low groups. There were also ER level differences between HER2-zero and HER2-low tumors; the median ER level was 75% for HER2-zero tumors and 90% for HER2-low tumors (p = 0.028). Overall, pCR was achieved in 24 (23.7%) patients. Among HER2-zero patients 21 (30%) had pCR while 3 (9.7%) patients had pCR in the HER2-low group (p=0.027). In the HR-positive subtype, there were still statistically significant pCR differences between the two groups. 15 patients had pCR in the HR-positive group; among these, 13 (87%) patients had HER2-zero tumors, while 2 (13%) of them had HER2-low tumors (p = 0.041). In the TNBC subtype, 9 patients had pCR; 8 (89%) of them had HER2 zero and 1 (11%) had HER2-low tumors, but there was no statistical significance in the TNBC group (p = 0.642).
Our results show that HER2-low tumors have a different response to NACT. Both in the overall group and the HR-positive subgroup, HER2-low tumors had significantly lower pCR rates. Because of the cross-talk between HR signaling and HER2 signaling, low HER2 expression may be responsible for treatment resistance in HR-positive BC.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Trastuzumab biosimilar were first tested and introduced in the metastatic setting. There use in the neoadjuant setting is based on equivalence on pathological complete response rate (pCR), which remain the preferable surrograte factor in Her2-positive tumors. Two biosimilars are available at ower institution since 2017 (Hertraz® 440mg Mylan and CanMab ® AbdiBrahim). The aim of this study is to compre efficacy of trastuzumab biosimilar compared to Referent Trastuzumab based on pCR.
A retrospctive study was conducted based on 193 files of stage I-III her2-positive breast cancer treated with neoadjuvant chemotherapy (NACT) including trastuzumab only, since pertuzumab is not available at our level. Baseline characteristics between the two groups were compared. A first analyse of relatio between the use trastuzumab and pCR rate was done, then a multivariate analysis added to this parameter significant predictive factors (TNM stage, molecular sub-groupe, ER/PR levels, Ki67, histology).
A total of 99 patients includes in the Referent group and 94 in the biosimilars group. Baseline characteristics are summarized in the table.
Referent trastuzumab Biosimilars Median age (min-max) 48.1 52.4 Premenopusal (%) 59.6 55.3 T: T1-2-3-4 (%) 6.1-44.4-22.3-28.3 3.2-28.7-31.9-36.2 N: 0-1-2-3 (%) 36.4-53.5-10.6-0 35.1-47.9-6.4-10.6 Stage: I-IIA-IIB-IIIA-IIIB-IIIC (%) 6.1-25.2-24.2-20.2-24.2-0 1.1-19.1-25.5-15.9-27.6-10.6 Histology: IDC-ILC-Other (%) 83.8-14.1-2 89.4-7.4-3.2 ER (median) 30.5% 42.5% PR (median) 20.6% 30.1% Ki67 (median) 37.4% 37.3% Molecular group (Luminal) 52.5% 71.3%
We noticed a statistically significant difference between luminal rate in the two arms (p=0.021) pCR rate in biosimilar arm was 41.5% vs 37.8% in the Referent groupe (p=0.331). In multivariate analysis none of the cited parameters was considered as a predictive factor of pCR.
Our study demonstrated the efficacy of trastuzumab biosomilar compared to Referent trastuzumab in the neoadjuvant setting, since the two arms whowed comparable pCR rates, even if more luminal tumors were recorded in the biosimilar arm, considered as resistance factor to neoadjuvant treatment. This is an important result considering different cost of the two options.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Oncotype DXBreast Recurrence Score® assay guides recommendations made to patients with ER+/HER2- breast cancer regarding post-surgery adjuvant therapy. Standard practice is to perform this on the surgical excision specimen following surgical treatment, but it is technically possible to perform the Oncotype DX® test on the diagnostic core biopsy (DCB). Testing the DCB should eliminate the wait for surgical excision specimen Recurrence Score® (RS) results, and patients could be more accurately counselled at an earlier time-point regarding their treatment pathway and adjuvant treatments expedited allowing more efficient streaming of follow up appointments.
PRE-DX is a UK based multi-centre, parallel group randomised controlled trial (2:1; Intervention:Control) which opened to recruitment in October 2022. The trial is comparing the impact on the patient pathway of performing the Oncotype DX test on the DCB pre-operatively (intervention) as opposed to the surgical excision specimen (control). Patients aged ≥ 18 year of age with ER+, HER2- tumours (grade 2 ≥20mm or grade 3 of any size and axilla N0 or N1 of any size / grade), with surgery planned as the primary definitive treatment and fit for chemotherapy are eligible. Patients are ineligible if they are already participating in another clinical trial. The primary endpoint is number of clinical touchpoints between treating team and patient from initial approach to offer and prescription of the first adjuvant treatment. Secondary endpoints include time from diagnosis to offer and prescription of the first adjuvant treatment, alteration in treatment sequence from original planned treatment, patient-reported anxiety scores, health cost impact analysis, and DCB failure rate for RS result. The study will recruit 330 patients from up to 25 participating National Health Service centres with recruitment expected to end in July / August 2023.
ISRCTN14337451.
Jess Hoag - Exact Sciences Purva Singla - Exact Sciences Gebra Cuyun Carter - Exact Sciences.
Newcastle upon Tyne Hospitals NHS Foundation Trust.
Genomic Health.
J. Cohen: Financial Interests, Personal and Institutional, Research Grant: Exact Sciences, AstraZeneca, ImaginAb. P. Roy: Financial Interests, Personal, Advisory Board: Exact Sciences. S. Reynia: Financial Interests, Personal and Institutional, Leadership Role: Exact Sciences; Financial Interests, Personal and Institutional, Stocks/Shares: Exact Sciences. H.J. Cain: Financial Interests, Personal, Advisory Board: Roche Medical, Exact Sciences, Baxter, Lilly, AstraZeneca, Merck & Co., Veracity; Financial Interests, Personal, Invited Speaker: Roche Medical, Exact Sciences, Baxter, Lilly, AstraZeneca, Merck & Co.; Financial Interests, Personal, Research Grant: Roche Medical; Financial Interests, Personal and Institutional, Research Grant: Exact Sciences. All other authors have declared no conflicts of interest.
A large component of the tumor microenvironment in breast cancer consists of cancer-associated fibroblasts (CAFs), a cell type which can influence tumor progression, angiogenesis and therapy resistance. Receptors on CAF are activated by ligands secreted from tumor cells resulting in establishment of a malignant paracrine crosstalk, supporting the tumor as a whole. Preclinical data suggests a specific role for tumor cell-secreted Platelet-derived growth factor-CC (PDGF-CC) in maintaining the triple-negative breast cancer (TNBC) phenotype through paracrine activation of PDGFR (Platelet-derived growth factor receptor) on CAFs. Inhibition of CAF PDGFR in preclinical TNBC breast tumor models resulted in tumors converting into a luminal ER subtype, with subsequent response to endocrine therapy. Imatinib, a PDGFR inhibitor, was tested in the preclinical setting leading to comparable results. To establish a proof-of-principle concerning if ER expression can be induced in patients, imatinib will be given to TNBC patients before surgery to analyze expression of ER before and after treatment.
The study is a window-of-opportunity phase II, single center clinical trial investigating the efficacy and feasibility of short term imatinib (400 mg per day for 10 days) for early TNBC patients planned for surgery, who are not eligible for neoadjuvant chemotherapy. The primary endpoint is to determine changes in ER expression before and after imatinib treatment by analyzing the diagnostic biopsy and the surgical specimen. If ER expression changes from 0% to 2% or more, or ER is changed from 1-9% to either ≥10% or at least 2% increase combined with a significant increase in luminal gene transcripts, the primary endpoint is met. Secondary endpoints include determining safety of short-term imatinib and assessing blood and tissue markers such as ctDNA (circulating tumorDNA), immune cell markers and analyses of activity in luminal gene expression programs. Thirty-five patients will be recruited with an interim analysis planned after recruitment of 20 patients. The study is now open for inclusion.
NCT05722795.
Vastra Gotalandsregionen/Department of Oncology, Gothenburg, Sweden.
Mats Paulsson Foundation, Cancera Foundation, The Swedish Cancer Society, Göran Grosskopf and Region Skåne ALF.
All authors have declared no conflicts of interest.
Physical exercise has been considered one of the relevant factors in breast cancer (BC) prevention and recovery. During cancer treatment, physical exercise has also been proven to help in coping with the side effects of chemotherapy and to shorten recovery following BC surgery. Moreover, some preliminary data showed that exercise can impact tumor growth and biology. However, the evidence describing the impact of exercise on cancer during neoadjuvant treatment remains scarce. Therefore, it is paramount to assess the impact of adding exercise during neoadjuvant therapy (NAT) on tumor characteristics and to elucidate the physical and psychological impact on patients, namely on their quality of life.
We aim to examine and compare the effects of two different exercise protocols (aerobic and resistance) against a relaxation control group on Ki-67 changes, as the primary outcome, in BC patients undergoing NAT. We hypothesize that both exercise groups will experience a more marked decrease in Ki-67 levels when compared to the control group. Secondary outcomes will include changes in body composition, physical fitness, quality of life, sleep efficiency and fatigue as well as dynamic changes in inflammatory and immune biomarkers, from baseline to end of NAT. A total of 132 histologically confirmed hormone-positive/HER2-negative (stage 0-III) patients with BC (≥ 18 years) scheduled for NAT (66 chemotherapy; 66 endocrine therapy) will be recruited and randomized to one of 3 groups: 1) aerobic training (moderate continuous cycling); 2) resistance training (3x 8-12 repetitions of 8 strength exercises; up to a maximum of 70%-maximum repetition); 3) control. The Ki-67 expression will be measured on the initial tumor biopsy and surgical specimen. Considering its multidisciplinary and translational nature, this trial will allow us to draw more robust conclusions on the impact of exercise on BC patients, laying a framework for future exercise-based interventions in cancer patients during NAT.
NCT05297773.
Champalimaud Foundation.
Has not received any funding.
All authors have declared no conflicts of interest.
The orally administered PROTAC ER degrader ARV-471 demonstrated potent ER degradation and tumor growth inhibition, including tumor regression, in preclinical models. In the first-in-human phase I/II study, once-daily (QD) ARV-471 monotherapy was well tolerated and showed antitumor activity in heavily pretreated patients with ER+/HER2- advanced breast cancer. Anastrozole, an aromatase inhibitor, is a standard treatment option for patients with ER+/HER2- localized breast cancer. Here we describe an open-label, randomized, noncomparative, multi-country phase II study (NCT05549505) to evaluate the safety and clinical activity of ARV-471 or anastrozole in patients with breast cancer amenable to definitive surgical resection.
The following patients are eligible for TACTIVE-N (N∼150): postmenopausal women (aged ≥18 years) with histologically or cytologically confirmed ER+/HER2- localized breast cancer with ER staining of ≥10% of tumor cell nuclei (Ki-67 score ≥5%, clinical T1c-T4c, N0-N2, M0 breast cancer). Patients with bilateral breast ductal carcinoma in situ, bilateral invasive breast cancer, or prior treatment for breast cancer are excluded. Patients will be randomized to receive ARV-471 or anastrozole orally QD until surgical resection approximately 5.5 months after starting treatment (cycle 6, day 18 ± 10 days). The primary objective is to evaluate the effect of ARV-471 or anastrozole on Ki-67 expression in tumors after 2 weeks of treatment. Secondary objectives include safety, pathological response (pathologic stage, pathologic complete response rate, and modified preoperative endocrine prognostic index score at the time of surgical resection), and clinical response (breast-conserving surgery rate, radiographic response rate during cycle 6, and best percentage change in caliper measurement on cycle 6 day 1).
NCT05549505.
Medical Writing Support: Beth Sesler, PhD, of Apollo Medical Communications, and funded by Arvinas Operations, Inc.
Arvinas Estrogen Receptor, Inc.
Arvinas Estrogen Receptor, Inc.
P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Sanofi Aventis; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Lilly, Seagen, Gilead; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BionTech, Cepheid; Non-Financial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v. K. Clifton: Financial Interests, Personal, Advisory Board: Biotheranostics, Pfizer; Financial Interests, Personal, Research Grant: Cancer and Aging Research Group; Financial Interests, Institutional, Research Grant: BMS. M. Lachowicz: Financial Interests, Institutional, Full or part-time Employment: Arvinas, Inc; Financial Interests, Institutional, Stocks/Shares: Arvinas; Other, From May 2017 until Feb 2022, I had a full time position as a Physician Assistant at the Yale New Haven Hospital Phase I clinic, which included being a sub-investigator on several Phase I/II Oncology clinical trials.: Yale New Haven Hospital. R. Gedrich: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas. J. Ranciato: Financial Interests, Personal, Full or part-time Employment: Arvinas. E. Zhi: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas; Financial Interests, Personal, Project Lead: Arvinas. J. Perkins: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Other, Patent Holder: Pfizer. S.A. Hurvitz: Financial Interests, Personal, Research Grant: Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, Cytomx, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, OBI Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics/Seagen, Zymeworks; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, AstraZeneca. All other authors have declared no conflicts of interest.
The decision of neoadjuvant treatment for high-risk HR+/HER2- EBC remains a challenge. Despite the availability of both CHT and ET, the risk of recurrence persists over time, highlighting the need for additional therapeutic strategies. In the TOT-HER3 trial, we have shown that a single dose of HER3-DXd, a first-in-class HER3 directed antibody drug conjugate, is associated with clinical response, increased immune infiltration and proliferation suppression, as well as a consistent and manageable safety profile in patients (pts) with HR+/HER2-negative early breast cancer (Prat et al. ESMO Breast 2022). These data have informed the design of the VALENTINE trial of HER3-DXd in the neoadjuvant setting.
VALENTINE is a parallel, exploratory, three-arm, randomised, open-label, exploratory study in pts with primary operable HR+/HER2-negative breast cancer with Ki67 IHC ≥ 20% and/or high genomic risk (defined by gene signature), aiming to evaluate the clinical benefit and biological effects of HER3-DXd (with/without letrozole (LET)) as a neoadjuvant treatment. A total of 120 treatment naïve pts will be randomly assigned in a 2:2:1 ratio to receive (1) HER3-DXd (5.6 mg/kg) every 21 days for 6 cycles; (2) HER3-DXd plus daily LET +/- LHRH analogs every 21 days for 6 cycles; (3) standard of care CHT consisting of 4 cycles of EC/AC (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 14/21 days) followed by weekly 80mg/m2 paclitaxel during 12 weeks. The primary endpoint is the rate of pathological complete response (ypT0/is ypN0) at surgery. Baseline, on-treatment (C2D1), and surgical specimens will be collected for molecular characterization and evaluation of response (ERBB3 gene expression, HER3 IHC; CelTIL change, research-based PAM50 subtypes). Additional samples for pharmacokinetic, genomic and circulating biomarkers will also be collected. Secondary endpoints include rate of residual cancer burden, overall response rate, invasive disease-free survival at 3 and 5 years and safety. An interim and final analysis are pre-planned.
EudraCT 2022-001181-36. NCT05569811, First Posted: February 18, 2021.
SOLTI Cancer Research Group.
Daiichi Sankyo Inc.
M. Oliveira: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo / AstraZeneca, Gilead, Pierre Fabre, Roche, Seagen, iTEOS, Relay Therapeutics; Financial Interests, Personal, Invited Speaker: Gilead, MSD, Novartis, Pfizer, Roche, Seattle Genetics, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer-Ingelheim, GSK, Roche, Seattle Genetics, Zenith Epigenetics, Gilead, Ayala Pharmaceuticals; Financial Interests, Invited Speaker: Roche; Non-Financial Interests, Invited Speaker: SOLTI Breast Cancer Research; Other, Travel Grant: Pierre Fabre, Eisai, Gilead, AstraZeneca. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. M. Munoz: Financial Interests, Personal, Expert Testimony: Roche, Novartis; Financial Interests, Personal, Other, International conference travel grants: Roche, Pfizer, Lilly, Gilead; Financial Interests, Personal, Advisory Board: Pierre Fabre, Seagen, AstraZeneca. C. Martinez Vila: Financial Interests, Personal, Invited Speaker, Melanoma Rising Stars Conference: Novartis; Financial Interests, Personal, Invited Speaker, Head and neck cancer Invited Speaker: BMS. P. Tolosa Ortega: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Lilly, Seagen, AstraZeneca, Daiichi Sankyo and MSD; Financial Interests, Personal, Advisory Board: Novartis, Adamed, Seagen and Daiichi Sankyo; Financial Interests, Personal, Full or part-time Employment, Medical Advisor and Madical Monitor: SOLTI. M. Margeli Vila: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Novartis, MSD, Gylead, Lilly, Piere Fabre; Financial Interests, Personal, Other, Travel expences: Gylead; Financial Interests, Institutional, Invited Speaker, I have received research funding for my institution from Pfizer: Pfizer. J.M. Cejalvo: Financial Interests, Institutional, Invited Speaker: Pfizer, Novartis. Y. Zheteyava: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. D.W. Sternberg: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. P. Fan: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. A. Santhanagopal: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. R. Sanchez Bayona: Financial Interests, Personal, Invited Speaker: Novartis, Lilly Oncology, GSK Oncology, AstraZeneca, Seagen, Clovis Oncology; Financial Interests, Personal, Other, Travel and accommodation: Pfizer; Financial Interests, Personal, Full or part-time Employment, Medical Advisor: SOLTI; Financial Interests, Personal, Other, Medical Monitor in HARMONIA Trial: Novartis. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation. All other authors have declared no conflicts of interest.
Immune checkpoint inhibitors (ICIs) are one of the major therapeutic advances in cancer treatment. Anti-PD(L)1 ICIs have been shown to improve progression-free survival and OS, in patients with metastatic triple-negative breast cancer (TNBC), and pCR and event-free survival in patients with early TNBC. Nevertheless, some patients treated with anti-PD(L)1 ICIs experience recurrence or do not achieve sustained clinical benefit. Expanding the efficacy and therapeutic target of currently available ICIs is an area of high unmet need. Several targeted agents (e.g. anti-VEGF, PI3KCA or AKT inhibitors) have been shown to impact the tumor-immune microenvironment (TIME) by influencing aspects of the immune response. Preclinical evidence supports the notion that AKT/VEGF inhibition can enhance anti-PDL1/PD1 efficacy through its effect on the TIME.
BIS Program is a window of opportunity trial designed to evaluate the biological effects of immunotherapy-based treatment combinations in patients (pts) with stage I-III, untreated, HER2-positive (HER2+)or TNBC that are eligible for upfront surgery or neoadjuvant systemic treatment (NST). The study, which will recruit 210 pts(147 in the TNBC cohort and 63 in the HER2+ cohort), builds on an adaptive, open, prospective randomized model that aims to determine whether short-treatment immunotherapy increases the level of activated GzmB+/CD8+ T cells between baseline and post-treatment samples. In the TNBC Cohort: pts are randomized 1:2:2:2 to observation, Atezolizumab (Atz), Atz + Ipatasertib or Atz + Bevacizumab; in the HER2+ cohort: pts are randomized 1:2 to observation or Atz + Trastuzumab + Pertuzumab. Primary endpoint: Two-fold increase in GzmB+/CD8+ T cell levels from baseline to post-study treatment samples. Secondary objectives: Effect of study treatment on pCR, immune biomarkers, and immune-related gene expression. Two FFPE and one frozen sample are collected at (1) the time of enrollment and (2)following surgical treatment in those who undergo upfront surgery or dedicated biopsy after study treatment in those who undergo NST. Blood samples will be collected at the time of enrollment, before surgery or the start of NST, and at the end of the study visit.
NCT05180006.
Gustave Roussy, Cancer Campus, Grand Paris.
This research collaboration was supported through the imCORE network on behalf of F. Hoffmann-La Roche.
J.T.M.L. M Ribeiro: Financial Interests, Personal, Advisory Board: Gilead Sciences, Inc.; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: eESO. F. André: Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi; Financial Interests, Institutional, Other, advisory board: Guardant Health; Financial Interests, Institutional, Other, Advisory board: MEDIMMUNE, Gilead, Relay therapeutics; Other, Founder: Pegacsy. S. Michiels: Financial Interests, Personal, Other, Statistical advice: Roche; Financial Interests, Personal, Other, DSMB member: Sensorion, Servier, Biophytis, Yuhan, IQVIA, Kedrion. F. Dalenc: Non-Financial Interests, Principal Investigator: Roche, AstraZeneca, gilead, Novartis. B. Pistilli: Financial Interests, Institutional, Advisory Board: AstraZeneca, Seagen, Lilly, Daiichi Sankyo, MSD; Financial Interests, Institutional, Invited Speaker: Gilead, Novartis, AstraZeneca, Gilead, Seagen, MSD, Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre, Daiichi Sankyo; Financial Interests, Personal, Other, travel support: AstraZeneca, Pierre Fabre, MSD, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Funding: Daiichi Sankyo; Non-Financial Interests, Project Lead: Unicancer. All other authors have declared no conflicts of interest.
Contralateral prophylactic mastectomy (CPM) has been performed for several decades in patients with unilateral breast cancer (BC). However, the survival benefits of CPM are controversial, particularly in young women.
The clinical data of 69,000 young female patients (age ≤ 40 years) who were diagnosed to have unilateral BC and underwent UM or CPM between January 1, 2000 and December 31, 2019 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. The following patients were excluded from the final analysis: age > 40 years, male, those with unconfirmed pathological diagnosis, those with bilateral BC, those lacking SEER cause-specific death classification, those lacking months of survival data, and those with uncertainty regarding UM or CPM.Propensity score matching (PSM) was performed between the CPM and UM groups. The overall survival (OS) rate and BC-specific survival (BCSS) rate were determined for both groups.
A total of 36528 patients (21600 and 14928 patients in the UM and CPM groups, respectively) were included in this study. The mean (SD) age of follow-up was 35.5 (4.0) years. The relative rate of CPM increased from 12.3% in 2000 to 55.7% in 2013 and then gradually decreased to 47.4% in 2019. After PSM, 13089 patients remained in each group. The CPM group showed a higher 5-year OS rate (82.1% vs. 75.8%) and a higher 5-year BCSS rate (83.5% vs. 77.7%) than the UM group. Multivariate Cox proportional hazards regression analysis showed that CPM significantly decreased 25% risk of all-cause mortality (OS, hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.70–0.80, P < 0.001) and 25% risk of BC-specific mortality (BCSS, HR: 0.75, 95% CI: 0.70–0.80; P < 0.001) in young BC patients as compared to UM. Almost consistent results were observed in subgroup analyses based on different TNM stages, molecular subtypes, race, tumor grade, marital status, radiotherapy status, and chemotherapy status, except for some.
This study suggests that CPM improved OS and BCSS benefits in young BC patients as compared to UM. Randomized clinical trials with a larger sample size are required in the future to confirm these results.
The authors would like to thank the anonymous reviewers for their insightful suggestions and careful reading of the manuscript.
Chong Qing Medical University.
Has not received any funding.
The author has declared no conflicts of interest.
Breast-conserving surgery (BCS) is the treatment of choice for women with early-stage BC. Several studies indicated a better outcome in patients undergoing BCS plus radiotherapy (RT) in comparison with mastectomy (MAST) +/- RT (PMID:33950173, 27344114). Indeed, in comparison with MAST, BCS reduces the extent of surgery, but the addition of radiotherapy (RT) makes it hard to understand whether the differences in outcome may be attributed to the extent of the surgery only.
We performed a competing risks re-analysis in terms of dynamics and crude cumulative incidence (CCI), of distant recurrence free survival (DRFS) from two historical randomized clinical trials which of the Istituto Nazionale dei Tumori of Milan: the “Milan 1” trial (n = 701; 1973-1980, PMID:7015141) which compared MAST with BCS plus RT (BCS+RT) and the “Milan 3” trial (n = 567; 1987-1989, PMID: 8387637) which adopted the same surgical conservative approach with (BCS +RT) or without (BCS -RT) RT. Clinical features such as primary tumour size, axillary lymph node status (N) and menopausal status were considered.
Concerning distant recurrence (DR) dynamics in Milan 1 trial, evidence of a different intensity of cause-specific hazard was found among subgroups related to surgery and lymph-node status (test of interaction effect: P=0.005), though with similar multi-peaked hazard patterns. Indeed, we observed that a MAST-related worse outcome is present in women with positive N (N+). Analysis of CCI reveals that, for the subgroup of N+ patients in Milan 3 trial, removal of RT from BCS (BCS -RT) results in 30% higher incidence of DR, comparable to the difference between MAST N+ and BCS+RT N+ patients in the Milan 1 trial.
In this re-analysis of historical randomized clinical trials, we report that the worse outcome of MAST in comparison with BCS may be mainly attributed to higher extensive surgery and that the effect of the extent of the surgery without RT is mostly confined to patients with N+ BC. The effect of RT, as assessed by the re-analysis of Milan 3 trial, is likely related to a combined effect of the control of local recurrences, and the potential systemic effect of RT.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Malignant phyllodes tumor is a subtype of fibroadenomas but with invasive behaviors that accounts for 1% of all breast cancers. About one in every 4 phyllode tumors is malignant. The available treatment modalities for malignant phyllode tumors are wide excision or mastectomy with adjuvant radiotherapy and in case of distant metastasis, adjuvant chemotherapy is added. However, Due to its scarcity, there are no enough data about the best treatment modality and that is the what our study aims to find.
We extracted the data of 1971 female patients from Surveillance, Epidemiological, and End Results (SEER) database. All of them had Malignant Phyllode tumor. We divided the patients into 3 groups; Conservative surgery, simple mastectomy, and radical mastectomy. For each group we further subdivided them into 3 more groups, surgery with no systemic therapy, adjuvant radiotherapy, and adjuvant chemotherapy. For each subgroup, we measured the relative 5-year survival. We also performed Kaplan-Meier curve and log rank test using SPSS 25 for survival analysis.
The 5-year relative survival of conservative surgery, simple mastectomy and radical mastectomy were (98.1%, 86.2%, 77.5% respectively;
The results of this study highlight that conservative surgery with no adjuvant therapy to be the treatment modality of choice as it has the best survival outcome. However, If the tumor is abnormally large, simple mastectomy is recommended instead. Regarding adjuvant therapy, Adjuvant radiotherapy shows better survival than adjuvant chemotherapy but both shows no survival benefit compared to surgery. So, we recommend that adjuvant radiotherapy to be cautiously used with selective patients. Additionally, adjuvant chemotherapy should be avoided to avoid unnecessary side effects.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Over 60% of the women who are diagnosed with breast cancer in the Netherlands are treated with systemic treatment, which may be administered before (neoadjuvant systemic therapy, NST) or after (adjuvant) locoregional treatment. Depending on the subtype, 10-75% of patients will have a pathologic complete response (pCR) after NST. In this patient group, risk of local recurrence is extremely low, with reported 5-year rates of 0-3.5%. The administration of adjuvant radiotherapy in these patients is not expected to contribute significantly to local recurrence and overall survival, but may cause considerable morbidity. Our aim is to show that omission of radiotherapy after breast conserving therapy in patients treated with NST who achieve a pCR is safe and will result in good quality of life.
The DESCARTES trial is a national, multicenter, single arm prospective cohort study. Radiotherapy is omitted in cT1-2N0 patients who achieve a pCR of the breast and lymph nodes after NST and breast conserving therapy. A pCR is defined as ypT0N0 (i.e. absence of invasive carcinoma and in-situ carcinoma in the breast). Primary endpoint is the 5-year local recurrence rate, which is expected to be <4%. In total, 595 patients are needed to achieve a power of >80% (one-side alpha of 0.05). Quality of life is measured using EORTC-QLQ-C30, EORTC-QLQ-BR23 and Cancer Worry Scale questionnaires at baseline, 1 and 4 years after surgery. Projected accrual is 5 years.
Local recurrence rate at 5 years is expected to be less than 4%. Secondary determinants are local non-salvageable recurrence free survival, quality of life, regional recurrence rate, distant recurrence free survival, disease-specific free survival and overall survival.
This trial will fill the lack of information on local recurrence rates when radiotherapy is omitted in selected patients. When the trial results are positive, the de-escalation of radiotherapy can be immediately offered to selected breast cancer patients with pCR after NST.
NCT05416164.
The authors.
The Dutch Cancer Society (KWF, project 13761).
All authors have declared no conflicts of interest.
PAOB is a rare malignant tumor that arises from endothelial cells. The efficacy of adjuvant radiotherapy remains uncertain. Some studies have reported significant differences in radiotherapy's ability to improve survival, others have not. Thus, we conducted this study to evaluate the effect of radiotherapy on overall survival (OS) and cancer-specific survival (CSS) in patients with PAOB without distant metastasis.
Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2019. Patients with a previous history of cancer or concurrent malignancies and with distant metastasis were excluded. Two groups were formed based on radiotherapy exposure: radiotherapy and non-radiotherapy. The clinicopathological features of each group were compared using chi-square tests. Kaplan-Meier estimator, log-rank tests, and cox proportional hazard regression were used to identify prognostic factors over OS and CSS.
In a study of 286 patients, 101 (35.3%) were exposed to radiotherapy while 185 (64.7%) were not. Most patients were aged 45 years or above (59.1%) and with the dominant race being white (n = 226). 54.5% had a tumor size of 50 mm or greater, with an average tumor size of 50.2 mm. Primary surgical resection was performed on 95.1% of patients and 34.6% had undergone chemotherapy. The non-radiotherapy group had better survival outcomes, with 5-year OS and CSS rates of 62% and 53.9%, respectively, compared to 42% for both in the radiotherapy group. Tumor size greater than 5 cm was identified as a poor prognostic factor for both OS and CSS, while chemotherapy was found to be a better prognostic factor for both. Age greater than 45 years was identified as a poor prognostic factor only for CSS. Interestingly, the use of radiotherapy did not result in improved OS and CSS (HR=0.91, 95%CI: 0.61-1.36 and HR=0.99, 95% CI: 0.64-1.54, respectively).
The results of the study indicated that radiotherapy may not improve survival outcomes in patients with PAOB. This study was the first of its kind to investigate PAOB without distant metastasis using a large sample size. Further randomized clinical trials are needed to confirm the efficacy of radiotherapy in PAOB treatment.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Deleterious or likely deleterious g
We retrospectively reviewed the medical records of women with g
Among the 65 women included, median age at primary diagnosis was 33y. Invasive ductal carcinoma (72.3%), ER+ (56.6%) and HER2+ (43.4%) were the main tumor characteristics. 24 pts (36.9%) received adjuvant RT, 69.2% received chemotherapy, 41.5% HER2-directed treatments and 44.6% endocrine therapy Proportion (%) of pts without the outcome of interest at 5, 10, 15y
Outcome 1 Outcome 2 Outcome 3 5y 86% 80% 87% 10y 81% 73% 73% 15y 76% 73% 42%
Pts with BC and g
Gustave Roussy, Department of Cancer Medicine.
Has not received any funding.
All authors have declared no conflicts of interest.
Appropriate adjuvant radiation therapy (RT) after breast cancer surgery is an important quality of care metric. Cancer treatment experience for immigrant women may differ due to challenges in navigating the health care system. This study compares the proportion of immigrant and Canadian born/long-term resident women receiving adjuvant RT and time to RT.
A population-level retrospective cohort-study using linked provincial administrative databases was conducted including women >=18 years of age with Stage I-III breast cancer diagnosed between 2010-2016 in Ontario, Canada. Women were classified as immigrants using the federal database if they arrived in Canada in or after 1985, and as Canadian-born/long-term residents if they were born in Canada or arrived prior to 1985. Dependent variables (age, co-morbidity, socioeconomic factors, stage, and treatments) were collected. Data on proportion of women undergoing RT and time from surgery to RT was collected. Multivariable analysis was performed adjusting for dependent variables.
Out of 54,090 patients, 46,930 (86.8%) were Canadian-born/long-term residents and 7,160 (13.2%) were immigrants. Immigrants were younger at diagnosis (54.3 vs. 63.0 years) and more often had Stage III disease (16.8% vs. 13.9%). Odds of receiving RT after breast conserving surgery (BCS) was 0.86 (95% CI 0.78-0.95), and 0.98 (95% CI 0.86-1.12) after mastectomy. Mean time from any surgery to RT was longer for immigrants (126.9 days vs. 117.1 days, p<0.001). Using a multivariable piecewise Cox regression model, excluding patients who received adjuvant chemotherapy before radiation, the hazard ratio for receipt of RT within 90 days for immigrants compared to Canadian long-term residents was 0.87 (95% CI; 0.83-0.92). Amongst immigrants, women from Latin America and the Caribbean had the longest wait times. There were no differences based on length of stay in Canada or immigration class.
Our study demonstrates a lower proportion of immigrant women receiving RT after BCS compared to Canadian-born/long-term resident women in Ontario, and a longer wait time for adjuvant RT. Further research is needed to explore system, provider, and patient factors that may be driving this difference.
The authors.
Funding for this study was provided by the McMaster Buffett Taylor Chair in Breast Cancer Research. Dr. Parvez is supported through career grant HHS Foundation W.E. Noonan Fellowship.
T. Whelan: Other, Personal, Other, In Kind sponsorship, unrelated to this work: Exact Sciences. All other authors have declared no conflicts of interest.
Wire guided localization is the gold standard technique for pre-operative localization of non-palpable breast cancers in patients undergoing wide local excision (WLE). It has logistical challenges as it needs to be performed on the day of surgery, requiring coordination of Breast, Radiology and Theatre teams. Reported complications include wire displacement, intra-operative difficulty localizing the tip, pneumothorax, and cardiac injuries. Magseed is an alternative localization technique using a magnetic seed, which can be placed up to 30 days pre-operatively. This is localized intraoperatively with a ‘Sentimag probe’. The iBRA-NET Localisation Study performed in UK demonstrated magseed localization as an effective technique in terms of patient convenience and satisfaction, accurate localisation and avoiding unnecessary scheduling delays/cancellations. Our breast unit changed from using wires to predominantly Magseed localisations in early 2020.
Data was retrospectively collected for all patients undergoing wire or Magseed localised WLE for non-palpable invasive breast cancer or ductal carcinoma-in-situ from 01/10/2019 to 01/10/2020. Accuracy was determined by the presence of cancer and wire/Magseed in the specimen or cavity shave, presence of clear margins, and need for re-excision. Complications within 30 days of surgery were also recorded. Statistical analysis was performed using IBM SPSS statistics version 24 (Univariate analysis). P values under 0.05 were considered significant.
Magnetic seed (n=43) Wire (n=49) p-value p-value in national audit Accurate localization 42 (97.7%) 48 (97.9%) 0.730 0.048* Re-operation rate 8 (18.6%) 13 (26.5%) 0.458 0.574 Positive/Close margins 9 (20.9%) 9 (18.4%) 0.797 0.342 Specimen weight 34g (7.70-378.3g) 29g (5.5-201.4g) 0.362 0.362 Minor wound infection 3 2 0.147 0.170 Major wound infection (needing IV antibiotics) 1 0 0.352 0.527 Unexpected re-admission to hospital within 30 days 1 0 0.721 0.676 Peri-operative problem Magseed/wire dislodged from lesion 1 0 0.467 0.039* Index lesion/clip not visible on specimen X-ray 3 1 0.261 0.406 Type of surgery Wide local excision 37 48 0.032* 0.002* Therapeutic mammoplasty 5 1 Other (LICAP) 1 0
Magseed can be introduced safely into the DGH setting, with non-inferior results compared to wire localisations. The technique has advantages for both patients and scheduling teams. Our findings support those of the National Localization Audit.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
The benefits of hypofractionated radiotherapy with FAST and FAST-forward protocols could be compromised by soft tissue reactions and cardiac toxicity caused by dose inhomogeneity and inaccurate heart sparing. This study aims to evaluate the dosimetric results of whole-breast hypofractionated radiotherapy with the field-in-field 3D conformal radiotherapy (3D-CRT) technique.
A mono-institutional consecutive cohort of 122 early-stage invasive breast cancer patients was treated using field-in-field 3D-CRT. Thirty-nine patients were treated with 28.5 Gy in 5 fractions once a week (FAST protocol) and eighty-three patients with 26 Gy in 5 consecutive fractions (FAST-forward protocol). Different parameters were evaluated to assess target coverage, dose conformity and homogeneity and hot spots in unspecified tissues. To assess breast dimensions, nipple-to-pectoral muscle distance (NPD) and maximum mediolateral thickness (MLT) along tangential fields were measured. Evaluated OARs were ipsilateral lung and heart with their respective dose constraints as required by the clinical protocols.
The median NPD and MLT were 4.65 cm [1.70-9.30] and 21.55 cm [11.26-32.30] respectively, with a median CTV of 380.50 cm3 [60.29-1255.13]. The median V95% was 99.45% [95.19-100], and the median 105% isodose volume was 0.74 cm3 [0.00-48.02] of whom 0.07 cm3 [0.00-5.22] in the first skin centimetre. This led to a median CI of 0.53 [0.33-1.00] and a median HI of 0.07 [0.03-0.19]. OARs dose-volume constraints were always respected. The median ipsilateral lung V8Gy was 7.32% [0.31-25.15]; as for the heart (left breast only), the median V1.5Gy was 6.45% [0.00-25.12] and median V7Gy was 0.34% [0.00-4.50].
Each plan achieved a clinically acceptable target coverage and homogeneity, with reduced superficial hot spots. These results suggested that field-in-field 3D-CRT can provide good quality FAST and FAST-forward breast RT plans, with the advantages of an efficient and cost-effective delivery technique. The clinical follow-up will give further critical feedback on treatment outcomes and toxicities.
The authors.
Has not received any funding.
M.C. Daniotti: Financial Interests, Personal, Full or part-time Employment: Università degli Studi di Milano; Non-Financial Interests, Personal, Training: Fondazione IRCCS San Gerardo dei Tintori. S. Trivellato: Financial Interests, Personal, Full or part-time Employment: Fondazione IRCCS San Gerardo dei Tintori. S. Carminati: Non-Financial Interests, Personal, Training: Università degli Studi di Milano, Fondazione IRCCS San Gerardo dei Tintori. P. Caricato: Financial Interests, Personal, Full or part-time Employment: Università degli Studi di Milano; Non-Financial Interests, Personal, Training: Fondazione IRCCS San Gerardo dei Tintori. S. Terrevazzi: Financial Interests, Personal, Full or part-time Employment: Fondazione IRCCS San Gerardo dei Tintori. C. Julita: Financial Interests, Personal, Full or part-time Employment: Fondazione IRCCS San Gerardo dei Tintori. R.M. Niespolo: Financial Interests, Personal, Full or part-time Employment: Fondazione IRCCS San Gerardo dei Tintori. S. Meregalli: Financial Interests, Personal, Full or part-time Employment: Fondazione IRCCS San Gerardo dei Tintori. A. Podhradska: Financial Interests, Personal, Full or part-time Employment: Fondazione IRCCS San Gerardo dei Tintori. E. Bonetto: Financial Interests, Personal, Full or part-time Employment: Fondazione IRCCS San Gerardo dei Tintori. S. Arcangeli: Financial Interests, Personal, Full or part-time Employment, Associate Professor: Università degli Studi di Milano - Bicocca; Financial Interests, Personal, Advisory Board, Scientific Consultant: SIURO. E. De Ponti: Financial Interests, Personal, Full or part-time Employment, Medical Physics Director: Fondazione IRCCS San Gerardo dei Tintori; Financial Interests, Personal, Full or part-time Employment, Professor: Università degli Studi di Milano Bicocca.
As further de-escalation of axillary surgery is ongoing, new biomarkers that convey the same prognostic information as sentinel node status are called for.
To predict sentinel node status, we trained a deep learning (DL) image analysis model on H&E-stained whole slide images (WSIs) of primary tumors. For training, we used cases from the INSEMA standard arm (n=762, ca. 94 % HR+/HER2-, 3.5 % G3, less than 1% pT3/4, 13 % SLN-positive) and a cohort from the Women’s Clinic in Mannheim, Germany (n=150, all HR+/HER2-, G2, pT1/2, ca. 16 % SLN positive). We also fitted a logistic regression with clinical data (pT stage, Ki-67) for this task. Models were tested on a holdout INSEMA set (n=381), and the image model also on the higher risk TCGA BRCA cohort (n=650, ca. 72% HR+, ca. 55% SLN+). Vice versa, we trained a model on TCGA WSIs and tested it on the other cohorts.
During training, the image and the clinical model yielded Areas under the Receiver Operating Characteristic Curve (AUROCs) of 0.62 and of 0.77 on the Mannheim WSIs, respectively. However, performance of the image model was random on the INSEMA (determined by blinded assessment) and TCGA BRCA test sets. The clinical classifier retained an AUROC of 0.62 on the INSEMA set. Inclusion of the image classifier output in the logistic regression did not improve performance on INSEMA. The image model trained on TCGA also yielded random performance on the INSEMA and Mannheim cohorts.
Image analysis algorithms trained on H&E stains of the primary tumors from INSEMA or TCGA using established techniques were unable to predict sentinel status, which may suggest a lack of systematic histological differences by lymph node status in these cohorts. Thus, DL-based WSI analysis may not be a good strategy to replace sentinel node assessment, especially in low- to intermediate-risk, hormone receptor-positive breast cancer.
NCT02466737.
The authors.
TB, MS and EKH were funded by the TPI grant to TJB by the German Federal Ministry of Health. INSEMA trial is supported by German Cancer Aid (Deutsche Krebshilfe, Bonn, Germany), Grant No. 110580 and Grant No. 70110580 to University Medicine Rostock.
F. Marmé: Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK/Tesaro, Clovis, Pfizer, Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Novartis, Roche, Gilead/immunomedics, EISAI, PharmaMar, GenomicHealth, Myriad, Seagen; Financial Interests, Institutional, Invited Speaker: Seagen, Daiichi Sankyo, GSK, AstraZeneca, Roche, AstraZeneca, Novartis, Roche, Eisai, Gilead/Immunomedics, MSD, German Breast Group, AGO Research GmbH, Vaccibody, GSK; Financial Interests, Institutional, Advisory Board: Roche, Immunicom; Financial Interests, Institutional, Funding: AstraZeneca, Lilly, Seagen. C. Denkert: Financial Interests, Personal, Advisory Board: MSD Oncology, Daiichi Sankyo, Molecular Health, AstraZeneca, Roche, Lilly; Financial Interests, Personal, Invited Speaker: AstraZeneca, VmScope digital pathology software; Financial Interests, Institutional, Research Grant: Roche, Myriad, German Breast Group. V. Nekljudova: Financial Interests, Institutional, Full or part-time Employment: GBG; Financial Interests, Institutional, Research Grant: AbbVie, AstraZeneca, BMS, Daichi-Sankyo,Gilead, Novartis, Pfizer, Roche; Non-Financial Interests, Institutional, Writing Engagements: Daiichi Sankyo, Gilead, Novartzis, Pfizer, Roche, Seagen; Other, Institutional, Other, EP14153692.0: Patent; Other, Institutional, Other, EP21152186.9: Patent; Other, Institutional, Other, EP15702464.7: Patent; Other, Institutional, Other, EP19808852.8: Patent; Other, Institutional, Royalties: VM Scope GmbH. S. Loibl: Financial Interests, Institutional, Advisory Board, Member: Amgen, AstraZeneca, BMS, Celgene, EirGenix, GSK, Lilly, Pierre Fabre, Roche, Seagen, AbbVie, Sanofi, Gilead, Merck, Novartis, Relay Therapeutics; Financial Interests, Institutional, Invited Speaker: AstraZeneca, DSI, Novartis, Pfizer, Roche, Gilead, Seagen; Financial Interests, Institutional, Advisory Board: DSI, Pfizer, Olema; Financial Interests, Personal, Invited Speaker: Medscape; Financial Interests, Personal, Full or part-time Employment, CEO: GBG Forschungs GmbH; Financial Interests, Institutional, Invited Speaker, Ki67: VM Scope GmbH; Financial Interests, Institutional, Research Grant: AstraZeneca, Celgene, Novartis, Immunomedics/Gilead, Pfizer, Roche, Daiichi Sankyo; Financial Interests, Institutional, Funding: AbbVie, Molecular Health; Financial Interests, Personal, Other, PIPenelope/Padma: Pfizer; Financial Interests, Personal, Other, SC PALOMA3: Pfizer; Financial Interests, Personal, Other, SC SOLAR1: Novartis; Financial Interests, Personal, Other, SC ASCENT: Immunomedics/Gilead; Financial Interests, Personal, Other, SC HERCLIMB: Seagen; Financial Interests, Personal, Other, SC Katherine: Roche; Financial Interests, Personal, Other, SC Capitello; EC Cambria 1: AstraZeneca; Financial Interests, Personal, Other, SC Inavo: Roche; Financial Interests, Personal, Other, SC Destiny B05; SC Destiny B09: Daiichi Sankyo; Non-Financial Interests, Principal Investigator, After publication of primary endpoint: PI Aphinity; Non-Financial Interests, Advisory Role, Group in Germany responsible for breast cancer guidelines: AGO Kommission Mamma; Non-Financial Interests, Member, German Gynaecological Oncology society: AGO; Non-Financial Interests, Member, German Cancer Society: DKG; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member, Member guideline committee; past chair in ESMO Breast: ESMO; Other, EP14153692.0No financial interest, Institutional: Patent; Other, EP21152186.9No financial interest, institutional: Patent; Other, EP15702464.7No financial interest, institutional: Patent; Other, EP19808852.8 No financial interest, Institutional: Patent. All other authors have declared no conflicts of interest.
One of the frequent complications for patients undergo mastectomy is post-mastectomy pain syndrome (PMPS). The postulated cause of PMPS is an injury of the intercostobrachial nerve (ICBN) during mastectomy, and/or radiation therapy. As the ICBN has a close connection with axillary lymph nodes, the risk of injury to this nerve is high during lymph nodes dissection. Studies comparing ICBN preservation and dissection for the management of PMPS are diverse and scarce. Therefore, this meta-analysis aimed to compare the efficacy of preservation of the ICBN versus its dissection for patients who underwent breast surgery.
We conducted computer literature search of Web of Science, PubMed, Cochrane CENTRAL, and Scopus from inception until October 2022. Relevant outcomes were pooled as an odds ratio (OR) using RevMan version 5.4 for Windows. The PROSPERO registration number for this study is CRD42022320452.
Data from 11 studies (980 patients) meeting our eligibility criteria. Six RCTs and five observational studies, were included in the final analysis. Our analysis favored preservation of the ICBN over its dissection in terms of anesthesia and hypoesthesia [OR 0.50, (95% CI, 0.31 to 0.82); P = 0.006] and [OR 0.33, (95% CI, 0.16 to 0.68); P = 0.003], respectively. Whereas, the overall effect favored ICBN dissection over preservation in the case of hyperesthesia [OR 4.34, (95% CI, 1.43 to 13.15); P = 0.01]. Conversely, no significant variance was detected between the two groups in terms of pain, paresthesia, analgesia, numbness, and diminished sensation.
Ultimately, this meta-analysis reveals that preservation of the ICBN through axillary lymph node dissection, when compared to its dissection, appeared to decrease the risk of some sensory disturbance parameters as anesthesia and hypoesthesia. Future analysis on a broader scale population is needed to more strongly assess the efficacy of ICBN preservation on a wider range of parameters.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Hypofractionation—delivering higher dosages per fraction in a shorter time—is common now. Hypofractionated radiotherapy for whole breast irradiation is preferred over CF-PMRT according to multiple randomized trials showing equivalent efficacy and safety. Post-mastectomy breast cancer hypofractionation is understudied. HF-PMRT with regional nodal irradiation has equal efficacy and toxicity to traditional fractionation (CF-PMRT).
87 of 92 histopathologically confirmed locally advanced breast cancer patients who underwent modified radical mastectomy and appropriate surgical axillary staging, WHO performance status 0-2, were eligible for this prospective, non-randomized trial from 2014–2015 and 2019–2021. HF-PMRT was 43.2 Gy in 16 fractions (2.7 Gy/fraction) or CF-PMRT was 50-50.4 Gy in 1.8-2.0 Gy/fraction to the chest wall and regional nodes with scar boost for high-risk patients. Locoregional recurrence-free survival. Overall survival, distant metastases control, disease-free survival, acute and late toxicity were secondary objectives.
Stage II and menopausal cases dominated HF-PMRT. Same age, co-morbidities, symptoms, and performance. HF-PMRT had 23.5 months of median follow-up and CF-PMRT 23. (10-39). HF-PMRT had 68% interruption days versus 8 for CF-PMRT (p<0.003). HF-PMRT had 86.3% two-year survival, CF-PMRT 100%, p = 0.126. The longer-follow-up 2014-2015 cohort showed three HF-PMRT deaths (13.6%) and no CF-PMRT deaths (1 patient died of brain metastasis after 26.9 months, another died of unknown cause after 47.5 months, and 1 died due to cardiopulmonary arrest after 17.9 months follow-up). HF-PMRT showed 68.18% disease-free survival, CF-PMRT 73.33%. No locoregional recurrence was reported. HF-PMRT showed 86.96% grade 1 acute cutaneous toxicity, CF-PMRT 53.6%. Six (8.70%) HF-PMRT and 14 (34.15%) CF-PMRT patients exhibited Grade 2 skin toxicity. Five (12.20%) CF-PMRT patients exhibited Grade 3 acute cutaneous toxicity, compared to none in HF-PMRT, p = 0.001.
This interim analysis suggests HF-PMRT is a promising therapeutic option. This observational study follows all patients for five years.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Sentinel lymph node biopsy (SLNB) in breast cancer patients who received neoadjuvant chemotherapy(NAC) has a problem of lower identification and higher false negative rates. To improve this, we compared the sentinel lymph node (SLN) identification rate between the dual method (DM) of indocyanine green fluorescence (ICG-F) plus a radioisotope (RI) and RI alone. In this study, we aimed to compare the prognosis according to the SLN mapping method through the lymphedema(LE) Quality of Life(QoL) in the same patient group.
We analyzed 62 patients who completed LE examinations and a questionnaire. We defined LE as a volume difference between limbs of 200ml or more or a difference within a limb of 200mL or more. The limb volume was measured before and after surgery using volumetry. In addition, the ratio of extracellular water (ECW) to total body water (TBW) and single frequency bioelectrical impedance (SFBIA) at 1kHz and 5kHz was measured using bioelectrical impedance analysis (BIA) for early detection of LE. We regarded ECW/TBW more than 0.39 as overhydrated and used the SFBIA ratio calculated as the ratio of the unaffected arm to the affected arm. QoL was assessed by the EORTC QLQ-BR23.
Among the total of 62 patients, 26 were in the DM group and 36 were in the RI group. LE occurred in 11(42.3%) patients in the DM group and 12(33.3%) patients in the RI group, and there was no statistically significant difference(p=0.470). The number of patients with ECW/TBW greater than 0.39 was respectively 1(3.9%) and 4(11.1%) (p=0.388). The SFBIA ratio measured at 1kHz was 1.01 (0.99-1.03, p=0.994) in both groups, and the same value was shown at 5kHz (p=0.926). As a result of EORTC QLQ-BR23, there was no significant difference in breast and arm symptoms (breast symptoms 16.67 vs. 16.67 p=0.960, arm symptoms 33.33 vs. 33.33 p=0.724).
This study is a prospective study comparing the prognosis before and after surgery according to the SLN mapping method. Compared with RI, DM showed no significant difference in the number of retrieved LNs, LE, and related symptoms. We suggest DM is a useful method that provides visual guidance and is sufficient to replace the RI alone method.
NCC2020-0233.
National Cancer Center.
Has not received any funding.
All authors have declared no conflicts of interest.
Risk-based cancer prevention is a major future strategy. “Interception” is a French pilot, mixed community-hospital and digital-physical programme based on 4 pillars: 1. community-based identification of people at high risk of cancer; 2. a One-Stop Shop (OSS) including individual visits and group workshops to inform and empower patients and design their shared personalised prevention plan; 3. Implementation of this plan in community practice; 4. Fast cancer care pathway if required. We assessed the pathway dedicated to women at increased non-genetic risk of BC (CANRISK-based 5-year risk of invasive BC >2.5%).
We analysed data of women at high risk of BC non linked to a germline variant seen between 02/2021 and 12/2022. Nutritional habits and physical activity assessments used the WCRF score. Perception of knowledge on risk, prevention and screening, and self-evaluated lifetime probability and compared probability of BC, were assessed before and 8 days after OSS (analogue visual scales); comparisons used paired Wilcoxon tests.
141 women at high non-genetic BC risk entered the programme. Mean age was 40.5 years [32.2-49], 81% had tertiary education. Recommended BC screening scheme was modified in 64% (increased mammography frequency: 36 (50%), addition of yearly MRI: 36 (50%)). Identified BC prevention targets were: insufficient physical activity (83%), overweight or obesity (36%), alcohol consumption (57% incl. 5% with >1 alcohol drink/day), current smoking (21%). 97% had at least 1 prevention target. The mean perceived knowledge on BC risk improved (58.0% before
A programme dedicated to women at high BC risk has the ability to improve screening measures in conformity with current guidelines (51%), identify relevant prevention targets (97%), improve knowledge on one’s individual situation by 50%, and improve perceived cancer risk’s accuracy.
Gustave Roussy Institute.
Odyssea (Charity).
L. Veron, S. Delaloge: Financial Interests, Institutional, Sponsor/Funding, Charity: Odyssea. G. Hesry: Financial Interests, Institutional, Full or part-time Employment: Odyssea. All other authors have declared no conflicts of interest.
Dietary factors have been consistently associated with breast cancer risk, but evidence for their effects in women with different genetic susceptibility of breast cancer is scarce, and little is known about their interaction with alcohol consumption.
We analyzed data from 261,857 female participants in the UK Biobank. Multivariable adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between dietary factors and breast cancer risk. We further assessed its interaction with alcohol consumption and polygenic risk score (PRS) for breast cancer.
Only processed meat and beef intake more than once a week were associated with a higher risk of breast cancer, especially in women who took alcohol ≥1/d [HR (95% CI):1.20(1.01, 1.42) and 1.35 (1.06, 1.73), respectively]. Fresh fruit intake was associated with reduced risk of breast cancer [HR (95% CI):0.76 (0.64, 0.89)]. There was an interaction between vegetable and fresh fruit intake and alcohol consumption (P for interaction<0.05). When further stratified by PRS, fresh fruit intake with ≥4 servings/d was associated with risk of breast cancer [HR(95% CI):0.87(0.78-0.96)] in women with the highest quantile of PRS, and additive interaction was found between them. Associations between diet and any breast cancer, by frequency of alcohol consumption
In women took alcohol <1/d In women took alcohol ≥1/d HR(95%CI) HR(95%CI) Processed meat Never 1.00 (REF) 1.00 (REF) <once/wk 1.10(1.01-1.18) 1.08(0.91-1.29) ≥once/wk 1.08(1.01-1.17) 1.20(1.01-1.42) Beef Never 1.00 (REF) 1.00 (REF) <once/wk 1.04(0.95-1.14) 1.27(0.99-1.63) ≥once/wk 1.05(0.96-1.16) 1.35(1.06-1.73) Fresh fruit <2 servings/d 1.00 (REF) 1.00 (REF) 2.0-2.9 servings/d 0.99(0.94-1.06) 0.90(0.80-1.02) 3.0-3.9 servings/d 0.99(0.93-1.05) 0.92(0.80-1.05) ≥4 servings/d 0.89(0.83-0.96) 0.76(0.64-0.89)
Processed meat, vegetable and fresh fruit were associated with risk of breast cancer, and the effect was stronger in those who took alcohol ≥1/d and with high PRS for breast cancer. A combined intervention by reducing alcohol and processed meat consumption while increasing vegetable and fresh fruit intake might contribute to the prevention of breast cancer in high risk women.
Fujian Medical University.
This abstract was supported by the Natural Science Foundation of China [grant no: 82204132], Natural Science Foundation of Fujian Province [grant no: 2021J01721], the Startup Fund for High-level Talents of Fujian Medical University [grant no: XRCZX2020007], and Startup Fund for Scientific Research, Fujian Medical University [grant no: 2019QH1002].
All authors have declared no conflicts of interest.
Exposure to environmental pollutants, such as Cadmium (Cd), plays a role in the development of breast (BC) and ovarian (OC) cancers. Cd acts as an endocrine disruptor through its binding to the estrogen receptor, promoting cell proliferation. Population may be exposed to Cd through cigarette smoke, dust fumes inhalation, contaminated food and drinking water. Pathogenetic variants (PVs) in the BRCA1/2 genes can be found in about 20% of patients (pts) with BC and serous OC. In these pts, absence in repair of DNA damage causes its accumulation and neoplasm development. Our aim was to evaluate the potential interference of environmental factors in the onset of BC or OC in women carrying PVs in BRCA1/2 genes.
We conducted an observational, multicentric, case-control, retrospective study of pts with a PV in BRCA1/2 genes and with BC, OC, or both diagnosed from 2012 to 2020 (Group 1, G1), or without cancer (Group 2, G2). Demographics, body mass index (BMI), occupation, type of mBRCA, and estroprogestinic (EP) use data were collected. Logistic regression was applied to investigate the relationship between adherence to Mediterranean diet (using PREDIMED questionnaire), physical activity (using IPAQ questionnaire), Cd exposure through smoking habits (SH), patients work environment, and cancer development.
We evaluated 91 patients, 52 (57.1%) in Group 1 and 39 (42.9%) in Group 2. 57 (62.6%) had a BRCA1 PV, and 34 (37.4%) a BRCA2 PV. The two groups showed significative differences regarding age (49.3 vs 39.6 yrs in G1 and G2, respectively; p<.0001); BMI (23.6 vs 18.4-p=.03); SH (p=.042); EP use (p=.001);. At univariate analysis, predictive factors for cancer incidence were: SH (OR 2.750; 95% CI 1.059 – 7.142-p=.038); BMI (OR 1.093; 95% CI 1.024 – 1,167-p=.007); EP use (0.278; 95% CI 0.120 – 0.646-p=.003). No relationship was found with adherence to Mediterranean diet and physical activity. At multivariate analysis, SH (OR 3.058; 95% CI 1.034 – 9.041-p=.043) and EP use (0.297; 95% CI 0.089 – 0.989-p=0.048) were predictive of cancer onset.
In this preliminary analysis, the development of cancer in patients with BRCA mutation was influenced by smoking habits and EP use.
Fabi Alessandra.
Has not received any funding.
All authors have declared no conflicts of interest.
Neurofibromatosis type 1 (NF1) is a condition predisposing to the development of benign and malignant tumors. Regarding breast cancer, an increased risk has not been widely recognized or accepted. Given the oncogenic potential, long-term surveillance is important.
We selected from a pool of 468 pts with NF1 from a site of reference in Portugal women >18 years and observed how they were screened for breast cancers (BC). Also, we evaluated the percentage of those who developed BC in our population, discussing the clinical evidence of increased BC risk in women with NF1 and the potential need for a high-risk screening protocol.
We identified 179 women with NF1, 19 cases being excluded due to missing data. 114pts (71%) with confirmation of diagnosis NF1, the majority with familial history and 47% with spontaneous mutation. 17 with mutations identified, c.17657C>G, p (His553Asp) being the most prevalent (2 pts). 67% were under the age 50 years (y) at the time of data analysis. The median age was 43y (15-82) and at diagnosis of NF1 was 26 (1-62). For women <30y, only 2 pts started breast screening, due to breast alterations on breast palpation. No tumor was found. Above that, 92 pts were screened, mammography and breast ultrasound (71 pts) were the most required exam, followed by breast magnetic resonance imaging (MRI) (18pts) and with both (3pts). The periodicity was not sustained, with the time between exams being variable (annual to 3/3y). Medium BI-RADS 2, but 13 pts with BI-RADS 3. 23 patients without any screening tests beside all body MRI. There were 17 cases of BC in the follow-up period, however, twelve occurred in women in their 40s (median age 43y at diagnosis); 73% were < 50. The majority of the population presented with a grade 2 tumour, with hormone-receptor-positive BC (10), followed by HER2 amplification (4) and TNBC (1). Also, 2pts had two BC during the follow-up. However, we observe an early stage BC (I-II), with only 2 patients progressing to first-line treatment, being the only deaths observed in our population.
Proposals for NF1 care and its specific manifestations have been developed but lack integration within routine care. This study reinforces that increased attention to the breast cancer risk in young women with NF1 is needed.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Understanding of Genetic factors and familial breast cancer introduced new treatment pathways for risk reduction among breast cancer patients. Genetic breast cancer is entirely a different subset and definately it needs a patient oriented planning. However educational background, awareness and knowledge of patients, availability of genetic testing and busy tertiary care hospital settings in LMIC are the challenges for the optimal management of Genetic and familial breast cancers. Current prospective questionnaire based study is aimed to evaluate knowledge and awareness of breast cancer patients pertaining to genetic aspect.
This prospective questionnaire-based study with an educational interventional component was carried out on 300 newly diagnosed female breast cancer patients at a high volume North Indian tertiary care cancer center. Aclinically validated structured questionnaire containing 19-questions to test knowledge, awareness of breastcancer, its genetic aspect, attitude toward genetic testing and prophylactic interventions was executed. The studywas conducted in three phases i.e., Questionnaire based Pre-intervention, Educational Intervention (Brief 20 min descriptive educational session) & Questionnaire based post-Intervention assessment (after 7 days). Stuart Maxwell test of marginal homogeneity was used for comparative assessment and positive percent changes were noticed.
Impact of educational intervention.
S.No Question Sporadic (n=250) Pre & Post educational intervention Positive Percentage change P Value Familial (n=50) Pre & Post educational intervention Positive Percentage change P Value 1 Awareness (A) and knowledge (K) regarding breast cancer 12.08 16.67 0.2231 2 A&K regarding breast cancer screening 28.12 0.001 60.8 0.0009 3 A&K regarding breast cancer treatment 81.01 0.001 90 0.0186 4 A &K regarding Familial/hereditary breast cancer 65.2 0.0001 100 0.0003 5 A&K regarding genetic risk factors including BRCA 9 0.0027 27.27 0.014 6 Willingness for genetic testing for self or family member 12.0 0.0001 66.6 0.056 7 Awareness regarding prophylactic interventions 43.3 0.0001 90.47 0.001
A single short educational interventions showed significant improvement in the awareness level, knowledge regarding breast cancer and its genetic aspect. Educational intervention has improved patient awareness and willingness for genetic testing and prophylactic intervention, more profoundly in hereditary cases. Hence, in LMIC educational tools can help in dealing with complexissues like genetic testing and risk reduction strategies.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Up to 50% of pts with breast cancer and germline pathogenic/likely pathogenic
We conducted a retrospective cohort study using the US Electronic Health Record-derived de-identified Flatiron Health database. We selected pts ≥18 years with HR+ HER2-negative eBC, diagnosed from March 2007–October 2022 with a confirmed ODX RS. g
A total of 3672 pts with a confirmed ODX RS (category: low n=961; intermediate n=2172; high n=539) were included. Median age was 62 years (IQR 53, 69), 75.6% were white and 83.4% received treatment at community oncology clinics. Of 1163 pts (31.7%) tested, 37 (3.2%) had g Rates of g *Between 2007 and 2010 only 8 ODX RS tests were performed, and so data are not shown. ODX RS, Oncotype DX Recurrence Score.
Rate of g 2011–2014 2015–2018 2019–2022 Overall 13.7% 22.4% 32.4% ODX RS High 12.1% 26.3% 30.8% ODX RS Intermediate 14.5% 21.5% 32.9% ODX RS Low 12.4% 22.2% 32.1%
In this modern retrospective cohort, ODX RS appeared higher in g
Writing and editorial assistance was provided by Sara Shaw PhD CMPP of BOLDSCIENCE Inc., funded by AstraZeneca and MSD.
AstraZeneca.
This study was supported by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who are codeveloping olaparib (MSD).
F. Lynce: Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer, Merck, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Eisai, CytomX, Incyte. R.A. Khan: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. L. Berrocal-Almanza: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. M. Miranda: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. L. Luo: Financial Interests, Personal, Full or part-time Employment, I am a full time employee at AstraZeneca AstraZeneca; Financial Interests, Personal, Stocks/Shares, I have AstraZeneca stocks/shares: AstraZeneca. X. Xu: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. All other authors have declared no conflicts of interest.
Germline BRCA1/2 mutation carriers have an increased risk of developing breast cancer, however the characterisation of histological features of the normal breast for these high-risk patients has not so far been performed on large-scale image collections. Hence, deep learning-based framework is proposed to identify subvisual morphometric phenotypes in normal breast tissue of women with different risk of developing cancer.
Digitised 1190 whole slide images of H&E-stained breast normal tissue images from women across different age groups were collected from 5 different biobanks, i.e., healthy donors, healthy patients derived from reduction mammoplasty, healthy patients with known germline
Our DL-based framework revealed inter and intra-variability of epithelial histological patterns in the normal breast of healthy women, underlying the physiological ageing process. The proportion of lobule types differed in normal breast tissue of <30y or >50y healthy women. In normal breast of younger women, densely packed acinar structures with a higher glandular-to-stromal ratio are predominant and display higher neighbourhood enrichment. Normal breast tissue of young breast cancer patients revealed histological tissue-ageing patterns deviating from their chronological age.
Our DL-framework exposed histological patterns associated with the variation of the underlying ageing process of normal breast tissue, which may indicate early signs of cancerous in high-risk germline BRCA1/2 carriers.
The authors.
KCL-China Scholarship Council (CSC).
All authors have declared no conflicts of interest.
Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis and can be classified into different molecular subtypes. There is a need to develop a computer-aided diagnosis system with artificial intelligence (AI) techniques to increase the accuracy of evaluating suspicious breast lesions and identifying subtypes.
A multi-gene analysis panel consisting of 14 genes and 2 reference genes was designed from the TCGA, and cBioportal datasets, which were determined in accordance with in silico analyses in 488 TNBC patients (TCGA:123, cBioportal:365). In the AI part of the study, a convolutional neural network model with 1,838,915 parameters was trained to classify Ultrasound (US) images as “normal, benign, malignant.” In the model, the images of the patients were trained with 1000 epochs.
Expression levels of related genes in paraffin-embedded tumors and normal tissues of 38 patients with TNBC were investigated by the RT-PCR method. When the gene expression differences of the tumor and normal tissues of the patients were compared,
It sheds light on the heterogeneous structure and the role of molecular subtyping in the tumorigenesis of TNBC patients and may contribute to routine clinical practice and the regulation of targeted therapy protocols.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast health data were collected from October 2019 to Decembers 2020 at the participating facilities and were anonymized for secondary analysis. Health care providers at the public primary health clinics or district hospitals were trained on Clinical Breast Exam (CBE) and on how to collect specimens for cytology and histology (Fine Needle Aspiration (FNA) and biopsy). Patients and health care providers were contacted by phone and interviewed on their experiences in accessing or providing breast health services.
Breast health data collected from October 2019 to Decembers 2020 at the participating facilities was anonymized for secondary analysis. Clients and health care provides were contacted by phone and interviewed on their experiences in accessing or providing breast health services.
28 nurses and 6 doctors were trained on Breast diagnostics. 1,103 patients received education on breast cancer, and were exposed to a self-breast exam demonstration followed by a CBE. Of those, 199 (18%) had an abnormal breast exam and were referred to a doctor. This resulted in 139 being eligible for further diagnostic test, but only 99 of them presented for these tests. Of those 81% had non-malignant results while 7% were confirmed with cancer of which 71% received treatment. Interviews revealed that delays in accessing referral facilities could be addressed by a one-stop model were all the essential exams are collected as opposed to referring them to different entities. Patients reported the need for navigation assistance and follow up reminders for their appointments and results at the different levels of their journey.
Reducing late diagnoses of breast cancer can be achieved by strengthening early detection through capacity building of Primary Health Care (PHC) providers and strengthening the patient pathway by institutionalizing patient navigation and streamlining the referral process to reduce the time it takes from diagnosis to treatment.
Jhpiego.
Roche Products.
All authors have declared no conflicts of interest.
MBC is a rare entity accounting for less than 1% of all breast cancer (BC), with a lack of reliable data in this specific subset.
FH, CP characteristics, OG testing results on constitutional pathogenic variants (PV) in known BC predisposition genes were retrospectively collected in all MBC patients (pts) who had an OG consultation at Oscar Lambret Center, Lille, France between 2000 and 2021. Outcomes were overall survival (OS) and event-free survival (EFS), defined as time from first diagnosis to first recurrence or death from any cause. Key patient data, Kaplan-Meier plots and outcomes were described by PV status.
Out of the 98 MBC pts included: 10 (10.2%) tested positive for a PV (6 BRCA2, 3 BRCA1, and 1 BRCA2 and RAD51C). Groups were similar regarding age (67.6 vs 61.8 years; p = 0.08), BMI, subtype or TNM stage. Although statistically not significant, PV carriers had more aggressive primary tumors (histological grade III 44.4% vs 20.7%; p = 0.2) and Ki67 levels (40% vs 23%; p = 0.3). Treatment strategies were similar. First degree FH of BC was more frequent in PV carriers (7/10 vs 26/88; p=0.03), but no differences in FH of ovarian, prostate, pancreatic cancer or melanoma were noted. One patient had FH of MBC (BRCA2 PV carrier). The median follow-up was 4.7 years (IQR 0.5-19.1). Overall, 13 deaths were reported and 13 pts were alive with breast cancer recurrence. OS was 87.5% in PV non-carriers vs 88.9% in PV carriers at 10 years. EFS was 84.8% vs 77.8% at 5 years. Second cancer were more frequent in PV carriers, with 5/10 pts diagnosed (3 prostate, 1 pancreatic and 1 colorectal cancer) vs 8/88 pts in the non PV carrier group (p=0.004).
High rates of BRCA1/2 PV were found in unselected MBC pts, warranting OG testing for all MBC pts. A familial history of BC was more frequent in PV carriers. No particular CP were associated with PV carriers, even if tumors seem to be more aggressive. BC survival outcomes were comparable regardless of mutational status but occurrence of another cancer in half of MBC pts with a PV confirms the indication of specific screenings.
Centre Oscar Lambret.
Has not received any funding.
All authors have declared no conflicts of interest.
The association between non-inherited factors, including lifestyle factors, and the risk of breast cancer (BC) in women and the association between BC and genetic makeup are only partly characterized. This study examined the association between healthier lifestyle habits and BC risk in genetically predisposed groups.
Classification of healthy lifestyle was based on Cancer Research UK guidance (healthy weight, regular exercise, no use of HRT for >5 years, no OC use, alcohol intake<3 times/wk). Three groups were established: favorable (4 healthy factors), intermediate (2-3 healthy factors), and unfavorable (1 healthy factor). The genetic contribution was estimated using the polygenic risk scores PRS of 305 preselected SNPs.Cox proportional hazards regression was used to assess the hazard ratios (HRs) of the lifestyles and PRS associated with a malignant neoplasm of the breast.
The association of lifestyle and BC within genetic subgroups showed lower HRs among women following a favorable lifestyle compared with intermediate and unfavorable lifestyles among all of the genetic groups: women with an unfavorable lifestyle had a higher risk of BC in the low genetic group (HR, 1.63; 95% CI, 1.13-2.34), intermediate genetic group (HR, 1.94; 95% CI, 1.46-2.58), and high genetic group (HR, 1.39; 95% CI, 1.11-1.74) compared with the reference group of favorable lifestyle. Intermediate lifestyle was also associated with a higher risk of BC among the low genetic group (HR, 1.40; 95% CI, 1.09-1.80) and the intermediate genetic group (HR, 1.37; 95% CI, 1.12-1.68).
A healthier lifestyle appeared to be associated with a reduced level of risk for BC, even if the women were at higher genetic risk for BC.
The author.
Has not received any funding.
The author has declared no conflicts of interest.
Breast cancer (BC) accounts for 9.1% of all new cancer cases diagnosed in the Republic of Belarus in 2019. This study assessed germinal BRCA1 «founder» mutations frequency and a risk of the disease progression according to BRCA1 status in patients (pts) with different HER2-negative molecular subtypes of BC.
Pts clinical characteristics were collected from N.N. Alexandrov National Cancer Centre of Belarus registry. Ki-67 cut-off was 20%. The main criterias for referring pts with BC for BRCA-testing were young age (<40 yrs) and family history of BC. The statistical differences in genotypes distribution and clinical characteristics among the groups were compared using the chi-square, exact Fisher, Log Rank and U tests.
496 records were provided from January 2018 through September 2022. Median follow up was 19 months; the mean age was 45 yrs.; TNBC – 37,1% (n=184), Luminal B – 30,0% (n=149) and Luminal A – 32,9% (n=163). There was no statistical difference in age and stage distribution between groups with different molecular subtypes of BC. BRCA1 «founder» mutations were detected in 20,4% cases (n=101) with a statistically significant prevalence in TNBC group (TNBC – 35,9%, Luminal B – 20,8%, Luminal A – 2,5%; p<0,001).). BRCA1-mut frequency in pts with early stages of the disease (I-II) was 43,7% in TNBC group and 18,1% in Luminal B (p<0,001). However, pts with advanced stages (III-IV) in both groups have similar frequency of BRCA1-mut (25,9% vs 24,2%). Pts with I-II stages of the disease and BRCA1-mut progressed less frequently during follow up period than BRCA1-WT (Luminal B: 13,3% vs 30,7%, p = 0,17; TNBC: 17,7% vs 36,2%, p<0,05). Pts with III stage of BC had similar tendency in risk of progression depending on BRCA1 status (mut vs WT) in both Luminal B (25,0% vs 45,5%) and TNBC (35,3% vs 48,7%), however non-significant. Also there were no statistical differences in PFS/OS between BRCA1-mut and BRCA1-WT pts with different molecular subtypes of BC.
Germinal BRCA1-mut in pts with Luminal A BC were rare even in selected cohort. BRCA1-mut TNBC more often diagnosed in pts with early stages and had lower risk of progression than BRCA1-WT. In pts with Luminal B HER2- molecular subtype this risk reduction effect was not significant.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer has been the most common cancer diagnosed among women in Taiwan since 2003. Genetic variants account for high risks of developing breast cancer was less studied in Asian population. Many researches had discovered variant polygenic risk score (PRS) to evaluate the risk of developing breast cancer. This study aims to determine a predictive breast cancer PRS for Taiwanese populations and assess the heterogeneity in the relationships with breast cancer risk by biomarker testing, age at diagnosis, clinical and pathological stages.
The development dataset comprised 28,443 control subjects and 1,501 case subjects from Taiwan Precision Medicine Initiative (TPMI) array and breast cancer registry lists in Taichung Veterans General Hospital (TCVGH). Samples were analyzed by using breast cancer associated PGS Catalog, and significant PGSs were selected by stepwise logistic regression. The best performing PGS was yielded and 1,501 breast cancer patients were evaluated for further heterogeneity of breast cancer risk analysis.
Logistic regression results showed PGS000508 were significantly associated with breast cancer risk after multiple testing (odds ratio, 3.57; P=1.0850 E-53). Dose-response association was observed. Women in the highest quartile had a significantly increased risk compared to women in the lower quartile( odds ratio, 1.95; 95% confidence interval 1.75-2.17; P=3.54 E-34). Over 1,501 breast cancer diagnosed women stratified by PRS distribution, the highest quartile women had more advanced pathological stage (p=0.03); younger age while first diagnosis (p=0.01) and positive hormone status (p=0.03) compared to women in the lower quartile.
Our study identified PGS000508 as a risk predictor of breast cancer among Taiwanese women as well as advanced pathological stage, positive hormone status and younger age at first diagnosis.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
SG is a Trop-2–directed antibody-drug conjugate approved for metastatic triple-negative BC in multiple countries and pretreated HR+/HER2– mBC in the US. In TROPiCS-02, SG significantly improved progression-free survival (PFS; median, 5.5 vs 4.0 mo; HR, 0.66; P=0.0003) and overall survival (OS; median, 14.4 vs 11.2 mo; HR, 0.79; P=0.020) vs treatment of physician’s choice (TPC) in patients (pts) with pretreated, endocrine-resistant HR+/HER2– mBC, with a manageable safety profile (Rugo et al. ESMO 2022). In the ASCENT study, UGT1A1 polymorphisms were associated with neutropenia, anemia, and diarrhea in SG-treated pts (Rugo et al. npj Breast Cancer 2022). Here, we report TROPiCS-02 safety analyses by UGT1A1 status.
Pts with HR+/HER2– mBC who received prior taxane, endocrine therapy, CDK4/6 inhibitor, and 2-4 prior chemotherapies (CT) were randomized 1:1 to SG or TPC. The primary endpoint was PFS by central review per RECIST 1.1; secondary endpoints included OS and safety. A post-hoc safety analysis was performed by UGT1A1 status.
Of 543 enrolled pts (median number of prior CT for mBC, 3; visceral metastases, 95%), 517 (SG, n=268; TPC, n=249) received ≥1 dose of study treatment. UGT1A1 status in SG pts was: *1/*1 (n=104; 38%; wild type), *1/*28 (n=119; 44%), and *28/*28 (n=25; 9%); the respective median relative dose intensity was 99%, 98% and 94%. In SG pts, grade ≥3 treatment-emergent adverse events (TEAEs) included neutropenia (52%), diarrhea (10%), anemia (8%), and febrile neutropenia (6%). In pts with UGT1A1 *1/*1, *1/*28, and *28/*28 genotypes, grade ≥3 TEAEs for SG included: neutropenia (45%, 57%, and 64%), diarrhea (6%, 13%, and 24%), anemia (6%, 8%, and 8%), and febrile neutropenia (6%, 7%, and 4%), respectively. Myeloid growth factors (initiated on/after first dose) were used to manage neutropenia in 54% of pts in the SG group (33%, *1/*1; 49%, *1/*28; 11%, *28/*28). TEAEs were managed similarly regardless of UGT1A1 status.
SG had a manageable safety profile consistent with previous reports and across UGT1A1 status. UGT1A1 testing is not required for SG use in pretreated, endocrine-resistant HR+/HER2– mBC.
NCT03901339.
Gilead Sciences, Inc.
Gilead Sciences, Inc.
F. Marmé: Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK/Tesaro, Clovis, Pfizer, Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Novartis, Roche, Gilead/immunomedics, EISAI, PharmaMar, GenomicHealth, Myriad, Seagen; Financial Interests, Institutional, Invited Speaker: Seagen, Daiichi Sankyo, GSK, AstraZeneca, Roche, AstraZeneca, Novartis, Roche, Eisai, Gilead/Immunomedics, MSD, German Breast Group, AGO Research GmbH, Vaccibody, GSK; Financial Interests, Institutional, Advisory Board: Roche, Immunicom; Financial Interests, Institutional, Funding: AstraZeneca, Lilly, Seagen. H.S. Rugo: Financial Interests, Personal, Funding: Puma Biotechnology, Mylan, Samsung Bioepis; Financial Interests, Institutional, Funding: Macrogenics, OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Odonate Therapeutics, Daiichi Sankyo, Seattle Genetics, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Ayala Pharmaceuticals. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna, Myovant, Bayer, Zetagen, Infinity Therapeutics, Umoja Biopharma; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. A. Bardia: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Genentech, Merck, Sanofi, Eisai, Lilly, Mersana, AstraZeneca/Daiichi, Menarini, Gilead; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Invited Speaker: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly.; Non-Financial Interests, Principal Investigator: Gilead, Mersana, AstraZeneca/Daiichi, Novartis, Pfizer, Genentech, Lilly, Merck, Sanofi. P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Daiichi Sankyo, Eisai; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation; Other, Spouse - Employee: Roche. W. Verret, T. Valdez, H. Wang: Financial Interests, Personal, Full or part-time Employment: Gilead Sciences, Inc.; Financial Interests, Personal, Stocks/Shares: Gilead Sciences, Inc. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardanth Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca.
CDK 4/6 inhibitors play an important role in hormone receptor (HR)-positive, HER2-negative advanced and metastatic breast cancer. Oral medications such as palbociclib offer advantages but pose a challenge for therapy adherence. An eHealth-based platform such as CANKADO can help to support therapy management by probing the quality of life (QoL) status of the patient continuously throughout the course of treatment and, ideally, providing a basis for intensified care when indicated.
PreCyle (NCT03220178) is a multicenter, randomized phase IV Intergroup trial to evaluate the impact of eHealth-based Patient-Reported Outcome (ePRO) assessment on QoL in patients with HR+ HER2-, locally advanced or metastatic breast cancer treated with palbociclib and endocrine therapy. Patients were randomized (2:1; stratified by line of treatment) to the active arm A (supported by CANKADO PRO-React) or the inform arm B (drug intake documentation only). This exploratory analysis reports the impact of CANKADO PRO-React on safety. Time to first serious adverse event (SAE) was estimated taking competing risks into account.
The safety population comprised 318 patients in Arm A (23.3% SAEs) and 161 in arm B (31.1% SAEs). While distributions of adverse events (AEs) were similar by arm on the whole, patients in the CANKADO active arm had a favorable hazard ratio of 0.67 (95%-CI: 0.46-0.97; p=.04) for time to first SAE and were significantly less likely overall to suffer an SAE than patients in the inform arm.
Safety analysis of the PreCycle trial demonstrates for the first time in a randomized prospective trial that interactive eHealth-based support has a substantial favorable impact on the risk of SAEs for patients with advanced and metastatic HR+/HER2- breast cancer on oral tumor therapy. While eHealth-based support may not prevent adverse events, CANKADO PRO-React could mitigate their progression to a serious adverse event, thus resulting in a substantial QoL benefit for patients.
EudraCT 2016-004191-22, NCT03220178.
palleos healthcare GmbH.
Pfizer.
N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Seagen, Medscape, Art Tempi, Onkowissen, Gilead, Sanofi, Exact Sciences; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Roche, Sandoz-Hexal, Seagen, Aptitude Health, Gilead, Sanofi; Financial Interests, Personal, Other, Husband: WSG (Husband); Financial Interests, Personal, Ownership Interest: West German Study Group; Financial Interests, Institutional, Funding: AstraZeneca, BMS, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Palleos, Seagen, TRIO, WSG; Non-Financial Interests, Member, Member German AGO Breast Guideline Committee: AGO Breast Committee; Non-Financial Interests, Member, Breast Cancer Educational Programs: ESO/ESCO; Other, Founding Editor: BreastCare Journal. R. Würstlein: Financial Interests, Personal, Advisory Role: Agendia, Amgen, Aristo, AstraZeneca, Celgene, Clovis Oncology, Daiichi Sankyo, Eisai, Exact Sciences, Gilead, Glaxo Smith Kline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Mylan, NanoString , Novartis, Odonate, Paxman, palleos , Pfizer, Pierre Fabre, PINK, PumaBiotechnology, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics/Seagen, Stemline, Tesaro Bio, Teva, Veracyte, Viatris; Non-Financial Interests, Personal, Full or part-time Employment: Breast Center, LMU University Hospital, Munich. D.I. Lüftner: Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Loreal, Novartis, Pfizer, Seagen; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Loreal , Novartis, Pfizer, Seagen; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Personal, Expert Testimony: Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Loreal , Novartis, Pfizer, Seagen; Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Loreal, Novartis, Pfizer, Seagen. O. Hoffmann: Financial Interests, Personal, Advisory Role: Roche, Novartis, MSD, Pfizer, AstraZeneca, Daiichi Sankyo, Hexal, Riemser, Celgene, Gilead, Lilly, Seagen; Financial Interests, Personal, Expert Testimony: Deutsche Krebsgesellschaft; Non-Financial Interests, Personal, Principal Investigator: Department of Gynecology and Obstetics, University Hospital of Essen Germany. T. Decker: Financial Interests, Personal, Advisory Board: Novartis, iOMEDICO. M. Reinisch: Financial Interests, Personal, Other, Honoraria: MSD, Lilly, AstraZeneca, Roche, Novartis, Pfizer, Seagen, Somatex. P. Staib: Financial Interests, Personal, Other, Honoraria: AbbVie, Amgen, AstraZeneca, Celgene, BMS, MSD, Pfizer, Merck Serono, Roche, Novartis; Financial Interests, Personal, Advisory Role: AbbVie, Amgen, AstraZeneca, BMS; Financial Interests, Personal, Speaker’s Bureau: AbbVie, Amgen, AstraZeneca, BMS, Roche, Pfizer; Financial Interests, Personal, Funding: AbbVie, Novartis, Celgene, Roche. O. Gluz: Financial Interests, Personal, Advisory Board: Roche, Lilly, Amgen, Novartis, Pierre Fabre, MSD, Celgene, Pfizer, Gilead, Molecular Health, Seagen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Exact Science; Financial Interests, Institutional, Invited Speaker: Roche; Non-Financial Interests, Leadership Role: West German Study Group; Non-Financial Interests, Personal, Proprietary Information: West German Study Group. P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Sanofi Aventis; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Lilly, Seagen, Gilead; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BionTech, Cepheid; Non-Financial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v. M. Schmidt: Financial Interests, Institutional, Research Grant: AstraZeneca, BioNTech, Eisai, German Breast Group, Genentech, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche; Financial Interests, Personal, Advisory Role: AstraZeneca, BioNTech, Eisai, Daiichi Sankyo, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, Seagen; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Novartis, Pfizer, Roche, Seagen; Financial Interests, Personal, Licensing Fees: EP 2951317B1, EP 2390370B1; Financial Interests, Personal, Advisory Board: AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, Seagen. All other authors have declared no conflicts of interest.
In ML-2, RIB + LET demonstrated statistically significant overall survival (OS) vs placebo (PBO) + LET (median [m], 63.9 vs 51.4 mo) in postmenopausal pts with HR+/HER2− advanced breast cancer (ABC). Pts in ML-2 were in the 1L (no prior endocrine tx for ABC). Prior (neo)adjuvant tx was allowed; however, for pts treated with a prior nonsteroidal aromatase inhibitor, a treatment-free interval (TFI; time from end of [neo]adjuvant tx to disease recurrence) > 12 mo was required. Here we present a subgroup analysis of pts in ML-2 with de novo metastatic disease and late recurrence (TFI > 12 mo from end of any [neo]adjuvant tx).
Pts in ML-2 were randomized 1:1 to 1L LET + RIB or PBO. Pts with de novo disease or late recurrence were analyzed for OS, progression-free survival (PFS), time to chemotherapy (TTC), and chemotherapy-free survival (CFS).
Of 668 pts, 18.4% had TFI ≤ 12 mo and were excluded from the analysis. A total of 545 pts were analyzed; 41.7% had de novo disease and 58.3% had late recurrence. Among pts with late recurrence, mTFI was 52.8 mo; 271/318 (85.2%) had a disease-free interval (DFI; time from initial diagnosis to disease recurrence) > 5 y and 148/318 (46.5%) had a DFI > 10 y. Baseline characteristics, including percentage of pts with de novo disease and late recurrence (Table), were balanced between arms. mOS with RIB vs PBO was 69.2 vs 54.3 mo (HR, 0.75 [0.60-0.93];
This exploratory analysis of ML-2, which excluded pts with TFI ≤ 12 mo (known poorer prognosis in 1L), demonstrated an OS HR consistent with that for the overall population. mOS surpassed that in the overall population (RIB, 69.2 mo vs PBO, 54.3 mo: an ≈15-mo improvement with 1L RIB over PBO).
RIB + LET PBO + LET 275 270 114 (41.5) 113 (41.9) 161 (58.5) 157 (58.1) 69.2 54.3 0.75 (0.60-0.93) .005 30.3 16.7 0.57 (0.46-0.70) < .001 54.1 40.9 0.74 (0.59-0.93) .004 42.5 36.1 0.75 (0.61-0.92) .002
NCT01958021.
Medical writing support was provided by Daniele Cary at MediTech Media, funded by Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals Corporation.
J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie, Agendia, Amgen, Aptitude, AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunome, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Novartis, Odonate Therapeutics, Pfizer, Puma, Prime, Roche, Seattle Genetics, Syndax, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre, Samsung, Sanofi. T. Beck: Financial Interests, Institutional, Research Grant, Institutional funding for doing research.: AbbVie, Alliance, Argenx, Ascentage Pharma Group, AstraZeneca, Biodesix, Bio-Thera, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech-Roche, Hutchison, Immunomedics, Gilead, MT GroupMerck, Nektar, Pfizer, Polynoma, Seattle Genetics, Serono-EMD, Tesaro, TG Therapeutics, Daiichi - Sankyo, Exact Sciences, Boehringer - Ingleheim, Laekna, Novocure, Mirati Therapeutics, Tarveda Therapeutics, Sumitomo Dainippon Pharma Oncology (formerly Boston Bio), Elpiscience Biopharma, Takeda, Vaccinex, Vincerx Pharma, Ultimovacs, Mersana. S. Chia: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Hoffman LaRoche, Eli Lilly; Financial Interests, Institutional, Research Grant, My institution received funds for participation in clinical trials by Novartis: Novartis; Financial Interests, Institutional, Research Grant, My institution received funds for participation in clinical trials by Pfizer: Pfizer; Financial Interests, Institutional, Research Grant, My institution received funds for participation in clinical trials by Hoffman LaRoche: Hoffman LaRoche; Financial Interests, Institutional, Research Grant, My institution received funds for participation in clinical trials by Eli Lilly: Eli Lilly. C. Isaacs: Financial Interests, Personal, Advisory Board: Genentech, PUMA, Seagen, AstraZeneca, Novartis, Gilead; Financial Interests, Personal, Other, Honoraria: Pfizer, ION, Novartis; Financial Interests, Personal, Royalties: Wolters Kluwer (UptoDate), McGraw Hill (Goodman and Gillman); Financial Interests, Institutional, Research Grant, Research support to institution: Tesaro/GSK, Seattle Genetics, Pfizer, AZ, BMS, Genentech, Novartis Medical Director SideOutFoundation (non-profit). M. De Laurentiis: Financial Interests, Personal, Speaker’s Bureau, Honoraria: Pfizer, Novartis, Roche, AstraZeneca, Eisai, Eli Lilly, Pierre Fabre, Daiichi Sankyo, Menarini, Gilead, Seagen, GSK; Financial Interests, Personal, Advisory Board, Honoraria: Pfizer, Novartis, Roche, AstraZeneca, Eisai, Eli Lilly, MSD, Pierre Fabre, Daiichi Sankyo, Menarini, Gilead, Seagen, GSK. S. Kuemmel: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Lilly, MSD, Novartis, Seagen, Pfizer, Roche, Somatex, Gilead, Sanofi; Financial Interests, Personal, Invited Speaker: ExactScience, pfm medical, MSD, Lilly, Gilead, Roche, Sanofi, Daiichi Sankyo; Financial Interests, Personal, Ownership Interest, Minority Ownership: WSG Study Group; Financial Interests, Personal and Institutional, Invited Speaker: Roche, Novartis; Financial Interests, Institutional, Invited Speaker: Roche, Novartis, Lilly, Somatex, AstraZeneca, MSD. K. Jhaveri: Financial Interests, Personal, Advisory Board, Consultant/Advisory Board: Novartis, AstraZeneca, Pfizer, BMS, Jounce Therapeutics, Taiho Oncology, Genentech/Roche, Lilly Pharmaceuticals/Loxo Oncology, AbbVie, Eisai, Blueprint Medicines, Seattle Genetics, Daiichi Sankyo, Gilead, Olema Pharmaceuticals, Sun Pharma Advanced Research Company Ltd., Menarini/Stemline; Financial Interests, Institutional, Funding, Research funding: Novartis, AstraZeneca, Pfizer, Genentech/Roche, Lilly Pharmaceuticals/Loxo Oncology, Gilead, Debio Pharmaceuticals, Zymeworks, PUMA Biotechnology, Merck Pharmaceuticals, Context Therapeutics. W. Janni: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Gilead; Financial Interests, Personal, Full or part-time Employment: Universitätsklinikum Ulm; Financial Interests, Institutional, Invited Speaker: Novartis, GSK, Sanofi, Amgen, Roche, Lilly; Non-Financial Interests, Leadership Role: Chair of AGO Breast Council. H.S. Rugo: Financial Interests, Institutional, Research Grant: Plexxikon, Macrogenics, OBI Pharma, Eisai, Pfizer, Novartis, Eli Lilly, GlaxoSmithKline, Genentech, Celsion, Merck; Financial Interests, Personal, Other, Travel, Accomodations, and Expenses: Novartis, Roche/Genentech, OBI Pharma, Bayer, Pfizer; Financial Interests, Personal, Speaker’s Bureau: Genomic Health. A. Lteif: Financial Interests, Personal and Institutional, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. G. Sopher: Financial Interests, Personal and Institutional, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. H. Hu: Financial Interests, Personal and Institutional, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. All other authors have declared no conflicts of interest.
Within HER2+ ABC, estrogen receptor (ER) negative or PAM50 non-luminal disease (HER2-enriched and Basal-like) are more immunogenic, have higher tumor-infiltrating lymphocytes and higher expression of immune-related genes. Here, we report the interim efficacy and safety data of the ATREZZO trial (NCT04759248).
ATREZZO is a single-arm, phase II trial evaluating atezolizumab, trastuzumab and vinorelbine combination in patients (pts) with HER2+, ER– or ER+ and PAM50 non-luminal subtypes ABC. Key inclusion criteria include progression to prior trastuzumab and antibody drug conjugate and presence of measurable disease. The primary endpoint was overall response rate (ORR). Tumor samples are mandatory to assess PAM50 and PD-L1 IHC (SP142) status. Based on a Simon’s two stage design, the analysis of the first stage was planned after 19 evaluable pts, if at least 3 pts achieved an objective response, the trial would continue up to recruit 55 evaluable pts for a target ORR ≥ 13. The evaluable population was defined as all pts who had received at least one dose of treatment and had at least one postbaseline tumor assessment.
61 pts were pre-screened, and 42 ER+ and non-luminal or ER- tumors were identified. From these, 23 pts were recruited, and 19 were evaluable for primary endpoint. Baseline pts characteristics: median age 58 years (33-72), ER+ 32% (6/19), visceral disease 90% (17/19), median of 3 (1-4) prior lines for ABC and PD-L1 IHC tumors+ 16% (3/19). At the time of data cut-off (Feb, 2022), 14 pts had stopped their treatment because of PD and 1 due to toxicity. 4 pts were still on treatment. The ORR was 31.6% (6/19, 95% CI 12.59-56.57), meeting the pre-specified ORR for the stage I of the trial. 42.1% of patients (8/19) experienced grade 3-4 AEs.
The stage I of ATREZZO met its pre-specified endpoint. Completion of the stage II part of the trial with the inclusion of up to 55 pts is warranted to assess the activity of this combination in this group of pts. Correlative studies are ongoing and will be presented at the meeting.
EudraCT 2020-000245-13, NCT04759248 First posted: October 6, 2022. Sponsor: SOLTI Cancer Research Group. This study was funded by Roche Farma S.A.
SOLTI.
Roche Farma S.A.
E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau. Educational activities: Roche; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Roche, Lilly, Novartis, Pfizer, Daiichi Sankyo, MSD; Financial Interests, Personal, Invited Speaker, Symposia and Education: Lilly; Financial Interests, Personal, Invited Speaker, Educational activities: Pfizer; Financial Interests, Personal, Advisory Board, Non-permanent advisor, Travel accommodation: AstraZeneca; Financial Interests, Personal, Other, Advisory Board: Gilead; Financial Interests, Personal, Other, Advisory Board, Invited speaker: Seagen; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Invited Speaker, Non-profit organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientific Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. P. Tolosa Ortega: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Lilly, Seagen, AstraZeneca, Daiichi Sankyo and MSD; Financial Interests, Personal, Advisory Board: Novartis, Adamed, Seagen and Daiichi Sankyo; Financial Interests, Personal, Full or part-time Employment, Medical Advisor and Madical Monitor: SOLTI. S. González-Santiago: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, GSK, Pierre Fabre; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, Travel expenses: Clovis, Pfizer. S. Escrivá-De-Romaní: Financial Interests, Personal, Other, Consulting Fees: AstraZeneca Daiichi Sankyo, F Hoffmann-La Roche Ltd., Pierre-Fabre, Seagen; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca Daiichi Sankyo, F Hoffmann-La Roche Ltd., Pfizer, Pierre-Fabre, Seagen, Novartis; Financial Interests, Personal, Other, Travel accommodations: AstraZeneca Daiichi Sankyo, F Hoffmann-La Roche Ltd., Pfizer, Pierre-Fabre, Kern; Financial Interests, Personal and Institutional, Other, Contracted Research: AstraZeneca Daiichi Sankio; Financial Interests, Personal and Institutional, Invited Speaker, Contracted research: F Hoffmann-La Roche Ltd.; Financial Interests, Personal and Institutional, Other, Contracted research: Byondis, Zymeworks, Synthon, MedSir, Solti. A. Lopez Gonzalez: Financial Interests, Institutional, Invited Speaker: Novartis, Pfizer; Financial Interests, Institutional, Advisory Board: Seagen. S. Pernas Simon: Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pfizer; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Novartis, Daiichi Sankyo; Non-Financial Interests, Invited Speaker: SOLTI. J. Ponce: Financial Interests, Personal, Advisory Board: Seattle Genetics, Novartis, AstraZeneca/Daiichi Sankyo, Roche; Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, AstraZeneca/Daiichi Sankyo, Seattle Genetics, Lilly. O. Martínez-Sáez: Financial Interests, Personal, Advisory Board: Reveal Genomics. J.M. Cejalvo: Financial Interests, Institutional, Invited Speaker: Pfizer, Novartis. I. Blancas López-Barajas: Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, Lilly, Pfizer, Roche; Financial Interests, Personal, Advisory Role: AstraZeneca, Roche, Novartis, Eisai, Celgene, Pfizer, Lilly, Pierre Fabre, Bristol Myers Squibb, Daiichi Sankyo, Grünenthal, Seagen, Veracyte; Financial Interests, Personal, Other, Support for attending meetings and/or travel: AstraZeneca, Roche, Novartis, Pfizer, Lilly, Pierre Fabre, Bristol Myers Squibb , Daiichi Sankyo. G. Villacampa: Financial Interests, Personal, Speaker’s Bureau: MSD, GSK, Pierre Fabre; Financial Interests, Personal, Advisory Role: AstraZeneca. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Veracyte, Novartis; Financial Interests, Personal, Advisory Board: Roche, Genentech. All other authors have declared no conflicts of interest.
SG is a Trop-2–directed antibody-drug conjugate approved in multiple countries for pts with pretreated mTNBC and in the US for pts with pretreated HR+/HER2— metastatic breast cancer. SG has a manageable safety profile, with neutropenia and diarrhea as the most common grade ≥3 adverse events (AEs). Here, we evaluated the relationship of these two AEs with clinical outcomes in pts with mTNBC.
Pts with mTNBC who received SG in the phase III ASCENT study (NCT02574455) were included. A post hoc analysis was conducted to estimate the relationship of AEs (neutropenia [including febrile neutropenia] or diarrhea, separately) with clinical outcomes (progression-free survival and overall survival).
For the 254 SG-treated pts in this analysis, baseline characteristics were similar among pts who did and did not experience neutropenia or diarrhea. For SG, the incidence of grade ≥3 neutropenia was 54% (n=138) and grade ≥2 diarrhea was 32% (n=81); no grade 5 events occurred. The relationship between occurrence of grade ≥3 neutropenia and grade ≥2 diarrhea with outcomes among pts who received SG is described in the table.
In this post hoc analysis of ASCENT, clinical outcomes for pts with pretreated mTNBC who did and did not experience AEs of grade ≥3 neutropenia or grade ≥2 diarrhea were consistent with the overall intention-to-treat population and were not adversely impacted by the occurrence of these AEs. Active monitoring and early intervention using management strategies for neutropenia and diarrhea in line with established guidelines may allow for longer treatment durations and sustained benefit from SG. ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival; SG, sacituzumab govitecan; TPC, treatment of physician’s choice.
Grade ≥2 diarrhea Grade ≥3 neutropenia ITT 6.9 (4.2-8.3) 4.9 (3.7-5.7) 5.6 (4.0-6.5) 4.9 (4.1-5.9) 4.8 (4.1-5.8) 1.7 (1.5-2.5) HR (95% CI) 0.72 (0.52-0.98) 0.91 (0.68-1.21) 0.43 (0.35-0.54) 14.3 (11.8-16.7) 10.9 (9.5-13.8) 13.5 (10.8-14.5) 11.2 (10.1-14.1) 11.8 (10.5-13.8) 6.9 (5.9-7.7) HR (95% CI) 0.69 (0.50-0.94) 0.99 (0.74-1.32) 0.51 (0.41-0.62)
NCT02574455.
Hameda Khandaker, PhD, and Shala Thomas, PhD, CMPP, at Team 9 Science.
Gilead Sciences, Inc.
Gilead Sciences, Inc.
E. de Azambuja: Financial Interests, Personal, Advisory Board: Roche/GNE, Novartis, Seagen; Financial Interests, Personal, Invited Speaker: Zodiac, Libbs, Pierre Fabre, Lilly, Astra-Zeneca; Financial Interests, Institutional, Research Grant: Roche/GNE, AstraZeneca, GSK/Novartis, Servier; Financial Interests, Institutional, Other, Travel Grant: Roche/GNE; Financial Interests, Institutional, Invited Speaker: MSD, ABCSG, Nektar, Gilead, Immunomedics, Synthon, Odonate Therapeutics; Financial Interests, Invited Speaker, Chair of the Gilead Sciences Research Scholars Program in Solid Tumours: Gilead; Financial Interests, Invited Speaker, Aphinity, Lorelei, Impassion03: Roche; Financial Interests, Invited Speaker, AURORA: Breast International Group; Financial Interests, Invited Speaker, Olympia: Astra-Zeneca; Financial Interests, Personal, Other, Travel grant: Astra-Zeneca; Non-Financial Interests, Advisory Role, Member of the cardio-oncology council: European Society for Cardiology (ESC); Non-Financial Interests, Advisory Role, Belgium governmental institution for cancer: KCE; Non-Financial Interests, Other, Editorial board member: ESMO Open; Non-Financial Interests, Advisory Role: Anticancer Fund. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Takeda, Sandoz, Ipsen, Libbs, Knight, Daiichi Sankyo, Lilly, Pfizer, Novartis, Roche; Financial Interests, Personal, Other, Travel grant to attend ASCO 2022: Gilead; Financial Interests, Institutional, Invited Speaker, 2-year research grant paid to my Institution: Gilead. H.S. Rugo: Financial Interests, Personal, Funding: Puma Biotechnology, Mylan, Samsung Bioepis; Financial Interests, Institutional, Funding: Macrogenics, OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Odonate Therapeutics, Daiichi Sankyo, Seattle Genetics, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Ayala Pharmaceuticals. A. Bardia: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Genentech, Merck, Sanofi, Eisai, Lilly, Mersana, AstraZeneca/Daiichi, Menarini, Gilead; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Invited Speaker: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly.; Non-Financial Interests, Principal Investigator: Gilead, Mersana, AstraZeneca/Daiichi, Novartis, Pfizer, Genentech, Lilly, Merck, Sanofi. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna, Myovant, Bayer, Zetagen, Infinity Therapeutics, Umoja Biopharma; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. J. O'Shaughnessy: Financial Interests, Personal, Funding: AbbVie Inc., Agendia, Amgen Biotechnology, Aptitude Health, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene Corporation, Clovis Oncology, Daiichi Sankyo, Eisai, G1 Therapeutics, Genentech, Gilead Sciences, GRAIL, Halozyme Therapeutics, Heron Therapeutics, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Nektar Therapeutics, Novartis, Pfizer, Pharmacyclics, Pierre Fabre Pharmaceuticals, Puma Biotechnology, Prime Oncology, Roche, Samsung Bioepis, Sanofi, Seagen, Syndax Pharmaceuticals, Taiho Oncology, Takeda, Synthon. R.J. Delaney: Financial Interests, Personal, Full or part-time Employment: Gilead Sciences, Inc.; Financial Interests, Personal, Stocks/Shares: Gilead Sciences, Inc. S. Zha: Financial Interests, Personal, Full or part-time Employment: Gilead Sciences, Inc., University of Pittsburgh; Financial Interests, Personal, Stocks/Shares: Gilead Sciences, Inc.; Financial Interests, Personal, Funding: Gilead Sciences, Inc. T. Valdez: Financial Interests, Personal, Full or part-time Employment: Gilead Sciences, Inc.; Financial Interests, Personal, Stocks/Shares: Gilead Sciences, Inc. K. Kalinsky: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Eli Lilly, Pfizer, Novartis, Eisai, AstraZeneca, Immunomedics, Merck, Seattle Genetics, Cyclacel, Oncosec, 4D Pharma, Puma; Financial Interests, Personal, Stocks/Shares, Employment + Stock = spouse: Grail; Financial Interests, Personal and Institutional, Invited Speaker, Consultant: Novartis, Eli Lilly, AstraZeneca, daicchi sankyo; Financial Interests, Personal and Institutional, Invited Speaker, consultant: Genentech; Financial Interests, Institutional, Invited Speaker, consultant: Pfizer; Financial Interests, Institutional, Invited Speaker: Seattle Genetics, Ascentantage; Financial Interests, Personal, Other, Consultant: Myovant, Takeda, Menarini; Financial Interests, Personal, Other, consultant: Menarini; Other, Support for attending meetings and/or travel: Eli Lilly, AstraZeneca, Pfizer; Other, Steering Committee: Immunomedics, AstraZeneca, Ambryx, Genentech. E. Agostinetto: Financial Interests, Personal, Funding: Eli Lilly, Sandoz, AstraZeneca, Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili, Daiichi Sankyo. All other authors have declared no conflicts of interest.
Early dynamic patterns (DP) of ctDNA and TKa provide improved prediction of progression free survival for pts with HR+ HER2− ABC treated with RIB+LET enrolled in the BioItaLEE trial. Here we evaluate their association with tumor response.
Of the 287 pts enrolled, 236 with post-baseline imaging evaluation were included in the present analyses. Clinical benefit rate (CBR) was defined according to Recist Critera 1.1. According to presence or absence of MUT ctDNA at cycle (C)1 day (D)1 and C1D15, ctDNA DP were defined as: Confirmed Wild Type (WT) (WT/WT), New mutated (MUT) (WT/MUT), Cleared (MUT/WT), confirmed MUT (MUT/MUT). TKa DP were defined as TKa inhibited (INH; +/-/-), rebounded (+/-/+) and insufficiently INH (+/+/+) according to the presence (+) or absence (-) of TKa at C1D1, C1D15 and C2D1. Multivariate logistic regression models adjusting for pts status, tumor type, visceral metastases and number of organs involved were used to correlate CBR with ctDNA and TKa dynamics.
Overall CBR was 73.3%. CBR according to ctDNA and TKa DP is shown in the table. In the logistic model, MUT/MUT vs WT/WT pts had an Odds Ratio (OR) of 0.42 (p=0.033). OR of TKa rebounded vs. TKa INH pts and TKa insufficiently INH vs. TKa INH pts were 0.38 (p=0.019) and 0.24 (p=0.008) respectively (Table).
Logistic model CBR (%) OR (95% CI) p-value ctDNA DP (n) WT/WT (105) 80 Reference WT/MUT (17) 71 0.48 (0.15; 1.57) 0.226 MUT/WT (47) 68 0.44 (0.20; 1.00) 0.050 MUT/MUT (50) 66 0.42 (0.19; 0.93) 0.033 TKa DP (n) INH (60) 85 Reference Rebounded (128) 69 0.38 (0.17; 0.85) 0.019 Insufficiently INH (31) 61 0.24 (0.08; 0.69) 0.008
DP of either ctDNA and TKa were associated with tumor response to RIB+LET. Our data suggest that insufficient inhibition of TKa at C1D15 may be a surrogate marker for tumor progression. If further confirmed, TKa measurement may be helpful for patients needing a rapid evaluation of tumor response.
NCT03439046.
Novartis Farma S.p.A.
Novartis Farma SpA, Italy.
G. Arpino: Financial Interests, Personal, Writing Engagements, Medical writing: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi Sankyo, Novartis, Roche, Pfizer, Eli Lilly, Gilead, Seagen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, Novartis, Roche, Seagen, Viatris; Financial Interests, Personal, Other, Support for attending meetings: Daiichi Sankyo, Roche, Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Novartis, Gilead, Roche, Seagen. G. Bianchini: Financial Interests, Personal, Advisory Role: Novartis, Eli Lilly, Pfizer, Roche, AstraZeneca, Neopharm Istrael, Amgen, MSD, Chugai, Sanofi, Daiichi Sankyo, Eisai, Gilead, Seagen, Exact Science, Agendia, Seagen. L. Malorni: Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Seagen. R. Caputo: Financial Interests, Personal, Invited Speaker: Novartis, Eli Lilly, Veracyte, Seagen; Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly, Roche, Gilead, MSD, AstraZeneca, Daiichi Sankyo. A. Zambelli: Financial Interests, Personal, Advisory Board: Roche, Novartis, Eli Lilly, Pfizer, Daiichi Sankyo, AstraZeneca, Seagen, Exact Science, MSD. F. Puglisi: Financial Interests, Institutional, Research Grant: AstraZeneca, Eisai, Roche; Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly; Financial Interests, Personal, Invited Speaker: Pfizer. L. Del Mastro: Financial Interests, Institutional, Research Grant: Eli Lilly, Novartis, Roche, Daiichi Sankyo, Seagen; Financial Interests, Personal, Advisory Role: Eli Lilly; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Eli Lilly, AstraZeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Science, Ipsen; Financial Interests, Personal, Other, Support for attending meetings or travel: Roche, Pfizer, Eisai, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Novartis, Roche, Eli Lilly, Pfizer, Daiichi Sankyo, Exact Science, Gilead, Pierre Fabre, Eisai, AstraZeneca, Agendia, GSK, Seagen. M.A. Colleoni: Financial Interests, Institutional, Research Grant: Roche. F. Montemurro: Financial Interests, Personal, Advisory Role: Roche, Novartis, Daiichi Sankyo, AstraZeneca, MSD, Eli Lilly, Pierre Fabre. G.V. Bianchi: Financial Interests, Personal, Advisory Board: Novartis, Daiichi Sankyo, AstraZeneca, Seagen, Eli Lilly; Financial Interests, Personal, Invited Speaker: Roche, BMS. I. Paris: Financial Interests, Personal, Advisory Board: Novartis, Seagen, Gilead, Italfarmaco, Pfizer, Seagen, Gilead; Financial Interests, Personal and Institutional, Invited Speaker: Eli Lilly; Financial Interests, Personal, Training: AstraZeneca, Sophos. M.E. Cazzaniga: Non-Financial Interests, Personal, Advisory Board: Novartis. M. Orditura: Non-Financial Interests, Institutional, Advisory Role: AORN Caserta Oncologia Medica. C. Zamagni: Financial Interests, Personal, Research Grant: Novartis, Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Eisai, GSK; Financial Interests, Personal, Other, Support for attending meeting or travel: Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Eisai, GSK, Exact Science, Clovis; Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Eisai, GSK, Daiichi Sankyo. M.B. Suter: Financial Interests, Personal, Full or part-time Employment: Novartis. N. Fenderico: Financial Interests, Personal, Full or part-time Employment: Novartis. M. De Laurentiis: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Novartis, Roche, Pfizer, Seagen, Daiichi Sankyo, MSD, GSK, Sanofi, Celltrion, Organon, Eisai, Pierre Fabre, Menarini, Gilead; Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly, Novartis, Roche, Pfizer, Seagen, Daiichi Sankyo, MSD, GSK, Sanofi, Eisai, Pierre Fabre, Menarini, Gilead. All other authors have declared no conflicts of interest.
Following the introduction of olaparib into the early and mBC settings, there have been questions about optimal sequencing and decision-making between olaparib and capecitabine. While there are no data to support decisions in the early setting, the phase III randomised OlympiAD trial (NCT02000622) showed significantly longer PFS with olaparib vs single-agent chemotherapy of the physician’s choice (TPC; capecitabine, eribulin, or vinorelbine), in patients with g
Patients were randomised to olaparib 300 mg twice daily (n=205) or TPC (n=97; of which n=43 received capecitabine 2500 mg/m2 for 14 days every 21 days). Analyses were conducted in all patients and those with triple-negative BC (TNBC).
In all analysed populations, olaparib was associated with improved median PFS vs TPC or capecitabine (Table). Safety was aligned with published data. PFS by blinded independent central review ∗OlympiAD was powered to assess the PFS benefit between olaparib vs TPC in this population.
Population Olaparib Comparator (TPC or capecitabine) HR (95% CI) Events n/N (%) Median, months Events n/N (%) Median, months All patients Olaparib vs TPC 163/205 (79.5) 7.0 71/97 (73.2) 4.2 0.58 (0.43–0.80); p=0.0009* Capecitabine-eligible patient subgroup: Olaparib vs capecitabine 72/95 (75.8) 8.2 32/43 (74.4) 4.2 0.55 (0.34–0.89) Patients with TNBC Olaparib vs TPC 81/102 (79.4) 5.6 40/48 (83.3) 2.9 0.43 (0.29–0.63) Capecitabine-eligible patient subgroup: Olaparib vs capecitabine 34/44 (77.3) 5.9 20/23 (87.0) 2.9 0.32 (0.16– 0.64)
Olaparib was associated with longer PFS vs TPC or capecitabine with an acceptable safety profile in g
NCT02000622.
Writing and editorial assistance was provided by Sara Shaw PhD, CMPP of BOLDSCIENCE Inc., funded by AstraZeneca and MSD.
AstraZeneca.
This study was supported by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who are codeveloping olaparib (MSD).
M. Robson: Financial Interests, Personal, Other, Review guideline pathways: Change Healthcare; Financial Interests, Personal, Invited Speaker, Speaker at CME events (NOT speaker's bureau): Physician's Education Resource, Research to Practice, Intellisphere, MJH Holdings; Financial Interests, Personal, Advisory Board, Speaker at CME events (NOT speaker's bureau): MyMedEd; Financial Interests, Institutional, Invited Speaker, Funding for research study (ICEBERG, dating to 2007): AstraZeneca; Financial Interests, Personal, Invited Speaker, Steering Committee Member for CAPITELLO-290, uncompensated: AstraZeneca; Financial Interests, Institutional, Other, Co-PI for Merck IIT of neoadjuvant olaparib/pembrolizumab in BRCA carriers, no personal compensation: Merck; Financial Interests, Personal, Invited Speaker, Steering Committee member for KEYLNK-009, no compensation: Merck; Financial Interests, Institutional, Invited Speaker, Local PI of KEYLNK009: Merck; Financial Interests, Institutional, Other, Local co-PI of clinical trial of ZEN03694 and talazoparib in TNBC, no personal compensation: Pfizer; Non-Financial Interests, Advisory Role: Zenith Pharmaceuticals, Epic Biosciences, Daiichi Sankyo, Tempus Labs; Non-Financial Interests, Personal, Other, Editorial services for writing of reports for ABRAZO clinical trial: Pfizer; Non-Financial Interests, Personal, Other, Editorial services for medical writing of reports resulting from OlympiAD trial: AstraZeneca; Non-Financial Interests, Member: ASCO. S. Delaloge: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Pierre Fabre, Orion, Sanofi, Rappta, Cellectis, Isis/servier; Financial Interests, Institutional, Invited Speaker: Exact Sciences, Pfizer, Seagen, Lilly, AstraZeneca, MSD, Roche Genentech, BMS, Puma, AstraZeneca, Orion, Sanofi, Pfizer; Financial Interests, Institutional, Advisory Board, ad board: Besins Healthcare; Financial Interests, Institutional, Invited Speaker, ESMO symposium: Gilead; Financial Interests, Institutional, Advisory Board, scientific board: Elsan; Financial Interests, Institutional, Funding: GE; Financial Interests, Institutional, Invited Speaker, clinical research funding to my institution: Taiho; Non-Financial Interests, Invited Speaker, Société Française de Sénologie et Pathologie Mammaire: SFSPM; Non-Financial Interests, Principal Investigator, H2020 funding: European Commission. S.M. Domchek: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Clovis Oncology, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: AstraZeneca, Clovis Oncology. P.F. Conte: Financial Interests, Personal, Advisory Board, advisory board for alpelisb trial: Novartis; Financial Interests, Institutional, Research Grant: merch Kga. S. Im: Financial Interests, Personal, Advisory Board, No payment: AstraZeneca, Bertis, Daiichi Sankyo, Eisai, GSK, Hanmi, Lilly, MSD, Novartis, Pfizer, Roche; Financial Interests, Personal and Institutional, Principal Investigator, Clinical trial budget: AstraZeneca, Daiichi Sankyo, Eisai, Hanmi, Lilly, MSD, Novartis, Pfizer, Roche; Financial Interests, Institutional, Research Grant, Clinical trial budget: AstraZeneca, Boryung Pharm; Financial Interests, Institutional, Research Grant: Dae Woong, Eisai, Pfizer, Roche; Financial Interests, Personal, Advisory Board: Idience. B. Xu: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca; Financial Interests, Personal, Invited Speaker: Pfizer, Roche; Financial Interests, Institutional, Research Grant: Henrui. A. Armstrong: Financial Interests, Personal, Advisory Board: Gilead Sciences, MSD; Financial Interests, Personal, Other, Travel, accommodation, expenses: Gilead Sciences, MSD Oncology, Novartis; Financial Interests, Personal, Stocks/Shares, Owned by immediate family member: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca/MedImmune. N. Masuda: Financial Interests, Personal, Invited Speaker: Chugai, AstraZeneca, Eisai, Eli Lilly, Pfizer, Dai-ichi Sankyo; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Kyowa-Kirin, MSD, Novartis, Pfizer, Sanofi, Ono Pharma; Non-Financial Interests, Invited Speaker: Japan Breast Cancer Research Group, Japanese Breast Cancer Society. R. Hettle: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Fielding: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. N.M. Tung: Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca. E. Senkus-Konefka: Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly, Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca, Cancérodigest, Eli Lilly, Gilead, high5md, Novartis, Pfizer, MSD; Financial Interests, Personal, Other, commenting on scientific meeting in social media: Curio Science; Financial Interests, Personal, Other, travel expenses: Gilead, Egis, Novartis, Roche; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Eli Lilly, Pfizer; Financial Interests, Personal, Royalties: Springer; Financial Interests, Personal and Institutional, Invited Speaker: Amgen, Eli Lilly, Novartis, OBI Pharma, Samsung; Financial Interests, Personal and Institutional, Other, SI: AstraZeneca, Roche, Pfizer.
Trilaciclib protects CDK4/6-dependent hematopoietic stem and progenitor cells during chemotherapy (CT; myeloprotection). SG is an antibody–drug conjugate indicated to treat pts with mTNBC. In the phase III ASCENT trial, SG significantly extended survival vs single-agent CT but was associated with increased neutropenia (any grade [G], 63% vs 43%; G3/4, 51% vs 33%) and diarrhea (any G, 59% vs 12%; G3/4, 10% vs < 1%; Bardia et al.
Eligible adult pts (≥ 2 prior systemic therapies [≥ 1 in the metastatic setting]; measurable disease; confirmed hormone receptor-/HER2-negative status; ECOG PS 0/1) receive intravenous trilaciclib 240 mg/m2 prior to SG 10 mg/kg on Days 1 and 8 of each 21-day cycle until disease progression/toxicity. Tumor assessments occur at screening, every 6 weeks to week 36, then every 9 weeks until disease progression/subsequent anticancer therapy. Endpoints include antitumor efficacy, myeloprotection, and safety/tolerability.
As of January 17, 2023, 26 (of 45 planned) female pts had been enrolled and completed a median (range) of 4 (2–15) cycles. Pts had received a median of 2 (2–5) prior lines of therapy, including taxanes (n = 20) and immune checkpoint inhibitors (n = 18). See table; objective response rate by PD-L1 status will be presented. One pt had AEs that led to discontinuation of both study drugs.
∗PR, n = 6 (30%); 1 pt with PR continued therapy after PD (21% increase in sum of longest diameters)
AEs (safety population; N = 26) Any G, n (%) G3/4, n (%) - - Complete response (CR) 0 -
Preliminary data suggest trilaciclib prior to SG has the potential to reduce the rate and severity of multiple AEs compared with results from trials of SG alone, and warrant its continued evaluation.
NCT05113966.
Medical writing assistance was provided by Philip Reardon, PhD, from Alligent Europe (Envision Pharma Group), funded by G1 Therapeutics, Inc.
G1 Therapeutics, Inc.
G1 Therapeutics, Inc.
L. Seneviratne: Financial Interests, Personal, Invited Speaker, Payment or honararia for lectures, presentations, speakers bureaus, manuscript writing or educational event: Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca. K.K. Harnden: Financial Interests, Personal, Invited Speaker: Merck, Daiichi Sankyo, AstraZeneca, Seagen, Eisai. M. Mardones: Financial Interests, Personal, Other, Gilead Sciences Payments for consultant work: Gilead Sciences. M.A. Danso: Financial Interests, Personal, Advisory Role: Novartis, Pfizer, Immunomedics, Seattle Genetics; Financial Interests, Personal, Other, Honoraria: Amgen. D. Berz: Financial Interests, Personal, Other, Consulting fees: Jazz Pharma, Sun Pharma; Financial Interests, Personal, Invited Speaker: Jazz Pharma, Sun Pharma, Mirati, EMD Serono, Caris Life Science, AstraZeneca; Financial Interests, Personal, Other, Support for attending meetings and/or travel: Jazz Pharma, Sun Pharma, Mirati, EMD Serono, Caris Life Science, AstraZeneca. J. O'Shaughnessy: Financial Interests, Personal, Advisory Role: AbbVie Inc., Agendia, Amgen Biotechnology, Aptitude Health, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene Corporation, Clovis Oncology, Daiichi Sankyo, Eisai, G1 Therapeutics, Genentech, Gilead Sciences, GRAIL, Halozyme Therapeutics, Heron Therapeutics, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Nektar Therapeutics, Novartis, Pfizer, Pharmacyclics, Pierre Fabre Pharmaceuticals, Puma Biotechnology, Prime Oncology, Roche, Samsung Bioepis, Sanofi, Seagen, Syndax Pharmaceuticals, Taiho Oncology, Takeda, Synthon; Financial Interests, Personal, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie Inc., Agendia, Amgen Biotechnology, Aptitude Health, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene Corporation, Clovis Oncology, Daiichi Sankyo, Eisai, G1 Therapeutics, Genentech, Gilead Sciences, GRAIL, Halozyme Therapeutics, Heron Therapeutics, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Nektar Therapeutics, Novartis, Pfizer, Pharmacyclics, Pierre Fabre Pharmaceuticals, Puma Biotechnology, Prime Oncology, Roche, Samsung Bioepis, Sanofi, Seagen, Syndax Pharmaceuticals, Taiho Oncology, Takeda, Synthon. D. Patt: Financial Interests, Personal, Invited Speaker: Ideology, Pfizer, DSI; Financial Interests, Personal, Member of the Board of Directors: ASCO; Financial Interests, Personal, Leadership Role: Community College Alliance. A. Bardia: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Genentech, Merck, Sanofi, Eisai, Lilly, Mersana, AstraZeneca/Daiichi, Menarini, Gilead; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Invited Speaker: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly.; Non-Financial Interests, Principal Investigator: Gilead, Mersana, AstraZeneca/Daiichi, Novartis, Pfizer, Genentech, Lilly, Merck, Sanofi. A. Beelen: Financial Interests, Institutional, Funding, Funding to support all aspects of the study: G1 Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: G1 Therapeutics Inc.; Financial Interests, Personal, Full or part-time Employment: G1 Therapeutics Inc. T. Oyekunle: Financial Interests, Institutional, Funding, Funding to support all aspects of the study: G1 Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: G1 Therapeutics Inc.; Financial Interests, Personal, Full or part-time Employment: G1 Therapeutics Inc. V. Dell: Financial Interests, Institutional, Funding: G1 Therapeutics Inc.; Financial Interests, Institutional, Other, Medical writing: G1 Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: G1 Therapeutics Inc.; Financial Interests, Personal, Full or part-time Employment: G1 Therapeutics Inc. S.A. Hurvitz: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Lilly; Financial Interests, Personal, Other: Roche, Pfizer; Financial Interests, Personal, Stocks/Shares, An Immediate Family Member: Ideal Implant; Financial Interests, Personal, Invited Speaker, An Immediate Family Member: ROM Tech; Financial Interests, Personal, Funding, Honoraria: Daiichi Sankyo/AstraZeneca; Financial Interests, Institutional, Funding: Genentech/Roche, Novartis, GlaxoSmithKline, Sanofi, Pfizer, Amgen, OBI Pharma, Puma Biotechnology, Dignitana, Bayer, Biomarin, Lilly, Merrimack, Cascadian Therapeutics, Seattle Genetics, Daiichi Sankyo, Macrogenics, Ambryx, Immunomedics, Pieris Pharmaceuticals, Radius Health, Arvinas, Zymeworks, Gilead Sciences, Phoenix Molecular Designs, CytomX Therapeutics, Samumed, Dantari, Orin, Greenwich LifeSciences, AstraZeneca/Daiichi Sankyo, G1 Therapeutics. All other authors have declared no conflicts of interest.
OP-1250 is small molecule CERAN/SERD that binds to and completely blocks transcriptional activity of wild-type and mutant ER. OP-1250 was well tolerated in a phase I/II monotherapy study (OP-1250-001), and the recommended phase II dose is 120 mg once a day (qd). OP-1250 with palbociclib showed synergistic activity in preclinical models. Here we report updates of pharmacokinetics (PK), drug-drug interactions (DDI), safety and efficacy from a study of OP-1250 with palbociclib (OP-1250-002).
Pts with advanced or MBC with progression on or after ≤1 line of endocrine therapy (prior CDK4/6 inhibitors and chemotherapy were allowed) were enrolled into sequential cohorts to receive escalating doses of OP-1250 PO qd with palbociclib 125 mg PO qd for 21 of 28 days, using a 3+3 design, followed by dose expansion.
As of January 23, 2023, 20 pts have been treated with palbociclib and OP-1250 doses of 30/60/90/120 mg (n=3/3/3/11). Fourteen received prior CDK4/6 inhibitor; 11 received prior palbociclib. No DLTs occurred. The most common (≥4 pts) treatment emergent adverse events (AEs) were neutropenia, nausea, vomiting, anemia, gastroesophageal reflux, constipation, and thrombocytopenia (all were Grade 1-2, except neutropenia). Grade 3 neutropenia occurred in 11 pts (55%). No Grade 4 AEs occurred. The exposure of OP-1250 (n=18) was consistent with the monotherapy study. Palbociclib exposure at steady state was comparable to published monotherapy data when combined with OP-1250 at all dose levels tested. Anti-tumor activity has been observed including partial responses.
OP-1250 did not affect palbociclib PK and no DDIs have been observed with this combination. OP-1250 and palbociclib combination was well tolerated, safety was consistent with individual profiles of each drug as a monotherapy. Tumor responses were observed in this heavily pretreated population. Expanding on our previous report (SABCS 2022), these data provide rationale to continue exploring OP-1250 with the approved dose of palbociclib. Updated data will be presented. (NCT0526610).
NCT0526610.
Olema Oncology.
Olema Oncology, Pfizer.
D. Faltaos: Financial Interests, Personal, Full or part-time Employment: Olema Oncology; Financial Interests, Personal, Stocks/Shares: Olema Oncology. M. Shilkrut: Financial Interests, Full or part-time Employment: Olema Oncology; Financial Interests, Stocks/Shares: Olema Oncology. R. Wilson: Financial Interests, Personal, Full or part-time Employment: Olema Oncology. All other authors have declared no conflicts of interest.
In the OlympiAD phase III trial, olaparib significantly prolonged progression-free survival (PFS) vs chemotherapy in patients (pts) with germline-
In this open-label trial, pts with germline or somatic
251/252 pts in the g Efficacy results by ER expression ∗number of events or responses/number of evaluable pts.CI, confidence interval; CRR, clinical response rate; DOCR, duration of clinical response; IQR, interquartile range; NR, not reached; OS, overall survival; PFS, progression-free survival.
ER <1% 92/117* 6.8 (5.5–9.0) 24/29* 8.3 (4.5–12.6) 89/105* 8.4 (7.6–11.0) 67/117* 20.1 (16.5–26.9) 20/29* 22.9 (13.0–35.1) 54/105* 27.4 (23.0–NR) 59/116* 50.9 (41.4–60.3) 12/28* 42.9 (24.5–62.8) 51/104* 49.0 (39.1–59.0) 59/116* 8.3 (3.8–26.5) 12/28* 7.2 (5.3–14.1) 51/104* 7.4 (4.3–17.7)
Real-world results of the phase IIIb LUCY trial support the clinical effectiveness of olaparib in pts with g
NCT03286842.
Writing and editorial assistance was provided by Leigh-Ann Booth, PhD of BOLDSCIENCE Inc., funded by AstraZeneca and MSD.
AstraZeneca.
This study was supported by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, who are codeveloping olaparib (MSD).
K.A. Gelmon: Financial Interests, Personal, Advisory Board: AstraZeneca, Ayala, Gilead, Lilly, Merck, Novartis, Pfizer, Seagen; Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca, BMS, Pfizer. P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Sanofi Aventis; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Lilly, Seagen, Gilead; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BionTech, Cepheid; Non-Financial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v. S. Delaloge: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Pierre Fabre, Orion, Sanofi, Rappta, Cellectis, Isis/servier; Financial Interests, Institutional, Invited Speaker: Exact Sciences, Pfizer, Seagen, Lilly, AstraZeneca, MSD, Roche Genentech, BMS, Puma, AstraZeneca, Orion, Sanofi, Pfizer; Financial Interests, Institutional, Advisory Board, ad board: Besins Healthcare; Financial Interests, Institutional, Invited Speaker, ESMO symposium: Gilead; Financial Interests, Institutional, Advisory Board, scientific board: Elsan; Financial Interests, Institutional, Funding: GE; Financial Interests, Institutional, Invited Speaker, clinical research funding to my institution: Taiho; Non-Financial Interests, Invited Speaker, Société Française de Sénologie et Pathologie Mammaire: SFSPM; Non-Financial Interests, Principal Investigator, H2020 funding: European Commission. Y.H. Park: Financial Interests, Personal and Institutional, Writing Engagements, Financial and non-financial relationships are declared: Novartis, Pfizer, Merck, Roche, Lilly, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal and Institutional, Advisory Board, Financial and non-financial relationships are declared: Novartis, Pfizer, Merck, Roche, Lilly, AstraZeneca, Eisai, Daiichi Sankyo, Menarini, Gilead Sciences, Boryung; Financial Interests, Personal and Institutional, Principal Investigator, Financial and non-financial relationships are declared: Novartis, Pfizer, Merck, Roche, Lilly, AstraZeneca, Daiichi Sankyo, Menarini, Gilead Sciences, Boryung, Gencurix; Financial Interests, Personal and Institutional, Invited Speaker, Financial and non-financial relationships are declared: Pfizer, Merck, Roche, Lilly, AstraZeneca, Eisai, Daiichi Sankyo; Financial Interests, Personal and Institutional, Research Grant, Financial and non-financial relationships are declared: Pfizer, Merck, Roche, Lilly, AstraZeneca, Gencurix, Genome Insight, NGenbio. A.F. Eisen: Financial Interests, Institutional, Invited Speaker, Local PI for Brevity Study: RNA Diagnostics; Financial Interests, Institutional, Invited Speaker, Local PI for LUCY study: Astra-Zeneca. Z. Kemp: Financial Interests, Personal, Invited Speaker: AstraZeneca, Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Principal Investigator: AstraZeneca. J. Sohn: Financial Interests, Personal, Stocks/Shares, Immediate Family Member: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: MSD, Roche, Novartis, AstraZeneca, Lilly, Pfizer, GSK, Daiichi Sankyo, Sanofi, Boehringer Ingelheim, Seagen. C.V. Timcheva: Financial Interests, Personal, Advisory Board, Guidelines for the treatment o TNBC: Gilead; Financial Interests, Personal, Other, PI of clinical trial: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker, PI for several clinical trials performing in the hospital: AstraZeneca, Parexel; Financial Interests, Personal and Institutional, Invited Speaker, Pi for several clinical trials perforing in the hospital: Roche; Financial Interests, Personal and Institutional, Invited Speaker, PI for some clinical trials performing in the hospital: Novartis; Financial Interests, Personal and Institutional, Invited Speaker, PI for the clinical trial performing in the hospital: I3Research; Non-Financial Interests, Principal Investigator, Investigator initiated trial on metastatic CRC: Merck. T. Park-Simon: Financial Interests, Personal and Institutional, Invited Speaker: Roche, GSK, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, Seagen, Gilead, Eisai, MSD; Financial Interests, Personal and Institutional, Advisory Board: Roche, GSK, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, Seagen, Gilead, Eisai, MSD; Financial Interests, Personal and Institutional, Principal Investigator: Roche, GSK, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, Seagen, Gilead, Eisai, MSD. A. Anton Torres: Financial Interests, Personal, Invited Speaker: AstraZeneca-Daiichi Sankyo, Eli Lilly, Seagen; Financial Interests, Personal, Advisory Board: AstraZeneca-Daiichi Sankyo, Eli Lilly, Gilead; Financial Interests, Personal, Expert Testimony: Pfizer, Eli Lilly. E. John, N. Lukashchuk, K. Baria: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. I. Gibson: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. J. Balmaña: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer; Financial Interests, Institutional, Invited Speaker: Pfizer, AstraZeneca, MedSir. All other authors have declared no conflicts of interest.
Treatment with a CDK4/6 inhibitor (CDK4/6i) combined with endocrine therapy (ET) is the front-line (1L) standard of care for HR+/HER2- advanced breast cancer (ABC). Resistance to a CDK4/6i can arise in a number of ways, including adaptive activation of the PI3K/mTOR pathway, which may be prevented by addition of a PI3K/mTOR inhibitor to the 1L CDK4/6i + ET regimen. To evaluate this hypothesis, we conducted a phase Ib study of gedatolisib, a pan-PI3K/mTOR inhibitor, palbociclib (palbo), a CDK4/6i, and ET (letrozole [LET] or fulvestrant) in 138 women with HR+/HER2- ABC. Promising preliminary antitumor activity was observed (Wesolowski, SABCS 2022). Here, we report updated baseline characteristics, safety, and efficacy data in treatment naïve patients (pts) treated with gedatolisib + palbo + LET.
We analyzed the treatment naive subgroup of pts with HR+/HER2- ABC who were treated with gedatolisib + palbo + LET as 1L treatment (Escalation and Expansion Arms A; n=41). The primary endpoint was investigator assessed objective response rate (ORR). Secondary endpoints included safety, duration of response, and progression free survival (PFS).
Of these 41 pts, 95% had Stage 4 disease, 37% had metastases to the liver, 17% had metastases to the lung, 93% had measurable lesions, and 24% had PIK3CA mutations. The most common Grade 3-4 adverse events (AE) in the treatment naïve subgroup were neutropenia (61%), rash (39%), stomatitis (29%), and leukopenia (22%). Five of 41 pts (12%) discontinued treatment due to an AE. As of December 12, 2022, for Expansion Arm A, median PFS was 48.6 months (n=30) and ORR was 85% (n=26, measurable and evaluable disease). When treatment naïve pts from both arms are combined, mPFS was 48.6 months (n=41) and ORR was 79% (n=33, measurable and evaluable disease).
The gedatolisib + palbo + LET combination demonstrated promising activity in treatment-naïve pts with ABC. The safety profile of gedatolisib + palbo + LET was similar to palbo + LET. These encouraging results warrant further evaluation of gedatolisib in combination with a CDK4/6i + LET in the front-line setting.
NCT02684032.
Celcuity, Inc.
Celcuity, Inc.
H.S. Rugo: Financial Interests, Personal, Research Grant: AstraZeneca, Ayala, Boehringer Ingelheim, Daiichi Sankyo, Genentech, Gilead Sciences, Lilly, Macrogenics, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, Seattle Genetics, Sermonix Pharmaceuticals; Financial Interests, Personal, Other, Honoraria: Blueprint, Mylan, Puma Biotechnology. R. Wesolowski: Financial Interests, Personal, Other, advisory boards, scientific steering committee: Celcuity; Financial Interests, Personal, Advisory Board: Seagen. E. Stringer-Reasor: Financial Interests, Personal, Advisory Board: AstraZeneca, Immunomedics, Novartis, Lilly, OncoSec, Merck, Seattle Genetics, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Other, Honoraria: Breast Cancer Index, Lilly, Mylan; Financial Interests, Personal, Research Grant: Susan G. Komen for the Cure, V Foundation; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Cascadian Therapeutics, Lilly; Non-Financial Interests, Personal, Other, Uncompensated Relationship: Genentech. H. Han: Financial Interests, Personal, Advisory Board: Novartis, Gilead, AstraZeneca; Financial Interests, Personal, Other, Speaker's Bureau: Lilly; Financial Interests, Institutional, Invited Speaker: Zymeworks, arvinas, AbbVie, Daiichi Sankyo, Marker therapeutics, Pfizer, Seagen, Quantum Leap Healthcare Collaborative. J. Specht: Financial Interests, Personal, Other, Investigator Meeting participant: A2 Biotherapeutics; Financial Interests, Personal, Advisory Board: GE Healthcare, GSK, Sensei Biotherapeutics; Financial Interests, Personal, Other, Consultant: Volastra Therapeutics; Financial Interests, Institutional, Research Grant: Seattle Genetics, Pfizer, Merck, Xencor, Genentech, Celcuity, Minerva, Myriad Pharmaceuticals, Cascadian Therapeutics, AbbVie, Nektar. C. Dees: Financial Interests, Personal, Advisory Board: Novartis, Sanofi. P. Kabos: Financial Interests, Personal, Research Grant: AstraZeneca, Genentech, Lilly, Pfizer, Radius Health, Sanofi; Financial Interests, Personal, Advisory Board: Lilly. U.N. Vaishampayan: Financial Interests, Personal, Advisory Board: Merck, BMS, Exelixis, Gilead, Pfizer, Bayer; Financial Interests, Personal, Invited Speaker: Exelixis, Sanofi, Bayer; Financial Interests, Personal, Research Grant: Merck, BMS. S.A. Wander: Financial Interests, Personal, Advisory Board: Foundation Medicine, Veracyte, Hologic, Biovica, Pfizer, Eli Lilly, Puma Biotechnology; Financial Interests, Personal, Invited Speaker: Eli Lilly, Guardant Health, 2ndMD; Financial Interests, Institutional, Research Grant: Genentech, Eli Lilly, Pfizer, Nuvation Bio, Regor Therapeutics. J. Lu: Financial Interests, Personal, Other, Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds), Salar: Ambrx; Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Pfizer, Sanofi, Seagen. K. Gogineni: Financial Interests, Personal, Other, Honoraria: AmerisourceBergen; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Research Grant: Pfizer, Calithera Biosciences, Merck, Genentech, Seagen. A. Spira: Financial Interests, Institutional, Leadership Role: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, BMS, Bayer; Financial Interests, Personal, Advisory Board: Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone, Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research and Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Regeneron, Lilly, Black Diamond Therapeutics; Financial Interests, Institutional, Advisory Board: Array BioPharma, AstraZeneca/MedImmune, Merck, BMS, Blueprint Medicines; Financial Interests, Personal, Research Grant: LAM Therapeutics, Regeneron; Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, BMS, Loxo, Arch Therapeutics, Gritstone. A. Schott: Financial Interests, Personal, Other, Editorial, Intellectual Property: Up to Date; Financial Interests, Personal, Other, Travel: ASCO; Financial Interests, Personal, Other, Intellectual Property: University of Michigan; Financial Interests, Institutional, Research Grant: Arvinas, Celcuity, Takeda, Relay Therapeutics. M. Abu-Khalaf: Financial Interests, Institutional, Research Grant: Novartis, Merck, Pfizer, Genentech/Roche, Immunomedics, AstraZeneca, HiberCell, Gilead Sciences; Financial Interests, Personal, Advisory Board: Pfizer, BioTheranostics, Immunomedics, Lyell Immunopharma, HiberCell; Financial Interests, Personal, Other, global grant- Investigator Meeting: Pfizer. S. Mutka: Financial Interests, Personal, Full or part-time Employment: Celcuity; Financial Interests, Personal, Stocks/Shares: Celcuity, Alpine Immune Sciences. S. Suzuki: Financial Interests, Personal, Full or part-time Employment: Celcuity; Financial Interests, Personal, Other, Consulting: Artiva Biotherapeutics, Elevation Oncology, Kartos Therapeutics, Tellios Pharma. I. Gorbatchevsky: Financial Interests, Personal, Full or part-time Employment: Celcuity; Financial Interests, Personal, Stocks/Shares: Celcuity. R.M. Layman: Financial Interests, Personal, Research Grant: Celcuity, Accutar Biotechnology, Eli Lilly, Novartis, Pfizer, Puma, Zentalis; Financial Interests, Personal, Advisory Board: Celcuity, Eli Lilly, Novartis.
The oral PROTAC protein degrader ARV-471 binds and degrades wild-type (WT) and mutant ER. The phase II expansion (VERITAC) of a phase I/II study (NCT04072952) tested 2 ARV-471 doses (200 mg once daily [QD] and 500 mg QD) in heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer. ARV-471 200 mg QD was selected as the phase III monotherapy dose based on comparable efficacy and favorable tolerability vs 500 mg QD and robust ER degradation (data cutoff: Jun 6, 2022). We present updated data for ARV-471 200 mg QD after 5 additional months of follow-up.
ARV-471 was administered to pts with ER+/HER2- locally advanced/metastatic breast cancer who had received ≥1 prior endocrine therapy for ≥6 months, ≥1 cyclin-dependent kinase (CDK)4/6 inhibitor, and ≤1 chemotherapy regimen. The primary endpoint was clinical benefit rate (CBR; rate of confirmed complete or partial response or stable disease ≥24 weeks).
As of Nov 1, 2022, 35 pts (median age: 63 y [range: 42–79]; 97% female) received ARV-471 200 mg QD. Pts had a median of 4 prior regimens (range: 1–9); 100% prior CDK4/6 inhibitors, 74% prior fulvestrant, and 74% prior chemotherapy (46% in metastatic setting). CBR with ARV-471 200 mg QD was 37.1% (95% CI: 21–55) in all evaluable pts (n=35) and 47.4% (95% CI: 24–71) in evaluable pts with mutant
After longer follow-up, ARV-471 200 mg QD continued to show clinical activity and was well tolerated in heavily pretreated pts with ER+/HER2- advanced breast cancer. The ongoing phase III VERITAC-2 study (NCT05654623) is evaluating ARV-471 200 mg QD vs fulvestrant.
NCT04072952.
Justine Lempart, PhD, of Apollo Medical Communications, and funded by Arvinas Operations, Inc.
Arvinas Estrogen Receptor, Inc.
Arvinas Estrogen Receptor, Inc.
S.A. Hurvitz: Financial Interests, Personal, Research Grant: Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, Cytomx, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, OBI Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics/Seagen, Zymeworks; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, AstraZeneca. A. Schott: Financial Interests, Personal, Research Grant: Pfizer, Genentech, Arvinas, Takeda; Financial Interests, Personal, Proprietary Information: Imbio, LLC. C.X. Ma: Financial Interests, Personal, Other, Consulting Fees: Olaris, Novartis, Gilead, AstraZeneca, Sanofi-Genzyme, Biovica, Jacobio, Natera, Inivata, Athenex, Bayor, OncoSignal; Financial Interests, Personal, Funding: Pfizer, Puma. R. Nanda: Financial Interests, Personal, Advisory Board: AstraZeneca, BeyondSpring, Cardinal Health, Fujifilm, Immunomedics/Gilead, Infinity, iTeos, Merck, OBI, Oncosec, Seagen; Financial Interests, Personal, Other, Research Funding: Arvinas, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Odonate Therapeutics, OncoSec, Pfizer, Seattle Genetics, Taiho. G. Zahrah: Financial Interests, Personal, Research Grant: Arvinas. N. Hunter: Financial Interests, Personal, Research Grant: Arvinas. A. Tan: Financial Interests, Personal, Research Grant: Arvinas. M.L. Telli: Financial Interests, Personal, Other, Research: Arvinas; Financial Interests, Personal, Other, Consulting: Merck, Immunomedics, Genentech/Roche, G1 Therapeutics, Natera, Pfizer, OncoSec, Blueprint Medicines, Guardant Health, Novartis, AstraZeneca, Sanofi, RefleXion Medical, Gilead Sciences; Financial Interests, Institutional, Research Grant: Novartis, PharmaMar, AbbVie, Calithera Biosciences, Genentech, GSK, Medivation, OncoSec, Vertex, Biothera, Tesaro, Pfizer, EMD Serono, Bayer, Hummingbird Biosciences. J. Anampa: Financial Interests, Personal, Other, Research: Arvinas. R. Jeselsohn: Financial Interests, Personal, Research Grant: Pfizer, Lilly; Financial Interests, Personal, Advisory Board: Carrick Therapeutics, Luminex. P. Munster: Financial Interests, Institutional, Research Grant: Cyteir Therapeutics, Inc., InventisBio Co., Ltd., Amgen, PMV Pharmaceuticals, Genentech, Inc., Revolution Medicines, Inc., Bliss Biopharmaceutical (Hangzhou) Co., Ltd., Arvinas Estrogen Receptor, Inc., Arch Oncology, Hoffman-La Roche, JS InnoPharm, LLC, Seagen Inc., Tempest Therapeutics, Jannsen, Deciphera Pharmaceuticals LLC, Clovis Oncology, Inc., ORIC Pharmaceuticals, Merck Sharp & Dohme LLC, Pfizer, Novartis; Financial Interests, Personal, Other, Consulting Fees: Alessa, RasCal, AtlasMedx; Financial Interests, Personal, Ownership Interest: Alessa, RasCal, AtlasMedx, EpiAxis; Financial Interests, Personal, Royalties: Alessa, RasCal, AtlasMedx, EpiAxis; Financial Interests, Personal, Other: EpiAxis. E. Zhi: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas; Financial Interests, Personal, Project Lead: Arvinas. R. Gedrich: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas. C. Mather: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas. H. Han: Financial Interests, Personal, Advisory Board: Novartis, Gilead, AstraZeneca; Financial Interests, Personal, Other, Speaker's Bureau: Lilly; Financial Interests, Institutional, Invited Speaker: Zymeworks, arvinas, AbbVie, Daiichi Sankyo, Marker therapeutics, Pfizer, Seagen, Quantum Leap Healthcare Collaborative. E. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, Arcus, AstraZeneca, Daiichi Sankyo, Seagen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Millennium, Rgenix, Arqule, Clovis, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Immunomedics, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, FujiFilm, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, InventisBio, Verastem, eFFECTOR Therapeutics, CytomX, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Jacobio, Atlas MedX, Ellipses, Incyte, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Cascadian Therapeutics, Artios, BeiGene, Bliss BioPharmaceuticals, Context Therapeutics, Cullinan-Florentine, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Relay Therapeutics, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Tolmar, Torque Therapeutics.
AKT pathway activation is implicated in resistance to endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in pts with HR+/HER2– ABC. In CAPItello-291, C+F significantly improved progression-free survival vs F in pts with aromatase inhibitor-resistant HR+/HER2– ABC (HR 0.60; 95% CI 0.51–0.71; p<0.001) and pts with AKT pathway-altered tumours (HR 0.50; 95% CI 0.38–0.65; p<0.001). Simultaneous inhibition of AKT and CDK4/6 pathways may improve clinical outcomes by resensitising tumours to ET and CDK4/6i.
This phase Ib/III study is evaluating the safety/efficacy of C+P+F vs placebo+P+F in HR+/HER2− ABC. Phase Ib used a Keyboard design (mTPI-2), and pts received C (320mg [C320] or 400mg [C400] twice daily, 4 days on/3 days off), P (100mg [P100] or 125mg [P125] once daily for 21 days of each 28-day cycle) and F (500mg [F500] every 28 days + loading dose on cycle 1 day 15); prior CDK4/6i was permitted. Phase Ib primary endpoints: safety/tolerability; confirmation of recommended phase III dose (RP3D). Serial ctDNA monitoring was performed and C/P pharmacokinetics were evaluated. Data cut-off: 31 Oct 2022.
In 39 heavily pre-treated (median prior chemotherapies: 2 [range 0–8]) pts with a median age of 59 years (range 38–82), 7 dose-limiting toxicities (DLTs; mainly neutropenia related) were seen in 6 pts across doses and did not prevent escalation/expansion. C400+P125+F500 (n=12) was identified as the RP3D (1 DLT; Grade [G] 3 neutropenia). Most common adverse events were diarrhoea (69%; 1/27 G3), neutropenia (54%; 19/21 G≥3), fatigue and nausea (both 41%; all G1/2). No treatment-related deaths or new safety risks were identified. Preliminary efficacy and ctDNA data from pts treated at the RP3D will be presented. No clinically relevant drug–drug interaction was observed.
C+P+F was tolerable in heavily pre-treated pts with HR+/HER2− ABC, with no marked safety differences among dose levels. DLTs were consistent with the expected safety profile.
NCT04862663.
AstraZeneca-funded medical writing support was provided by Suzanne Patel, PhD, from BOLDSCIENCE Inc.
AstraZeneca.
AstraZeneca.
E. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, Arcus, AstraZeneca, Daiichi Sankyo, Seagen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science, Theratechnologies; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals; Financial Interests, Institutional, Cascadian Therapeutics. B. Pistilli: Financial Interests, Institutional, Advisory Board: AstraZeneca, Seagen, Lilly, Daiichi Sankyo, MSD; Financial Interests, Institutional, Invited Speaker: Gilead, Novartis, AstraZeneca, Gilead, Seagen, MSD, Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre, Daiichi Sankyo; Financial Interests, Personal, Other, travel support: AstraZeneca, Pierre Fabre, MSD, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Funding: Daiichi Sankyo; Non-Financial Interests, Project Lead: Unicancer. V. Borges: Financial Interests, Personal and institutional, Invited Speaker: Seagen, AstraZeneca, Cogent, Olema; Financial Interests, Personal and institutional, Advisory board: Seagen, AstraZeneca, Cogent, Olema; Financial Interests, Personal and institutional, Advisory role: Seagen, AstraZeneca, Cogent, Olema; Financial Interests, Personal and institutional, Principal investigator: Seagen, AstraZeneca, Cogent, Olema. M. Campone: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Sanofi, Menarini, Gilead, Seagen; Financial Interests, Personal, Invited Speaker: Novartis, Lilly; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Lilly. T. Foukakis: Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Gilead Sciences; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Expert Testimony: Veracyte, Exact Sciences, Affibody; Financial Interests, Personal, Royalties, Authorship of two chapters in UpToDate: Wolters Kluwer; Financial Interests, Institutional, Invited Speaker, Clinical trial support (research grant and study drug): Pfizer, AstraZeneca; Financial Interests, Institutional, Invited Speaker, Clinical trial support (research grant and study drug): Novartis. P.K.H. Lau: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Institutional, Invited Speaker, Clinical trial: AstraZeneca, Roche/Genentech, MSD, Beigene, Ambrx, Pimera, Gilead Sciences. E. Lim: Financial Interests, Institutional, Advisory Board: Gilead, Novartis, Pfizer, Roche, AstraZeneca, MSD, Lilly; Financial Interests, Institutional, Invited Speaker: Roche, Gilead, Novartis, Lilly, AstraZeneca, Roche, Lilly, Novartis, Gilead, AstraZeneca; Financial Interests, Institutional, Research Grant: Pfizer, Novartis; Non-Financial Interests, Leadership Role, Scientific Advisory Committee: Breast Cancer Trials Australia; Non-Financial Interests, Leadership Role, Principal Cancer Theme Lead, Faculty of Medicine: University of New South Wales; Non-Financial Interests, Leadership Role, Faculty: Garvan Institute of Medical Research; Non-Financial Interests, Leadership Role, Director Cancer Research: St Vincent's Hospital Sydeny. I. Lugowska: Financial Interests, Personal, Invited Speaker, The reports of clinical trials: Roche, BMS, Macrogenics, Amgen; Financial Interests, Institutional, Other, Research grants: Roche; Financial Interests, Institutional, Other, Research grant: Agenus; Financial Interests, Personal and Institutional, Invited Speaker: Agenus, Roche, BMS, Janssen, Astra, Incyte, Macrogenics, Checkpoint Inhibitors, Celon, Pfizer, MSD, Debio; Non-Financial Interests, Project Lead: MSCI; Non-Financial Interests, Advisory Role, Board Member: EORTC. J. Collins, C. Gresty, C. Miller, R. Sommavilla: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. D. Sudhan: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. H.S. Rugo: Financial Interests, Personal, Advisory Role: Napo Pharmaceuticals, Scorpion Therapeutics, Blueprint Medicines, Puma Biotechnology; Other, Personal, Other, Travel, Accommodations, Expenses: Merck, AstraZeneca, Gilead Sciences; Financial Interests, Institutional, Funding: OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Astellas Pharma, Pionyr, Taiho Oncology, Veru, GlaxoSmithKline. All other authors have declared no conflicts of interest.
The long-term efficacy of oral metronomic vinorelbine + capecitabine (mNC) in the treatment of Chinese patients with HER-2 negative metastatic breast cancer (MBC) stays unclear. Thus, we conducted a phase II trial to assess the efficacy and safety of mNC in patients with HER-2 negative MBC in China.
The eligible patients with HER2-negative MBC received oral metronomic vinorelbine 40 mg on day 1, day 3, day 5 every week and capecitabine 500mg three times daily (tid) after meals every 3 weeks until disease progression or unacceptable toxicity occurred, or withdraw of consent. The primary endpoint was 1-year progression-free survival (PFS) rate. Objective response rate (ORR) (complete and partial response [CR + PR]) and disease control rate (DCR) (CR + PR + stable disease [SD]), clinical benefit rate (CBR) (CR + PR + SD ≥ 6 months) and toxicities comprised the secondary endpoints. Analyses were carried out on the intention-to-treat (ITT) population. The Kaplan-Meier plot was utilized to create median PFS plots. A log-rank test was utilized to compare PFS between the two groups. Univariable Cox proportional regression analysis was conducted to assess the association between various patients or tumor characteristics and disease progression.
29 patients with HER2-negative MBC were enrolled. 17 patients received mNC as first-line chemotherapy , 12 patients received mNC as second-line and 1 patient received mNC as > second-line. The median follow-up time was 25.4 months. The CBR, ORR and DCR were 62.1%, 31.0% and 96.6%, respectively. The mPFS was 12.5 months (range, 1.1-28.1). 1-year PFS rate was 54.1%. Subgroup analysis showed CBR was 64.6% and 58.3% in first-and second-line subgroups, respectively. The mPFS was 15.5 months for first-line and 11.2 months for second-line subgroup. 1-year PFS rate was 65.2% for first-line and 41.6% for second-line subgroup. The most common grade 3/4 AEs included neutropenia (10.3%) and nausea/vomiting (6.9%).
A doublet metronomic chemotherapeutic regimen with oral mNC is a well-tolerated and effective anti-tumor regimen for HER2-negative MBC in China.
NCT05747326.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Leptomeningeal metastases (LM) in patients with breast cancer (BC) is rare but associated with poor prognosis. Specific factors associated with prognosis of patients with LM have not been characterized in a large patient cohort. We aimed to evaluate prognostic factors in BC patients with LM from the Brain Metastases in Breast Cancer (BMBC) Registry.
Patient’s and tumor’s main features were retrieved from the BMBC. Median overall survival (mOS) was defined as the time from first diagnosis of central nervous system metastases (CNS) to death from any cause. Median progression-free survival (mPFS) was defined as the time from first diagnosis of CNS to progression in CNS, extracranial metastases or death.
A total of 781 patients with LM and BC were included in the analysis (781/3858, prevalence of 20.2%). 354 (45.3%) patients had LM without BM. A mPFS was3.9 months (95%CI 3.4-4.5) and a mOS was 4.9 months (95% 4.3-5.7). Older age (>=60 vs. <60 years, HR 2.07, 95%CI 1.53-2.79) and a worse ECOG performance status (2-4 vs. 0-1 HR 2.03, 95% CI 1.52-2.71) were significantly associated with a higher risk of death in the multivariate analysis. Endocrine treatment (for hormone-receptor-positive BC) was significantly associated with a lower risk of death (HR 0.43 95%CI 0.28-0.65). Also, whole brain radiotherapy was associated with a lower risk of death (HR 0.62 95%CI 0.45-0.87). Furthermore, BC subtype correlated significantly with prognosis in patients with LM. Patients with luminal-like BC and patients with a triple negative BC had a significant higher risk of death than patients with a triple-positive BC (HR 1.55, 95%CI 1.05-2.28 resp. HR 2.47, 95%CI 1.59-3.85). Additional analyses, including a comparison with patients without LM in the BMBC cohort will be presented.
Patients with LM have a short survival. The identified prognostic factors can support the clinicians to identify the group of patients with a better survival who could possibly benefit from a more intense treatment regimen. Financial support for the management of BMBC Registry was provided by an unrestricted research grant from Daiichi Sankyo to GBG.
The authors.
Financial support for the management of BMBC Registry was provided by an unrestricted research grant from Daiichi Sankyo to GBG.
E. Agostinetto: Financial Interests, Institutional, Speaker’s Bureau: Eli Lilly, Sandoz, AstraZeneca; Financial Interests, Institutional, Other, Support to attend medical conferences, Outside present work: Eil Lilly, Roche, Novartis, Genetics, Instituto Gentili, Daiichi Sankyo. F. Schettini: Financial Interests, Institutional, Other, Travel Support: Novartis, Gilead; Financial Interests, Institutional, Speaker’s Bureau: Novartis; Financial Interests, Institutional, Other, Consulting Fees: Daiichi Sankyo, Gilead. M. Vaz Batista: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Other, Medical Monitor in a Clinical Trial: MedSir. M. Schmidt: Financial Interests, Personal, Other: AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche, Seagen; Financial Interests, Institutional, Research Grant: AstraZeneca, BioNTech, Eisai, Genentech, GBG, Novartis, Palleos, Pantarhei bioscience, Pierre Fabre, Seagen; Other, Institutional, Other, EP 2390370 B1: Patent; Other, Institutional, Other, EP 2951317 B1 issued: Patent. C. Denkert: Financial Interests, Personal, Advisory Board: MSD Oncology, Daiichi Sankyo, Molecular Health, AstraZeneca, Roche, Lilly; Financial Interests, Personal, Invited Speaker: AstraZeneca, VmScope digital pathology software; Financial Interests, Institutional, Research Grant: Roche, Myriad, German Breast Group. I. Witzel: Financial Interests, Institutional, Speaker’s Bureau: Seagen, Daiichi Sankyo, AstraZeneca, Lilly, Novartis, Gilead, Roche, MSD; Financial Interests, Institutional, Other, Travel Support: Roche, Pfizer. J. Rey: Financial Interests, Institutional, Full or part-time Employment: GBG; Financial Interests, Institutional, Research Grant: AbbVie, AstraZeneca, BMS, Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche; Financial Interests, Institutional, Writing Engagements: Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, Seagen; Other, Institutional, Other, EP14153692.0: Patent; Other, Institutional, Other, EP21152186.9: Patent; Other, Institutional, Other, EP15702464.7: Patent; Other, Institutional, Other, EP19808852.8: Patent; Other, Institutional, Royalties: VM Scope GmbH. S. Loibl: Financial Interests, Institutional, Advisory Board, Member: Amgen, AstraZeneca, BMS, Celgene, EirGenix, GSK, Lilly, Pierre Fabre, Roche, Seagen, AbbVie, Sanofi, Gilead, Merck, Novartis, Relay Therapeutics; Financial Interests, Institutional, Invited Speaker: AstraZeneca, DSI, Novartis, Pfizer, Roche, Gilead, Seagen; Financial Interests, Institutional, Advisory Board: DSI, Pfizer, Olema; Financial Interests, Personal, Invited Speaker: Medscape; Financial Interests, Personal, Full or part-time Employment, CEO: GBG Forschungs GmbH; Financial Interests, Institutional, Invited Speaker, Ki67: VM Scope GmbH; Financial Interests, Institutional, Research Grant: AstraZeneca, Celgene, Novartis, Immunomedics/Gilead, Pfizer, Roche, Daiichi Sankyo; Financial Interests, Institutional, Funding: AbbVie, Molecular Health; Financial Interests, Personal, Other, PIPenelope/Padma: Pfizer; Financial Interests, Personal, Other, SC PALOMA3: Pfizer; Financial Interests, Personal, Other, SC SOLAR1: Novartis; Financial Interests, Personal, Other, SC ASCENT: Immunomedics/Gilead; Financial Interests, Personal, Other, SC HERCLIMB: Seagen; Financial Interests, Personal, Other, SC Katherine: Roche; Financial Interests, Personal, Other, SC Capitello; EC Cambria 1: AstraZeneca; Financial Interests, Personal, Other, SC Inavo: Roche; Financial Interests, Personal, Other, SC Destiny B05; SC Destiny B09: Daiichi Sankyo; Non-Financial Interests, Principal Investigator, After publication of primary endpoint: PI Aphinity; Non-Financial Interests, Advisory Role, Group in Germany responsible for breast cancer guidelines: AGO Kommission Mamma; Non-Financial Interests, Member, German Gynaecological Oncology society: AGO; Non-Financial Interests, Member, German Cancer Society: DKG; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member, Member guideline committee; past chair in ESMO Breast: ESMO; Other, EP14153692.0No financial interest, Institutional: Patent; Other, EP21152186.9No financial interest, institutional: Patent; Other, EP15702464.7No financial interest, institutional: Patent; Other, EP19808852.8 No financial interest, Institutional: Patent. V. Mueller: Financial Interests, Institutional, Speaker’s Bureau: Amgen, AstraZeneca, Daiichi Sankyo, Eisai, GSK, Pfizer, MSD, Medac, Novartis, Roche, Teva, Seagen, Onkowissen, high5 Oncology, Medscape, Gilead, Pierre Fabre, Medscape; Financial Interests, Institutional, Other, Consulting Honoraria: Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Sanofi, Seagen, Gilead, Pierre Fabre; Financial Interests, Institutional, Other, Travel Support: Roche, Pfizer, Daiichi Sankyo, Gilead. All other authors have declared no conflicts of interest.
Trastuzumab (T) and chemotherapy (CT) is a standard treatment in patients (pts) with HER2-positive (+) advanced breast cancer (ABC) at later lines of therapy. Lapatinib (L) and T have proven to be active in the same setting. The present study evaluated the efficacy, toxicity and quality of life (QoL) of T+L versus T + physician’s choice CT in pts with HER2+ ABC pretreated with at least two lines of anti-HER2 treatment.
In this open-label, multicenter, phase II trial, pts were randomly assigned 1:1 to receive either T+L with endocrine therapy at the physician’s discretion in case of hormone receptor positive ABC (arm A) or T+CT (arm B). The primary endpoint was the clinical benefit rate (CBR) and the secondary endpoints included overall survival (OS), progression-free survival (PFS), quality of life (QoL), and safety.
Between 2015 and 2020, 59 pts were randomized and evaluated for the present analyses. After a median (m) follow-up of 57.5 months (mo), the CBR was 20.7% (95% CI 9.4-39.3) vs 26.7% (95% CI 13.1-44.9; P= 0.76), the mOS was 29.9 mo (95% CI 19.6-NE) vs 31.1 mo (95% CI 26.1-NE; hazard ratio [HR] 1.07, 95% CI 0.57-2.0; P=0.82) and mPFS was 3.6 mo (95% CI 3.0-5.3) vs 6.1 mo (95% CI 4.0-14.3; HR 0.63, 95% CI 0.37-1.37; P=0.08) in arm A vs arm B, respectively. Any grade (G) adverse events (AEs) occurred in 86.2% and 66.7% of pts in arm A and B, respectively. The incidence of G3-4 AEs was 24.1% and 13.3% in arm A and B, respectively. The impact on QoL significantly favored arm A (P=0.03).
AEs Overall (N=59) Arm A (N=29) Arm B (N=30) Patients with at least one AE 45 (76.3) 25 (86.2) 20 (66.7) Diarrhea 14 (23.7) 11 (37.9) 3 (10) Fatigue 13 (22) 7 (24.1) 6 (20) Abdominal pain 7 (11.9) 3 (10.3) 4 (13.3) Anemia 7 (11.9) 4 (13.8) 3 (10) Neutropenia 5 (8.5) 0 (0) 5 (16.7) Nausea 5 (8.5) 3 (10.3) 2 (6.7) Thrombocytopenia 5 (8.5) 4 (13.8) 1 (3.3) Paresthesia 4 (6.8) 0 (0) 4 (13.3) Fever 3 (5.1) 3 (10.3) 0 (0) Skin disorders 3 (5.1) 3 (10.3) 0 (0)
No difference in efficacy was observed between T+L and T+CT. QoL deterioration was less frequent in pts in T+L arm though a higher number of any AEs was observed in these patients compared with those who received T+CT. Overall
EudraCT 2013-005044-29; Date when the record was first entered in the EudraCT database: 16-05-2014.
Oncotech.
Novartis, GSK.
C. De Angelis: Financial Interests, Personal, Advisory Board, Consultant fees, travel expenses: Roche, AstraZeneca, GSK; Financial Interests, Personal, Advisory Board, consultant fees, travel expenses: Lilly; Financial Interests, Personal and Institutional, Advisory Board, Honoraria, research funding, travel expenses: Novartis; Financial Interests, Personal, Advisory Board, Honoraria, travel expenses: Pfizer; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Institutional, Funding: Daiichi Sankyo; Financial Interests, Personal, Other, Travel expenses: Celgene. M. Pagliuca: Other, Personal, Other, Travel expenses: Gilead, Pfizer. T. Gamucci: Financial Interests, Personal, Advisory Board: Seagen, Pfizer, Eisai, Daiichi Sankyo, AstraZeneca, Novartis. M. Mansutti: Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly, Gentili, Gilead, Novartis, Pfizer, Seagen, Roche. Z. Ballatore: Financial Interests, Personal, Other, Honoraria: Ipsen, Novartis, Roche. M. De Laurentiis: Financial Interests, Personal, Advisory Board: Roche, Novartis, Eli Lilly, Pierre Fabre, AstraZeneca, MSD, Seagen, Gilead, Daiichi Sankyo, Pfizer, Exact Science, Ipsen, Takeda, Sanofi Genzyme. R. Bordonaro: Financial Interests, Personal, Speaker’s Bureau, Honoraria, consulting or advisory role: Novartis, AstraZeneca, Sanofi, Amgen, Roche, Pfizer, Janssen-Cilag, BMS; Financial Interests, Personal, Speaker’s Bureau, Consulting or advisory role: Bayer. S. Cinieri: Financial Interests, Personal, Other: Lilly Oncology, Seagen, AstraZeneca. A. Fabi: Financial Interests, Personal, Other, Honoraria: Roche, Pfizer, Eli Lilly, Novartis, Eisai, AstraZeneca, Exact Science, Epihonpharma, Daiichi Sankyo, Gilead, Seagen. L. Del Mastro: Financial Interests, Personal, Invited Speaker, Educational meeting: Novartis, Symposia, Andromeda E20, Vyvamed srl; Financial Interests, Personal, Invited Speaker, Lecture: Ipsen; Financial Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche; Financial Interests, Personal, Invited Speaker, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board, Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests, Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal, Advisory Board, Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD; Financial Interests, Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina; Financial Interests, Personal, Invited Speaker, Author for BC text: Pensiero Scientifico Editore; Financial Interests, Personal, Advisory Board, Breast cancer: Uvet; Financial Interests, Personal, Other, Author slide kits and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pfizer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL; Financial Interests, Personal, Other, Author slide kits: Forum service; Financial Interests, Personal, Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other, consultant: Kardo srl; Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl; Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca, Agendia, Gilead; Financial Interests, Personal, Other, Interview: Infomedica srl; Financial Interests, Personal, Other, Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Personal, Other, Consultancy: Eli lilly; Financial Interests, Institutional, Funding, National coordinating PI: Roche; Financial Interests, Institutional, Funding, Local PI: AstraZeneca, Roche, Eli Lilly, Daiichi Sankyo, Novella Clinical, Novartis; Non-Financial Interests, Institutional, Product Samples, Genomic Test: FoundationOne. F. Puglisi: Financial Interests, Personal, Other, Honoraria: Amgen, Daiichi Sankyo, Celgene, Lilly, Gilead, Ipsen, MSD, Novartis, Pierre Fabre, Pfizer, Seagen, Takeda, Viatris; Financial Interests, Personal, Other, Honoraria, research funding: AstraZeneca, Eisai, Roche. S. de Placido: Financial Interests, Personal, Advisory Role: Novartis, Roche, Celgene, AstraZeneca, Amgen, Eisai, Lilly, Pfizer, Gentili. M. Giuliano: Financial Interests, Institutional, Funding: Novartis, AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Exact Sciences, Lilly, MSD, Novartis, Seagen; Financial Interests, Personal, Advisory Board, Travel expenses: Pfizer, Roche; Financial Interests, Personal, Other, Travel expenses: Celgene. G. Arpino: Financial Interests, Personal, Advisory Board, Travel expenses: Roche, Pfizer, Lilly, MSD, AstraZeneca, Novartis; Financial Interests, Institutional, Funding: Roche, Pfizer, Lilly, AstraZeneca, Novartis, MSD. All other authors have declared no conflicts of interest.
CDK4/6i + ET are recommended as 1L treatment in pts with HR+ HER2– mBC. However, treatment outcome in pts with
This was a retrospective cohort study of pts with HR+ HER2– mBC who received 1L CDK4/6i + ET captured in the Flatiron Health Data Repository from Jan 2011–June 2022. Primary endpoint was RW progression-free survival (PFS); RW overall survival (OS) was a secondary endpoint. Univariate (UV) and multivariate (MV; adjusted for ET and CDK4/6i) Cox proportional hazards models were used to compare outcomes in pts with deleterious g/t
The study included 4609 pts (145
Pts with
Events/N Median (95% CI); months 1922/4288 22.0 (20.7–23.7) 1105/2123 18.2 (16.9–20.1) 817/2165 29.9 (26.9–33.6) 99/141 14.3 (10.0–16.5) g 55/78 12.4 (9.0–17.8) t 44/63 15.1 (8.2–18.0) 19/31 9.7 (7.2–18.4) 75/102 14.3 (8.3–17.5) 5/8 NA Fulvestrant 638/1298 18.0 (16.2–21.0) 36/45 8.9 (5.3–17.8) Non-steroidal aromatase inhibitor 1241/2857 24.5 (22.0–27.4) 63/92 14.6 (11.0–18.4) Other 43/133 23.4 (16.1–NA) 0/4 NA 1726/4288 49.7 (48.3–53.1) 69/141 40.7 (31.0–51.5) NA, non-analysable
AstraZeneca-funded medical writing support was provided by Suzanne Patel, Ph.D., from BOLDSCIENCE Inc.
AstraZeneca.
AstraZeneca.
E. Nizialek, I. Gibson: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. S. Khosla: Financial Interests, Personal and Institutional, Leadership Role: AstraZeneca. E. Sofianopoulou, N. Lukashchuk, J.S. Brown: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. M. Robson: Financial Interests, Personal, Other, Review guideline pathways: Change Healthcare; Financial Interests, Personal, Invited Speaker, Speaker at CME events (NOT speaker's bureau): Physician's Education Resource, Research to Practice, Intellisphere, MJH Holdings; Financial Interests, Personal, Advisory Board, Speaker at CME events (NOT speaker's bureau): MyMedEd; Financial Interests, Institutional, Invited Speaker, Funding for research study (ICEBERG, dating to 2007): AstraZeneca; Financial Interests, Personal, Invited Speaker, Steering Committee Member for CAPITELLO-290, uncompensated: AstraZeneca; Financial Interests, Institutional, Other, Co-PI for Merck IIT of neoadjuvant olaparib/pembrolizumab in BRCA carriers, no personal compensation: Merck; Financial Interests, Personal, Invited Speaker, Steering Committee member for KEYLNK-009, no compensation: Merck; Financial Interests, Institutional, Invited Speaker, Local PI of KEYLNK009: Merck; Financial Interests, Institutional, Other, Local co-PI of clinical trial of ZEN03694 and talazoparib in TNBC, no personal compensation: Pfizer; Non-Financial Interests, Advisory Role: Zenith Pharmaceuticals, Epic Biosciences, Daiichi Sankyo, Tempus Labs; Non-Financial Interests, Personal, Other, Editorial services for writing of reports for ABRAZO clinical trial: Pfizer; Non-Financial Interests, Personal, Other, Editorial services for medical writing of reports resulting from OlympiAD trial: AstraZeneca; Non-Financial Interests, Member: ASCO. P. Razavi: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Epic Science, Inivata, SAGA Diagnostics, Prelude Theraputics, Paige.ai; Financial Interests, Personal, Ownership Interest: Odyssey Biosciences; Financial Interests, Institutional, Funding: Grail Inc., Novartis; Financial Interests, Institutional, Research Grant: AstraZeneca, Tempus, Guardant, Biotherenostics, Epic Sciences, Inviate; Non-Financial Interests, Advisory Role: Tempus. All other authors have declared no conflicts of interest.
Although 1% is the recommended cutoff for defining triple-negative breast cancer (TNBC), growing evidence suggests that 10% cutoff may better recapitulate TNBC. Conversion to TNBC at relapse is associated with poor survival. We primarily aim to assess the prognostic impact of phenotypic conversion to estrogen receptor (ER)-low BC in patients experiencing relapse.
Relapsing BC patients from two Institutions were included. Patients were categorized in: TNBC (ER=0%, HER2-0/low), ER-low (ER=1-9%, HER2-0/low), Luminal (ER=10-100%, HER2-0/low), HER2+. Overall survival (OS) and post-relapse survival (PRS) were adopted as endpoints.
877 patients were included. The proportion of ER-low tumors was 3.2% on primary BC and 2.9% on relapse. When assessing the prognostic impact of primary BC phenotype, TNBC and ER-low retained a similar and significantly poorer prognostic impact than Luminal and HER2+ BC. In detail, median OS [mos] was: TNBC 68.6, ER-low 47.6, Luminal 125.4, HER2+ 121.4, p<0.001). PRS analysis described the same phenomenon (p<0.001) Superimposable findings were observed when considering the prognostic impact of tumor phenotype at relapse (OS, p<0.001; PRS, p<0.001). At relapse, 6.4% of TNBC, 2.5% of Luminal and 1.9% of HER2+ primary BC cases switched to ER-low phenotype (overall conversion rate to ER-low BC: 2.8%). Among Luminal BC patients, those converting to ER-low at relapse showed the worst outcome, with poorer survival than those maintaining Luminal BC or converting to either TNBC or HER2+. In detail, median OS [mos] was: concordant Luminal 134.7, conversion to ER-low 54.4, conversion to TNBC 80.4, conversion to HER2+ 129.9, p<0.001; median PRS [mos] was: concordant Luminal 51.4, conversion to ER-low 12.4, conversion to TNBC 29.6, conversion to HER2+ 44.4, p<0.001.
ER-low BC was associated with unfavorable prognosis, similar to TNBC and significantly poorer than Luminal and HER2+. Luminal BC patients converting to ER-low phenotype experienced the worst survival rates, even worse than those converting to TNBC, possibly due to the limited access to TNBC treatment algorithms. Our study supports the assimilation of ER-low BC to TNBC.
The authors.
Fondazione AIRC under 5 per mille 2019 - ID. 22759 program, DOR funding from the University of Padua.
F. Miglietta: Financial Interests, Personal, Invited Speaker, outside the submitted work: Novartis, Roche, Gilead. G. Griguolo: Financial Interests, Personal, Advisory Board, outside the submitted work: Gilead; Financial Interests, Personal, Speaker’s Bureau, outside the submitted work: Lilly, Novartis; Financial Interests, Personal, Other, outside the submitted work: Pfizer, Amgen, Daiichi Sankyo/AstraZeneca. T. Giarratano: Financial Interests, Personal, Invited Speaker, outside the submitted work: Roche, Novartis, Lilly. F. Girardi: Financial Interests, Personal, Invited Speaker, outside the submitted work: AstraZeneca; Financial Interests, Personal, Other, outside the submitted work: Lilly, Gilead, Takeda. C.A. Giorgi: Financial Interests, Personal, Invited Speaker, outside the submitted work: Novartis. M. Fassan: Financial Interests, Personal, Advisory Board, outside the submitted work: Astellas Pharma, GlaxoSmithKline, Roche, MSD Oncology, AstraZeneca, Pierre Fabre; Financial Interests, Personal, Research Grant, outside the submitted work: QED Therapeutics, Macrophage Pharma, Diaceutics. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Amgen, GSK; Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Sanofi, merck serono, Exact Sciences, Eisai, Olema Oncology; Financial Interests, Personal, Expert Testimony: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Eli Lilly, Roche, BMS, Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, Glaxo Smith kline, Daiichi Sankyo, Nerviano; Non-Financial Interests, Member: ASCO. M.V. Dieci: Financial Interests, Personal, Advisory Board, outside the submitted work: Lilly, Novartis, Exact Sciences, Pfizer, Seattle Genetics, MSD, Gilead Sciences; Financial Interests, Institutional, Other, outside the submitted work: Patent pending HER2DX licensed to University of Padova. All other authors have declared no conflicts of interest.
CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the established first-line (1L) therapy for patients (pts) with hormone receptor (HR)-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC). Data supporting the best treatment choice at progression on CDK4/6i+ET is limited.
We collected data from pts with HR+/HER2- mBC who received treatment after progression to CDK4/6i+ET in five Italian Institutions. Progression-free survival 2 (PFS2), the primary endpoint, was calculated from initiation of CDK4/6i to disease progression (PD) on subsequent line of therapy or patient death. The PFS2-PFS1 difference and PFS2/PFS1 ratio were also estimated. We compared outcomes between pts receiving chemotherapy (CT)- or ET-based regimens immediately after CDK4/6i+ET.
As of January 2023, 511 pts were included. Median patient age was 59 years, 26.2% had
After progression to CDK4/6i, ET-based regimens are associated with longer PFS2 and OS when compared to CT. However, this likely reflects clinical benefit from previous CDK4/6i+ET. For pts with short PFS on CDK4/6i+ET, CT may be a more effective option.
The authors.
Has not received any funding.
R. Caputo: Financial Interests, Personal, Other, Advisory or speaker bureau: Novartis, Lilly, Roche, AstraZeneca, MSD, Gilead, Daiichi Sankyo, Veracyte, Seagen, Pfizer, Eisai. C. Vernieri: Financial Interests, Personal, Invited Speaker: Novartis, Eli Lilly, Istituto Gentili; Financial Interests, Personal, Advisory Board: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Research Grant: Roche. E. Munzone: Financial Interests, Personal, Advisory Board: Eisai, Exact Science, MSD Oncology, Daiichi Sankyo/AstraZeneca, Pfizer, Seagen. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Takeda, Sandoz, Ipsen, Libbs, Knight, Daiichi Sankyo, Lilly, Pfizer, Novartis, Roche; Financial Interests, Personal, Other, Travel grant to attend ASCO 2022: Gilead; Financial Interests, Institutional, Invited Speaker, 2-year research grant paid to my Institution: Gilead. M. De Laurentiis: Financial Interests, Personal, Invited Speaker, or honoraria: AstraZeneca, Amgen, Celgene, Daiichi Sankyo, Eisai, Eli Lilly, Exact Science, Gilead, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen, Takeda, Ipsen; Financial Interests, Personal and Institutional, Funding: Novartis, Roche, Lilly, Puma Biotechnology, Pfizer, Daiichi Sankyo, MSD, MacroGenics, BMS. G. Viale: Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Speaker’s Bureau: Novartis, Lilly; Financial Interests, Personal, Other, Travel expenses: Pfizer, Lilly. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Invited Speaker, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Invited Speaker, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Officer, ESMO Clinical Practice Guidelines Chair: ESMO. C. Criscitiello: Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Eli Lilly, Roche, Gilead; Financial Interests, Personal, Advisory Board: MSD, Seagen, AstraZeneca, Daiichi Sankyo. All other authors have declared no conflicts of interest.
Palbociclib (PB), a cyclin-dependent kinase 4/6 inhibitor, has become a standard of care in HR+/HER2- advanced/metastatic breast cancer (ABC) in Europe since EMA approval in 2016. This study examines clinical characteristics and outcomes in ABC patients treated with PB and an aromatase inhibitor (AI) in routine clinical practice in Europe.
A multicenter retrospective medical record review collected data on adult patients with HR+/HER2- ABC in Europe who received first-line PB+AI between September 2016 and July 2020. Sites screened all patients who received PB+AI during the study time frame and abstracted data for patients who met all eligibility criteria. We report here results from Germany, Spain and the UK; data from 4 additional European countries will be reported when data collection is complete. Study measures were descriptively analyzed, with the Kaplan-Meier method used to estimate real-world progression-free survival (rwPFS).
Data were abstracted and analyzed for 668 patients from 47 sites. Median age at ABC diagnosis was 64.4 years (33.8% ≥70 yo), 99.6% were female, 82.9% were white, and median follow-up was 32.7 months. Of females (665), 14.1% were premenopausal at first-line PB+AI initiation. 38.5% of patients had de novo disease. At ABC diagnosis, 24.9% had bone only disease and 46.7% had visceral disease (Table). Objective response and clinical benefit rate were 35.8% and 80.7%, respectively. The median rwPFS (95% CI) was estimated to be 31.8 (27.7-35.4) months (Table).
N % 668 100.0 <50 101 15.1 50-69 341 51.1 ≥70 226 33.8 Stage I–III (resectable) 380 56.9 Stage III–unresectable 18 2.7 Stage IV 239 35.8 Unknown 31 4.6 De novo 257 38.5 ≤12 months 152 22.8 >12 months 221 33.1 Unknown 38 5.7 0 161 24.1 1 176 26.3 ≥2 58 8.7 Not recorded 273 40.9 239 35.8 Months (95% CI) Median 31.8 (27.7-35.4) rwPFS rate % (95% CI) 12 months 77.2 (73.8-80.3) 24 months 59.5 (55.5-63.2) 36 months 45.2 (41.0-49.4)
This real-world study affirms the favorable clinical outcomes demonstrated for first-line PB+AI in the previous clinical trials and supports its utilization as frontline treatment for this patient population. This study presents pooled analysis of 3 European countries and variability in practice patterns and disease management may exist among countries.
Editorial support was provided by Oxford PharmaGenesis, Inc., Newtown, PA, with funding provided by Pfizer Inc.
Pfizer Inc., USA.
Pfizer Inc., USA.
O. Oikonomidou: Financial Interests, Personal, Advisory Board: Pfizer Inc., AstraZeneca, Novartis, Exact Sciences, Eisai, Daiichi Sankyo, Roche, Gilead, Lilly, Merck, Tesaro; Financial Interests, Personal, Other, Travel grant: Eisai, Roche, Pfizer Inc., Amgen, AstraZeneca, Novartis, Lilly; Financial Interests, Institutional, Research Grant: Pfizer Inc., Med Diagnostics, Novartis, M2C, Roche, BCI, Genomic Health. E. Galve-Calvo: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Gilead, Pfizer Inc.; Financial Interests, Personal, Expert Testimony: Pierre Fabre, Eisai, Novartis, Roche. A. Wöckel: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Celgene, Eisai, Lilly, Novartis, Pfizer, Roche, Tesaro, Sirtex, MSD, Pierre Fabre, Clovis, Organon, Seagen, Exact Sciences, Gilead, Daiichi Sankyo. R. Parikh, A. Hitchens, V. Derrien Ansquer, G. Frugier, M. Jimenez, K. Davis: Financial Interests, Personal, Full or part-time Employment: RTI Health Solutions. C. Chen, E. Gauthier, B. Li, E. Broughton: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks/Shares: Pfizer Inc.
CDK4/6 inhibitors combined with endocrine therapy have revolutionized the management of luminal advanced breast cancer (ABC). In case of visceral crisis (VC), chemotherapy is still recommended because of its supposed quicker efficacy. The ABC 5 ESO-ESMO international consensus guidelines clarified the definition of VC, using specific situations. However, many clinical scenarios remain unclear. To aid the practitioner in treating these patients with a poor prognosis, we aim to establish a standardized and reproductible definition of VC in ABC.
A three-step modified Delphi method was used to establish consensus. 52 experts from the French Breast Cancer Intergroup Unicancer (UCBG) were invited to participate as the expert panel. In both rounds, they had to score items on a six-option scale. In round 2, the questionnaire was modified according to the answers in round 1. A specific scoring method was used to define the consensual items. Round 3 will consist of a face-to-face expert meeting to discuss nonconsensual criteria.
Items considered as defining VC after two rounds were: symptomatic lung lesions, symptomatic peritoneal carcinosis resistant to medical treatment, grade 3 cytolysis, symptomatic cytopenia regardless of grade, grade 4 cytopenia independently of symptoms, and massive liver tumor burden, with a cutoff value to be determined. Panelists excluded from VC definition: the presence of asymptomatic lung, brain, liver or bone lesions, increase in LDH level, any kind of pain, grade 1 cytopenia, hypercalcemia resolved by medical treatment, reversible hyperbilirubinemia after drainage and peritoneal or pleural effusions before drainage. Some items remain nonconsensual after two rounds, such as symptomatic pleural or peritoneal effusions despite drainage, symptomatic brain lesions, or the cutoff value of hyperbilirubinemia.
To our knowledge, this is the first study aiming to define VC using specific clinical situations. The acquired definition could help the clinician in his daily practice, and become a base for the inclusion and exclusion criteria of clinical trials. The findings reported are preliminary, as the final expert meeting will be held in spring 2023.
The authors.
Has not received any funding.
M.J. Rodrigues: Financial Interests, Personal, Advisory Board: AZ, GSK, Immunocore; Financial Interests, Personal and Institutional, Research Grant: MSD, BMS, Daiichi. P.H. Cottu: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer, lilly; Financial Interests, Personal, Expert Testimony: Roche; Financial Interests, Institutional, Invited Speaker: daichi, lilly, gilead; Financial Interests, Institutional, Funding: Novartis. J. Pierga: Financial Interests, Personal, Other: Roche, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi; Financial Interests, Personal, Advisory Board: Roche/Genentech, Novartis, Lilly, Pfizer, AstraZeneca, AbbVie, MSD, Daiichi, Seattle Genetics, Gilead, Eisai, Pierre Fabre oncologie; Financial Interests, Personal, Speaker’s Bureau: Roche, Novartis, Pfizer, Lilly, AstraZeneca, Daiichi, Gilead. T. Bachelot: Financial Interests, Personal, Advisory Board: Roche, Novartis, AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Novartis, Roche, AstraZeneca, Seagen, Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca. N. Penel: Financial Interests, Institutional, Research Grant, Research grant for clinical trials in sarcoma filed: Bayer HealthCare. A. Moreira: Financial Interests, Personal, Advisory Board: Daiichi, AstraZeneca, Gilead. All other authors have declared no conflicts of interest.
Breast cancer (BC) pioneered precision medicine with immunohistochemistry (IHC) defined subtypes and early advent of targeted therapies. Trastuzumab deruxtecan (T-DXd) has expanded traditional HER2 definitions to include HER2-low (H2L) tumors, defined as HER2 IHC score of 1+ (>10% cells stained), or as 2+ (>10%) and negative in-situ hybridization (ISH) assay. Studies suggest H2L BC is not a separate clinical entity, strongly determined by hormone receptor (HR) status. We sought to understand the impact of H2L on current standards of care (SOC).
Retrospective analysis was performed on 24,824 advanced BC with available genomic, transcriptomic, subtyping, and treatment data. Tumors were tested at Caris Life Sciences via NextGen DNA Sequencing (592 gene panel or whole exome) and RNA (whole transcriptome). BC subtypes were defined by IHC/ISH per accepted definitions. PD-L1 was determined by IHC (SP142 immune cells [IC] ≥ 1%). CODEai, a real-world evidence database was used to access clinical outcomes from insurance claims data, with Kaplan–Meier estimates for overall survival (OS) and 95% CI calculated from time of first treatment to last contact.
Patients with HR positive (HR+)/H2L tumors treated with CDK4/6 inhibitors (n=1,348) had similar OS compared to pts with HR+/HER2 0 (n=3,027; 1,179 vs 1,105 days; HR=0.89, CI 0.82–0.98, p=0.012). 27.2% of HR+/H2L pts had activating PIK3CA mutations. Among HR+ PIK3CA mutated tumors, H2L pts treated with alpelisib showed no difference in OS (n=27; 342 days) vs. HER2 0 alpelisib treated pts (n=42; 566 days, HR=1.23, CI 0.66 – 2.29, p=0.517), with limited sample size. 13.9% of H2L TNBC pts were PDL-1+. Pts with H2L PD-L1+ TNBC BC treated with immune checkpoint inhibitors (ICI; atezolizumab, pembrolizumab, nivolumab; n=49) showed improved OS vs. HER2 0 (n=233; 991 vs 524 days; HR=0.61, CI 0.37–0.99, p=0.046).
HR+/H2L BC pts treated with SOC endocrine therapy demonstrate no difference in OS compared to HER2 0, and thus, should exhaust endocrine therapy options before initiating T-DXd or chemotherapy until indicated by prospective trials. Combinations of T-DXd plus ICI in PDL1+ H2L BC may be promising opportunities for further investigation.
The authors.
Caris Life Sciences provided in-kind support via data use agreement.
S.L. Graff: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, Eli Lilly. T. Adeyelu: Financial Interests, Personal, Full or part-time Employment: Caris LifeSciences. A. Elliott: Financial Interests, Personal, Full or part-time Employment: Caris LifeSciences. E. Rodriguez: Financial Interests, Personal, Advisory Role: AstraZeneca, Novartis, Janssen Oncology, Bristol Myers Squibb Foundation, Oncocyte, Regeneron, Amgen, Pfizer. J. Meisel: Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis, Genenetech, Glaxo Smith Kline, Novartis, Pfizer, Puma, Sanofi Genzyme, Seagen; Financial Interests, Institutional, Research Grant: Seagen, Pfizer, AstraZeneca, Olema. M. Gatti-Mays: Financial Interests, Personal, Advisory Board: GE Health, Seagen. E. Hsu: Financial Interests, Personal, Research Grant: Bristol Myers Squibb. K.I. Lathrop: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Encore Education; Financial Interests, Personal, Speaker’s Bureau: Biotheranostics. V. Kaklamani: Financial Interests, Personal, Research Grant: Eisai; Financial Interests, Personal, Advisory Role: Puma, AstraZeneca, Gilead, Tersera; Financial Interests, Personal, Invited Speaker: Pfizer, Gilead, Genentech, Genomic Health, Novartis, AstraZeneca, Daiichi, Seagen. M. Oberley: Financial Interests, Personal, Stocks/Shares: Caris LifeSciences; Financial Interests, Personal, Full or part-time Employment: Caris LifeSciences. G. Sledge: Financial Interests, Personal, Full or part-time Employment: Caris; Financial Interests, Personal, Research Grant: Pfizer, Eli Lilly; Financial Interests, Personal, Advisory Board: Verseau, Syndax, Caris; Financial Interests, Personal, Member of the Board of Directors: Tessa Therapuetics. S. Sammons: Financial Interests, Personal, Research Grant: AstraZeneca, AbbVie, Bristol Myers Squibb, Eli Lilly, Seagen, Sermonix; Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi Sankyo, Eli Lilly, Incyclix, Merck, Pfizer, Seagen, Sermonix, Novartis. All other authors have declared no conflicts of interest.
ASCENT demonstrated the efficacy of Sacituzumab govitecan (SG) in patients (pts) with metastatic triple-negative breast cancer (mTNBC), and led to EMA approval in November 2021.
We set up an ambispective bicentric cohort study to assess the real-world effectiveness and safety of SG in pts with mTNBC. This study included pts treated through the French Early Access Program from May 2021 to January 2023. Pts provided written consent for their clinical data to be reported.
The cohort included 103 pts with a median age of 55 years [26-89]; 7/74 pts (9%) had BRCA1/BRCA2 germline mutation, 15 pts (15%)
Our real-world data in mTNBC pts are consistent with results of the ASCENT trial in terms of ORR and safety, but observed PFS and OS are numerically shorter, including pts with brain metastases.
Institut Curie.
Has not received any funding.
D. Loirat: Financial Interests, Personal, Advisory Board, Travel expenses, Honoraria: MSD, Novartis, AstraZeneca; Financial Interests, Personal, Advisory Board, Honoraria: Lilly; Financial Interests, Institutional, Advisory Board, Travel expenses,: Gilead; Financial Interests, Personal, Other, Travel expenses, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria, Travel expenses: Seagen, Exact Sciences; Financial Interests, Personal, Other, Honoraria: EISAI. L. Escalup: Financial Interests, Personal, Advisory Board: Mylan. P. Vaflard: Financial Interests, Personal, Advisory Role: Gilead. P.H. Cottu: Financial Interests, Personal, Advisory Board, Travel/Accomodation, honoraria: Pfizer, Roche/Genentech; Financial Interests, Personal, Advisory Board, honoraria: Lilly; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant, honoraria: Pfizer; Financial Interests, Personal, Other, honoraria: Seagen, NanoString Technologies, Pierre Fabre. J. Pierga: Financial Interests, Personal, Advisory Board, Honoraria, Travel expenses: Roche/Genentech, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, HonorariaTravel expenses: Lilly; Financial Interests, Personal, Advisory Board: AbbVie, MSD, Seattle Genetics, Eisai, Pierre Fabre Oncologie; Financial Interests, Personal, Advisory Board, Honoraria: Gilead. All other authors have declared no conflicts of interest.
If HER2-low breast cancer (BC) as a new separate clinical entity is a matter of debate, little is known on the incidence and the prognostic impact of brain or leptomeningeal metastases (BLMM) in this subgroup of patients (pts). Our objectives were to compare the cumulative incidence of BLMM and associated outcomes among pts with HER2-low, HER2-negative (HER2-) and HER2-positive (HER2+) metastatic BC (mBC).
This cohort study was conducted from the Epidemiological Strategy and Medical Economics (ESME) mBC platform and included pts with mBC treated between 2012 and 2020 in 18 French comprehensive cancer centers. Cumulative incidence of BLMM was estimated using a competing risk methodology with death defined as competing event.
19585 pts were included with 6118 (31.2%), 9943 (50.8%), 3524 (18.0%), having HER2-low, HER2- and HER2+ mBC respectively. BLMM were present at first diagnosis of mBC in 4.5%, 5.4% and 10.6% of pts with HER2-low, HER2- and HER2+ disease respectively. BLMM were the unique metastatic site at first diagnosis of mBC in 1.4%, 1.9% and 5.3% of pts with HER2-low, HER2- and HER2+ respectively. During the course of the disease, cumulative incidence of BLMM at 5 years was 18.9% [95%CI 17.8;20.1], 21.0% [20.0;21.9] and 33.7% [31.7;35.7] in HER2-low, HER2- and HER2+ pts. In HER2-low subgroup, cumulative incidence at 5 years was 17.6% [16.3;18.8] and 27.6% [95%CI 24.2;31.0] in HR+ and HR- mBC. The median overall survival (mOS) after BLMM diagnosis was 5.3 months [95%CI 4.2;6.8], 4.4 months [3.9;5.3] and 22.6 months [19.4;27.1] in HR-/HER2-low, HR-/HER2- and HR-/HER2+ pts. The mOS after BLMM was 7.0 months [95%CI 5.9;7.9], 6.2 months [5.5;6.9] and 25.2 months [21.8;27.8] HR+/HER2-low, HR+/HER2- HR+/HER2+ pts.
The prognosis of pts with HER2-low mBC with BLMM appears close to that of HER2- pts, and significantly worse than that of HER2+ pts. Development of new treatment strategies, such as antibody drug conjugates, with higher activity on central nervous system is eagerly awaited for pts with HER2-low or HER2- mBC.
The authors.
Has not received any funding.
W. Jacot: Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai, Novartis, Roche, Pfizer, Eli Lilly, MSD, BMS, Chugai, Seagen, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca, Daiichi Sankyo; Financial Interests, Invited Speaker: Roche, Novartis, Daiichi Sankyo, Daiichi Sankyo. T. Bachelot: Financial Interests, Personal, Advisory Board: Roche, Novartis, AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Novartis, Roche, AstraZeneca, Seagen, Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca. V.C. Dieras: Financial Interests, Personal, Advisory Board, National advisory board: Pierre Fabre Oncologie; Financial Interests, Personal, Advisory Board, Steering Committee, consultant, Symposium, travel expenses: Roche Genentech; Financial Interests, Personal, Advisory Board, + Symposia and travel expenses: Novartis; Financial Interests, Personal, Advisory Board, Advisory boards, symposia, travel expenses: Pfizer; Financial Interests, Personal, Advisory Board, Symposia, travel expenses: Lilly, AstraZeneca, MSD; Financial Interests, Personal, Advisory Board, Symposia, travel expenses: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, symposia, travel expenses: Seagen, Gilead; Financial Interests, Personal, Advisory Board, Steering Committee: AbbVie; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Other, IDMC: Sanofi; Financial Interests, Personal and Institutional, Other, IDMC: Sanofi; Financial Interests, Institutional, Invited Speaker: Roche Genentech, AstraZeneca; Financial Interests, Institutional, Invited Speaker, Steering Committee: Lilly; Financial Interests, Institutional, Invited Speaker, + IDMC: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, PI: Seagen. E.G.C. Brain: Financial Interests, Personal, Invited Speaker, Webinars, optimized endocrine therapy for older breast cancer patients: Eli Lilly; Financial Interests, Personal, Advisory Board, Palbociclib and older breast cancer patients: Pfizer; Financial Interests, Personal, Invited Speaker, Symposium HER2+ MAO conference 03/21: Seagen; Financial Interests, Personal, Invited Speaker, ELEVATE 10/2021 and ABC 11/2021 meeetings: Pfizer; Financial Interests, Personal, Other, IDMC DESTINY 05: Daiichi; Financial Interests, Personal, Advisory Board, GCSF and FN in older patients: Sandoz; Financial Interests, Institutional, Invited Speaker, APPALACHES study EORTC 1745: Pfizer; Financial Interests, Institutional, Invited Speaker, TOUCH study (IBCSG 55/GERICO study): Pfizer; Financial Interests, Institutional, Invited Speaker, DEESTINY 09: Daiichi; Financial Interests, Institutional, Invited Speaker, DESTINY 06: Daiichi; Financial Interests, Institutional, Invited Speaker, SERENA 06: AstraZeneca; Financial Interests, Institutional, Invited Speaker, AMEERA 6: Sanofi. J. Ferrero: Financial Interests, Personal, Advisory Board: Pfizer, Exact sciences, Novartis; Financial Interests, Personal, Invited Speaker: Lilly. T. Filleron: Other, Consulting (compensated to my institution): Cellectis. L. Bosquet: Financial Interests, Institutional, Full or part-time Employment, In charge of scientific projects at Unicancer, Health Data and Partnership Department: Unicancer. B. Pistilli: Financial Interests, Institutional, Advisory Board: AstraZeneca, Seagen, Lilly, Daiichi Sankyo, MSD; Financial Interests, Institutional, Invited Speaker: Gilead, Novartis, AstraZeneca, Gilead, Seagen, MSD, Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre, Daiichi Sankyo; Financial Interests, Personal, Other, travel support: AstraZeneca, Pierre Fabre, MSD, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Funding: Daiichi Sankyo; Non-Financial Interests, Project Lead: Unicancer. J. Frenel: Financial Interests, Personal, Advisory Board: Pfizer, Novocure, Pierre Fabre, Eisai, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: GSK, Amgen; Financial Interests, Institutional, Advisory Board: Exactscience, Lilly, Daiichi Sankyo, AstraZeneca, Clovis Oncology; Financial Interests, Institutional, Invited Speaker: Novartis, MSD; Financial Interests, Invited Speaker: AstraZeneca, Seagen, MSD, Daiichi; Non-Financial Interests, Principal Investigator: Novartis, Lilly, AstraZeneca, Pfizer, Daiichi, MSD. All other authors have declared no conflicts of interest.
Trastuzumab deruxtecan has shown efficacy in ABC pts with low HER2 positivity by immunohistochemistry (IHC) and a negative in situ hybridization (ISH), termed H-Low (HER2 1+, or 2+ with negative ISH). A better understanding of this heterogeneous group is needed.
This analysis from RegistEM study (NCT02819882) compares characteristics and outcomes of H-Low and H-0 pts diagnosed with ABC from Jan-16 to Dec-19. With a cut-off 14-Nov-22, and an ongoing database, 1232 HER2- pts were included, 713 H-0 and 519 H-Low (IHC1+ 54%, IHC2+ ISH- 46%). Pts were split in 4 groups based on HER2 and hormone receptor (HR). HER2 and HR were available from a tumor sample obtained before the 1st-line (1L).
Age, gender, race, menopausal status and ABC location (distant metastases and unresectable locally advanced disease) were similar between groups at ABC diagnosis. HER2 expression (accounting H-Low and HER2+) was higher in de novo metastatic vs early BC pts. Distribution according to bone, soft tissue and visceral metastases was similar in HR+ groups; more soft tissue and visceral metastases were reported in HR- groups. No. of metastatic locations was similar in H-0 pts regardless of HR status, but more pts with 2-3 organs involved were observed in the H-Low HR- group. No statistically significant differences were observed in PFS and OS between H-0 and H-Low (even considering IHC1+ and IHC2+ & ISH- separately), regardless of HR status. Looking at primary and metastatic paired tumors, a third of HR+ pts changed from H-0 to H-Low and vice versa, and nearly 50% of HR- pts changed from H-Low to H-0; HER2+ (HR+ or HR-) BC barely changed.
Our results show that H-Low have similar characteristics and outcomes than H-0 BC pts. In HER2- pts, the disease behavior is conditioned by HR status in absence of therapies targeted to H-Low population.
NCT02819882.
GEICAM, Spanish Breast Cancer Group Research.
Roche Farma, S.A.; Novartis Farmacéutica, S.A.; Celgene, S.L. (a BMS company); Pfizer, S.L.U.; AstraZeneca Farmacéutica Spain, S.A. in alliance with Daiichi Sankyo Spain, S.A.U.; Lilly, S.A.U.; Seagen, S.L.U.; Gilead Sciences, S.L.
I. Alvarez Lopez: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Novartis, Roche, Gilead; Financial Interests, Personal, Funding: AstraZeneca, Pfizer, Novartis, Roche; Financial Interests, Personal, Other, Meetting travel and inscription expenses: Pfizer, Roche, Eisai, Eli Lilly. A.L. Guerrero Zotano: Financial Interests, Personal, Funding: Lilly; Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Pierre Fabre, Exact Science Novartis; Financial Interests, Personal, Other, Travel, accommodation, expenses: Pfizer, Novartis, Gilead; Financial Interests, Personal, Speaker’s Bureau: Roche, MSD, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, Exact Science, Pierre Fabre. S. Antolín-Novoa: Financial Interests, Personal, Other, Consulting fees: Gilead. A. Tibau: Financial Interests, Personal, Other, Honoraria: Lilly, Novartis. M. Corbellas Aparicio: Financial Interests, Other, Travel, accommodations, expenses: GSK. J. Cruz Jurado: Financial Interests, Personal, Advisory Board: Roche, Pfizer, Novartis, Lilly, Glaxo, Eisai, Pierre Fabre, PharmaMar, Daiichi, AstraZeneca, Glaxo, Seagen, Gilead; Financial Interests, Personal, Other, Honoraria: Roche, Pfizer, Novartis, Lilly, Glaxo, Eisai, Pierre Fabre, PharmaMar, Daiichi, AstraZeneca, Glaxo, Seagen, Gilead. S. Lopez-Tarruella Cobo: Financial Interests, Personal, Speaker’s Bureau: Lilly; Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Roche, Pfizer, Pierre Fabre, Lilly, Seagen, Daiichi Sankyo, Gilead Sciences, MSD, GlaxoSmithKline, Stemline, Menarini and Veracyte. F. Rojo: Financial Interests, Personal, Advisory Role: Astellas, AstraZeneca, BMS, Daiichi Sankyo, Janssen, Pierre Fabre, Roche, Novartis, Pfizer, Merck. All other authors have declared no conflicts of interest.
We assessed the use and outcomes of first-, second- and third-line chemotherapy in patients diagnosed with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (ABC).
All consecutively diagnosed patients with HR+/HER2-ABC in 2007-2020 in ten Dutch hospitals were retrieved from the SONABRE registry (NCT-03577197). Last follow-up was collected in 2022. The proportion of patients starting a specific line of chemotherapy was assessed using the competing risk method. Median progression-free survival (PFS) and overall survival (OS) were calculated from start of chemotherapy using the Kaplan-Meier method.
Of the 3146 patients diagnosed with HR+/HER2-ABC, 54% started a first-, 32% a second- and 18% a third-line of chemotherapy within 120 months from diagnosis, regardless of prior endocrine-based therapy. At start of first-, second- and third-line of chemotherapy, median age was respectively 63, 61 and 60 years, 73%, 78% and 71% had a WHO performance status of 0-1, 48%, 51% and 47% received chemotherapy in the (neo)adjuvant setting, and 80%, 88% and 91% had visceral metastases. When chemotherapy started in 2014-2022, first-, second- and third-line chemotherapy comprised capecitabine in respectively 54%, 35% and 19%, taxanes in 29%, 34% and 24%, and an AC-containing regimen in 12%, 6% and 5% of patients. Median PFS and OS were 6.7 and 15.9 months from starting first-line, 4.9 and 10.5 months from starting second-line and 3.9 and 8.2 months from starting third-line chemotherapy.
Patients diagnosed with HR+/HER2-ABC with an indication for chemotherapy have advanced disease and a poor prognosis. Capecitabine and taxanes were most often used in the first three lines of chemotherapy.
The authors.
The SONABRE Registry is supported by Novartis BV; Roche; Pfizer; Eli Lilly & Co.; Daiichi Sankyo; Gilead and AstraZeneca. Funding sources had no role in the conceptualization or writing of the abstract.
S.M.E. Geurts: Financial Interests, Institutional, Funding: Novartis BV, Roche, Pfizer, Ely Lilly, Daiichi Sankyo, Gilead, AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca. M. Meegdes: Financial Interests, Institutional, Funding: Novartis BV, Roche, Pfizer, Eli Lilly, Daiichi Sankyo, Gilead, AstraZeneca. A. Fallois: Financial Interests, Institutional, Funding: Novartis BV, Roche, Pfizer, Eli Lilly, Daiichi Sankyo, Gilead. I.J.H. Vriens: Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Research Grant: Pfizer. V.C.G. Tjan-Heijnen: Financial Interests, Personal, Advisory Board: E Lilly, AstraZeneca, Novartis; Financial Interests, Institutional, Research Grant: E Lilly, Novartis, Pfizer, AstraZeneca, Roche, Gilead. All other authors have declared no conflicts of interest.
Oral selective estrogen receptor degraders (SERDs) are a promising treatment after disease progression on first-line endocrine therapy (ET) for hormone receptor-positive (HR+), HER2 negative advanced breast cancer (aBC) patients. This systematic review and meta-analysis of randomized clinical trials (RCTs) aimed to assess the efficacy of oral SERDS versus standard of care (SOC) ET according to ESR1 mutation (ESR1mut).
We searched PubMed, Embase, Cochrane, Web of Science, and congresses websites (ASCO and ESMO) for RCTs including HR+/HER2 negative aBC patients who were randomized to oral SERDs versus SOC ET and had received at least one prior line of ET. Outcomes of interest were progression-free survival (PFS) according to ESR1mut and objective response (ORR). Heterogeneity was evaluated with I2 statistics, and random-effect models were fitted.
Of 519 studies screened, four RCTs were included, comprising 1290 patients, of whom; 41% harbored ESR1mut, 92.5% were postmenopausal, and 66% had visceral metastasis. Prior treatment for aBC included iCDK4/6 (73.3%), chemotherapy (21.6%), and; 25.2% of patients received ≥ two prior ET. In a pooled analysis, oral SERDs significantly improved PFS compared to SOC ET (HR 0.76 [95% CI 0.63-0.93 p=0.007]). ESR1mut patients treated with SERDs achieved a significant prolonged PFS than SOC ET (HR 0.59 [95% CI 0.45-0.77 p<0.001]), which was not seen in the wild-type ESR1 group (HR 0.84 [95%CI 0.67-1.04 p=0.11]). ORR was 11% in patients treated with SERDs and 7.4% in SOC ET (p=0,06). N: number; SERD: Selective Estrogen Receptor Degrader; SOC: standard of care; ET: endocrine therapy; mut: mutant; NA: not available.
Trial Phase N Follow-up Median, months Oral SERD (N) SOC ET (N) ESR1mut Bidard, 2022 III 477 15.1 Elacestrant (239) Fulvestrant, AI (238) 228 Oliveira, 2022 II 147 16.6 Arm 1: camizestrant 75mg (74) Fulvestrant (73) 88 146 Arm 2: camizestrant 150mg (73) 88 Tonaley, 2022 II 290 NA Amcenestrant (143) Fulvestrant, AI, tamoxifen (147) 120 Jimenez, 2022 II 303 7.89 Giredestrant (151) Fulvestrant, AI (152) 90
Oral SERDs improved PFS compared to SOC ET for ESR1mut HR+/HER2 negative metastatic breast cancer, but not for unselected patients.
The authors.
Has not received any funding.
M. Lobo: Financial Interests, Personal, Invited Speaker: MSD, Novartis. S.M. Sanches: Financial Interests, Personal, Invited Speaker: MSD, AstraZeneca, Daiichi Sankyo. M.G. Cesca: Financial Interests, Personal, Invited Speaker: Novartis, Zodiac, Daiichi; Financial Interests, Personal, Principal Investigator: AstraZeneca, Sanofi, Seagen. All other authors have declared no conflicts of interest.
Innovative targeted therapies have demonstrated progression-free and overall survival benefit for HER2 positive metastatic Breast Cancer (mBC). However, this disease still has a significant impact on patients’ lives. HERmione is a declarative crossed-view survey conducted among patients living with HER2 positive mBC and oncologists, to identify patients' unmet needs, and to better understand their experiences and perceptions of treatments to provide solutions.
Between July and October 2022, a total of 273 patients living with HER2-positive mBC have participated online to this survey via the Patient Advocacy Group “Mon Réseau Cancer du Sein” intranet, and a web based application developed by Wefight. Answers were also collected via the Steering Committee member by submitting a survey directly to their patients. Furthermore, 40 oncologists treating these types of cancers were asked some of these questions to provide a crossed-view survey.
The survey reveals a significant impact of the disease on patient Quality of Life (QoL), both on physical and mental health[1]. While the disease has a strong impact on QoL, results showed that nursing support is not systematic. Barely 40% of patients reported being accompanied by a nurse. A comparative analysis showed a significant impact of this support on their level of information and their sense of proximity with healthcare teams. Meanwhile, patients also express clear expectations regarding therapeutic innovations. Oral treatments are perceived as having more advantages than injectable ones, primarily because they allow patients to avoid time-consuming trips to healthcare facilities (76%). On the other hand, 46% of patients perceive oral treatments as reducing interactions with medical teams.
HERmione allowed to identify the patients ‘journey unmet needs. While this disease has significant impacts on their QoL, better support, particularly by nurses, would allow to enhance disease experience. HERmione also shows that patients are attached to the oral route, allowing a greater autonomy. Patients' involvement in treatment decisions as well as the support they receive are key factors that can influence their therapeutic evolution.
Wefight.
Seagen.
C. Rigault: Financial Interests, Personal and Institutional, Invited Speaker: Pfizer, Lilly. G. Freyer: Financial Interests, Personal and Institutional, Invited Speaker: Seagen, Roche, AstraZeneca, Pfizer, Novartis, GSK, MSD, BMS, Daiichi Sankyo, Lilly. All other authors have declared no conflicts of interest.
Sacituzumab govitecan was approved by the FDA and EMA in 2021 for pts with unresectable mTNBC who received 2+ prior systemic therapies, with ≥1 therapy in advanced disease. To understand the effect of time to relapse (TTR)/disease-free interval from early to advanced disease on survival after second line (2L), this study evaluated overall survival (OS) in pts with 2 lines of treatment for mTNBC.
A retrospective medical record review identified adult females in the UK and GER who were initially diagnosed with early-stage disease that recurred to mTNBC and had 2L treatment for mTNBC between January 2015 and December 2019. TTR was calculated from the end of last systemic early-stage breast cancer treatment to recurrence to mTNBC. Real-world progression-free survival and OS were estimated by the Kaplan-Meier method. Cox regression model assessed the association of TTR on 2L OS, adjusting for demographics and clinical characteristics.
Data were abstracted for 420 pts (205 UK, 215 GER) at mean age 56.4±10.2 years. Most pts had visceral metastases (72%) and were treated with chemotherapy-only regimens in first-line (1L; 82%) and 2L (85%). Immunotherapy- and target-based regimens comprised 17% of 1L and 14% of 2L treatments. TTR was ≤12 mo for 48% and >12 mo for 52% of pts. Median OS (95% CI, mo) from 2L was 14.3 (13.0-15.8) overall; 14.4 (11.8-16.7) for TTR ≤12 mo; 14.1 (12.7-16.6) for TTR >12 mo. Multivariate Cox regression showed 2L OS was not associated with TTR (HR=0.88 [95% CI, 0.70-1.11]) but associated with 2L regimen type, country, stage at advanced diagnosis, and distant metastases sites (Table).
This evaluation of real-world clinical outcomes showed similar 2L OS between patients with TTR >12mo and TTR ≤12mo.
Patient characteristics and 2L OS regression analysis 1Includes distant lymph nodes, adrenal gland, chest wall, skin, pericardium.
2L HR (95% CI) 420 TTR, n (%) ≤12 mo 202 (48.1) >12 mo 218 (51.9) 0.88 (0.70-1.11) Country, n (%) UK 205 (48.8) GER 215 (51.2) 0.56 (0.44-0.72) Stage at advanced diagnosis, n (%) Unresectable IIIB, IIIC 173 (41.2) IV 247 (58.8) 1.33 (1.04-1.69) Distant metastases at start of 2L treatment, n (%) Visceral ± Bone 304 (72.4) Brain ± Visceral ± Bone 64 (15.2) 2.77 (2.07-3.71) Bone 13 (3.1) 0.52 (0.21-1.27) Other1 39 (9.3) 0.57 (0.36-0.89) 2L regimen, n (%) Chemotherapy only 358 (85.2) IO-/target-based 59 (14.0) 0.57 (0.39-0.85) Other 3 (0.7) 0.48 (0.07-3.47)
Gilead Sciences, Inc.
Gilead Sciences, Inc.
P.S. Hall: Financial Interests, Institutional, Funding: Gilead Sciences, Inc., Lilly, Eisai, Novartis, Merk, Gilead, Sanofi, Roche, Seagen, Medical Research Council and the National Institute for Health Research, UK. L. Chang, M. Summerhayes, I. Ntalla, M. Gharaibeh: Financial Interests, Personal, Full or part-time Employment: Gilead Sciences, Inc.; Financial Interests, Personal, Stocks/Shares: Gilead Sciences, Inc. R. Parikh: Financial Interests, Personal, Full or part-time Employment: RTI Health Solutions; A. Hitchens: Financial Interests, Personal, Full or part-time Employment: RTI Health Solutions. K. Davis: Financial Interests, Institutional, Funding: Gilead Sciences, Pfizer, Eisai. N. Sjekloca: Financial Interests, Personal, Stocks/Shares: Gilead Sciences. V. Derrien Ansquer: Financial Interests, Personal, Full or part-time Employment: RTI Health Solutions. E. Bergamaco: Financial Interests, Personal, Full or part-time Employment: Gilead Sciences, Inc.; Financial Interests, Personal, Stocks/Shares: Gilead Sciences, Inc.; Financial Interests, Personal, Funding: Gilead Sciences, Inc.; Financial Interests, Personal, Advisory Board: Gilead Sciences, Inc. P.A. Fasching: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Hexal, Lilly, Pierre Fabre, Seagen, Agendia, Sanofi Aventis; Financial Interests, Personal, Invited Speaker: Novartis, Daiichi Sankyo, Eisai, Merck, Sharp & Dohme, AstraZeneca, Lilly, Seagen, Gilead; Financial Interests, Personal, Other, Medical Writing Support: Roche; Financial Interests, Institutional, Invited Speaker: BionTech, Cepheid; Non-Financial Interests, Member: ASCO, Arbeitsgemeinschaft für Gynäkologische Onkologie e.V., Translational Research in Oncology, Deutsche Gesellschaft für Senologie e.v.
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) combined with endocrine therapy are the standard of care for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) mBC. However, real-world comparative effectiveness of CDK4/6is plus an AI versus an AI alone for patients with visceral metastases are limited.
This retrospective study used electronic health records from the US Flatiron Health database. The study included women and men with HR+/HER2− mBC and lung or liver metastases treated with first-line (1L) Pal plus an AI or an AI alone between February 2015 to March 2020 in routine clinical practice with a data cutoff date of September 2020. Patient characteristics were balanced between each treatment cohort by stabilized inverse-probability treatment weighting (sIPTW) and propensity score matching (PSM) as a sensitivity analysis. The weighted Cox proportional hazards model was used to compute hazard ratios (HR) and 95% CIs for overall survival (OS) and real-world progression-free survival (rwPFS).
This study included 891 patients total (n = 622 with lung metastasis, n = 376 with liver metastasis, and n = 107 with both). Pal + AI was associated with prolonged OS and rwPFS in mBC patients with lung and liver metastases (Table); PSM results were consistent with these findings. For all 891 patients with lung or liver metastases, OS and rwPFS were significantly prolonged in the Pal + AI group versus AI alone group following sIPTW (HR = 0.64;
Pal + AI versus an AI alone demonstrated prolonged OS and rwPFS in routine practice, supporting the use of 1L Pal + AI for patients with HR+/HER2− mBC with visceral metastatic diseases.
aUnadjusted; bafter sIPTW; NR, not reached.
Metastatic Site and Outcome, months (95% CI) Pal + AI AI Alone Hazard Ratio (95% CI) Lung n = 326 n = 296 Median OSa NR (46.9–NR) 34.2 (29.1–46.0) 0.58 (0.46–0.75) OSb NR (46.9–NR) 35.7 (30.3–50.8) 0.62 (0.48–0.81) rwPFSa 18.9 (15.0–24.4) 12.9 (10.6–16.2) 0.57 (0.46–0.70) rwPFSb 20.2 (15.7–27.3) 13.5 (10.5–17.4) 0.55 (0.44–0.69) Liver n = 211 n = 165 Median OSa 31.2 (25.6–37.8) 17.6 (13.0–22.6) 0.63 (0.48–0.83) OSb 31.4 (25.1–37.8) 21.4 (14.8–31.6) 0.73 (0.52–1.01) rwPFSa 9.7 (7.8–11.1) 5.5 (3.6–7.9) 0.58 (0.44–0.76) rwPFSb 9.9 (7.5–11.5) 5.6 (3.4–8.7) 0.57 (0.42–0.77)
Editorial support, conducted in accordance with Good Publication Practice (GPP3) and the International Committee of Medical Journal Editors (ICMJE) guidelines, was provided by Kevin Woolfrey, PhD of Oxford PharmaGenesis, Inc., Newtown, PA, USA with funding provided by Pfizer Inc.
Pfizer Inc.
Pfizer Inc.
A. Brufsky: Financial Interests, Personal, Advisory Board, reports advisory/consultancy fees from AstraZeneca, Pfizer Inc., Novartis, Lilly, Genentech/Roche, Seagen, Daiichi Sankyo, Merck, Agendia, Sanofi, and Puma and research support from Agendia and AstraZeneca. X. Liu, B. Li, L. McRoy, C. Chen: Financial Interests, Personal, Stocks/Shares, are employees of and stockholders: Pfizer Inc. R.M. Layman: Financial Interests, Personal, Advisory Board, reports advisory/consultancy fees from Novartis, Lilly, and Celcuity, and research/grant funding from Pfizer Inc., Novartis, Lilly, GlaxoSmithKline, Zentalis, Puma, and Celcuity. H.S. Rugo: Financial Interests, Personal, Other, reports sponsored research to her institution from Pfizer Inc., Merck, Novartis, Lilly, Roche, Daiichi Sankyo, Seagen, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, Ayala, and Gilead and honoraria from PUMA, Samsung, and Mylan.
Trastuzumab deruxtecan (T-DXd) is highly effective in metastatic HER2+ patients (pts). Elderly pts are underrepresented in trials. The impact of BMI and drug distribution is unclear. Drug-drug interactions (DDIs) can modify the metabolism and toxicity profile. In this multicentric retrospective study, we evaluate outcomes and toxicities in subgroups of pts treated with T-DXd.
HER2+ pts who received T-DXd were included. RECIST 1.1 and CTCAE v5 criteria were used to define response and adverse events (AEs). DDI was evaluated using Drug-PIN® which provides a score and tier (green for no significant DDIs, yellow to red for increasing DDIs). We considered age, HR status, menopausal status, line of treatment, BMI (<25 vs ≥25) and DDIs as relevant features.
143 pts were enrolled. Median(m) age was years 66 (37-84). Elderly pts were: 53% >65y, 35% >70y and 24% >75y. T-DXd was administered as the I/II or further line in 20 and 123 pts (average 4 lines; range 1-11). 75% of pts were HR+. mBMI was 24. mDrug-PIN score was 6.3 (1.7-190). 11, 3 and 2 pts had a yellow, dark yellow and red interaction tier. The ORR was 68% and mPFS was 16 months (mo). mPFS was similar in different age-based groups (>65y p=0.92; >70y p=0.68; >75y p=0.75) and among pre and post-menopausal pts (p=0.79). mPFS in I/II vs subsequent lines was 17 vs 15 mo (p=0.098). HR status did not impact PFS (p=0.078). There was no association between DDi and PFS. BMI>=25 was significantly associated with better PFS (18 vs 13 mo; 12mo-PFS 76% vs 50% p=0.02). Multivariate analysis with BMI and line of treatment, confirms BMI>25 as a biomarker of improved PFS (p=0.023). Most common AE was nausea (32%). AEs and severe AEs were similar among pts with >65y (p=0.15), >70y (p=0.46); >75y (p=0.32). AEs were more common in pts with BMI>25 (70% vs 48% p=0.01) while no association was found with severe AE (p=0.07). Asthenia and nausea were associated with an elevated DDI(score 5 P= 0.001 and p=0.02).
T-DXd is effective and safe in a real-world population and in elderly pts. Pts with BMI>25 have improved PFS. No difference in PFS and AEs was reported according to line of treatment, menopausal status and HR. DDI seems to be associated with specific toxicities such as nausea and asthenia.
Andrea Botticelli.
Has not received any funding.
A. Botticelli: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Lilly, Amgen, Sofos, Gilead, BMS; Financial Interests, Personal, Invited Speaker: MSD, Amgen, BMS. S. Scagnoli: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Roche, Lilly, BMS, MSD. S. Pisegna: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Pfizer, Roche, AstraZeneca. D. Santini: Financial Interests, Personal, Advisory Board: Amgen, Janssen, Astellas, Bayer, Servier, Novartis, MSD, Merck, Pfizer, Ipsen. M. De Laurentiis: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, celgene, Daiichi Sankyo, EIsai, Eli lilly, Exact science, Gilead, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen. R. Caputo: Financial Interests, Personal, Advisory Board: Roche, Lilly, Gilead, Daiichi Sankyo, Pierre-Fabre; Financial Interests, Personal, Invited Speaker: Novartis, MSD. A. Orlandi: Financial Interests, Invited Speaker: Amgen, Pfizer, Daiichi Sankyo; Financial Interests, Advisory Board: Lilly, Novartis, Gilead. M. Palleschi: Financial Interests, Advisory Board: Novartis, Lilly. M.A. Fabbri: Financial Interests, Invited Speaker: Lilly, Roche, Gilead; Financial Interests, Advisory Board: Pfizer, Novartis. G. D'Auria: Financial Interests, Advisory Board: Amgen, Lilly, Eisai, Novartis, Pfizer. P. Marchetti: Financial Interests, Personal, Advisory Role: BMS, Roche, Genentech, MSD, Novartis, Amgen, Incyte, Merck Serono, Pierre-Fabre. A. Fabi: Financial Interests, Personal, Advisory Board: Roche, Pfizer, Novartis, Gilead, Sophos, Seagen, AstraZeneca, Lilly, Pierre Fabre, Exact Science. All other authors have declared no conflicts of interest.
Patients (pts) with germinal
We conducted a retrospective, multicentre observational study to assess the benefit of PARPi post-PBC and viceversa in pts with g
59 pts from 5 centers were included. Pts characteristics and outcomes are reported in the table. PARPi-mPFS in metastatic setting of pts from Gr1 (N=9) was 4.8 months (mo). DCR was of 67%. In Gr2 (N=31), mPFS with PBC and subsequent PARPi were 4.3 and 4.5 mo; DCRs were of 97% and 45%. Age<46 and platinum free interval (PFI)>6mo were associated with longer PARPi-PFS (p=.009 and .016). PBC-PFS>6mo and PFI>6mo were associated with longer PARPi-DCR (p=.031 and .032). Pts in Gr3 (N=21) reported a mPFS of 5.0 with PARPi and 1.8 mo with subsequent PBC, DCRs were of 67 and 14%. PARPi in earlier lines (1-2) was associated with longer PBC-PFS (p=.020). PARPi-PFS>9mo and PARPi-FI>6mo were associated with longer PBC-DCR (p=.015 and .026).
Pts characteristics and outcomes NA: not applicable; (NA)-PBC: (neoadjuvant) platinum-based chemotherapy; TNBC: triple negative BC
Gr1 (N=9) Gr2 (N=31) Gr3 (N=21) Age at diagnosis – median (range) 38 (29-62) 40 (28-72) 39 (28-62) Visceral disease – % 67% 81% 86% 0% 13% 24% BRCA1/BRCA2/NA – % 56/44/0% 48/39/13% 29/62/10% TNBC/Luminal-like – % 67/33% 52/48% 33/67% PARP line (1-2/>2) – % 67/33% 29/71% 5/95% N. of line – median (range) NA 2 (2-5) 2 (1-10) 3 (2-12) 3 (1-11) 4 (2-13) PFS – median (range) NA 4.8 (0.9-25.4) 4.3 (1.5-23.8) 4.5 (0.3-35.7) 5.0 (0.9-12.4) 1.8 (0.1-5.0) DCR – % NA 67% 97% 45% 67% 14%
Sensitivity and resistance to PARPi and PBC partially overlap in BC. mPFS on PBC/PARPi and PFI/PARPi-FI represent two potential predictive factors of DCR for the subsequent treatment with PARPi/PBC.
The authors.
Has not received any funding.
R. Berardi: Financial Interests, Personal, Advisory Board: AstraZeneca, Boeringher Ingelheim, Novartis, MSD, Otsuka, Lilly, Roche, Amgen, GSK, EISAI; Financial Interests, Institutional, Funding: Roche, AstraZeneca. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Amgen, GSK; Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Sanofi, merck serono, Exact Sciences, Eisai, Olema Oncology; Financial Interests, Personal, Expert Testimony: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Eli Lilly, Roche, BMS, Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, Glaxo Smith kline, Daiichi Sankyo, Nerviano; Non-Financial Interests, Member: ASCO. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Invited Speaker, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Invited Speaker, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Officer, ESMO Clinical Practice Guidelines Chair: ESMO. All other authors have declared no conflicts of interest.
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are standard first-line (1L) therapy for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC); however, patient (pt) and clinical factors may influence 1L treatment (tx) choice. We assessed 1L tx patterns, pt characteristics, and baseline comorbidities of adults with HR+/HER2- mBC.
Data were collected from Jul 2022 to present using the Adelphi Disease Specific Programme™ (DSP), a cross-sectional survey of oncologists in France, Germany, Italy, Spain, and the UK. We report results for abstracted medical records of pts with HR+/HER2- mBC receiving 1L tx. Pt demographics, disease characteristics, and comorbidities reported from a prespecified list at mBC diagnosis were analyzed descriptively.
Among 962 pts included, 75% started 1L tx in 2022, 16% in 2021, and 10% in 2020 or before. The mean pt age at mBC diagnosis was 62 years. 51% had visceral metastases (mets) and 25% had bone-only disease. 73% received CDK4/6i + ET, while chemotherapy-containing regimens (CT) and ET monotherapy (EM) were used in 12% and 9%, respectively. Pts receiving EM were more likely to be older, have worse ECOG performance status (PS), and have bone only disease than pts receiving CDK4/6i + ET or CT. Conversely, pts on CT were more likely to be younger or have visceral mets. The most common comorbidity types were cardiovascular (36%), metabolic (11%), and gastrointestinal (5%) conditions. On average, pts on EM had more comorbidities than those on CT or CDK4/6i + ET. Pt Demographics/Clinical characteristics by 1L therapy aPARPi, CDK4/6i + Combo ET/Other, mTORi b<5% Unknown/MissingcLiver, lung, malignant effusion, adrenal, stomach, peritoneum dExcludes bone only
Total (n=962) EM (n=86) Any CT (n=120) CDK4/6i + ET (n=700) Othera (n=56) Median (IQR) 64 (16) 76 (14) 58 (16) 64 (15) 51 (21) ≥70 y, n (%) 245 (27) 58 (70) 14 (13) 170 (25) 3 (6) Bone only 240 (25) 28 (33) 12 (10) 189 (27) 11 (19) Visceralc 487 (51) 33 (38) 86 (72) 335 (48) 34 (59) Non-viscerald 67 (7) 11 (13) 8 (7) 42 (6) 7 (12) 0-1 796 (83) 49 (57) 99 (82) 595 (85) 55 (95) ≥2 165 (17) 36 (42) 21 (18) 105 (15) 3 (5) Mean (SD) 0.8 (1.2) 1.3 (1.6) 0.6 (1.0) 0.7 (1.0) 0.5 (0.9)
Across 5 European countries, most pts received CDK4/6i + ET, consistent with international guidelines. Age, PS, site of mets, and comorbidities may influence guideline deviations. The pt sample may not represent all pts with mBC. More research and statistical analyses are needed to understand tx choices in this setting.
Pfizer Inc.
Pfizer Inc.
R.L. Mahtani: Financial Interests, Personal, Advisory Board, RM has served as a consultant/advisor: Agendia, Amgen, AstraZeneca, Biotheranostics, Daiichi, Eisai, Genentech, Immunomedics, Lilly, Merck, Novartis, Pfizer, Puma, Sanofi, Seagen. K.A. Hanson, E. Broughton: Financial Interests, Personal, Stocks/Shares, employees and stockholders of Pfizer Inc.: Pfizer Inc. K. Lewis: Financial Interests, Personal, Full or part-time Employment, Katie Lewis is an employee of Adelphi Real World,: Adelphi Real World. G. Foley: Financial Interests, Personal, Stocks/Shares, employees and stockholders of Pfizer Inc.: Pfizer Inc. A. Lambert: Financial Interests, Personal, Full or part-time Employment, employee of Adelphi Real World,: Adelphi Real World. C. Chen: Financial Interests, Personal, Stocks/Shares, employees and stockholders of Pfizer Inc.: Pfizer Inc. C. Criscitiello: Financial Interests, Personal, Speaker’s Bureau, CC reports personal fees for consulting, advisory role and speakers’ bureau: Roche, Novartis, Pfizer, Lilly, MSD, AstraZeneca, Gilead, Seagen, and Daiichi Sankyo.
Early metastatic relapse of triple-negative breast cancer (mTNBC) patients (pts), at <12 months (mos) from end of curative therapy represents a highly aggressive disease that requires clinical and molecular characterization compared to those with late relapse (≥12 mos).
We used clinical and molecular data from pts with mTNBC enrolled in the ongoing precision medicine trial STING (NCT04932525). Genomic analysis was carried out for each patient by using the FoundationOne CDx and Liquid assay. Comparisons used a Pearson's chi-squared Wilcoxon test.
From December 2020 to November 2022, 67 pts with mTNBC were included: 40 early relapse (<12 mos) and 27 late relapses. 50 ctDNA and 44 tissue were performed, at least one molecular alteration was found in 90% (n=45) ctDNA and 77% (n=34) tissue profiling pts. Pts with early relapse had no difference in mutations than late relapse in ctDNA (96% [n=26] vs 83% [n=19]
Pts with early relapse have very \"difficult to treat\" disease. No differences in cancer-related alterations were observed in these pts, but a substantial rate of targetable alterations, hence a great interest in molecular profiling to identify new effective therapies.
The authors.
Has not received any funding.
F. André: Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi; Financial Interests, Institutional, Other, advisory board: Guardant Health; Financial Interests, Institutional, Other, Advisory board: MedImmune, Gilead, Relay therapeutics; Other, Founder: Pegacsy. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Invited Speaker: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. B. Pistilli: Financial Interests, Institutional, Advisory Board: AstraZeneca, Seagen, Lilly, Daiichi Sankyo, MSD; Financial Interests, Institutional, Invited Speaker: Gilead, Novartis, AstraZeneca, Gilead, Seagen, MSD, Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre, Daiichi Sankyo; Financial Interests, Personal, Other, travel support: AstraZeneca, Pierre Fabre, MSD, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Funding: Daiichi Sankyo; Non-Financial Interests, Project Lead: Unicancer. All other authors have declared no conflicts of interest.
The combination of docetaxel (D) with trastuzumab and pertuzumab (T+P) remains the standard first-line in metastatic HER2-positive breast cancer (BC), based on the results of the CLEOPATRA trial. However, all patients (pts) do not benefit equally from this therapy. We explored the association between survival outcomes and initial tumoral response to D+T+P.
We performed an exploratory analysis of CLEOPATRA (NCT00567190) using data extracted from the Vivli database (ID:00007856). The primary objective was to assess the overall survival (OS) of pts treated with D+T+P according to their response at the first tumor assessment at 9 weeks. Secondary objective was progression-free survival (PFS). Response was classified as complete (CR), partial (PR), or stable (SD), according to RECIST1.0 based on central review as per original trial. Pts without first tumor assessment were excluded. We performed a log-rank test to compare Kaplan-Meier curves, and uni- and multivariate analysis. We applied Extended Cox Regression Model to consider a possible guarantee-time bias.
In D+T+P arm, 362/402 pts were included: 12.7% (46/62) with CR, 67.1% (243/362) with PR, and 20.2% (73/362) with SD. In CR group, 47.8% of pts had de novo disease (61.3% in PR, 43.8% in SD, Fisher’s exact test p=0.015), 69.6% had visceral disease (83.3% in PR, 67.1% in SD, p=0.005), 60.9% were hormone receptor (HR) negative (51.9% in PR, 49.3% in SD, p=NS). After a median (m) follow-up of 4.1 years, pts in CR group had a significantly longer PFS compared to PR or SD (log-rank p<0.001), and a longer OS compared to PR or SD (mOS not reached (NR), 57.3 mo (interquartile (IQR) 32.1-NR) and 43.4 mo (IQR 22-103.5) in the CR, PR, and SD group, respectively, p=0.002). In multivariate analysis, a high body mass index was associated with better OS in SD group (HR=0.93 95%; confidence interval (CI) (0.88-0.99) p=0.023), ECOG ≥1 with worse OS in PR group (HR=1.66 95% CI (1.17-2.36) p=0.005). The outcome benefit of CR was equal in HR- and HR+ tumors, p=NS.
Obtaining an early radiological CR with D+T+P confers significantly longer OS and PFS, whereas no difference is observed once compared with PR and SD.
Institut Jules Bordet.
Has not received any funding.
E. Agostinetto: Financial Interests, Personal, Invited Speaker: Eli Lilly, Sandoz, AstraZeneca; Financial Interests, Personal, Royalties: Eli Lilly, Roche, Novartis, Genetics, Istituto Gentili, Daiichi Sankyo. C. Molinelli: Financial Interests, Personal, Royalties: Novartis, Lilly. D. Martins Branco: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Novartis, Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Other, Meeting/travel grant: Novartis, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Institutional funding for an observational research project: Novartis; Financial Interests, Institutional, Research Grant, Institutional funding for an investigator-initiated clinical trial: F. Hoffmann-La Roche Ltd.; Non-Financial Interests, Invited Speaker: Associação de Investigação e Cuidados de Suporte em Oncologia - Portuguese MASCC affiliate; Non-Financial Interests, Leadership Role, Portuguese Young Oncologists Committee Chair: November 2020 - May 2022: Sociedade Portuguesa de Oncologia; Non-Financial Interests, Leadership Role, Oncology Committee Chair: January 2020 - January 2021: Health Parliament Portugal. G. Nader Marta: Financial Interests, Personal, Royalties: Roche, Bayer. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Takeda, Sandoz, Ipsen, Libbs, Knight, Daiichi Sankyo, Lilly, Pfizer, Novartis, Roche; Financial Interests, Personal, Other, Travel grant to attend ASCO 2022: Gilead; Financial Interests, Institutional, Invited Speaker, 2-year research grant paid to my Institution: Gilead. E. de Azambuja: Financial Interests, Personal, Advisory Board: Roche/GNE, Novartis, Seagen; Financial Interests, Personal, Invited Speaker: Zodiac, Libbs, Pierre Fabre, Lilly, AstraZeneca; Financial Interests, Institutional, Research Grant: Roche/GNE, AstraZeneca, GSK/Novartis, Servier; Financial Interests, Institutional, Other, Travel Grant: Roche/GNE; Financial Interests, Institutional, Invited Speaker: MSD, ABCSG, Nektar, Gilead, Immunomedics, Synthon, Odonate Therapeutics; Financial Interests, Invited Speaker, Chair of the Gilead Sciences Research Scholars Program in Solid Tumours: Gilead; Financial Interests, Invited Speaker, Aphinity, Lorelei, Impassion03: Roche; Financial Interests, Invited Speaker, AURORA: Breast International Group; Financial Interests, Invited Speaker, Olympia: Astra-Zeneca; Financial Interests, Personal, Other, Travel grant: Astra-Zeneca; Non-Financial Interests, Advisory Role, Member of the cardio-oncology council: European Society for Cardiology (ESC); Non-Financial Interests, Advisory Role, Belgium Governmental Institution for Cancer: KCE; Non-Financial Interests, Other, Editorial board member: ESMO Open; Non-Financial Interests, Advisory Role: Anticancer Fund. All other authors have declared no conflicts of interest.
Since breast cancer is less common in men than in women, data on the use of new therapeutic agents, including cyclin-dependent kinase 4-6 (CDK 4-6) inhibitors, are limited in patients with metastatic hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) male breast cancer. Therefore, we aimed to investigate the treatment responses of metastatic HR+, HER2- male breast cancer patients treated with CDK 4-6 inhibitors in a multicenter real-life cohort.
Male patients with a diagnosis of HR+ and HER2- metastatic breast cancer, treated with any CDK 4-6 inhibitor, were included in the study. Demographic and clinical characteristics of the patients were recorded. We aimed to determine progression-free survival (PFS) time, response rates and drug related side effects.
A total of 25 patients from 14 institutions were recruited. The mean age at diagnosis was 57 years. Median follow-up was 19.53 (95% CI: 14.04-25.02) months. The overall response rate was 60%. While the median PFS was 20.6 months in the whole cohort, it was not reached in those using CDK 4-6 inhibitors in first line and 10 months in the subsequent lines (
In our study, we found that CDK 4-6 inhibitors are effective and safe options in men with HR+ and HER2- metastatic breast cancer, as in women. Our results support the use of CDK 4-6 inhibitor-based combinations in the first-line treatment of HR+ and HER2- metastatic male breast cancer.
Hacettepe University Ethics Boards and Commissions.
Has not received any funding.
All authors have declared no conflicts of interest.
The treatment of human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (mBC) has changed dramatically with the introduction of several new anti-HER2 agents. In 2021, Trastuzumab Deruxtecan (TDXd) was approved in the UK for treating HER2+ mBC in the third line setting. Our objective was to examine the efficacy and tolerability of TDXd in a real-world UK patient population.
Data for HER2+ mBC treated with TDXd were collected from 17 UK hospitals between December 2019 and January 2023. Clinical and demographic data were collected from medical and pharmacy records, including radiological response, the rate of dose reduction or discontinuation of TDXd, including whether this was related to interstitial lung disease (ILD).
135 HER2+ mBC patients were treated with TDXd. 36% had de novo metastatic disease. The median age at TDXd initiation was 55 years (range 29-85) with a median treatment duration of 9 cycles (range 1-28). At TDXd initiation, the median number of previous metastatic lines of treatment was 2 (range 0-7). 88% patients had visceral disease. 12 patients (9%) were initiated on a reduced dose and 50 further patients (37%) required at least one dose reduction. 152 treatment breaks were given to 83 patients (61%) due to: infection or neutropaenia (n=28), other toxicity (n=53), ILD investigation (n=22), patient request (n=41), other concurrent illness (n=7) and cardiac investigation (n=1). At data cut-off, 74 patients (55%) had discontinued TDXd treatment due to: disease progression (n=52), ILD (n=9), other drug toxicity (n=9) and patient choice (n=4). 13 patients have not had imaging to assess radiological response to TDXd: 5 awaiting first scan, and 8 progressed clinically. Best radiological response in the remaining 122 patients was: complete response in 5 (4%), partial response in 79 (65%), stable disease in 26 (21%) and progressive disease in 12 (10%).
The dose of TDXd was reduced in 25% of patients on the DB02 clinical trial; in this real-world data set the proportion of patients requiring a dose reduction was significantly higher at 37%. Data collection is ongoing in a larger cohort with longer follow up to better inform progression free survival in this real-world population.
The authors.
Has not received any funding.
S. Frank: Financial Interests, Institutional, Invited Speaker: Amgen, AstraZeneca, Chugai, Eisai, Eli Lilly, Gilead, Merck, Mundipharma, Novartis, Pfizer; Financial Interests, Institutional, Advisory Board: Roche, Seagen, Amgen, AstraZeneca, Eli Lilly; Financial Interests, Institutional, Sponsor/Funding: Daiichi Sankyo. A.A. Konstantis: Financial Interests, Institutional, Invited Speaker: Novartis, Roche, Exact Sciences, Gilead; Financial Interests, Institutional, Advisory Board: MSD, Exact Sciences, Novartis, Amgen; Financial Interests, Institutional, Sponsor/Funding: BMS, MSD, Astellas, Ipsen, EUSA, Lilly, Roche. J.W. King: Financial Interests, Institutional, Invited Speaker: Exact Science, Pfizer, Roche, Novartis, Lilly, Eisai, Prosigna, AstraZeneca, MSD, Gilead, Seagen. All other authors have declared no conflicts of interest.
Treatment options for pre-treated patients with metastatic triple-negative breast cancer (mTNBC) remain limited. The TROP-2-targeting antibody drug-conjugate sacituzumab govitecan (SG) recently demonstrated superior efficacy over single agent chemotherapy in mTNBC patients with at least 2 lines of prior chemotherapy. The aim of this study was to assess the real-world safety and efficacy of sacituzumab govitecan in the UK.
Data were retrospectively collected from 16 major UK cancer centres. This study included all mTNBC patients who received at least one dose of sacituzumab govitecan as part of the UK compassionate use programme. Patients were required to have had at least 2 prior lines of chemotherapy. Key endpoints include progression-free survival (PFS), overall survival (OS) and safety. Kaplan-Meier survival analysis was calculated using Prism.
A total of 132 patients were included. The median age was 56 years (range 28-91 years); all patients were performance status (PS) 0-3 (39 pts PS0, 76 pts PS1, 16 pts PS2, 1 pt PS3); 75% (99/132) had visceral metastases including 24 patients with central nervous system (CNS) disease. SG treatment was 2nd line in 28% and 3rd line in 31% of pts in the metastatic setting. 41% of pts had received 3 or more prior lines of chemotherapy. Median PFS was 5.2 months and median OS was 8.7 months (n= 126, 6 pts excluded due to incomplete data). Subgroup analysis of pts with CNS disease showed a PFS of 5.1 months; OS was not reached. 11/24 pts with CNS disease were treated with radiotherapy (RT) to the CNS prior to or during treatment with SG. Pts with CNS disease who did not receive RT at any point had a PFS of 1.6 months and OS of 2.6 months. SG dose reduction was required in 54% of pts due to adverse events (AEs). Most common AEs were fatigue (all grade, 82%; G1, 44%; G2, 22%; G3, 14%; G4, 1%), neutropenia (all grade, 55%; G1, 9%; G2, 16%; G3, 15%; G4, 14%), diarrhoea (all grade, 58%; G1, 25%; G2, 18%; G3, 11%; G4, 4%), and nausea (all grade, 38%; G1, 24%; G2, 10%; G3, 3%).
This study provides the first real-world experience of sacituzumab govitecan in the UK, confirming substantial anti-tumour activity in pre-treated mTNBC. The safety profile is consistent with clinical trial experience.
Dr. Michael John Devlin (Medical Oncology, Barts NHS Trust, London, UK) has equally contributed to the study.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
We assessed the use and outcomes of first- and second-line chemotherapy in patients diagnosed with metastatic triple-negative breast cancer (mTNBC).
All consecutively diagnosed patients with mTNBC in 2014-2020 in ten Dutch hospitals were retrieved from the SONABRE registry (NCT-03577197). Last follow-up was collected in 2022. The proportion of patients starting a specific line of therapy was assessed using the competing risk method. Median progression-free survival (PFS) and overall survival (OS) were calculated from start of chemotherapy using the Kaplan-Meier method.
Of the 386 patients diagnosed with mTNBC, 72% started a first-line and 38% a second-line of chemotherapy. At start of first- and second-line chemotherapy, 29% and 25% had de novo mTNBC, 49% and 57% bone metastases, 66% and 71% visceral metastases and 9% and 15% central nervous system metastases. First- and second-line chemotherapy included capecitabine in respectively 32% and 34%, taxanes in 25% and 27%, other single-agent chemotherapy in 6% and 17%, an AC-containing regimens in 14% and 5% and other combination-chemotherapy in 23% and 17% of patients. Median PFS and OS were 5.9 and 11.7 months from starting first-line and 3.8 and 8.7 months from starting second-line chemotherapy.
In real-world clinical practice, first- and second-line chemotherapy for mTNBC included most often the single-agent chemotherapies capecitabine and taxanes. The prognosis of patients with mTNBC is poor, with a median survival of less than a year from start of first-line chemotherapy.
The authors.
The SONABRE Registry is supported by Novartis BV; Roche; Pfizer; Eli Lilly & Co.; Daiichi Sankyo; Gilead and AstraZeneca. Funding sources had no role in the conceptualization or writing of the abstract.
S.M.E. Geurts: Financial Interests, Institutional, Funding: Novartis BV, Roche, Eli Lilly, Daiichi Sankyo, Gilead, Pfizer; Financial Interests, Personal and Institutional, Funding: AstraZeneca. M. Meegdes, N. Teeuwen, M. De Boer: Financial Interests, Institutional, Funding: Novartis BV, Roche, Pfizer, Eli Lilly, Gilead, AstraZeneca. V.C.G. Tjan-Heijnen: Financial Interests, Personal and Institutional, Funding: Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca; Financial Interests, Institutional, Funding: Daiichi Sankyo, Gilead. All other authors have declared no conflicts of interest.
PALBOSPAIN is an observational, multicenter study to evaluate real-world practice patterns and outcomes of first-line treatment for advanced breast cancer (ABC) with Palbociclib. Results from real-world progression free survival (rwPFS) and overall survival (OS) in the total population and according to endocrine sensitivity have been previously reported. Here, we provide subgroup analysis according to age, sites and number of metastatic locations, menopausal status, and dose received.
Patients diagnosed with HR+/HER2- ABC who had started first-line treatment with palbociclib between November 2017 and November 2019 were included.
762 patients received Palbociclib in combination with AIs (69.4%) or fulvestrant (30.1%). Median age was 61.9 years (17.5% < 50 y; 51.8% 50-70 y; 30.7% > 70 y). 114 patients were premenopausal (15%). A total of 418 patients had visceral disease (54.9%). At baseline, patients with 1, 2-3 and >3 metastatic locations were 42.7%, 43% and 14.3% respectively. Results of real-world Response Rate (rwRR) and rwPFS are shown in the table. A total of 377 (49.5%) patients required a dose reduction. Among patients who had a first dose reduction, 164 (21.5%) required a second dose reduction. Median rwPFS was 28 months (CI 95% 25-33) in patients who had ≥ 1 dose reductions and 19 months (CI 95% 16-23) in patients who maintained the initial dose (HR 0.71; CI 95% 0.58-0.85, p=0.003).
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NA, not available; NR, not reached
rwRR rwPFS CR PR SD PD N (%) N (%) N ( %) N ( %) Months CI 95% <50 15 (11.3) 50 (37.6) 46 (34.6) 19 (14.3) 27 (21-35) 50-70 22 (5.6) 145 (36.7) 152 (38.5) 57 (14.4) 21 (19-26) >70 13 (5.6) 87 (37.2) 88 (37.6) 31 (13.2) 27 (22-37) Premenopausal 13 (11.4) 44 (38.6) 40 (35.1) 15 (13.2) 27 (20-35) Postmenopausal 37 (5.7) 238 (36.3) 246 (38) 92 (14.2) 24 (21-27) Yes 21 (7.4) 17 (41.4) 141 (33.7) 63 (15.1) 20 (18-23) No 29 (8.4) 109 (31.7) 145 (42.2) 44 (12.8) 30 (25-36) 1 24 (7.4) 100 (30.8) 136 (41.8) 46 (14.2) 34 (28-39) 2-3 23 (7.0) 132 (40.2) 116 (35.4) 47 (14.3) 20 (18.24) >3 3 (2.8) 50 (45.9) 34 (31.2) 14 (12.8) 19 (14-24)
Age at start of the treatment and menopausal status were not associated with PFS. Patients with visceral metastasis and >1 sites of metastasis had shorter PFS. The incidence of dose reductions was higher compared with PALOMA-2 & 3 trials. However, dose reductions did not affect Palbociclib efficacy.
NCT04874025.
Department of Investigation and Clinical Trials of Hospital Clínico San Carlos (UICEC-IdISSC).
Pfizer.
F. Moreno Anton: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Daiichi Sankyo, AstraZeneca, Gilead, MSD, Roche, Seagen; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer, MSD; Financial Interests, Personal, Principal Investigator: Novartis. M. Bellet-Ezquerra: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Lilly, Stemline-Menarini; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Novartis, Lilly. L.M. Manso Sanchez: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer. P. Tolosa Ortega: Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Lilly, Seagen, AstraZeneca, Daiichi Sankyo and MSD; Financial Interests, Personal, Advisory Board: Novartis, Adamed, Seagen and Daiichi Sankyo; Financial Interests, Personal, Full or part-time Employment, Medical Advisor and Madical Monitor: SOLTI. R. Andrés Conejero: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Other: Pfizer. E. Galve-Calvo: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Gilead, Pfizer; Financial Interests, Personal, Expert Testimony: AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Novartis, Pfizer, Pierre Fabre, Roche; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Gilead, Pfizer; Financial Interests, Personal, Other: Roche. F. Ayala de la Pena: Financial Interests, Personal, Advisory Board: AstraZeneca, Celgene, Eisai, Novartis, Roche, Pfizer, Pierre Fabre, Lilly, Sanofi, Seagen, Daiichi Sankyo; Financial Interests, Personal, Sponsor/Funding: Roche, Celgene, MSD; Financial Interests, Personal, Other: Roche, Pfizer, Pierre Fabre, MSD. S. Lopez-Tarruella Cobo: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Pfizer, Novartis, Lilly, Gilead, GSK, Roche, Pierre Fabre, Seagen, Menarini_Stemline, Gebro Pharma; Non-Financial Interests, Invited Speaker: GEICAM, SEOM. B.A. Hernando Fernandez: Financial Interests, Personal, Advisory Board: Seagen, Lilly, GSK, PharmaMar, Pfizer, Tesaro; Financial Interests, Personal, Other: Pierre Fabre. N. Martinez Jañez: Financial Interests, Personal, Advisory Board: Roche, Daiichi Sankyo, AstraZeneca, Pfizer, Eisai. All other authors have declared no conflicts of interest.
Trastuzumab deruxtecan (TDXd) demonstrated unprecedented efficacy in patients (pts) with HER2+ metastatic breast cancer after at least a prior anti-HER2 regimen. However, few data are available about its efficacy in routine clinical practice. In this multicenter retrospective study we evaluated effectiveness and safety of TDXd in a real-world (
Clinical and pathological information about pts with HER2+ mBC who received TDXd were collected from 11 italian hospitals. Activity and toxicity were evaluated following RECIST 1.1 and CTCAE v5 criteria. The survival outcomes evaluation included PFS, milestone-PFS and OS.
One hundred forty-three patients were enrolled. Median age was 66 (range 33-84) and 4 men were included. Estrogen receptor (HR) was positive in 108 (75%) pts and negative in 35 (25%). TDXd was administered as first, second, third or subsequent line in 4 (3%), 16 (11%), 42 (29%), and 81 (57%) pts respectively. Among 123 pts with measurable disease, the ORR was 68% and the disease control rate was 91% (9 CRs, 74 PRs, and 30 SD). Nine (7%) pts had primary resistance to TDXd. With a median follow-up of 12 months (range: 1-31), the mPFS was 16 months. PFS was 84%, 59%, and 39% at 6, 12, and 18 months, respectively. A favorable trend in PFS was reported in pts receiving TDXd as I/II line vs further lines, though the difference did not reach statistical significance (17 vs 15 months, 76% vs 56%; p=0.098). OS was 90.8% at 6 months, 74% at 12, and 59% at 18 months, respectively. Median OS was 20 months. 89% of pts who received TDXd as I/II line were alive at 12 months vs 73% of subsequent lines (p=0.39). Any-grade toxicity was registered in 84 patients (59%). The most common toxicities reported were nausea (33%), neutropenia (21%), and asthenia (21%). Liver toxicity and diarrhea were uncommon (5%, and 1% respectively). Severe toxicities were registered in 18% of pts and the most frequent were neutropenia, nausea/vomiting, and interstitial lung disease observed in 15, 2 and 3 pts, respectively. Adverse events led to dose reduction in 37 pts (26%).
The efficacy and safety of TDXd were confirmed in an unselected
Andrea Botticelli.
Has not received any funding.
A. Botticelli: Financial Interests, Personal, Advisory Board: Roche, Novartis, MSD, Lilly, Pfizer, Amgen, BMS, Gilead; Financial Interests, Personal, Invited Speaker: Sofos. S. Pisegna: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Pfizer, Roche, AstraZeneca. S. Scagnoli: Financial Interests, Personal, Invited Speaker: Novartis, Lilly, MSD, Pfizer, BMS. M. De Laurentiis: Financial Interests, Personal, Speaker’s Bureau: Roche, Celgene, MSD; Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Eisai, Exact Science, Gilead, Novartis, Pfizer, Pierre Fabre, Roche; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Eli Lilly, Seagen. R. Caputo: Financial Interests, Personal, Invited Speaker: Roche, Eli Lilly, MSD, Gilead, Daiichi; Financial Interests, Personal, Advisory Board: Novartis, Pierre-Fabre. M. Palleschi: Financial Interests, Personal, Advisory Board: Novartis, Lilly. A. Orlandi: Financial Interests, Personal, Invited Speaker: Amgen, Pfizer, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Lilly, Novartis, Gilead. M. Giampaglia: Financial Interests, Personal, Invited Speaker: Novartis, Eli Lilly. M.A. Fabbri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Roche, Gilead. G. D'Auria: Financial Interests, Personal, Advisory Board: Eisai, Amgen, Pfizer, Lilly, Novartis. P. Vici: Financial Interests, Personal, Advisory Board: Novartis, Pfizer; Financial Interests, Personal, Invited Speaker: Eli Lilly, Eisai. P. Marchetti: Financial Interests, Personal, Advisory Role: BMS, Roche, Genentech, MSD, Novartis, Amgen, Merck, Pierre Fabre, Incyte. A. Fabi: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Gilead, Sophos, Seagen, AstraZeneca, Lilly, Pierre Fabre, Exact Science. All other authors have declared no conflicts of interest.
One third of ABC pts is currently represented by women aged over 70. However, this population remains under-represented in clinical trials. Recently, T-DXd revolutionized the treatment of HER2 positive ABC, demonstrating its efficacy in DESTINY-Breast trials. Its safety profile was manageable and most adverse events (AEs) were gastrointestinal in nature. Nevertheless, T-DXd was associated with the development of interstitial lung disease (ILD) in 10-15% of pts. Thus, some concerns could raise regarding those outcomes in elderly patients. The aim of this retrospective analysis was to evaluate the safety and efficacy of T-DXd in ABC pts over 70 in a real-life setting.
TREX-Old is an European retrospective registry evaluating the real-life use of T-DXd in ABC pts aged ≥ 70 among 4 centers across Austria, France, Italy and Portugal. Clinical and pathological characteristics, previous treatments and AEs were collected.
Overall, to date, 27 pts were enrolled. Median age was 74 years (range 70-81), with 10 patients over 75 (37%). The ECOG performance status was 0, 1 and ≥ 2 in 22%, 56% and 22% of pts, respectively. Among them, 37% had cardiovascular comorbidities. The median number of lines before T-DXd was 3 (1-13). At treatment initiation, 71% and 29% of pts had a visceral and non-visceral (bone only, skin or lymph nodes) disease, respectively. Eight pts (30%) started with a dose-reduction, and 8 pts (30%) had secondary dose adjustment. Overall, any-grade treatment-related AEs occurred in 19 pts (70%). Among them, nausea was the most common AE (37%), followed by asthenia (18%). Three out 27 pts (11%) developed ILD. Finally, at a median follow-up of 9.5 months (1-29), median PFS was 12 months, considering that only 8 pts progressed at time of current analysis.
With the limit of number and follow-up, our data suggest that T-DXd is not associated with new safety signals in pts ≥ 70 years. ILD occurrence was in line with previously reported data. Therefore, age should not be a criterion to discourage treatment with T-DXd. This registry is ongoing, and updated data will be presented.
The authors.
Has not received any funding.
G. Buono: Financial Interests, Personal, Invited Speaker: Novartis, Eli Lilly, Pfizer, AstraZeneca, Roche, Daiichi Sankyo, Exact Science, Genetic, Pierre-Fabre. E.V. Klocker: Financial Interests, Personal, Invited Speaker: Novartis, Eli Lilly, Daiichi Sankyo, AstraZeneca, Pierre-Fabre, Gilead, Roche. S. Nardin: Financial Interests, Personal, Other, travel expenses: Daiichi Sankyo. S. Braga: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Daiichi Sankyo, MSD. N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Seagen, Medscape, Art Tempi, Onkowissen, Gilead, Sanofi, Exact Sciences; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Roche, Sandoz-Hexal, Seagen, Aptitude Health, Gilead, Sanofi; Financial Interests, Personal, Other, Husband: WSG (Husband); Financial Interests, Personal, Ownership Interest: West German Study Group; Financial Interests, Institutional, Funding: AstraZeneca, BMS, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Palleos, Seagen, TRIO, WSG; Non-Financial Interests, Member, Member German AGO Breast Guideline Committee: AGO Breast Committee; Non-Financial Interests, Member, Breast Cancer Educational Programs: ESO/ESCO; Other, Founding Editor: BreastCare Journal. V.C. Dieras: Financial Interests, Personal, Advisory Board, National advisory board: Pierre Fabre Oncologie; Financial Interests, Personal, Advisory Board, Steering Committee, consultant, Symposium, travel expenses: Roche Genentech; Financial Interests, Personal, Advisory Board, + Symposia and travel expenses: Novartis; Financial Interests, Personal, Advisory Board, Advisory boards, symposia, travel expenses: Pfizer; Financial Interests, Personal, Advisory Board, Symposia, travel expenses: Lilly, AstraZeneca, MSD; Financial Interests, Personal, Advisory Board, Symposia,travel expenses: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, symposia,travel expenses: Seagen, Gilead; Financial Interests, Personal, Advisory Board, Steering Committee: AbbVie; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Other, IDMC: Sanofi; Financial Interests, Personal and Institutional, Other, IDMC: Sanofi; Financial Interests, Institutional, Invited Speaker: Roche Genentech, AstraZeneca; Financial Interests, Institutional, Invited Speaker, Steering Committee: Lilly; Financial Interests, Institutional, Invited Speaker, + IDMC: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, PI: Seagen. All other authors have declared no conflicts of interest.
Pts with HR+/HER2– mBC are typically treated with endocrine-based therapies (ET) until ET resistance develops, at which point Tx options are limited to CT-based regimens, and now antibody-drug conjugates (ADC). This real-world study aims to describe Tx patterns in pts with HR+/HER2– mBC treated with CT before the ADC era.
This retrospective, observational study used the ConcertAI Patient360™ dataset of electronic medical record data of pts from the US. Pts (aged ≥18 years old) with HR+/HER2– mBC and initiating their first CT in the metastatic setting from Jan 2011 - Jun 2021 were included. Time to next Tx or death (TTNTD) was calculated for all pts and for pts subsequently treated with a second, third, and fourth CT. Index date was the start date of each CT.
Pts (N=1545) included were female (99%) and White (76%); median age was 61 years. Most pts (80%) were treated in a community setting; 41%, 19%, and 18% received their first CT in 1L, 2L, and 3L, respectively. Sixty percent and 44% of pts had prior exposure to ET and CDK4/6i in the metastatic setting, respectively. Majority of pts received CT monotherapy across CT lines. Most used agents across CT lines are shown in the table; capecitabine and paclitaxel were most used in earlier lines of CT. Median TTNTD (95% CI) was 6.5 mo (5.9-7.1) in pts treated with first CT, and 6.4 mo (5.9-7.4), 4.6 mo (4.2-5.2), and 3.9 mo (3.5-4.3) in pts subsequently treated with a second (n=886), third (n=480), and fourth CT (n=260), respectively.
In this real-world study, capecitabine and paclitaxel were most commonly used in earlier lines of CT. TTNTD decreased with each subsequent CT received, indicating a high unmet need for more efficacious treatment options for ET-resistant HR+/HER2– mBC. Use of CT agents in pts with HR+/HER2– mBC *The proportion of pts may add up to greater than 100% as the subgroups are not mutually exclusive. CT, chemotherapy; mBC, metastatic breast cancer; pts, patients.
Treatment type* 1st CT N=1545 2nd CT n=886 3rd CT n=480 4th CT n=260 Paclitaxel 29% 35% 25% 17% Docetaxel 7% 5% 3% 4% Doxorubicin 11% 7% 12% 11% Epirubicin <1% <1% 1% <1% Cisplatin 1% 1% <1% <1% Carboplatin 6% 7% 8% 8% Capecitabine 45% 30% 22% 16% Gemcitabine 8% 13% 18% 22% Eribulin 3% 11% 19% 20% Vinorelbine 1% 4% 4% 11%
Gilead Sciences, Inc.
Gilead Sciences, Inc.
K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Roche, Vifor Pharma, Eli Lilly, Pierre Fabre, McCann Health, Roularta, Teva, Gilead Sciences, Pfizer, Gilead, MSD; Financial Interests, Institutional, Invited Speaker: Pfizer, Roche, Novartis, Eli Lilly, Mundi Pharma, MSD, Medscape, MSD; Financial Interests, Institutional, Other, Consultancy: Roche; Financial Interests, Personal, Other, Consultancy: Gilead, Novartis, MSD, Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Sanofi; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Institutional, Funding: Sanofi; Non-Financial Interests, Principal Investigator: EORTC 1745-ETF-BCG trial; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Invited Speaker: BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force; Non-Financial Interests, Advisory Role: Commission personalized medecine Federal Government Belgium; Non-Financial Interests, Advisory Role, External Scientific Advisor: European Medicine Agency. K. Jhaveri: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, AbbVie, Taiho Oncology, Seattle Genetics, Daiichi Sankyo, Loxo Oncology, Gilead, Blueprint Medicines, Biotheranostics; Financial Interests, Personal, Other, Consultant: Pfizer, Genentech, Sun Pharma Pvt Ltd.; Financial Interests, Institutional, Invited Speaker: Novartis, Pfizer, AstraZeneca, Lilly Pharmaceuticals, Genentech, Zymeworks, Gilead, Puma Biotechnology, Merck Pharmaceuticals; Non-Financial Interests, Leadership Role: Lilly/Loxo Oncology. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, ARC Therapeutics; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Mersana Therapeutics, Ellipses Pharma; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis, OncXerna, Myovant, Bayer, Zetagen, Infinity Therapeutics, Umoja Biopharma; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. I. Ntalla: Financial Interests, Personal, Full or part-time Employment: Gilead Sciences, Inc.; Financial Interests, Personal, Stocks/Shares: Gilead Sciences, Inc. A. Shah: Financial Interests, Personal, Full or part-time Employment: Gilead; Financial Interests, Personal, Stocks/Shares: Roche. N. Sjekloca: Financial Interests, Personal, Stocks/Shares: Gilead Sciences. K. Fraeman: Financial Interests, Personal, Full or part-time Employment: Gilead Sciences, Inc. L.A. Carey: Financial Interests, Personal, Royalties, immediate family member-royalty-sharing agreement, investorship interest in licensed IP to startup company, Falcon Therapeutics, that is designing neural stem cell-based therapy for glioblastoma multiforme.: Falcon Therapeutics; Financial Interests, Institutional, Funding, research funding: Syndax, Immunomedics, Novartis, Nanostring Technologies, AbbVie, Seattle Genetics, Veracyte; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: sanofi, Novartis, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, AstraZeneca/ Daiichi Sankyo, Apitude Health, Exact Sciences.
The majority of metastatic invasive lobular carcinoma (mILC) are hormone receptor (HR)-positive, HER2-negative and initially responds well to endocrine therapy (ET) in combination with targeted therapies (TT). However, once ET-refractory, data on the efficacy of single-agent chemotherapy regimens are limited. We investigated the efficacy of capecitabine (CAP) versus taxanes (TAX) in ET-refractory HR+ HER2- mILC patients.
In an observational investigation using data from the MD Anderson breast cancer prospectively collected electronic database, we searched for patients with a diagnosis of HR+ HER2- mILC who were exposed to prior lines of ET (either alone or in combination with TT) and who received first-line chemotherapy in the metastatic setting (ET-refractory mILC). We collected data on clinicopathological features, chemotherapy type, treatment duration and survival status. The Kaplan-Meier product-limit method was used to compare progression-free survival (PFS) and overall survival (OS) between the two different groups. Backward model selection was used to find the final multivariate Cox model for PFS and OS.
We reviewed 269 subjects: 173 (65%) received CAP and 96 (35%) received TAX. Patients characteristics were well balanced between the 2 groups: median age 52, 80% White, 61% had non-visceral disease, and 47% received only one prior ET. Subjects who received CAP had statistically significant better median PFS compared to TAX (8.8 vs 5.0 months, HR 0.63,
The analysis suggest that ET-refractory mILC subjects treated with CAP were associated with longer PFS but not OS compared to those treated with TAX.
The authors.
Has not received any funding.
J. Mouabbi: Financial Interests, Personal, Invited Speaker: BostonGene; Financial Interests, Personal, Advisory Board: Cardinal Health. D. Tripathy: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Exact Sciences, GlaxoSmithKline, AstraZeneca. R.M. Layman: Financial Interests, Personal, Funding: Pfizer, Eli Lilly, Novartis, GlaxoSmithKline, Puma, Zentalis, Celcuity. All other authors have declared no conflicts of interest.
PAB’s standard fixed dose of 125 mg may result in a high variability in efficacy and toxicity profile. The objective of this study was to evaluate the effect of DI on PFS in patients(pts) with HR+, HER2-negative MBC in a real-world setting.
Retrospective, longitudinal study for pts who started PAB as a 1st or 2nd line treatment at Catalan Institute of Oncology between Nov 2017-May 2021. DI was a ratio between the amount of PAB mg administered until disease progression or end of treatment and standard dosing (125mg daily for 3weeks on/1week off). DI was categorized as ≤80% and >80%. BWD of PAB was categorized as <2 mg/Kg and ≥2 mg/Kg. Adjustment factors were age, de novo MBC, line of treatment. Multivariate Cox regression model was used to estimate adjusted hazard ratios (aHRs) and 95% CIs.
220 pts were included, with a median follow-up of 22.8 months(m) for the primary endpoint (IR13.6–31.8m). Median age 63 years (IR 54–72.7) and PBC was 1st-line and 2nd-line treatment in 137(64.3%) and 45pts(21.1%), respectively. In 97.7% initial dose was 125mg/daily and median 1.9mg/Kg (IQR 1.6 – 2.2). Dosing reduction due to toxicity was required in 94pts (42.7%). Median DI along treatment was 88.7% (IR 74.8-98.1); 76 and 144pts were treated with DI ≤80% and >80%, respectively. Dose reduction due to grade III-IV neutropenia was higher in pts treated with DI ≤80% vs DI >80%: 84.2% vs 20.8% (p<0.001) and 93% vs 55.6% (p<0.001), respectively. At closing date, treatment was discontinued in 168pts (76.4%): 140 due to progression and 11 due to toxicity. Overall response rate was 76.1% vs 70.6% with DI ≤80% and >80%, respectively (17.9 vs 27.1% partial responses and 3 vs 4.7% complete responses). In the multivariate analysis, DI >80% (aHR 1.59, 95% CI: 1.06-2.39), PAB initial dose > 2mg/Kg (aHR 1.68, 95%: CI 1.15-2.44) and ≥2nd line therapy (aHR: 1.58; CI 1.08-2.31) were associated with higher risk of progression/death while de novo MBC was associated with lower risk (aHR 0.52, 95% CI: 0.32-0.87).
In our study, PAB dosing <2mg/kg and a DI <80% were associated with lower risk of PFS in pts with HR+/HER2-negative MBC.
The authors.
Has not received any funding.
M. Margeli Vila: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Novartis, MSD, Gylead, Lilly, Piere Fabre; Financial Interests, Personal, Other, Travel expences: Gylead; Financial Interests, Institutional, Invited Speaker, I have received research funding for my institution from Pfizer: Pfizer. S. Pernas Simon: Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pfizer; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Novartis, Daiichi-Sankyo; Non-Financial Interests, Invited Speaker: SOLTI. All other authors have declared no conflicts of interest.
APOBEC3 enzymes are a key source of mutagenesis in breast cancer. PI3K inhibitors are currently used in the treatment of
We developed a computational framework to screen for APOBEC3-induced mutations in
Using the WES of 696 pts with luminal disease from the TCGA-BRCA cohort, we identified 296 pts (42.5%) with
Our findings indicate that using a prioritized catalog of APOBEC3-induced mutations in
Kyrillus Shohdy.
Has not received any funding.
All authors have declared no conflicts of interest.
Cyclin 4/6 inhibitors (CDKIs) are currently used in patients with hormone-dependent breast cancer as first-line treatment for metastatic disease. One of their less frequent but equally limiting adverse events is skin toxicity. The purpose of the study was to report the incidence of skin toxicity in patients with breast cancer treated with CDKIs in our center.
Between November 2017 and December 2022, information from patients affected with metastatic breast cancer (MBC) treated with CDKIs at Hospital del Mar was retrospectively collected. A descriptive statistical analysis was performed. Toxicity was classified using CTCAE v5.0.
A total of 193 patients were included of whom 8.8% (17/193) presented some cutaneous reaction related to CDKIs. The median age at diagnosis of breast neoplasia was 53 years (range 40-84). Forty-seven percent (8/17 patients) had received Ribociclib while 53% had received Palbociclib. One patient required a change of CDKIs (from Ribociclib to Palbociclib) due to G2 skin reaction. The mean time between starting CDKIs and the appearance of the skin reaction was 10.8 months, with 64.7% (11/17) of the patients having a grade 2 reaction and 35.3% (6/17) having a grade 1 reaction. The most frequently observed skin lesions were cutaneous xerosis and prurigo lesions (4 patients), followed by eczema-like desquamative lesions (3 patients) and reactive or figured erythema (erythema multiforme [1], nonspecific erythematous plaques [3], granuloma annulare [1]). Other manifestations present in only one patient each were: morphea, bullous eruption, lichenoid eruption, hyperpigmentation and palmoplantar pustulosis. Five patients associated a second cutaneous manifestation: onychodystrophy (3), aphthosis (1) and palmoplantar keratoderma (1). Two of these patients presented a cutaneous reaction in relation to radiotherapy treatment, an effect known as radiation recall effect.
Although skin toxicity is not a very frequent reaction and in our series it did not lead to treatment discontinuation, it is necessary to monitor this toxicity and refer to dermatology when necessary in order not to discontinue the oncospecific treatment.
The authors.
Has not received any funding.
L.M. Masfarre Pinto: Non-Financial Interests, Institutional, Speaker’s Bureau: AstraZeneka; Non-Financial Interests, Institutional, Other, Travel expenses: MSD. N. Navarro Gorro: Non-Financial Interests, Institutional, Invited Speaker, Travel expenses: AstraZeneka, Kyowa Kirin; Non-Financial Interests, Institutional, Other, Travel expenses: MSD. J. Recuero: Non-Financial Interests, Institutional, Other, Travel expenses: Lilly. T. Martos Cardenas: Non-Financial Interests, Institutional, Other, Travel expenses: Pfizer. M. Martinez Garcia: Non-Financial Interests, Institutional, Other, Travel expenses: Roche, Pfizer; Non-Financial Interests, Institutional, Advisory Board: Roche, Celgene, Seagen, Boehringer, Pierre Fabre. M. Castro-Henriques Pinto-Machado: Non-Financial Interests, Institutional, Other, Travel expenses: Pfizer. N. Rodriguez de Dios: Non-Financial Interests, Institutional, Advisory Board: AstraZeneca; Non-Financial Interests, Institutional, Speaker’s Bureau: AstraZeneca, Siemens Healthineers. S. Servitja Tormo: Non-Financial Interests, Institutional, Speaker’s Bureau: Daiichi Sankyo, AstraZeneca, Roche, Novartis; Non-Financial Interests, Institutional, Advisory Board: Seagen , Genomic Health, MSD. All other authors have declared no conflicts of interest.
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are usually combined with fulvestrant or aromatase inhibitors for the treatment of patients with metastatic breast cancer (mBC). Drug-drug interactions may affect absorption by different mechanims, for instance, modification of digestive pH. Proton pump inhibitors (PPIs) are known to reduce the oral bioavailability of some anticancer drugs. Palbociclib is a weak base with pH-dependent solubility, therefore variations in gastric pH could affect its absorption. The objective of this study was to evaluate the interaction between PPIs and palbociclib by analizing progression-free survival (PFS) in patients with mBC.
This is a retrospective study approved by the local Ethics Committee. Patients had received palbociclib between January 2016 and December 2021. The following variables were collected: age, menopausal status, performance status, hormonal treatment (fulvestrant or aromatase inhibitors), visceral or non-visceral disease, first-line vs second-line treatment, ki67, and concomitant use of PPIs. PFS was defined as the time from starting treatment to progression of the disease. Survival was estimated with the Kaplan-Meier method, whereas Cox Regression models were used to estimate hazard ratios and the chi-square test for categorical variables.
A total of 169 patients were enrolled in the study: 80 received a PPI and 86 did not, without significant differences in clinical characteristics in both groups. The median PFS was 17.3 months (95% CI: 13.83-20.76), 36 months in first-line and 13 months in second and subsequent lines. Patients taking PPIs had a shorter median PFS (14.30 versus 42.6 months, p<0.001; HR 4.18: 95% CI 2.57-6.80; p<0.0001). Median PFS was 44 vs. 14 months in first-line ans 17 vs 9 months in second or subsequent lines. The line of treatment (first vs second or beyond) and ki67 had a significant influence on DFS, whereas the remaining clinical variables did not.
Patients with mBC treated with hormonal therapy plus palbociclib had poor PFS when receving a concomitant PPI. Although further studies are needed in the field, caution is recommended with the long-term use of PPIs in this population.
The authors.
Has not received any funding.
J. Álvarez Criado: Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Lilly. All other authors have declared no conflicts of interest.
Taxane-based therapy is commonly applied in patients with advanced breast cancer (BC). It is often accompanied with serious symptomatic adverse events (AEs) which can deteriorate patients’ quality of life (QoL). Eribulin is a non-taxane microtubule inhibitor with respect to less symptomatic AEs and prolonged overall survival. Here, we report the analysis of QoL based on PRO before and after initiating Eribulin in patients with advanced BC intolerant to taxane-based therapy.
Patients with advanced BC intolerant to taxane-based first/second-line therapy were screened from multi-centers in China. The PRO was measured by the well-validated taxane-based EORTC QLQ-C30 questionnaire at baseline and at 2 cycles after initialing Eribulin treatment. The questionnaire includes scales for four symptomatic AEs of microtubule therapy (peripheral neurotoxicity, nausea/vomiting, pain, insomnia) and a global health status for QoL (GHS/QoL).
Of the 333 enrolled patients, 152 with triple-negative BC, 122 with HR+/HER2- BC, and 59 with HER2+ BC. Significant improvement in all symptomatic AEs and the GHS/QoL (
The measurements for PRO indicated great improvement on QoL after switching to Eribulin in patients with advanced BC who previously received taxane-based therapy, irrespective of the pathological type and the combination of other chemotherapy regimens. Eribulin is reasonable to be applied in patients with advanced BC intolerant to taxane-based therapy.
Dimensions Baseline Post-treatment Peripheral neurotoxicity 57.9±20.3 34.3±15.6 <0.001 Nausea/vomiting 58.0±20.7 34.5±16.3 <0.001 Insomnia 58.2±20.2 35.1±19.1 <0.001 Pain 56.1±20.0 35.9±15.5 <0.001 Global health status 33.7±22.5 58.3±29.4 <0.001
The author.
Has not received any funding.
All authors have declared no conflicts of interest.
CDK4/6 inhibitors are standard of care at 1st and 2nd line for hormone receptor positive (HR+), human epidermal growth factor 2 negative (HER2-) advanced/metastatic breast cancer (ABC/MBC). Abemaciclib (ABE) was first authorized and available in 2018 via patient access schemes before approval for routine use by the National Institute for Health and Care Excellence (NICE). This study aims to assess treatment patterns and clinical benefit of ABE in a real-world setting.
A multicenter retrospective observational chart review was undertaken of women in the United Kingdom (UK) with HR+, HER2- ABC/MBC treated with ABE-containing regimens during 07/2021 to 05/2022 and with 3 months’ follow-up data post-ABE initiation, including those who may have received ABE via a commercial free access scheme. Descriptive statistics were used to summarize treatment, and outcomes (tumor response and progression free survival; PFS). Kaplan-Meier methods were used to estimate PFS with 95% confidence intervals (CIs).
174 adult women from 9 institutions across the UK were included. Median patient age at ABE initiation was 65.2 years. The majority (90%) had an ABE starting dose of 150mg twice daily. ABE was 1st, 2nd, 3rd, 4th, or 5th+ line treatment for 45.4%, 26.4%, 12.6%, 6.9% and 8.6% of patients, respectively. Hormone therapies given in combination with ABE were fulvestrant (81%) and aromatase inhibitors (AIs; letrozole or anastrozole [19%]). Best tumor response (136 patients); 0.7% had complete response, 27.9% had partial response, 59.6% had stable disease and 11.8% had disease progressed. Median PFS was 21.9 months across all patients (95% CI 19.4 months–not reached), with 1-year PFS rate of 81.1% (1st line), 68.2% (2nd line) and 58.2% (3rd line).
ABE, used in different treatment lines (including later lines in more heavily pretreated patients (≥3rd line)) in combination with fulvestrant or AIs, was associated with a median PFS of 21.9 months in a UK real-world setting. These data are comparable to those from clinical trials supporting the benefit of ABE in patients with HR+, HER2- ABC/MBC.
IRAS Project ID: 292980.
Protocol Number: 2019-8661.
REC Reference: 21/YH/0061.
CPMS ID 47932 HRA approval granted on 11 March 2021.
Eli Lilly and Company Ltd. Indianapolis, IN, USA.
Eli Lilly and Company Ltd.
J.W. King: Non-Financial Interests, Personal, Advisory Board: Roche, Eli Lilly and Company, Novartis, Bristol Myers Squibb, Exact Science, Prosigna, Gilead, Eisai, AstraZeneca, Seagen; Non-Financial Interests, Personal, Invited Speaker: Roche, Eli Lilly and Company, Novartis, Bristol Myers Squibb, Prosigna, AstraZeneca, Seagen. W. Fakhouri: Non-Financial Interests, Institutional, Full or part-time Employment, Employee and shareholder of Eli Lilly and Company: Eli Lilly and Company; Financial Interests, Personal and Institutional, Stocks/Shares, Employee and shareholder of Eli Lilly and Company: Eli Lilly and Company. R.S. Jarvis: Non-Financial Interests, Institutional, Full or part-time Employment, Employee and shareholder of Eli Lilly and Company: Eli Lilly and Company; Financial Interests, Personal and Institutional, Stocks/Shares, Employee and shareholder of Eli Lilly and Company: Eli Lilly and Company. W. Badreldin: Non-Financial Interests, Institutional, Full or part-time Employment, Employee and shareholder of Eli Lilly and Company: Eli Lilly and Company; Financial Interests, Personal and Institutional, Stocks/Shares, Employee and shareholder of Eli Lilly and Company: Eli Lilly and Company. G. Harper: Non-Financial Interests, Institutional, Sponsor/Funding, Employed by Adelphi Real World, who received funding from Eli Lilly and Company to complete study: Eli Lilly and Company. L. Bateman: Non-Financial Interests, Institutional, Sponsor/Funding, Employed by Adelphi Real World, who received funding from Eli Lilly and Company to complete study: Eli Lilly and Company. C. Palmieri: Financial Interests, Institutional, Research Grant: Pfizer, Daiichi Sankyo, Seagen, Gilead, Exact Science; Non-Financial Interests, Personal and Institutional, Advisory Board: Pfizer, Roche, Daiichi Sankyo, Seagen, Gilead, Exact Science, Eli Lilly and Company, Novartis; Non-Financial Interests, Personal and Institutional, Other, Support for travel and conferences: Roche, Novartis, Gilead. M. Nathan: Financial Interests, Personal and Institutional, Invited Speaker: Roche, Seagen, AstraZeneca, Eli Lilly and Company; Financial Interests, Personal, Invited Speaker: Novartis, Pfizer; Financial Interests, Institutional, Invited Speaker: Merck Sharp and Dohme.
CDK4/6 inhibitors combined with endocrine therapy are now first-line of treatment in metastatic hormone positive Her2 negative breast cancer – unless visceral crisis is present. Palbociclib, ribociclib and abemaciclib all showed significant PFS benefit. Our research focused on real life survival data of these drugs.
A total of 97 metastatic HR+/Her2- breast cancer female patients were selected from our database who received CDK 4/6 inhibitors plus letrozole first-line treatment. Treatment was initiated between 2018-2021. Due to low number of patients receiving abemaciclib at that time, only palbociclib and ribociclib was included in this interim analysis. Median age of patients was 60 years. Patients were stratified according to CDK 4/6 partner (palbociclib or ribociclib), level of estrogen receptor expression (0-50 vs 50-80 vs 80-100%) and MIB1 labeling index (0-20% or above 20%). Location of metastases was also considered (bone-only or visceral metastases). Primary end point was PFS, with a total of 53 occurred events until first primary analysis.
PFS was 23.71 months, similar to those of PALOMA-2 and MONALEESA-2. No statistical difference was found between the mPFS of palbociclib and ribociclib subgroups. ER expression was found to be correlated with mPFS, patients with lower levels of ER expression had significantly shorter mPFS (16.54 vs 23.71 vs 53.54 months). mPFS was better in patients with bone-only disease (53.54 vs 23.71 months). However, in the subgroup of patients with high ER expression, mPFS was found to be very similar among patient with bone-only and visceral disease (53.54 vs 66.29 months). MIB1 labeling index seems to affect mPFS as well, as patients with a higher initial MIB1 index have better mPFS (21.68 vs 28.82. months). This difference seems to be even more profound in patients with visceral disease (20.0 vs 39.61 months).
Real-world data of patients receiving palbociclib or ribociclib in combination with letrozole show that these CDK4/6 inhibitors are more effective in patients with higher ER expression. MIB1 expression also seem to be correlated with mPFS, patients with higher MIB1 have better prognosis, although more research is needed.
University of Debrecen Faculty of Medicine Department on Oncology.
Has not received any funding.
All authors have declared no conflicts of interest.
Activation of the phosphatidylinositol-3-kinase (PI3K) pathway is responsible of activating the phosphorylation cascade that regulates cell survival and metabolism. Mutations in this pathway may occur in 28-46% of HR+/HER2- advanced breast cancers. It is known that the presence of this mutation confers a worse prognosis. We set out to analyze if PI3K mutations in different exons confer resistance to treatments directed against this target and to cyclin inhibitors (inh-CDK4/6).
We have analyzed 96 patients with advanced breast cancer HR+/HER2- subsidiaries of treatment with PI3K-targeted therapy in the hospital of Jaén from February/20 to January/23. To detect PIK3CA mutations we used the cobas ® diagnostic kit that detects: exons 1 (R88Q), 4, 7 (C420R), 9 (E542K, E545K/A/D/G, Q546E/R) and 20 (H1047R/Y/L).
We obtained 26% mutations in PI3K (5% exon 1, 40% exon 9, 55% exon 20). All in women with a mean age at diagnosis of 48 years and 56 at diagnosis of metastases, located at bone 65%, lung 35%, liver 23% and CNS 4% All patients have been treated with inh-CDK4/6. The median progression-free survival (mSLP) is 17 months (1-60). In patients with exon 1 mutation, mSLP is 25 months, in exon 9, 13 (2-43) and in exon 20, 19 (1-60) 60% of the patients have progressed to inh-CDK4/6 and as next treatment we used alpelisib. In 58% corresponds to 2 line in metastatic disease. The mSLP is 5 months (1-22) with a median follow-up of 14 months (1-34) and 69% of events. In patients with mutation in exon 1 the mSLP is 2 months, in exon 9, 5 (1-13) and in exon 20, 9 (2-22). Treatment was associated with an antiestrogen (77%) with a mSLP 7 months (1-22) or an aromatase inhibitor with a mSLP 3 months (2-10). 53% suffered grade 3 adverse effects (G3 AE): hyperglycemia (80% exon 9, 16% exon 20), diarrhea (20% exon 9) and skin rash (16% exon 20). 14% discontinued treatment due to toxicity.
The PFS with alpelisib is lower than reported in the SOLAR1 study and is similar to Bylieve study, whose population is most similar to our sample. Exon 20 carriers are those who obtain a higher PFS, as well as those who receive it with an antiestrogen. Exon 9 carriers have a higher rate of G3 AE With respect to inh-CDK4/6, the PFS corresponds to the literature, with exon 20 carriers obtaining a higher PFS.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) are the standard of care treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- aBC). However, optimal treatment after progression on CDK4/6i has not been established and real-world data may help to fill this knowledge gap.
Two hundred twenty-one patients with HR+/HER2- aBC treated with CDK4/6i plus ET at Medical Oncology and Breast Unit of ASST Spedali Civili Brescia from November 2017 to February 2023 were retrospectively evaluated. The main aim of the study was to evaluate clinical benefit rate (CBR) of the subsequent lines of therapy after CDK4/6i. Secondary aims were to report objective response rate (ORR) and progression-free survival (PFS).
Median age was 60 years. CDK4/6i were administered as first-line therapy in 26.2%, as second-line in 40.3%, and as a third or further line in 33.5% of patients. After a median follow-up of 30.5 months, 126 patients (57%) experienced a disease progression and had a median PFS of 14.3 months: the most common sites of disease progression were liver (42%), bone (31.7%), and lungs (12%). A total of 112 patients received a further line of treatment: 13.4% received ET monotherapy (either fulvestrant or aromatase inhibitor), 13.4% ET plus target therapy (such as an mTOR inhibitor), 42% metronomic chemotherapy (CT), and 31.2% received intravenous CT (either anthracyclines, taxanes, eribulin, or other drugs). A higher CBR was noted in patients receiving metronomic CT, in comparison to intravenous CT and ET with or without target therapy (51.9% vs 31.5% vs 16.7%, respectively, p = 0.04). Median PFS after CDK4/6i was 9 months (5.93-12.06). Associations between ORR after CDK4/6i and patients’ clinical characteristics will be presented at the meeting.
These single-center retrospective data suggest that CT, in particular metronomic CT, may show better favorable outcomes after progression on CDK4/6i. Evidence from prospective, randomized clinical trial is warranted.
Oncologia Medica - ASST Spedali Civili Brescia.
Has not received any funding.
R. Pedersini: Financial Interests, Institutional, Research Grant: Novartis, Seagen; Financial Interests, Personal and Institutional, Advisory Board: Eli Lilly. A. Berruti: Financial Interests, Personal, Advisory Board: Amgen, Astellas, Janssen, Ipsen; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker, Public speaking in international webinar: HRA; Financial Interests, Institutional, Funding: Astellas, Janssen; Non-Financial Interests, Institutional, Product Samples: Sanofi, Novartis. All other authors have declared no conflicts of interest.
Approximately 30%-%0% of patients with HER2-positive breast cancer will develop central nervous system (CNS) metastasis. Trastuzumab deruxtecan (T-DXd) is known to have clinically relevant activity in HER2- positive metastatic breast cancer (MBC) patients who have progressed on prevsious lines of treatment. DESTINY-Breast01 and DESTINY-Breast03 highlighted the intracranial response and long-lasting clinical activity of T-DXd in HER2- positive MBC patients. In this study we aim to assess the response in the CNS in our Irish population on T-DXd.
We performed a restrospective chart review of patients with MBC receiving treatment with T-DXd in 5 cancer centres in Ireland between 2020 and 2023. A subgroup analysis of patients with CNS metastasis was performed to assess patient response within the CNS.
A total of 64 patients were identified as receiving treatment with T-DXd for MBC in 5 cancer centres. Of these, 27 (41%) patients had CNS involvement, 26 had intracranial metastasis and 1 had leptomeningeal disease. The average age of this cohort was 54.5 years. All patients were HER2 positive with 24 (89%) positive by immunohistochemistry (3+ staining) and two patients positive by florescent in situ hybridization. Sixteen (59%) patients were hormone receptor positive. The average number of previous lines of treatment in the metastatic setting was 3.7(including trastuzumab, pertuzumab, docetaxel, capecitabine Neratinib, gemcitabine and lapatinib). A total of twelve (44%) patients had a response in the CNS (11 partial response and 1 complete response). Two patients (7%) had stable disease. Seven (26%) had progression of disease. Data was unavailable for 6 patients who are awaiting restaging.
In this cohort the response rate of 44% is comparable to that seen in the DESTINY Breast01 subgroup analysis which showed a response rate of 58%. T-DXd continues to show a significant response rate in this important population of patients.
The Authors.
Has not received any funding.
All authors have declared no conflicts of interest.
A meta-analysis of all Ph3 trials with CDKi plus endocrine therapy (ET) has established 13% incidence of LT of any grade (vs 5.4% with ET alone). However, the clinical characteristics of these pts and the predictive factors associated with developing LT remain unknown.
All MBC pts treated with first-line CDKi in Vall d’Hebron Hospital from 2018 to 2022 were analyzed retrospectively. LT was defined as ≥G2 AST/ALT elevation. Clinical and laboratory characteristics, oncologic disease status, and evolution of liver function tests for those pts were registered.
Among 472 pts treated, 26 (5.5%) developed LT, G2 in 11 (42%), G3 in 13 (50%) and G4 in 2(8%) without LT related-deaths. LT occurred in 3%, 8% and 11.6% of pts receiving palbociclib, abemaciclib and ribociclib, respectively. Baseline characteristics: median (M) age 61y, premenopausal 54%, overweight/obese 59%, 11.5% alcohol consumers, 27% current/former smokers, 27% stage IV
Characteristics Palbociclib Abemaciclib Ribociclib LT pts/Total pts 8/283 9/112 9/77 M days until LT 116 63 98 LT resolved 87% 75% 100% M days to resolution 28 26 46 Relapse of LT 20% 75% 66% M days until relapse 14 20 11
In our cohort of pts 5.5% developed LT. LT reached G3 in 58% of cases, mainly with ribociclib. A high proportion of those pts had ≥25 BMI and 31% had liver steatosis. LT was mainly reversible with no fatal cases. These results could help to develop prediction scores to identify patients at risk of developing severe LT.
Kreina Sharela Vega Cano.
Has not received any funding.
O. Mirallas: Financial Interests, Personal, Invited Speaker: ROVI, Roche; Financial Interests, Institutional, Invited Speaker: Merck; Other, Travel Expenses: Kyowa kirin, Almirall; Other, Travel Expenses and Conference Fee: Sanofi. E. Zamora: Financial Interests, Personal, Invited Speaker, Review session for medical oncologists: Eisai, Lilly; Other, Registration to ESMO Congress 2022 (virtual): Novartis; Other, Registration to: Eisai. M. Cruellas Lapena: Financial Interests, Institutional, Invited Speaker: ROCHE. C. Saura Manich: Financial Interests, Personal, Advisory Board: AX'Consulting, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd., Gilead, ISSECAM, Lilly, MediTech, Medical Statistics Consulting, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, Seagen, Solti, Zymeworks, Pharmalex Spain SLU; Financial Interests, Personal, Expert Testimony: AX's Consulting SARL, Boehringer Ingelheim, Bristol Meyers Squibb, INDITEX, Merck Sharp & Dohme España, Novartis, SACE Medhealth SL, Simon Kucher &Partners SL, Genentech, Innoup, Millenium, Sanofi, Seattle Genetics; Financial Interests, Personal, Other, SC: Byondis B.V., German Breast Group, Glaxo, International Breast Cancer Study Group (IBCSG), MacroGenics, Medsir, Menarini, Merus, Merus, Netherlands Cancer Institute (NKI), Queen Mary (University of London), Seagen, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, GlaxoSmithKline, MacroGenics, Immunomedics, Innoup Farma, International Breast Cancer Study Group (IBCSG), Medica Scientia Innovation Research, Menarini Ricerche, Merus, Novartis, Pfizer, Puma, Roche, Sanofi-Aventis, Seattle Genetics, SOLTI; Financial Interests, Institutional, Invited Speaker: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), SOLTI group (Academic research group in breast cancer), Geicam (Spanish Breast Cancer Research Group), American Association for Cancer Research (AACR). M. Bellet-Ezquerra: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Lilly, Stemline-Menarini; Other, Speaker'sBureau and Travel Expenses: Pfizer; Other, Speaker's Bureau: Novartis, Lilly. All other authors have declared no conflicts of interest.
The considering both various studies and the EBCTCG meta-analysis, it is reported that the therapeutic effect is correlated with the rate of ER positivity in breast cancer patients receiving endocrine therapy.In this study, it was aimed to evaluate the effect of the percentage of HR positivity on treatment response and prognosis in patients with HR+ HER2- MBC who received CDK 4/6 inhibitor with ET.
In the study, patients who were followed up and treated in Dokuz Eylul University Medical Oncology Department between January 2020-December 2022, diagnosed with HR+ HER-2- MBC and treated with ET (anastrazole, exemestane, fulvestrant, letrozole)+ CDK 4/6 inhibitor (palbociclib and ribociclib) were evaluated retrospectively. Patients with >18 years were included in the study. Appropriate statistical analyzes were used.
The median age at diagnosis of 149 patients included in the study was 55.0 years (26.2-90.2).51.3% (n=77) of the patients were denovo metastatic, and 64% of the patients received CDK 4/6 inhibitor + ET as the first two-line therapy. 18% (n=27) of the patients progressed. 90.7% (n=136) of the patients were still alive. Mean PFS was 26.1 months (95%CI; 22.0-30.2) and mean OS was 34.3 months (95%CI; 31.4-37.2). When we evaluated PFS according to ER positivity rate, the group with ER>50% had numerically longer mean PFS (26.2 months vs. 20.3 months, respectively, p=0.430). Similarly, in the group with ER >50% in OS, the OS was numerically longer, 24.9 versus 34.6 months (p=0.222).When we evaluated the disease control rate (DCR), although it was not statistically significant, DCR was numerically higher in the group with ER>50% as a 81.1% versus 73.7% (p=0.314). While the survival rate was most highest in the group with ER >50%/PR >50% as a 93%, the survival rate was most lowest in the ER 10-49%/ PR negative group as 85.7% (p=0.640).
In conclusion, to the best of our knowledge, this study showed for the first time in the literature that the percentage of hormone receptor positivity has a predictive and prognostic role in HR+ HER-2 MBC patients who were treated with ET with CDK 4/6 inhibitor. The percentage of HR positivity is also important at these patient.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
There is limited data on the effect of CDK 4/6 inhibitors in the patients with advanced HR-positive and HER2-low tumors.
Here we report real-life data retrospectively collected from 448 patients with ER-positive/HER2-negative advanced breast cancer treated with ribociclib and palbociclib (only both of them reimbursed) plus endocrine therapy from June 2016 to June 2022. The outcome of the patients with HER2-0 (IHC score) and HER2-low (HER2 IHC score1+ and 2+) tumors were compared.
443 of the patients were female (98.9%). Median age was 58 (25-90). While the HER2 IHC score was 0 in 295 of the patients (65.8%), the HER2 IHC score was 1-2 (HER2-low) in 153 patients (34.2%). Median OS could not be calculated at follow-up, with an estimated 71% of patients alive at 36 months. The median PFS was 29.4 months (95 CI, 16.3-42.6). mPFS in the HER2-negative patient group was 27.7 (95% CI, 11.2-44.2) months and there was no significant difference in mPFS for patients receiving palbociclib or ribociclib in this subgroup (p=0.11). There were 117 patients in the IHC 1 positive subgroup of HER2-low patients, and 22 patients had disease progression. mPFS was NE (at 12 months, 82% of patients and at 24 months, 57% of patients were progression free). There were 36 patients in the IHC 2 positive subgroup of HER2-low patients, and 6 patients had disease progression. mPFS was NE (at 12 months, 72% of patients were progression free). No significant difference was found between patient population with HER2-negative, HER2 IHC 1+ and HER2 IHC 2+ and ISH negative tumors in terms of mPFS (p=0.163). In addition, when evaluated separately in IHC 1 positive and IHC 2 positive subgroups, there was no significant difference in terms of mPFS in those treated with palbociclib and ribociclib (p=0.50 and p=0.70, respectively).
Although the number of patients decreased when subdivided in our study, real-life data showed that HER2-low expression did not show a statistically significant impact on survival in patients treated with ribociclib and palbociclib in the metastatic first-line setting.
Turkish Oncology Group Study.
Has not received any funding.
All authors have declared no conflicts of interest.
Endogenous tumor necrosis factor-α (TNF-α) has known anti-tumor effects; however, its activity is inhibited by soluble TNF receptors (sTNF-R1, -R2) produced by tumors. Systemic administration of recombinant TNF-α is limited due to unacceptable toxicity (except in isolated limb perfusion). Triple-negative breast cancers, including those with BRCA1/2 mutations, are candidates for novel immunotherapies. This study used extracorporeal apheresis (Immunopheresis) with the LW-02 Column to selectively remove sTNF-Rs from plasma to promote TNF-α’s anticancer action resulting in objective tumor responses.
This trial [NCT04004910] evaluated column performance (removal of sTNF-Rs), safety, and clinical efficacy (via RECIST 1.1) of LW-02 Column Immunopheresis in advanced breast cancer patients who failed 2 or more lines of systemic therapy. The trial enrolled 46 patients, 3 with germline BRCA1 mutations. Patients received LW-02 Column Immunopheresis 3x/week, as monotherapy or combined with chemotherapy for 16 weeks (or longer if patients were stable or improved clinically). Each treatment processed up to 2 plasma volumes.
Column performance data (from a prior data cutoff for 1700 procedures) found median reductions of sTNF-Rs from plasma after 30-minutes of Immunopheresis of 95.6% and 82.2% for sTNF-R1 and sTNF-R2, respectively. Safety and efficacy results are from data through 31 January 2023. About safety, of 665 AEs, 22 (3.3%) were deemed to have had a causal relationship to treatment with the LW-02 Column (including 2 SAEs). Median treatment durations were 9.7 and 14.5 wks for all patients and for patients treated ≥4 wks, respectively (and 55.9 wks for the subset of 3 patients with confirmed BRCA1 mutations, 2 are still being treated). Similarly, median OS was 17.9 and 27.6 and 55.9 wks for the same groups. CBR results for patients treated ≥4 wks was 39% and 67% for the 3 BRCA1 patients (the latter reflecting 1 CR and 1 PR).
LW-02 Column Immunopheresis is safe and effectively removes sTNF-Rs from advanced breast cancer patients and contributes to efficacy improvements. Additional trials will examine its role in patients with BRCA1 mutations and other tumor profiles.
NCT04004910.
Immunicom, Inc.
Immunicom, Inc.
P.J. Wysocki, P. Tomczak, T. Jankowski, T. Nowikiewicz: Financial Interests, Personal and Institutional, Principal Investigator: Immunicom, Inc. V. Manax, L. Florin, R. Segal, K.M. Djazouli, S. Bilgrami, A. Marleau, A. Ostrowski: Financial Interests, Personal, Full or part-time Employment: Immunicom, Inc.
ILC is the second most common BC type after the invasive carcinoma of no special type (NST). It mostly presents as estrogen receptor (ER) and progesterone receptor (PR) positive, human epidermal growth receptor 2 (HER2) negative and with a low marker of proliferation (Ki67) which results in a luminal A subtype and E-cadherin loss. Additionally, it appears to have a metastatic pattern that differs from the NST. This registry study aims to show clinical and pathological parameters in patients with early and advanced ILC.
Clinical and pathological data of 683 patients diagnosed with ILC were retrospectively collected and descriptively analyzed. Of these, 206 patients (30.2%) subsequently developed a local recurrence and/or distant metastasis.
The majority of ILC patients presented with low Ki67, positive ER and PR, HER2-negativity and an intermediate grade tumor. E-cadherin loss was detected in 96.2% (n=427, 256 unknown). In summary, 0.4% of patients exhibited a pTis, 45.7% a pT1, 37.3% a pT2, 15.5% a pT3 and 1.1% a pT4 tumor (n=451, 26 unknown), while 68% of patients had pN0, 20.3% pN1, 7.3% pN2 and 4.3% pN3 status (n=438, 39 unknown). ILC tumors with a subsequent metastatic event initially showed similar data to non-metastatic tumors, although metastatic tumors have the highest rate in pT2 with 44.4% but 39.2% presented with pN0 in. Distant metastases were detected at the following sites: bones (43.7%; n=90), local recurrence (33.4%; n =69), peritoneum (12.6%; n=26), liver (11.2%; n=23), gynecological metastasis (10.7%; n=22) (multiple sites per person possible). Patients who progressed showed a slightly different profile, with a particular increase in cerebral lesions (24%, n=24).
This registry study summarizes histopathological data of ILC patients and shows a high rate of metastatic events despite initially good prognostic factors. The metastatic sites in this cohort resemble other studies and differ from NST in the frequency of visceral metastasis or metastasis inside the abdominal cavity (28.2%, n=58) in our cohort. This should be taken into consideration for planning surveillance for ILC patients in survivorship care.
AG Karsten-Speiser, Department of Gynecology with Breast Center, Charité - Universitätsmedizin Berlin.
Has not received any funding.
P. Jank: Financial Interests, Personal and Institutional, Stocks/Shares: Myriad Genetics Inc. M.M. Karsten: Financial Interests, Personal, Invited Speaker: Roche, Gilead, Sysmex. All other authors have declared no conflicts of interest.
Eftilagimod alpha (efti), a soluble LAG-3 protein, acts as an MHC class II agonist that enhances immunity by mediating antigen presenting cell and CD8 T-cell activation. Data from a randomized, phase IIb trial of efti plus paclitaxel compared to placebo plus paclitaxel in patients (pts) with HR+ HER2– metastatic breast cancer (MBC) (AIPAC; NCT02614833) showed sustained pharmacodynamic activity that was linked to improved overall survival (OS) in the efti arm. AIPAC-003 is a randomized, double-blind, placebo-controlled phase III trial testing efti plus paclitaxel in HER2-neg/low MBC pts, including an initial open-label dose optimization lead-in (DOL) component to determine the optimal biological dose (OBD) of efti in this combination.
Enrolment for the DOL will begin in March 2023 in max. 66 pts. Primary endpoints (EP) in the DOL include safety and tolerability of 90 mg vs 30 mg efti and defining the OBD of efti in combination with weekly paclitaxel. Determination of the OBD will be based on the totality of safety and tolerability data together with overall response rate (ORR) and pharmacodynamic marker (CD8+ T cells, absolute lymphocyte count) data. In the phase III component approx. 771 pts will be randomized to receive either paclitaxel + efti or paclitaxel + placebo in a double-blinded fashion. The primary EP for the proposed phase III is OS. Key secondary EPs include progression free survival and ORR by RECIST 1.1, quality of life and safety. Pts will receive paclitaxel (80 mg/m2 I.V. on D1, 8 and 15 in a 4-week cycle), in combination with efti or placebo (DOL: 30 or 90 mg efti; Phase III: OBD of efti or placebo) S.C. on D1 and 15 in a 4-week cycle for up to 12 months. Key inclusion criteria: Pts with either a) HR+ and HER2-neg/low and endocrine therapy-resistant MBC or b) TNBC not eligible for anti-PD-1-based therapy. Pts must have measurable disease, ECOG PS 0-1 and no prior chemo for metastatic disease.
Immutep S.A.
Immutep S.A.
F.P. Duhoux: Other, Consulting or Advisory: Roche,Pfizer, AstraZeneca, Lilly, Novartis, Amgen, Daiichi Sankyo, Pierre Fabre, Gilead Sciences, Seattle Genetics, MSD Oncology; Other, Travel, Accommodations, Expenses: Amgen, Roche, Teva, Pfizer, Daiichi Sankyo/AstraZeneca. M. Oliveira: Other, Consulting or Advisory Role: Roche/Genentech, AstraZeneca, Seattle Genetics, ITeos Therapeutics, Daiichi Sankyo/AstraZeneca, Gilead Sciences, Relay Therapeutics; Other, Travel, Accommodations, Expenses: Eisai, Pierre Fabre, Gilead Sciences, AstraZeneca Spain; Other, Honoraria: Roche, Novartis, Pfizer, MSD, Eisai Europe, Seattle Genetics, Gilead Sciences; Other, Research Funding: Roche/Genentech, AstraZeneca, Seattle Genetics, Boehringer Ingelheim, GlaxoSmithKline, Zenith Epigenetics, Gilead Sciences, Ayala Pharmaceuticals. J. Peguero: Other, Employment: Oncology Consultants; Other, Leadership Role: Director, Research Department. F. Triebel: Other, Employment: Immutep SAS; Other, Stock and Other Ownership Interests: Immutep Ltd.; Other, Patents, Royalties, Other Intellectual Property: Being an inventor on patents on LAG-3 owned by Immutep SAS. All other authors have declared no conflicts of interest.
ARV-471 is an oral PROTAC ER degrader that binds to and degrades both wild-type ER and
Eligible pts (aged ≥18 years) have histologically or cytologically confirmed ER+/HER2- metastatic, recurrent, or unresectable breast cancer; received 1–3 prior lines systemic therapy in the advanced/metastatic setting, including ≥1 endocrine therapy and ≤1 chemotherapy; and progression on or intolerance to a CDK4/6 inhibitor. Pts may not have received prior ARV-471 or an mTOR-targeting therapy. ARV-471 combined with everolimus is administered orally in 28-day cycles. The primary endpoints are dose-limiting toxicities to determine the recommended phase II dose for ARV-471 in combination with everolimus, and type, frequency, and severity of adverse events and laboratory abnormalities. Secondary endpoints are preliminary antitumor activity (overall response rate, clinical benefit rate, and duration of response) and pharmacokinetic parameters of ARV-471 plus everolimus.
NCT05501769.
Medical writing support: Justine Lempart, PhD, of Apollo Medical Communications, and funded by Arvinas Operations, Inc.
Arvinas Estrogen Receptor, Inc.
Arvinas Estrogen Receptor, Inc.
A. Schott: Financial Interests, Personal, Other, Contracted Research: Pfizer, Takeda, Genentech, Arvinas; Financial Interests, Personal, Other, Receipt of Intellectual Property Rights/Patent Holder: Imbio, LLC. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp& Dohme, GSK, Leuko, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardant Health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca. S. Ivie: Financial Interests, Personal, Full or part-time Employment: Arvinas Operations, Inc. R. Gedrich: Financial Interests, Personal, Full or part-time Employment: Arvinas Operations, Inc.; Financial Interests, Personal, Stocks/Shares: Arvinas Operations, Inc. E. Zhi: Financial Interests, Personal, Full or part-time Employment: Arvinas; Financial Interests, Personal, Stocks/Shares: Arvinas; Financial Interests, Personal, Project Lead: Arvinas. J. Ranciato: Financial Interests, Personal, Full or part-time Employment: Arvinas. J. Perkins: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Other, Patent Holder: Pfizer. E. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, Arcus, AstraZeneca, Daiichi Sankyo, Seagen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Immunomedics, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, FujiFilm, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, InventisBio, Verastem, eFFECTOR Therapeutics, CytomX, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Jacobio, Atlas MedX, Ellipses, Incyte, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Cascadian Therapeutics, Artios, BeiGene, Bliss BioPharmaceuticals, Context Therapeutics, Cullinan-Florentine, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Relay Therapeutics, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Tolmar, Torque Therapeutics. All other authors have declared no conflicts of interest.
ARV-471 is an oral PROTAC ER degrader that binds to and degrades wild-type ER and clinically relevant mutants. ARV-471 directly recruits the ubiquitin-proteasome system to degrade ER, whereas selective ER degraders (SERDs) indirectly cause ER degradation. In a first-in-human phase I/II study, ARV-471 monotherapy was well tolerated and showed clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer. The phase III monotherapy dose (200 mg once daily [QD]) was chosen due to comparable efficacy and favorable tolerability relative to 500 mg QD and robust ER degradation in paired tumor biopsies. The randomized phase III VERITAC-2 study (NCT05654623) will compare efficacy and safety of ARV-471 vs the SERD fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy and endocrine therapy (ET).
Eligible patients (aged ≥18 years) have a confirmed diagnosis of ER+/HER2- locoregional recurrent or metastatic breast cancer not amenable to surgical resection or radiation; 1 prior line of combination CDK4/6 inhibitor therapy and ET; ≤1 additional line of ET; most recent ET given for ≥6 months before disease progression; and radiological disease progression during or after the last line of therapy. Prior chemotherapy in the locally advanced or metastatic setting and prior fulvestrant are not permitted. Patients (N∼560) are randomized 1:1 to receive 200 mg ARV-471 orally QD continuously or fulvestrant intramuscularly on days 1 and 15 in the first 28-day cycle and on day 1 in subsequent cycles; patients are stratified by
NCT05654623.
Medical writing support: Justine Lempart, PhD, of Apollo Medical Communications, and funded by Arvinas Operations, Inc.
Arvinas Estrogen Receptor, Inc.
Arvinas Estrogen Receptor, Inc.
E. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, Arcus, AstraZeneca, Daiichi Sankyo, Seagen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Millennium, Rgenix, Arqule, Clovis, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, FujiFilm, Novartis, Boehringer Ingelheim, Immunomedics, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, InventisBio, Verastem, eFFECTOR Therapeutics, CytomX, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Jacobio, Atlas MedX, Ellipses, Incyte, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals, Cascadian Therapeutics, Context Therapeutics, Cullinan-Florentine, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Relay Therapeutics, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Tolmar, Torque Therapeutics. C.X. Ma: Financial Interests, Personal, Other, Consulting Fees: Olaris, Novartis, Gilead, AstraZeneca, Sanofi-Genzyme, Biovica, Jacobio, Natera, Inivata, Athenex, Bayor, OncoSignal; Financial Interests, Personal, Other, Research Funding: Pfizer, Puma; Financial Interests, Personal, Research Grant: Arvinas. M. De Laurentiis: Financial Interests, Personal, Other, Consulting: Roche, Novartis, Pfizer, Lilly, Amgen, AstraZeneca, MSD, Pierre Fabre, Seattle Genetics, Gilead Sciences, Ispen, Takeda, Genzyme; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Royalties: Roche, Novartis, Pfizer, Lilly, Amgen, Pierre Fabre, AstraZeneca, MSD, Seattle Genetics, Gilead Science, Takeda, Ispen; Financial Interests, Personal, Research Grant: Novartis, Roche, Puma Biotechnology, Lilly, Pfizer, Daiichi Sankyo, MSD, Macrogenics, Bristol Myers Squibb, Genzyme, AstraZeneca, Eisai. H. Iwata: Financial Interests, Personal, Advisory Board: Chugai, Daiichi Sankyo, AstraZeneca, Lilly, Sanofi; Financial Interests, Personal, Invited Speaker: Chugai, Daiichi Sankyo, AstraZeneca, Lilly, Pfizer, Sanofi, Taiho; Financial Interests, Personal and Institutional, Invited Speaker: Chugai, Daiichi Sankyo, AstraZeneca, MSD, Amgen, Sanofi, Lilly, Novartis, Bayer, Pfizer, Kyowa Hakko Kirin, Behringer, Nihon Kayaku. S.A. Hurvitz: Financial Interests, Personal, Research Grant: Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, Cytomx, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, OBI Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics/Seagen, Zymeworks; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, AstraZeneca. S.A. Wander: Financial Interests, Personal, Advisory Board, Consulting: Foundation Medicine, Veracyte, Hologic, Biovica, Eli Lilly, Pfizer, Puma Biotechnology; Financial Interests, Personal, Invited Speaker: 2ndMD, Elli Lilly, Guardant Health; Financial Interests, Personal, Research Grant: Genentech, Eli Lilly, Pfizer, Nuvation Bio, Regor Therapeutics. M.A. Danso: Financial Interests, Personal, Advisory Role: Novartis, Pfizer, Immunomedics, Seattle Genetics; Financial Interests, Personal, Royalties: Amgen. D.R. Lu, Y. Liu, L. Tran: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. J. Perkins: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Royalties: Pfizer. S. Anderson: Financial Interests, Personal, Full or part-time Employment: Arvinas Operations, Inc.; Financial Interests, Personal, Stocks/Shares: Arvinas Operations, Inc. M. Campone: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Sanofi, Lilly, Pfizer, Seagen, Gilead, Daiichi Sankyo; Financial Interests, Personal, Other, Consultant: Sanofi, Novartis, Daiichi Sankyo, PET-Therapy, Menarini, Diaccurate; Financial Interests, Personal, Speaker’s Bureau: Novartis, Lilly; Financial Interests, Personal, Other, Travel: Pfizer, Novartis, Roche, AstraZeneca, Lilly.
SG is an antibody-drug conjugate targeting human trophoblast cell surface antigen 2 that has shown superior progression-free survival (PFS) and overall survival versus single-agent chemotherapy in pts with heavily pretreated TN and hormone receptor-positive/HER2-negative advanced breast cancer. Common adverse events (AEs) with SG include diarrhea and neutropenia, with neutropenia as the main reason for dose reduction and treatment discontinuation. We aim to evaluate prophylactic L and G-CSF to mitigate these AEs.
PRIMED (NCT05520723) is a multicenter, open-label, single arm, phase II clinical trial. Selection criteria include (a) Pts aged ≥18 years with taxane-pretreated unresectable locally advanced or mTNBC; (b) At least one and up to two prior chemotherapeutic regimens for advanced disease; (c) ECOG performance status of 0-1; (d) Evaluable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. Pts will receive SG at doses of 10 mg/kg given intravenously on days 1 and 8 every 21-day cycle until disease progression, unacceptable toxicity, or patient withdrawal. L (2 mg orally twice a day or 4 mg once a day [QD], days 2, 3, 4, 9, 10, and 11) and G-CSF (0.5 MU/kg/day subcutaneously QD, days 3, 4, 10, and 11) will be administered during the first two treatment cycles. Co-primary endpoints are incidence of grade ≥2 diarrhea and grade ≥3 neutropenia after two treatment cycles. Secondary endpoints include incidence of all grade neutropenia, diarrhea, and additional AEs per NCI-CTCAE v.5.0 during the course of the study, discontinuation rate, dose reduction rate, objective response rate, clinical benefit rate, duration of response, time to response, best percentage of change from baseline in size of target tumor lesions, and PFS. Primary analysis will evaluate the rate of pts with grade ≥2 diarrhea (H0: ≥25%; H1: ≤14%) and grade ≥3 neutropenia (H0: ≥40%; H1: ≤28%). Fifty pts will be enrolled to attain 80% power. Interim analysis will assess the first 25 pts and the study will be stopped if ≥6 pts have grade ≥2 diarrhea and ≥9 pts have grade ≥3 neutropenia.
NCT05520723.
Medica Scientia Innovation Research (MEDSIR).
Gilead Sciences.
J.M. Pérez-García: Financial Interests, Personal, Advisory Role: Lilly, Roche, Eisai, Daiichi Sankyo, AstraZeneca, Seattle Genetics, Gilead; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Full or part-time Employment: MEDSIR. M. Gion Cortes: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other, Travel expenses: Roche, Pfizer. A. Martinez Bueno: Financial Interests, Personal, Other, Travel expenses, accomodation and registration fees: GSK, Roche; Financial Interests, Personal, Invited Speaker: Seagen, GSK. X. González Farre: Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Other: AstraZeneca. I. Blancas López-Barajas: Financial Interests, Personal, Research Grant: AstraZeneca, Lilly, Pfizer and Roche; Financial Interests, Personal, Other, Honoraria and Advisor Collaboration: AstraZeneca, Roche, Novartis, Eisai, Celgene, Pfizer, Lilly, Pierre-Fabre, Bristol Myers Squibb, Daiichi Sankyo, Grünenthal, Seagen and Veracyte; Financial Interests, Personal, Other, Meeting attendance and/or travel: AstraZeneca, Roche, Novartis, Pfizer, Lilly, Pierre-Fabre, Bristol Myers Squibb and Daiichi Sankyo. E. López-Miranda: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Gilead, Novartis; Financial Interests, Personal, Invited Speaker: Pfizer, Roche. J. Fazal-Salom, A. Lazaris, E. Shimizu: Financial Interests, Personal, Full or part-time Employment: MEDSIR. M. Ruiz Borrego: Financial Interests, Personal, Other: Pfizer, Novartis, AstraZeneca, Daiichi Sankyo. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, MERCK SHARP& DOHME, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca. A. Llombart Cussac: Financial Interests, Personal, Funding: Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Gilead, Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Lilly, Roche, Pfizer, Novartis; Financial Interests, Personal, Speaker’s Bureau: Lilly, AstraZeneca, Merck Sharp & Dohme; Financial Interests, Personal, Other: Roche, Pfizer, AstraZeneca; Financial Interests, Personal, Stocks/Shares: MEDSIR, Initia-Research. All other authors have declared no conflicts of interest.
The oligometastatic (OM) disease state with few metastases represents a specific entity between localised and disseminated cancer and has a superior outcome compared to patients with disseminated disease. Standard treatment for patients with OM breast cancer (OMBC) consists of systemic therapy. Several novel drugs have been implemented during the last decades but data show unchanged long-term prognosis for luminal and triple negative BC. Local treatment for patients with MBC is mainly used for symptomatic metastases. Stereotactic ablative body radiotherapy (SABR) delivers high doses with good therapeutic effects, low toxicity while sparing surrounding tissues. Published outcomes from 2 randomised phase II trials using SABR (COMET and NRG BR002) demonstrate contradicting results, suggesting a randomised trial in OMBC is needed.
TAORMINA is an international, multicentre, randomised phase III trial for patients with OMBC, comparing systemic therapy alone (control arm) with systemic therapy combined with SABR toward all OM sites (investigational arm) as 1st line therapy. The primary aim is to determine if the addition of SABR improves progression-free survival. Secondary endpoints are response rate, time to development of new lesions, safety, toxicity, quality of life and overall survival. In addition, the study aims to evaluate potential biomarkers of response and early progression. A total of 386 patients will be enrolled in at least 6 countries. Patients are randomised 2:1 (investigational vs control). A PET-CT is required before registering in the trial to ensure a maximum of 5 metastases restricted to 1-2 organs. SABR cannot be given before the 1st evaluation after 3 months showing at least stable disease. Patients with de novo OMBC shall complete planned (neo)adjuvant treatment including local treatment of the primary breast tumour. Patients are evaluated every 3rd month for 3 years, every 6 months to five years and thereafter annually until 10 years or progression. Patients with progress are managed according to institutional practice and survival data are collected yearly.
NCT05377047.
Västra Götalandsregionen, Department of Oncology/Swedish Association of Breast Oncologists (SABO).
1) The Swedish Research Council; 2) King Gustav V Jubilee Clinic Research Foundation at Sahlgrenska University Hospital.
All authors have declared no conflicts of interest.
Cancer related fatigue is a distressing condition and correlated with decrease in quality of life of patients with malignant conditions. In continuation of our previous research, we assessed long term anti-fatigue effects of melatonin in patients with the breast cancer.
The study was a randomized, controlled, parallel-group, trial. Patients with non metastatic breast cancer were randomly assigned to receive melatonin (The intervention group) or placebo. Ninty-two patients were randomly enrolled in each group. The intervention group received oral melatonin (18 mg/day) from 1 week before until 2 years after the adjuvant treatments (adjuvant chemotherapy and radiotherapy). The levels of fatigue were assessed before and after intervention using Brief Fatigue Inventory (BFI) in both groups. To analyze data, the Student's t-test and the Chi-square test were used at a significance level of P ≤ .05.
The BFI score was similar prior to the intervention in both groups. After the intervention, not only both the mean fatigue score and severity of fatigue were significantly lower in melatonin group (P≤ .05) (Table), a greater decrease in fatigue score in intervention group is evident overtime. (P≤0.001).
Before intervention 1 month after intervention 2 years after intervention a) Group Mean ±SD Mean Mean Placebo 5.56±1.59 4.80±1.02 2.93±1.04 Intervention 5.72±1.68 3.97±1.29 1.99±1.02 P-value 0.671 0.007 0.001 b) Source of variation F P-value Group 3.02 0.087 Time 204.15 <0.001 Group by time 9.157 0.001 c) Group Count (%) Count (%) Count (%) Placebo 20 (55.6) 29 (80.6) 13 (43.3) Intervention 29 (76.3) 16 (42.1) 6 (18.2) P-value 0.059 0.001 0.030 d) Group Cochran’s Q Test statistics P-value Placebo 10.941 0.004 Intervention 27.30 <0.001 a) Mean BFI score over time by groups; b) Results of repeated measurement analysis of variance; c) The number of patients with severe fatigue over time by groups; d) Results of generalized estimating equation
Our findings support using melatonin as a safe and effective therapeutic medicine for decreasing the levels of fatigue and improving the quality of life of patients with breast cancer. Considering the improved survival of patients with breast cancer and given the long-term adverse effects of suffering from breast cancer and its treatments on various aspects of patients life, a more extended psychological and medical supports might be essential.
Both Drs. Keshpour Amlashi and Seyed Alireza Javadinia have equally contributed to the study.
IRCT20180426039421N3.
The authors.
Hamadan University of Medical Sciences, Hamadan, Iran.
All authors have declared no conflicts of interest.
Breast cancer (BC) is the most commonly diagnosed cancer and the second cause of cancer-specific death in women worldwide. Increasing evidence suggests that gut microbial dysbiosis may have a role to play in the pathogenesis, treatment and prognosis of BC.
The “BiotaCancerSurvivors” was a prospective, longitudinal, observational, unicentric and case-control study that aimed to analyse whether the gut microbiota differs between cancer survivors and a database of healthy controls. In this first analysis, samples from 23 BC survivors (group 1) and 291 healthy female controls (group 2) were characterised through the V3 and V4 regions that encode the “16S rRNA” gene of each bacteria. The samples were sequenced by Next Generation Sequencing (NGS), and the taxonomy was identified by resorting to Kraken2 and improved with Bracken, using a curated database called 'GutHealth_DB'. The α and β-diversity analyses were used to determine the gut microbiota's richness and evenness. Mann-Whitney U test was applied to assess differential abundance between both groups. Firmicutes/Bacteroidetes ratio was calculated using Kruskal-Wallis chi-squared test.
The α-diversity was significantly higher in group 1 (p=.28e-12 for the Chao index and p= 1.64e-12 for the ACE index). Shannon index wasn't statistically different between the two groups (p=.72). The microbiota composition was different between both groups: a null hypothesis was rejected for PERMANOVA (p=9.99e-05) and Anosim (p=.04) and was not rejected for β-dispersion (p=.158), using Unifrac weighted distance. Relative abundance of 14 phyla, 29 classes, 25 orders, 64 families, 116 genera and 74 species differed significantly between both groups. F/B ratio was signicantly lower in group 1 than in group 2, p<0.001.
We observed significant taxonomic disparities between BC survivors and healthy controls. Additional studies are needed to clarify the involved mechanisms and explore the relationship between microbiota and BC survivorship. Still, the data we possess so far, instills a need for further exploration of this field, given the potential microbiota role as a prognostic biomarker for BC survivorship.
We want to thank CUF Oncologia and to all voluntary women enrolled in the BiotaCancerSurvivors study.
The authors.
Has not received any funding.
D. Alpuim Costa: Financial Interests, Institutional, Full or part-time Employment: Portuguese Navy; Financial Interests, Institutional, Research Grant: Cuf Oncology, AstraZeneca; Financial Interests, Institutional, Advisory Role: NTT DATA; Financial Interests, Institutional, Principal Investigator: Gilead, Merck Sharp & Dohme, Nanobiotix; Financial Interests, Institutional, Invited Speaker: Merck KGaA, Nestlé, Pfizer, Uriage, Novartis. All other authors have declared no conflicts of interest.
Over the last decades, living conditions of breast cancer (BC) survivors have received special attention particularly in young BC survivors who specially face difficulties related to fertility and sexuality.
Non-metastatic BC women diagnosed from 2009 to 2016, aged <= 40 years at diagnosis were identified through the FRANCIM Network. Participants completed self-report questionnaires including standardized measures (sexuality, Health Related Quality of Life (HRQoL), anxiety, depression, deprivation, social support and alcohol consumption); and fertility issues. Sexuality profiles were identified by ascending hierarchical classification.
In total, 561 BC survivors from 14 French cancers Registries participated in the survey (response rate of 29%). The mean age at diagnosis was 35.9 (SD=3.8). Main tumors characteristics were AJCC stage 2-3 (61%), Hormone Receptor positive (76%), HER2 positive (24%), and Tumor grade >2 (91%). Most patients underwent lumpectomy (72%), chemotherapy (60%), radiotherapy (85%), endocrine therapy (71%) and few patients underwent targeted therapies (23%). More than 5 years after diagnosis, 48% reported sexual dysfunction. About 47% of women received information about the impact of BC treatment on fertility, and 34% reported that they received information about fertility preservation. Among 18% of women who had pregnancy project at diagnosis, 35% became pregnant after treatment. Ascending hierarchical clustering allowed to identify 3 distinct sexuality profiles from worse sexual function to the best respectively in 20%, 30% and 50%. Deprivation and treatment with endocrine therapy (especially tamoxifen) were associated with an increased risk of sexual dysfunction. The highest average score of HRQoL was in the physical functioning scale (82.2) and the lowest was in vitality (48.2).
This study showed that more than five year after diagnosis, BC survivors experienced difficulties related to sexuality. Specific interventions in this population should focus on in the management of sexual dysfunction and the improvement of the HRQoL.
Centre Georges-François Leclerc.
This work was supported by the Fonds de Dotation PFIZER INNOVATION FRANCE and the European Regional Development Fund (FEDER).
All authors have declared no conflicts of interest.
Breast cancer (BC) survivors often present increased cardiovascular (CV) risk. Only recently a cardio-oncology rehabilitation-based framework for cancer patients at increased CV risk was proposed. We aimed to compare a center-based cardiac rehabilitation (CBCR) program compared with a community-based exercise training (CBET) on BC survivors.
An exploratory analysis of the breast cancer survivors included in the CORE trial (NCT05132998) is presented. CORE was a single-center, randomized controlled trial enrolling high CV risk adult cancer survivors. Participants were randomized to an 8-week CBCR (including ET, psychological management, and health education) or CBET, twice a week. Primary endpoint was cardiorespiratory fitness (CRF) (assessed by the VO2peak, derived from a symptom-limited cardiopulmonary exercise test). Secondary endpoints included changes in quality of life (QoL), asthenia, and muscle strength.
Fifty-one BC survivors were included (CBCR=24, CBET=27), mean age of 54 years old ± 9 (range 34-76). All patients underwent surgery. Majority of patients had stage 1 disease (CBCR 50%, CBET 63%), underwent (neo)adjuvant anthracyclines (CBCR 88%, CBET 93%) and adjuvant radiotherapy (CBCR 88%, CBET 82%). Regarding cardiovascular risk factors, dyslipidemia was the most prevalent risk factor (CBCR 46%, CBET 44%), followed by arterial hypertension (CBCR 46%, CBET 33%). Both arms well balanced. There was a significant difference between groups in VO2peak, in favor of the CBCR (p=0.035). We observed a significant improvement in QoL (p=0.003) and asthenia (p=0.004), in CBCR arm while no difference in muscle strength (p=0.786). No serious adverse events were reported.
BC survivors benefited from CBCR in terms of CRF. Given the high cardiovascular risk in this specific group patients, this data provides novel insights into optimized preventive strategies in this patient population. Furthermore, the improvement observed in QoL and asthenia is of clinical importance and might correlate with a positive impact in the interference of activities of daily living.
NCT05132998.
OncoMove-Associação de Investigação de Cuidados de Suporte em Oncologia (AICSO).
Has not received any funding.
All authors have declared no conflicts of interest.
The transgender population face inequalities throughout the cancer pathway. Much of this stems from a lack of access to specialist knowledge of gender-affirming care and how it intersects with cancer. Breast cancer care in particular presents challenges for both patients and clinicians given the interaction with sex hormones , potential to exacerbate dysphoria and differing management in cisgender men vs. cisgender women. Breast cancer risk remains of concern in trans people. The best estimate of breast cancer incidence is trans men and non-binary people assigned female at birth (TMNB) is only 5 times less than in cisgender women. In trans women and non-binary people assigned male at birth (TFNB) the incidence is only 3 times less than in cisgender women. However cancer registries in most countries fail to accurately record gender identity and trans status.
In response to this need, we established the UK Cancer and Transition Service (UCATS), a national multidisciplinary team meeting and clinic where any transgender patient with active or historical cancer can access specialist advice and support. This was coproduced with patient and public involvement and input from a specialist cancer charity.
We discuss 6 cases of breast cancer in TMNB where cancer and gender-affirming care were mutually impacted by each other. Two of these lead to the establishment of UCATS and a further 4 were managed by the service. Challenges experienced by patients and clinicians included access to satisfactory reconstructive options, access to and management of gender-affirming hormones, and choice of anti-oestrogenic therapy.
We recommend introduction similar services internationally and inclusion of gender identity and trans status in cancer registries to improve data collection on cancer risk. Further research is required on the use of gender-affirming hormones in hormone receptor-positive breast cancer in adjuvant and metastatic settings.
Chelsea and Westminster Hospitals NHS Trust.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer (BC) survivors frequently complain of functional limitation of the shoulder following cancer treatments. Despite the physical and psychological implications, the optimal management of this disabling condition is still debated. Thus, the aim of this study was to assess the long-term effects of a comprehensive rehabilitation program, including ultrasound (US) guided injection of the sub-acromial deltoid bursa (SAD) combined with a physical rehabilitation protocol.
In this randomized controlled study, adult BC survivors with SAD bursitis were assessed for eligibility and randomly assigned to Group A and Group B. Both groups received corticosteroid US guided injection into the SAD bursa, while only Group A received 5 rehabilitation sessions, 1 hour each. Outcomes were assessed at baseline, after one week (T1), three months (T2), and six months (T3). It was assessed the Numerical Pain Rating Scale (NPRS), handgrip strength (HGS) test, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the Oxford Shoulder Score (OSS), Global Perceived Effect (GPE), and safety.
Thirty-seven women were randomly assigned to Group A (n=19; mean age: 56.05 ± 10.30 years) and Group B (n=18; mean age: 58.39 ± 12.09 years). No adverse events were reported. Statistically significant within-group differences were found in both groups in terms of NPRS at T1, T2, and T3 (p <0.05). The between-group analysis showed no differences (p > 0.05) at T1; however, at T2 significant differences were reported in terms of NPRS (2.16 ± 1.39 vs 4.78 ± 1.77; p <0.05), HGS (25.11 ± 3.20 vs 20.33 ± 4.92; p<0.001), OSS (17.00 ± 3.27 vs 33.11 ± 6.471; p<0.0001), and EORTC QLQ-C30 (Functional, Symptom and Global Health subscales, p<0.05). Furthermore, NPRS remained significantly lower in Group A compared to Group B (2.56 ± 1.05 vs 4.65 ± 1.13; p <0.05) at T3.
A comprehensive rehabilitation strategy including US guided injection and physical rehabilitation exercise may be considered safe, feasible, and effective for long-term management of SAD bursitis in BC patients.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Generalized edema is one of the most common side effects of docetaxel treatment and hazard quality of life in patients with breast cancer. Although damage in lymphatic endothelial cells is considered as the mechanism of the side effects, no standard treatment has been established to relieve the symptoms other than diuretics. This study was designed to evaluate the usefulness of the Aroma lymphatic Trissage (ALT) program in improving the quality of life (psychological stability) along with alleviation of the lower extremity after docetaxel treatment in patients with breast cancer.
Study was conducted on the 37 patients with breast cancer who visited the cancer center at the Korea University Anam hospital from January 2021 to March 2022. Patients were eligible if they experienced Grade 2 or higher-grade lower extremity edema after taxane-based chemotherapy. ALT was performed for 40 minutes twice a week for 4 weeks, in total 8 sessions. The primary endpoint was to evaluate the effect of ALT on the lower extremity edema, which was measured by the circumference of the thigh, calf, and ankle. The secondary endpoint was a change in Quality of life. EORTC-Q-C30 questionnaire and FACT-TAXANE were used.
Thirty-nine patients were enrolled and 2 patients dropped out. A total of 37 patients finished the study. There was a significant decrease (p<.001) in the lower extremity edema after the 4-week ALT. The mean circumference of the extremity was as follows at baseline and 6-week time-point; 56.17±5.02 to 54.22±4.83 (thigh), 37.34±3.06 to 35.91±2.83(calf), 22.46±1.74 to 21.61±1.67 (ankle). Moreover, both EORTC-QLQ-C30 and FACT-TAXANE questionnaire showed significant improvement after the intervention; 71.81±13.01 to 57.30±9.35 in mean EORTC-QLQ-C30 (p<0.001) and 87.27±17.27 to 66.49±17.25 in mean FACT-TAXANE score (p<0.001).
Results in this study showed that Aroma lymphatic Tressage (ALT) program has a positive effect on the relief of lower extremity edema caused by taxane-based chemotherapy, and the quality of life of breast patients. Based on the results, ALT might be applied as a complementary intervention to improve edema in the lower extremities after taxane-based chemotherapy.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Women commonly experience menopausal symptoms including vasomotor symptoms (VMS) e.g. hot flashes whilst on adjuvant endocrine therapy (AET) after breast cancer. VMS treatment options are limited in this population. The REAL-world evIdence on vasomotor and other Symptoms in menopausal womEn (REALISE) study aimed to evaluate VMS treatment status and symptom burden in women taking AET after breast cancer.
The 2020 Adelphi VMS Disease Specific Programme™, a large, cross-sectional survey-based dataset was conducted between February - October in France, Germany, Italy, Spain, the United States, and United Kingdom. Oncologists (n=77) provided demographic, clinical, and treatment status data on adult women in breast cancer remission taking AET and experiencing VMS; patients were then asked to complete a voluntary self-report form including symptoms and the Menopause-Specific Quality of Life tool. Patients were stratified into treated (currently receiving VMS treatment) and untreated (never received treatment) groups. Analyses were descriptive.
Of the 183 women providing self-report data (mean age 54.1 years [SD 9.9]; mean age at onset of induced menopause 48.8 years [SD 10.0]; 84.7% white), 54.1% were treated (69.7% with SSRI/SNRI), with median treatment duration of 34.8 weeks (IQR 26.1, 52.1); and 40.4% were untreated. Patients reported HF (92.2%), sweating (67.6%), difficulty sleeping (64.8%), anergia (56.4%), and mood symptoms (55.9%) most commonly over the prior week. Reporting of HF (treated: 95.8%; untreated: 89.2%), difficulty sleeping (65.6%; 63.5%), and mood symptoms (60.4%; 48.7%) was consistent regardless of treatment status. Patients in both groups reported moderate to severe bother of HF (treated: 47.9%; untreated: 27.4%), mood symptoms (22.9%; 24.3%), and sleep difficulties (25.3%; 27.4%, respectively).
Women in breast cancer remission receiving AET experienced a high VMS and concomitant symptom burden, yet 40.4% were not receiving treatment. Patients reported feelings of bother in relation to their VMS, mood and sleep over the last week regardless of treatment status, showing a need for new more effective treatment options for this underserved group.
Editorial assistance was provided by Highfield Communication Consultancy, Oxford, UK.
Bayer AG.
Bayer AG.
M. Scott, M. Harvey: Financial Interests, Personal, Full or part-time Employment: Adelphi Real World. N. Schoof, S. Su Saydam, C. Moeller: Financial Interests, Personal, Full or part-time Employment: Bayer AG. C. Caetano, C. Janssenswillen: Financial Interests, Personal, Full or part-time Employment: Bayer Consumer Care. V.L. Banks: Financial Interests, Personal, Full or part-time Employment: Bayer UK.
High rate of breast cancer (BC) survivors is registered. Increased longevity is associated with increased cardiovascular disease (CVD) risk. Screening for cardiac defects could then be an interesting approach since it can lower the risk of cardiovascular complications.
In this prospective study, all BC patients treated ≥ 5 years ago were screened for CVD. We identified BC patients with no history of CVD at diagnosis, treated between 1998 and 2017 and followed them through December 2022. We used for CVD screening, electrocardiogram (EKG) and transthoracic echocardiogram (TTE). CVD were categorized as asymptomatic or symptomatic. We considered to be CVD risk factors: age, obesity, hypertension, diabetes mellitus, dyslipidemia, anthracycline, trastuzumab, aromatase inhibitor, left-sided radiation. For analysis we used univariate and multiple logistic regression with a backward elimination method.
296 patients were identified, with an average age of 47.6 years (32-65) at diagnostic and 59.2 years (37-82) at screening. 46% were postmenopausal at diagnosis. 32.6% had Hypertension, 13.5% Diabetes mellitus, 29.3% Dyslipidemia, 34.9% Obesity. 93.6% received cardiotoxic treatment (92.6% Anthracyclines, 7.6% Trastuzumab, 38.8% Aromatase inhibitor, 53.0% Left sided radiation). Median interval from diagnosis to screening was 10.4 years (range 5.8–23.4). CVD occured in 21.6% patients. 3.7% was clinical CVD : heart failure (1.7%), atrial fibrillation (0.7%), stable angina (0.7%), myocardial infraction (0.3%), severe aortic stenosis (0.3%). The remaining 17.9% of CVD were detected on EKG and TTE in asymptomatic patients: 9.8% valvular regurgitation, 5.7% left ventricular hypertrophy, 1.0% diastolic dysfunction, 0.7% systolic dysfunction, 0.7% heart block. Multiple logistic regression analysis revealed that increasing age, hypertension, and the combination doxorubicin plus left-sided radiation plus aromatase inhibitor (OR = 1,44; 95% CI, 1.14–1.61; p < 0,01) were significant risk factors.
Our results suggest that Bi-modality CVD screening in BC survivors could be an interesting approach since most CVD were asymptomatic and occurred in high-risk patients. This should allow reduce severe forms of CVD and cardiovascular death.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Due to COVID-19 mass immunizations, most of the social restrictions were waived with subsequent effects on health-related quality of life (HR-QoL). Therefore, our hypothesis was that COVID-19 vaccination impacted HR-QoL in patients with breast cancer and gynecologic malignancies.
From 15/03/2022 - 11/08/2022, fully vaccinated patients with breast cancer treated in the gynecologic outpatient clinics of the LMU University Hospital were surveyed. Evaluated were demographic data (age, comorbidities) and clinical parameters as well as HR-QoL-related parameters (occupational situation, responsibilities in daily life). In addition, a newly designed questionnaire with 12 items and a 5-point Likert scale was used, covering the aspects of health and therapy, social environment, participation in daily life, and overall assessment. Higher scores in the questionnaire indicate a higher impact of COVID-19 vaccination on the patients’ HR-QoL.
By 11/08/2022, 79/83 (95.1%) of the patients had received at least three doses of COVID-19 vaccine. 55.4% of the patients surveyed were <55 years (median: 51 years, range 30-86 years). The patients had early (59.0%) or metastatic breast cancer (41.0%). The patients mostly received chemotherapy (32.5%), targeted therapies (20.5%), or a combination of both (19.3%). 86.7% of patients reported that COVID-19 vaccination had a positive impact on their HR-QoL. 84.3% participated more in their everyday life (e.g., work, or social life), and 72.3% of the patients spent more time practicing sports after receiving complete vaccine protection. Patients with comorbidities had significantly lower mean total scores (p<0.01) indicating less impact of the vaccine on their HR-QoL.
Our study points out that vaccination against COVID-19 had a positive impact, especially regarding participation in everyday life, on HR-QoL in patients with breast cancer and gynecological malignancies.
Breast Center/ LMU Munich.
Has not received any funding.
S. Mahner: Financial interests, Personal, Research Grant: AbbVie, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Hubro, Medac, MSD, Novartis, Nykode, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, Tesaro.Financial interests, Personal, Advisory Board: AbbVie, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Hubro, Medac, MSD, Novartis, Nykode, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, Tesaro. Financial interests, Personal, Other, Honoraria or Travel expenses: AbbVie, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Hubro, Medac, MSD, Novartis, Nykode, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, Tesaro. N. Harbeck: Financial interests, Personal, Other, Horaria for lectures and/or consulting: AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Sanofi, Sandoz, Seagen. All other authors have declared no conflicts of interest.
Breats cancer is a major health problem in elderly ( ≥ 70 years) women. Increase incidence with age and the progressive increase in life expectancy mean that the numbers in elderly breast cancer diagnosis are increasing. These patients do not always receive the proper treatment and despite this the survival of this population is not always depends on cancer, there are other competing causes of death typical of the aging population.
A retrospective observational analysis of women ≥ age 70 diagnosed with breast carcinoma in HUPHM between 2014 and 2020 was made. Clinical, pathological data and stages at diagnosis were analyzed. We checked our patients with the national death center (official national registry) thus obtaining an exact date of death and the cause of death. Data updated in January 2023 , ensuring a minimum follow-up of 24 months. We excluded deaths from Covid or of unknown cause to avoid bias.
A total of 421 patients were analyzed, mean age of 78.6 years and median follow-up of 48 months. 28% of patients had died at the time of analysis, 11% due to cancer and 17% from other causes. If we analyze the population deceased by cancer, no deaths are detected in patients diagnosed with carcinoma in situ (4% of the population), in stage I (30% of the population) the cumulative incidence of cancer death at 5 years is 3%, 7% In stage II (30% of the population), 15% in stage III (16%) and 70% in stage IV (12%). Death by other causes are more frequent in early breast cancer, the cumulative incidence at 5 years are 10% in stage I, 22% in stage II, 44% in satge III and just 10% in stage IV. The most frequent causes of death in this population were caridovascular events and infections. There are no differences in 5-year mortality according to histological subtypes 20%, 12%, 25% and 12% for triple negative, Rh+/HER2-, RH+/her2+ and RH-/HER2+ respectively.
Although elderly patients do not receive optical treatments, mortality from cancer in early stages is incidental at 5 years, a different scenario is seen in metastatic disease in which the patient's prognosis depends mainly on the oncological disease, Therefore, an effort should be made in the treatment of these patients with metastatic breast cancer since adequate treatments can have a clearly positive impact on the survival of patients.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Muscle loss has been identified as a negative prognostic factor in various types of cancer, including breast cancer. In particular, muscle loss is a significant prognostic factor in patients with metastatic cancer. While chemotherapy is a crucial treatment for breast cancer that can improve survival rates, it also has significant side effects, such as severe infections due to reduced white blood cells, bone marrow failure, fluid retention, and heart toxicity. However, muscle loss as a result of chemotherapy in breast cancer patients has not been widely recognized. Recent studies on cancer treatment and prognosis have highlighted muscle loss as an important concern, and this study aims to determine the extent of muscle loss in breast cancer patients after undergoing chemotherapy.
This retrospective study analyzed patients who underwent surgery for early breast cancer between 2015 and 2019. Demographic data and clinicopathological features were analyzed, and the lumbar skeletal muscle index (psoas muscle) in computed tomography (CT) was used as a marker of muscle mass. Muscle index was compared in abdominal CT taken before surgery and abdominal CT taken 1 year later.
Of the 408 patients included in the study, 228 received adjuvant chemotherapy, and 180 patients did not receive adjuvant chemotherapy. The muscle index of patients who did not receive chemotherapy decreased by 0.4cm2/m2, while that of patients who received chemotherapy decreased by 1.2cm2/m2 (p = 0.028). In multivariate analysis, chemotherapy and age over 50 were identified as the main risk factors for muscle mass reduction (p = 0.02, 0.03, respectively). Clinicopathologic features of 408 patients
Variables Chemotherapy Pts (N=228) Non-chemotherapy Pts (N = 180) P values Age 54.8 ± 10.4 (28-67) 56.1 ± 9.6 (30-69) 0.445 Stage 0.001 I 40 (17.5 %) 116 (64.4%) II 160 (70.2%) 61 (33.9%) III 28 (12.3%) 3 (1.7%) Hormone receptor Positive 155 (68%) 158 (88%) 0.001 Negative 73 (32%) 22 (12%) HER2 receptor Positive 70 (31%) 20 (11%) 0.048 Negative 158 (69%) 160 (86%) BMI 24.7 24.1 0.78 Muscle mass index (MI) 46.6 cm2/m2 46.9 cm2/m2 0.66 MI reduction -1.2 cm2/m2 -0.4 cm2/m2 0.028
This study demonstrates that significant muscle loss occurs in patients who receive chemotherapy after surgery for early breast cancer. In particular, patients aged 50 or older who have received chemotherapy need to pay attention to muscle reduction.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer (BC) is the 2nd leading cause of cancer-related death in women worldwide. Increased BC mortality in diabetic patients was reported in prior studies. However, the interplay between ethnicity, race, and diabetes was not explored. This study analyzes the influence of type 2 diabetes (T2D) on BC mortality across ethnic and racial groups.
We studied a population of 2,366,551,531 by using the CDC Multiple Cause of Death database (ICD, 10th revision) between 2005 and 2020. We identified all women who died of BC, code C50, as underlying cause of death (UCD), regardless of T2D. Then we identified the same UCD among women with T2D, code E11, as multiple cause of death. Age-adjusted mortality rates (AAMR) per million persons (PMP) were calculated, standardized to 2000 US census, and stratified by ethnicity and race [Hispanic (H), non-Hispanic (NH), Black (B), and White(W)].
In the general population (GP), a total of 659738 deaths from BC were identified, with an overall AAMR of 211.5 PMP (B: 287, W: 206.6, H: 141.3, NH: 218.9). AAMR declined from 2005 to 2020 by 22% among B from 327.1 to 253.8 PMP, 20% among W from 235.3 to 187.1 PMP, 14% among H from 152.9 to 131.3 PMP, and 20% among NH from 248.8 to 198.4 PMP. In T2D population, a total of 9535 BC deaths were identified, with an overall AAMR of 3.0 PMP (B: 4.6, W: 2.8, H: 3.4, and NH: 2.9). AAMR increased from 2005 to 2020 by 37% among B from 4.1 to 5.6 PMP, 65% among W from 2.3 to 3.8 PMP, 78% among H from 2.3 PMP to 4.1 PMP, and 60% among NH from 2.5 PMP to 4.0 PMP.
Popultion Ethnicity or race Death AAMR PMP AAMR trend 98203 287 - 22% 541169 206.6 - 20% 41519 141.3 - 14% 618219 218.9 - 20% 1513 4.6 + 37% 7596 2.8 + 65% 915 3.4 + 78 8620 2.9 + 60%
This is one of the largest population based studies analyzing BC mortality. Between 2005 and 2020, BC mortality was reduced in GP and increased in T2D in all races and ethnicities included in the study. AAMR in B was higher than W in both populations. Unlike GP, T2D had a higher AAMR in H than NH. Additionally, the highest rate of mortality increase in T2D was noted in W and H. More studies are warranted to identify causes of the rise among T2D and stratigies to reduce the racial and ethnic gaps.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Patients (p) with solid tumor have an increased risk of severe coronavirus disease 2019 (COVID-19) and associate higher mortality compared to general population. Cancer patients were not included in pivotal trials of COVID-19 vaccines. A high proportion of p with solid tumors develop immunological responses following vaccination, and subsequent doses can result in seroconversion in those who were previously seronegative after the two first doses. In Advanced Breast Cancer (ABC) p knowledge of vaccine effects is scarce.
Prospective observational study analysed the serological response to COVID-19 vaccine in a series of patients (p) with ABC treated in a single institution. Between 01/03/2021 and 19/05/2021 we analysed the serological response by serial determination of COVID-19 antibodies (Ab) 21 or 28 days after each dose and 3, 6, 9 and 12 months (m) after the second dose. We considered an antibody titration of 2500 total Ig/ml as a robust antibody response (RAR).
N=43 p. with ABC, 100% female; median age: 69 years (y). Comorbidity: 29 p (67%) hypertension, 6 p (14%) active smoking. Histological subtype: 21 p (49%) luminal, 19 p (44%) Her2 + and 3 p (7%) triple negative (TN). Treatment: 2 p (5%) chemotherapy (CT), 3 p (7%) immunotherapy and 29 p (88%); First-line: 20 p (48%), 2ndline 8 p (19%), 3rdor successive line 14 p (33,4)[MMDP1]. A previous COVID-19 infection: 1 p (2,3%); In the period of study 8 p were tested positive for COVID-19. Type of vaccine: Pfizer/BioNTech (Comirnaty): 33 p (78%) and Moderna (Spikevax) 10 p (23%). Adverse effects: 2 p (4.7%) with one requiring hospitalization (2.3%). After the first vaccine, 2/32 p (6.3%) had RAR. Following a second dose, the RAR rose to 8/35 p (23%). At 3 and 6 m after the second dose a RAR was observed in 4/23 p (17.4 %) and 10/25 p (40%) respectively. A 3rddose increased the RAR robust to 13/16 p ( 81%), and in those receiving a 4thvaccine (9/43) 77.8% achieved a robust Ab response. At the end of the follow-up, 7 p (16%) (7/43) died of cancer. The efficacy of vaccines was similar to general population regardless of cancer diagnosis and treatments.
In our series of ABC patients tested for COVID-19 vaccine seroconversion, a robust serological response was shown especially after the 3rdand 4thdose (in up to 80% of patients).
The authors.
Has not received any funding.
E. Galve-Calvo: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Gilead, Novartis, Pfizer. All other authors have declared no conflicts of interest.
Despite increasing evidence on the safety of pregnancy after anticancer treatments in breast cancer survivors, many physicians and patients continue to have concerns about a potential detrimental effect of pregnancy in patients with prior history of hormone receptor-positive breast cancer.
A systematic literature search of Medline, Embase and Cochrane library with no language or date restriction up to January 1st, 2023, was performed. We included retrospective or prospective case-control and cohort studies as well as prospective clinical trials comparing survival outcomes of premenopausal female with reported pregnancy or not after diagnosis and treatment of hormone receptor-positive breast cancer. Included patients were childbearing potential age women with a prior history of hormone receptor-positive early breast cancer. Outcomes of interest were disease-free survival (DFS) and overall survival (OS). Hazard ratios (HR) with 95% confidence intervals (CI) were extracted.
Eight studies were eligible to be included in the final analysis. A total of 3,805 patients with hormone receptor-positive breast cancer were included in this analysis, of whom 1,285 had a pregnancy after treatments. In the 3 studies (n=987 patients) reporting on DFS, no difference was observed between patients with or without a subsequent pregnancy (HR 0.96, 95% CI 0.75 – 1.24, p=0.781). Six studies (n=3,504 patients) reported OS: patients with a pregnancy after breast cancer had better OS than those without a pregnancy (HR 0.46, 95% CI 0.27 – 0.77, p<0.05). At the subgroup analysis on timing of pregnancy after breast cancer, no detrimental effect of pregnancy in terms of DFS was observed for patients achieving a late pregnancy (defined as 2 or 5 years after diagnosis) as compared to patients without a subsequent pregnancy (HR 1.08, 95% CI 0.80 – 1.46, p=0.611). Improved DFS was observed in patients with an early pregnancy (HR 0.63, 95% CI 0.47 – 0.85, p<0.05).
Our results strengthen the evidence that having a pregnancy in women with prior history of hormone receptor-positive breast cancer is safe.
The authors.
Associazione Italiana per la Ricerca sul Cancro (AIRC).
I.V. Vaz Luis: Financial Interests, Institutional, Invited Speaker: Amgen, Pfizer/Edimark, Pfizer/Edimark, AstraZeneca; Financial Interests, Institutional, Advisory Board, Consulting/ AB: Novartis; Financial Interests, Institutional, Expert Testimony: Sandoz; Financial Interests, Institutional, Funding: Resilience; Non-Financial Interests, Member, Member of WG: ASCO. C. Saura Manich: Financial Interests, Personal, Advisory Board: AX'Consulting, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann - La Roche Ltd., Gilead, ISSECAM, Lilly, MediTech, Medical Statistics Consulting, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, Seagen, Solti, Zymeworks; Financial Interests, Personal, Expert Testimony: AX's Consulting SARL, Boehringer Ingelheim, Bristol Meyers Squibb, INDITEX, Merck Sharp & Dohme España, Novartis, SACE Medhealth SL, Simon Kucher &Partners SL, Genentech, Innoup, Millenium, Sanofi, Seattle Genetics; Financial Interests, Personal, Other, SC: Byondis B.V., German Breast Group, Glaxo, International Breast Cancer Study Group (IBCSG), Macrogenics, Medsir, Menarini, Merus, Merus, Netherlands Cancer Institute (NKI), Queen Mary (University of London), Seagen, Synthon Biopharpaceuticals; Financial Interests, Institutional, Research Grant: Aragon Pharmaceuticals, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, German Breast Group Forchungs, Glaxosmithkline, Immunomedics, Innoup Farma, International Breast Cancer Study Group (IBCSG), Macrogenics, Medica Scientia Innovation Research, Novartis, Menarini Ricerche, Merus, Millennium Pharmaceuticals, Pfizer, Puma, Roche, Sanofi-Aventis, Seattle Genetics, Queen Mary, University of London, SOLTI, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis; Financial Interests, Institutional, Invited Speaker: Byondis B.V.; Non-Financial Interests, Member: Spanish Society of Medical Oncology (SEOM), American Society for Clinical Oncology (ASCO), SOLTI group (Academic research group in breast cancer), Geicam (Spanish Breast Cancer Research Group), American Association for Cancer Research (AACR). H.A. Azim: Financial Interests, Personal, Other, Consultant: Diaccurate; Financial Interests, Personal, Full or part-time Employment: Pierre Fabre Sante SA, Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma; Non-Financial Interests, Member: American Society of Clinical Oncology. E. de Azambuja: Financial Interests, Personal, Advisory Board: Roche/GNE, Novartis, Seagen; Financial Interests, Personal, Invited Speaker: Zodiac, Libbs, Pierre Fabre, Lilly, Astra-Zeneca; Financial Interests, Institutional, Research Grant: Roche/GNE, AstraZeneca, GSK/Novartis, Servier; Financial Interests, Institutional, Other, Travel Grant: Roche/GNE; Financial Interests, Institutional, Invited Speaker: MSD, ABCSG, Nektar, Gilead, Immunomedics, Synthon, Odonate Therapeutics; Financial Interests, Invited Speaker, Chair of the Gilead Sciences Research Scholars Program in Solid Tumours: Gilead; Financial Interests, Invited Speaker, Aphinity, Lorelei, Impassion03: Roche; Financial Interests, Invited Speaker, AURORA: Breast International Group; Financial Interests, Invited Speaker, Olympia: Astra-Zeneca; Financial Interests, Personal, Other, Travel grant: Astra-Zeneca; Non-Financial Interests, Advisory Role, Member of the cardio-oncology council: European Society for Cardiology (ESC); Non-Financial Interests, Advisory Role, Belgium governmental institution for cancer: KCE; Non-Financial Interests, Other, Editorial board member: ESMO Open; Non-Financial Interests, Advisory Role: Anticancer Fund. F.A. Peccatori: Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Invited Speaker: Roche Diagnostic; Non-Financial Interests, Leadership Role, Scientific Director: European School of Oncology. L. Del Mastro: Financial Interests, Personal, Invited Speaker, Educational meeting: Novartis, Symposia, Andromeda E20, Vyvamed srl; Financial Interests, Personal, Invited Speaker, Lecture: Ipsen; Financial Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche; Financial Interests, Personal, Invited Speaker, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board, Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests, Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal, Advisory Board, Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD; Financial Interests, Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina; Financial Interests, Personal, Invited Speaker, Author for BC text: Pensiero Scientifico Editore; Financial Interests, Personal, Advisory Board, Breast cancer: Uvet; Financial Interests, Personal, Other, Author slide kits and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pfizer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL; Financial Interests, Personal, Other, Author slide kits: Forum service; Financial Interests, Personal, Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other, consultant: Kardo srl; Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl; Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca, Agendia, Gilead; Financial Interests, Personal, Other, Interview: Infomedica srl; Financial Interests, Personal, Other, Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Personal, Other, Consultancy: Eli lilly; Financial Interests, Institutional, Funding, National coordinating PI: Roche; Financial Interests, Institutional, Funding, Local PI: AstraZeneca, Roche, Eli Lilly, Daiichi Sankyo, Novella Clinical, Novartis; Non-Financial Interests, Institutional, Product Samples, Genomic Test: FoundationOne. A.H. Partridge: Financial Interests, Personal, Royalties, Royalties received for authorship of Breast Cancer Survivorship section: UpToDate; Non-Financial Interests, Leadership Role, co-Chair of Breast Committee: Alliance for Clinical Trials, National Cancer Institute; Non-Financial Interests, Other, Board of Directors, Member 2022-2026: ASCO. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Takeda, Sandoz, Ipsen, Libbs, Knight, Daiichi Sankyo, Lilly, Pfizer, Novartis, Roche; Financial Interests, Personal, Other, Travel grant to attend ASCO 2022: Gilead; Financial Interests, Institutional, Invited Speaker, 2-year research grant paid to my Institution: Gilead. All other authors have declared no conflicts of interest.
Vasomotor symptoms (VMS) are common side-effects experienced by women receiving adjuvant endocrine therapy for hormone receptor-positive (HR+) breast cancer that can have a substantial impact on quality of life and may lead to the discontinuation of therapy. Hormone therapy is contraindicated in women with HR+ breast cancer, and there is an unmet need for well-tolerated and effective nonhormonal treatments to safely address these symptoms. Elinzanetant is a selective neurokinin-1,3 receptor antagonist currently being evaluated for the treatment of VMS associated with menopause in the phase III OASIS program.
OASIS 4 (NCT05587296) is an ongoing, multicentre, multicountry, double-blind, randomized, placebo-controlled, phase III study evaluating the efficacy and safety of elinzanetant 120 mg in women aged 18–70 years at high risk of developing or with a personal history of HR+ breast cancer receiving tamoxifen or aromatase inhibitors. Participants recording at least 35 moderate or severe VMS over 7 days are suitable for inclusion. Following a 6-week screening period, approximately 405 participants will be randomised at a 2:1 ratio to receive either once-daily elinzanetant 120 mg for 52 weeks or a matching placebo for 12 weeks followed by elinzanetant 120 mg for 40 weeks. After treatment, participants will undergo a 4-week follow up. Primary endpoints are the mean change in moderate or severe VMS frequency from baseline to weeks 4 and 12. Key secondary endpoints are mean change in Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form (PROMIS SD SF) 8b and Menopause-Specific Quality-of-Life (MENQOL) questionnaire from baseline to week 12. Other secondary endpoints are mean change in moderate or severe VMS severity from baseline to weeks 4 and 12 and moderate or severe VMS frequency from baseline to week 1 and over time. Primary and key secondary endpoints will be analysed using a mixed model with repeated measures. Safety will be primarily assessed using adverse event reporting throughout the duration of the study.
NCT05587296.
Medical writing assistance was provided by Emma Case, Highfield, Oxford, UK with sponsorship from Bayer.
Bayer.
Bayer AG.
F. Cardoso: Financial Interests, Personal, Other, Consultancy: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, Prime Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva; Financial Interests, Personal, Advisory Board: Gilead, IQVIA, Touchime; Financial Interests, Institutional, Invited Speaker: Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Bayer, Daiichi, Eisai, Fresenius GmbH, Genentech, GlaxoSmithKline, Ipsen, Incyte, Nektar Therapeutics, Nerviano, Novartis, Macrogenics, Medigene, MedImmune, Merck, Millenium, Pfizer, Pierre-Fabre, Roche, Sanofi-Aventis, Sonus, Taiho Oncology, Tesaro, Tigris, Wilex, Wyeth, Gilead; Non-Financial Interests, Leadership Role, President: ABC Global Alliance and ABC Consensus Conference and Guidelines; Non-Financial Interests, Member: ESMO, ESO, EORTC, BCG, IBCSG, SOLTI, ASCO, AACR, EACR, SIS, ASPIC. L. Zuurman, C. Caetano: Other, Institutional, Full or part-time Employment: Bayer CC AG. C. Seitz, S. Parke: Other, Institutional, Full or part-time Employment: Bayer AG. K. Laapas: Other, Institutional, Full or part-time Employment: Bayer Oy. All other authors have declared no conflicts of interest.