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.