P. Fasching (Erlangen, Germany)
University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, University Erlangen-NurembergenAuthor Of 3 Presentations
Invited Discussant 93MO and 94MO (ID 259)
2O - Association of RAD51 with Homologous Recombination Deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial (ID 244)
Abstract
Background
Current genetic and genomic tests that measure HRD show limited predictive value. We compare the performance of a functional HRD test based on scoring RAD51 nuclear foci with genetic/genomic HRD tests, and assess its capacity to select patients (pts) with primary TNBC sensitive to platinum-based neoadjuvant chemotherapy (NACT).
Methods
A retrospective, blinded analysis from the GeparSixto randomized trial was conducted on TNBC pts who received neoadjuvant paclitaxel plus non-pegylated liposomal doxorubicin (Myocet®) and bevacizumab (PM) or PM plus carboplatin (PMCb). Functional HRD biomarkers (RAD51, BRCA1 and yH2AX nuclear foci) were quantified in formalin-fixed paraffin-embedded (FFPE) tumor samples on a tissue microarray format (TMA). Concordance analyses were performed between the RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (myChoice® CDx). Associations with clinical outcomes were studied by logistic (pathological complete response, pCR) and Cox (disease-free survival, DFS) regression models. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low).
Results
RAD51, BRCA1 and yH2AX were successfully scored in 133/200 TMA cores (67%). Functional HRD by RAD51-low was evidenced in 81/133 tumors (62%). The RAD51 test identified 93% of tBRCA-mutated tumors and 45% of the non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% (95%CI 79-93%). In pts with RAD51-high tumors, the pCR rate was similar between treatment arms (PMCb 31% vs PM 39%, odds ratio (OR) 0.71, 0.23-2.24, p=0.561). Pts with RAD51-low tumors benefited from PMCb (66% vs 33%, OR 3.96, 1.56-10.05, p=0.004; interaction test p=0.023). The addition of Cb showed a trend towards better DFS in both RAD51-high (hazard ratio (HR) 0.40, 0.12-1.29, p=0.125) and RAD51-low (HR 0.45, 0.16-1.25, p=0.124) groups.
Conclusions
The RAD51 test is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51-testing in the clinical decision making.
Clinical trial identification
NCT01426880.
Legal entity responsible for the study
Violeta Serra, ERAPERMED.
Funding
Has not received any funding.
Disclosure
A. Llop-Guevara: Research grant/Funding (self): AECC (INVES20095LLOP); Research grant/Funding (self): La Caixa Foundation and European Institute of Innovation and Technology/Horizon 2020 (LCF/TR/CC19/52470003). A. Schneeweiss: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, Non-remunerated activity/ies, Medical writing grant: Roche; Research grant/Funding (institution): AbbVie; Honoraria (self), Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Lilly. G. Villacampa: Honoraria (self): MSD; Honoraria (self): AstraZeneca. P. Jank: Research grant/Funding (institution): EU funding EraPerMed JTC2019 \"RAD51predict\"; Research grant/Funding (institution), Shareholder/Stockholder/Stock options: Myriad Genetics, Inc. M. van Mackelenbergh: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Genomic Health; Honoraria (self): Mylan; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Roche. P.A. Fasching: Honoraria (self): Novartis; Research grant/Funding (institution): Biontech; Honoraria (self): Pfizer; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Merck Sharp & Dohme; Research grant/Funding (institution): Cepheid; Honoraria (self): Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Seattle Genetics; Honoraria (self): Roche; Honoraria (self): Hexal. F. Marmé: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Clovis; Honoraria (self): GSK/Tesaro; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): Celgene; Honoraria (self): Seagen; Honoraria (self): Myriad Gen; Honoraria (self): PharmaMar; Honoraria (self): Eisai; Honoraria (self): Janssen-Cilag. R. Dienstmann: Honoraria (self): Roche; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Merck Sharp Dohme; Honoraria (self): Amgen; Honoraria (self): Sanofi; Honoraria (self): Servier; Honoraria (self): Ipsen. J. Balmaña: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer. C. Denkert: Research grant/Funding (institution): European Commission H2020; Research grant/Funding (institution): German Cancer Aid Translational Oncology; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): MSD Oncology; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Research grant/Funding (institution): Myriad; Honoraria (self): Merck; Shareholder/Stockholder/Stock options: Sividon diagnostics; Licensing/Royalties, patent royalties: MScope digital pathology software; Licensing/Royalties, patent pending: WO2020109570A1 - cancer immunotherapy; Licensing/Royalties, patent issued: WO2015114146A1 and WO2010076322A1- therapy response. S. Loibl: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Honoraria (institution): Seagen; Research grant/Funding (institution): Immunomedics/Gilead Sciences Inc; Honoraria (institution): prIME/Medscape; Honoraria (institution): Eirgenix; Research grant/Funding (self), Research grant/Funding (institution): DSI; Honoraria (institution): BMS; Honoraria (institution): Merck; Honoraria (institution): Puma; Speaker Bureau/Expert testimony: Chugai; Licensing/Royalties, patent pending: EP14153692.0-Immunsignature in TNBC. V. Serra: Research grant/Funding (institution): ISCIII (CPII19/00033); Research grant/Funding (institution): TRANSCAN-2 (AC15/00063; Research grant/Funding (institution): AECC (LABAE16020PORTT); Research grant/Funding (institution): ERAPERMED2019-215. All other authors have declared no conflicts of interest.
91O - Pooled analysis of patient (pt)-reported outcomes (PROs) in the MONALEESA (ML)-2, -3, and -7 trials: additional results and key subgroup findings (ID 240)
Abstract
Background
The phase III ML-2, -3, and -7 trials assessed ribociclib (RIB) with different endocrine therapy (ET) partners in pts with hormone receptor–positive, HER2-negative (HR+/HER2−) advanced breast cancer (ABC). Quality-of-life (QOL) results were previously reported for each ML trial and as a pooled analysis. Here, we report on individual dimensions of the EORTC QLQ-C30 PROs, including relevant pt subgroup data from a pooled analysis of the ML trials.
Methods
PROs were collected with EORTC QLQ-C30 questionnaires. QOL was assessed for all pts in ML-2, pts without prior ET for ABC in ML-3, and pts receiving RIB or placebo (PBO) + a nonsteroidal aromatase inhibitor in ML-7. A linear effects model was used to calculate the least-squares mean changes from baseline in global health status (GHS), nausea and vomiting, diarrhea, and anxiety/depression, and these were interpreted using minimally important differences. GHS was also assessed for pt subgroups including age, race, and molecular subtype by PAM50.
Results
A total of 1528 pts were included. Time to definitive deterioration (TDD) for diarrhea and anxiety/depression was prolonged for RIB vs PBO (Table). Diarrhea, anxiety/depression, and GHS across subgroups were improved or maintained from cycle 3 to end of treatment. Median TDD of GHS was longer for RIB vs PBO in pts regardless of age. Median TDD of GHS for RIB vs PBO was longer for White pts, similar for Asian pts, and shorter for pts of other races, although the n in the latter group was small. Median TDD of GHS for RIB vs PBO was longer in pts with luminal subtypes and was more than doubled for the HER2-enriched (HER2E; 30.4 vs 14.8 mo) subtype.
Conclusions
In this pooled analysis of the ML trials, RIB + ET showed delayed deterioration in QOL scores. TDD for GHS favored RIB vs PBO across most subgroups. These results support prior QOL analyses showing the value of RIB + ET in maintaining QOL for pts with HR+/HER2− ABC. aGHS by ≥10% NE, not estimable.
TDD, median mo RIB + ET (n=819) PBO + ET (n=709) HR (95% CI) All pts Nausea/vomiting ≥12 points 57.9 NE 1.04 (0.82-1.31) Diarrhea ≥10 points NE 55.2 0.76 (0.59-1.00) Anxiety/depression ≥30% 52.0 49.7 0.78 (0.63-0.96) Age (n)a <40 y (171) 35.9 23.0 0.78 (0.46-1.30) 40 - <55 y (531) 34.2 27.7 0.75 (0.57-0.99) ≥55 y (826) 42.6 35.9 0.82 (0.65-1.05) Race (n)a Asian (254) 35.9 35.8 0.94 (0.60-1.46) White (1131) 41.5 32.2 0.73 (0.59-0.89) Other (143) 33.2 46.9 1.11 (0.61-2.00) Molecular subtype (n)a Luminal A + B (628) 41.7 35.9 0.86 (0.65-1.14) HER2E (105) 30.4 14.8 0.59 (0.29-1.20) Basal-like (49) 16.5 22.4 0.84 (0.34-2.06) Normal-like (152) 47.2 50.6 0.74 (0.41-1.32)
Clinical trial identification
NCT01958021, NCT02422615, NCT02278120.
Editorial acknowledgement
This abstract was developed with editorial assistance provided by Casey Nielsen, PhD of MediTech Media, LLC. Editorial support was funded by Novartis Pharmaceuticals Corporation.
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Funding
Novartis Pharmaceuticals Corporation.
Disclosure
P.A. Fasching: Research grant/Funding (institution): BioNTech; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Speaker Bureau/Expert testimony: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: Macrogenics; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Puma; Research grant/Funding (institution): Cepheid; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy: AstraZeneca. A. Bardia: Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Research grant/Funding (institution): Radius Health; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Immunomedics/Gilead; Advisory/Consultancy, Research grant/Funding (institution): Biothernostics Inc.; Advisory/Consultancy, Travel/Accommodation/Expenses: Taiho; Advisory/Consultancy: Daiichi Pharma/AstraZeneca; Advisory/Consultancy: Puma; Advisory/Consultancy, Travel/Accommodation/Expenses: Phillips; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: Mersana. A. Nusch: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Amgen. G. Jerusalem: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self): AbbVie; Honoraria (self): Daiichi Sankyo; Advisory/Consultancy: MedImmune; Advisory/Consultancy: Merck. N.S. El Saghir: Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Eli Lilly. E. Alba Conejo: Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): NanoString; Travel/Accommodation/Expenses: Celgene; Research grant/Funding (institution): Sysmex. S-A. Im: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Hanmi; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Eisai; Advisory/Consultancy: Amgen; Advisory/Consultancy: MediPacto; Research grant/Funding (institution): Roche; Honoraria (self): Lilly; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: GSK; Research grant/Funding (institution): Daewoong Pharm. W. Janni: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis. D. Chandiwana, B.R. Lanoue, A. Thuerigen, E. Gu: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. N. Harbeck: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca. All other authors have declared no conflicts of interest.
Presenter Of 2 Presentations
Invited Discussant 93MO and 94MO (ID 259)
91O - Pooled analysis of patient (pt)-reported outcomes (PROs) in the MONALEESA (ML)-2, -3, and -7 trials: additional results and key subgroup findings (ID 240)
Abstract
Background
The phase III ML-2, -3, and -7 trials assessed ribociclib (RIB) with different endocrine therapy (ET) partners in pts with hormone receptor–positive, HER2-negative (HR+/HER2−) advanced breast cancer (ABC). Quality-of-life (QOL) results were previously reported for each ML trial and as a pooled analysis. Here, we report on individual dimensions of the EORTC QLQ-C30 PROs, including relevant pt subgroup data from a pooled analysis of the ML trials.
Methods
PROs were collected with EORTC QLQ-C30 questionnaires. QOL was assessed for all pts in ML-2, pts without prior ET for ABC in ML-3, and pts receiving RIB or placebo (PBO) + a nonsteroidal aromatase inhibitor in ML-7. A linear effects model was used to calculate the least-squares mean changes from baseline in global health status (GHS), nausea and vomiting, diarrhea, and anxiety/depression, and these were interpreted using minimally important differences. GHS was also assessed for pt subgroups including age, race, and molecular subtype by PAM50.
Results
A total of 1528 pts were included. Time to definitive deterioration (TDD) for diarrhea and anxiety/depression was prolonged for RIB vs PBO (Table). Diarrhea, anxiety/depression, and GHS across subgroups were improved or maintained from cycle 3 to end of treatment. Median TDD of GHS was longer for RIB vs PBO in pts regardless of age. Median TDD of GHS for RIB vs PBO was longer for White pts, similar for Asian pts, and shorter for pts of other races, although the n in the latter group was small. Median TDD of GHS for RIB vs PBO was longer in pts with luminal subtypes and was more than doubled for the HER2-enriched (HER2E; 30.4 vs 14.8 mo) subtype.
Conclusions
In this pooled analysis of the ML trials, RIB + ET showed delayed deterioration in QOL scores. TDD for GHS favored RIB vs PBO across most subgroups. These results support prior QOL analyses showing the value of RIB + ET in maintaining QOL for pts with HR+/HER2− ABC. aGHS by ≥10% NE, not estimable.
TDD, median mo RIB + ET (n=819) PBO + ET (n=709) HR (95% CI) All pts Nausea/vomiting ≥12 points 57.9 NE 1.04 (0.82-1.31) Diarrhea ≥10 points NE 55.2 0.76 (0.59-1.00) Anxiety/depression ≥30% 52.0 49.7 0.78 (0.63-0.96) Age (n)a <40 y (171) 35.9 23.0 0.78 (0.46-1.30) 40 - <55 y (531) 34.2 27.7 0.75 (0.57-0.99) ≥55 y (826) 42.6 35.9 0.82 (0.65-1.05) Race (n)a Asian (254) 35.9 35.8 0.94 (0.60-1.46) White (1131) 41.5 32.2 0.73 (0.59-0.89) Other (143) 33.2 46.9 1.11 (0.61-2.00) Molecular subtype (n)a Luminal A + B (628) 41.7 35.9 0.86 (0.65-1.14) HER2E (105) 30.4 14.8 0.59 (0.29-1.20) Basal-like (49) 16.5 22.4 0.84 (0.34-2.06) Normal-like (152) 47.2 50.6 0.74 (0.41-1.32)
Clinical trial identification
NCT01958021, NCT02422615, NCT02278120.
Editorial acknowledgement
This abstract was developed with editorial assistance provided by Casey Nielsen, PhD of MediTech Media, LLC. Editorial support was funded by Novartis Pharmaceuticals Corporation.
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Funding
Novartis Pharmaceuticals Corporation.
Disclosure
P.A. Fasching: Research grant/Funding (institution): BioNTech; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Speaker Bureau/Expert testimony: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: Macrogenics; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy: Puma; Research grant/Funding (institution): Cepheid; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy: AstraZeneca. A. Bardia: Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Research grant/Funding (institution): Radius Health; Advisory/Consultancy, Leadership role, Research grant/Funding (institution), Travel/Accommodation/Expenses: Immunomedics/Gilead; Advisory/Consultancy, Research grant/Funding (institution): Biothernostics Inc.; Advisory/Consultancy, Travel/Accommodation/Expenses: Taiho; Advisory/Consultancy: Daiichi Pharma/AstraZeneca; Advisory/Consultancy: Puma; Advisory/Consultancy, Travel/Accommodation/Expenses: Phillips; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: Mersana. A. Nusch: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Amgen. G. Jerusalem: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self): AbbVie; Honoraria (self): Daiichi Sankyo; Advisory/Consultancy: MedImmune; Advisory/Consultancy: Merck. N.S. El Saghir: Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Eli Lilly. E. Alba Conejo: Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): NanoString; Travel/Accommodation/Expenses: Celgene; Research grant/Funding (institution): Sysmex. S-A. Im: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Hanmi; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Eisai; Advisory/Consultancy: Amgen; Advisory/Consultancy: MediPacto; Research grant/Funding (institution): Roche; Honoraria (self): Lilly; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: GSK; Research grant/Funding (institution): Daewoong Pharm. W. Janni: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis. D. Chandiwana, B.R. Lanoue, A. Thuerigen, E. Gu: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. N. Harbeck: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca. All other authors have declared no conflicts of interest.
Author Of 5 Presentations
- J. Furlanetto (Neu-Isenburg, Germany)
- M. Untch (Berlin, Germany)
- B. Sinn (Berlin, Germany)
- B. Lederer (Neu-Isenburg, Germany)
- A. Schneeweiss (Heidelberg, Germany)
- V. Mueller (Hamburg, Germany)
- M. Van Mackelenbergh (Kiel, Germany)
- E. Stickeler (Aachen, Germany)
- P. Fasching (Erlangen, Germany)
- C. Schem (Hamburg, Germany)
- T. Karn (Frankfurt am Main, Germany)
- F. Marmé (Mannheim, Germany)
- V. Nekljudova (Neu-Isenburg, Germany)
- S. Loibl (Neu-Isenburg, Germany)
17P - Impact of body mass index (BMI) on prognostic and predictive value of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC): a pooled analysis of six neoadjuvant trials.
Abstract
Background
Obesity is associated with T-cell dysfunction and reduced antitumor immune response. In TNBC, high sTILs seem to predict pathologic complete response (pCR) and favorable prognosis only in normal weight patients (Desmedt et al. Cancer Res 2020).
Methods
TNBC patients, who received anthracycline-taxane-based chemotherapy in GeparDuo, GeparTrio, GeparQuinto, GeparSixto, GeparSepto, and GeparOcto, with available BMI and pretreatment sTILs (centrally assessed) were considered. Patients with BMI <18.5 kg/m2 were excluded. Associations between BMI (normal weight, 18.5-<25 vs overweight/obese ≥25 kg/m2), sTILs (high ≥30% vs low <30) and pCR were assessed using Fisher`s exact test; between sTILs (continuous, dichtomized) and pCR (ypT0/is ypN0) according to BMI and interaction BMI*sTILs by logistic regression, between sTILs and disease-free survival (DFS) according to BMI and interaction BMI*sTILs by Cox regression.
Results
Of 1288 patients, 49.8% were normal weight, 50.2% overweight/obese; median age was 47 [21-78] vs 50 [21-76] years (p<0.001), cT3-4 12.0% vs 16.6% (p=0.021) and N+ 32.7% vs 37.0% (p=0.125). Normal weight patients had a higher pCR than overweight/obese patients (47.2% vs 39.9% p=0.009). Median sTILs was 30%, 50.4% of patients had high sTILs (normal weight 50.2% vs overweight/obese 50.6%, p=0.868). Higher level of sTILs was predictive for pCR both in normal weight (sTILs continuous OR 1.10, 95%CI 1.03-1.17, p=0.002) and in overweight/obese patients (OR 1.15, 95%CI 1.08-1.22, p<0.001). Interaction BMI*sTILs, p=0.302. Results were similar for dichotomized sTILs. Median follow-up was 54.7 months. Each 10% increase in sTILs was associated with an 11% reduction in the risk of a DFS event in normal weight (HR 0.89, 95%CI 0.82-0.95, p=0.001) and 8% in overweight/obese patients (HR 0.92, 95%CI 0.87-0.99, p=0.017). Interaction TILs*BMI, p=0.366.
Conclusions
Our results do not confirm differences in the predictive and prognostic role of sTILs according to BMI in TNBC as described previously. A joint analysis to explore the source of observed heterogeneity is planned.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
C. Denkert: Research grant/Funding (self): European Commission H2020; Research grant/Funding (self): German Cancer Aid Translational Oncology; Honoraria (self): Novartis, Roche, MSD Oncology, Daiichi Sankyo, AstraZeneca, Molecular Health; Research grant/Funding (self): Myriad; Honoraria (self): Merck, Sividon diagnostics; Licensing/Royalties, patent VMScope digital pathology software with royalties paid: patent VMScope digital pathology software; Licensing/Royalties, cancer immunotherapy pending: patent WO2020109570A1; Licensing/Royalties, therapy response issued: patent WO2015114146A1 and WO2010076322A1. M. Untch: Honoraria (self), Non-remunerated activity/ies: AbbVie; Honoraria (self), Non-remunerated activity/ies: Amgen GmbH; Honoraria (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self): BMS; Honoraria (self), Non-remunerated activity/ies: Celgene GmbH; Honoraria (self), Non-remunerated activity/ies: Daiichi Sankyo; Honoraria (self), Non-remunerated activity/ies: Eisai GmbH; Honoraria (self): Lilly Deutschland; Honoraria (self), Non-remunerated activity/ies: Lilly Int.; Honoraria (self), Non-remunerated activity/ies: MSD Merck; Honoraria (self), Non-remunerated activity/ies: Mundipharma; Honoraria (self), Non-remunerated activity/ies: Myriad Genetics; Honoraria (self), Non-remunerated activity/ies: Odonate; Honoraria (self), Non-remunerated activity/ies: Pfizer GmbH; Honoraria (self): PUMA Biotechnology; Honoraria (self), Non-remunerated activity/ies: Roche Pharma AG; Honoraria (self), Non-remunerated activity/ies: Sanofi Aventis Deutschland GmbH; Honoraria (self), Non-remunerated activity/ies: Teva Pharmaceuticals Ind Ltd.; Honoraria (self), Non-remunerated activity/ies: Novartis, Clovis Oncology; Honoraria (self): Pierre Fabre, Seatlle Genetics. A. Schneeweiss: Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Roche; Research grant/Funding (self): AbbVie; Honoraria (self), Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Research grant/Funding (self), Medical writing grant: Roche. V. Mueller: Speaker Bureau/Expert testimony: Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seagen, Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Tesaro, Nektar; Advisory/Consultancy: Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Tesaro and Nektar; Research grant/Funding (institution): Novartis, Roche, Seattle Genetics, Genentech. M. van Mackelenbergh: Honoraria (self): Amgen, AstraZeneca, Genomic Health, Mylan, Novartis, Pfizer, Pierre Fabre, Roche. P.A. Fasching: Honoraria (self): Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, Merck Sharp & Dohme, Lilly, Pierre Fabre, Seattle Genetics, Roche, Hexal; Research grant/Funding (self): Biontech, Cepheid. F. Marmé: Research grant/Funding (self): AstraZeneca; Honoraria (self): AstraZeneca, MSD, Clovis, GSK/Tesaro, Pfizer, Novartis, Lilly, Roche, Celgene, Seagen, Myriad, PharmaMar, Eisai, Janssen-Cilag. S. Loibl: Honoraria (institution), Research grant/Funding (institution), honorario for lectures and ad boards: Abbie, Celgene; Honoraria (institution), honorario for lectures: PriME/Medscape; Honoraria (self): Chugai; Honoraria (self), Honoraria (institution), Research grant/Funding (institution): Daiichi Sankyo; Honoraria (institution), honorarium for ad boards paid to: Lilly; Advisory/Consultancy, advisor honorarium paid to institute: BMS, Puma; Research grant/Funding (institution): Immunomedics; Honoraria (institution), Research grant/Funding (institution), honorarium for lectures and ad: AstraZeneca, Amgen, Novartis, Pfizer; Honoraria (institution), honorarium for lectures and ad: Pierre Fabre, Merck; Honoraria (institution), advisor honorarium paid to institute: EirGenix; Honoraria (institution), Research grant/Funding (institution), grant and honorarium paid to: Roche; Honoraria (institution): Seagen; Licensing/Royalties, pending: EP14153692.0. All other authors have declared no conflicts of interest.
- V. Vladimirova (Neu-Isenburg, Germany)
- A. Schneeweiss (Heidelberg, Germany)
- C. Jackisch (Offenbach am Main, Germany)
- K. Weber (Neu-Isenburg, Germany)
- C. Denkert (Marburg, Germany)
- S. Schmatloch (Kassel, Germany)
- T. Karn (Frankfurt am Main, Germany)
- P. Fasching (Erlangen, Germany)
- S. Braun (Offenbach am Main, Germany)
- C. Szeto (Santa Cruz, CA, United States of America)
- B. Sinn (Berlin, Germany)
- M. Van Mackelenbergh (Kiel, Germany)
- C. Schem (Hamburg, Germany)
- E. Stickeler (Aachen, Germany)
- P. Soon-Shiong (Santa Cruz, CA, United States of America)
- F. Marmé (Mannheim, Germany)
- V. Mueller (Hamburg, Germany)
- M. Untch (Berlin, Germany)
- V. Nekljudova (Neu-Isenburg, Germany)
- S. Loibl (Neu-Isenburg, Germany)
21P - BACH1 and HIF1α predict response to neoadjuvant nab-paclitaxel (nP) treatment in early breast cancer (BC)
Abstract
Background
Hypoxia occurs in most solid tumors including BC and may negatively impact treatment response. We investigate the incidence of BACH1 (a key regulator of mitochondrial metabolism) and HIF1α (a hypoxia-inducible factor) expressions and their correlation with clinical outcomes in early HER2-negative BC.
Methods
We correlated tumor BACH1 and HIF1α mRNA expression from available RNA-Seq data with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS) in the GeparSepto trial (NCT01583426), which randomized pts with early-stage BC to either neoadjuvant solvent-based paclitaxel (P) or nP followed by EC. BACH1 and HIF1α values were analyzed as a continuous variable and categorized as low and high by median cut-off. Multivariate logistic (for pCR) and Cox (DFS and OS) regressions were used to adjust for age, cT, and cN.
Results
RNA-Seq expression data was available for 279 out of 810 HER2-negative BC pts, median age was 49 years (range 22-76) and median follow-up 49.8 months (range 2.3-62.4). There was a positive correlation between BACH1 and HIF1A expression levels (Pearson correlation 0.498). Overall, BACH1 and HIF1α continuous expressions were significantly associated with increased pCR (OR=4.21 [95%CI 1.44-12.30), p=0.009), OR=2.08 [95%CI 1.14-3.82], p=0.018, respectively) but did not impact survival in multivariate models. The table shows effects of BACH1 and HIF1α expression in nP vs P arm, both high BACH1 and HIF1α expressions were significant independent predictors of pCR and were associated with numerically better survival *OR/HR (nP vs P groups) in multivariate model **interaction test (BACH1 high/HIF1α high by nP arm) p value, multivariate model.
Endpoint BACH1 HIF1α low high P** low high P** OR/HR* (95%C/I) P OR/HR* (95%CI) P OR/HR* (95%CI) P OR/HR* (95%CI) P ypT0 ypN0 0.84 (0.33-2.12) 0.716 2.86 (1.33-6.17) 0.007 0.042 0.67 (0.26-1.70) 0.396 2.91 (1.32-6.42) 0.008 0.018 DFS 0.93 (0.46-1.87) 0.839 0.70 (0.32-1.53) 0.375 0.534 1.58 (0.70-3.55) 0.272 0.62 (0.30-1.26) 0.187 0.096 OS 0.83 (0.33-2.09) 0.686 0.46 (0.16-1.36) 0.159 0.453 2.07 (0.60-7.18) 0.250 0.46 (0.18-1.17) 0.101 0.067
Conclusions
HER2-negative BC with elevated BACH1 and HIF1α expression benefits from nP-based treatment. There was a positive correlation between increased BACH1 and HIF1α levels for predicting pCR. We suggest that high BACH1 and HIF1α expressions enhance the efficacy of nP treatment, perhaps through triggering the hypoxic tumor adaptation.
Clinical trial identification
NCT01583426.
Legal entity responsible for the study
GBG Forschungs GmbH.
Funding
Has not received any funding.
Disclosure
A. Schneeweiss: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution), Non-remunerated activity/ies, Medical writing grant: Roche; Research grant/Funding (institution): AbbVie; Honoraria (self), Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Lilly. C. Denkert: Research grant/Funding (institution), Oncobiome project: European Commission H2020; Research grant/Funding (institution), INTEGRATE-TN project: German Cancer Aid Translational Oncology; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): MSD Oncology; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Molecular Health; Research grant/Funding (institution): Myriad; Honoraria (self): Merck; Shareholder/Stockholder/Stock options: Sividon diagnostics; Licensing/Royalties, patent royalties: VMScope digital pathology software; Licensing/Royalties, patent pending: WO2020109570A1 - cancer immunotherapy; Licensing/Royalties, patent issued: WO2015114146A1 and WO2010076322A1- therapy response. P.A. Fasching: Honoraria (self): Novartis; Research grant/Funding (institution): Biontech; Honoraria (self): Pfizer; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Merck Sharp & Dohme; Research grant/Funding (institution): Cepheid; Honoraria (self): Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Seattle Genetics; Honoraria (self): Roche; Honoraria (self): Hexal. M. van Mackelenbergh: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Genomic Health; Honoraria (self): Mylan; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Roche. F. Marmé: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Clovis; Honoraria (self): GSK/Tesaro; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Roche; Honoraria (self): Celgene; Honoraria (self): Seagen; Honoraria (self): Myriad; Honoraria (self): PharmaMar; Honoraria (self): Eisai; Honoraria (self): Janssen-Cilag. V. Mueller: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Seagen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Genentech; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Celgene; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self): Teva; Honoraria (self): Janssen-Cilag; Advisory/Consultancy: Hexal; Advisory/Consultancy: Nektar. M. Untch: Honoraria (institution), Non-remunerated activity/ies: AbbVie; Honoraria (institution), Non-remunerated activity/ies: Amgen; Honoraria (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (institution): BMS; Honoraria (institution), Non-remunerated activity/ies: Celgene; Honoraria (institution), Non-remunerated activity/ies: Daiichi Sankyo; Honoraria (institution), Non-remunerated activity/ies: Eisai; Honoraria (institution), Non-remunerated activity/ies: Lilly Deutschland and Int.; Honoraria (institution), Non-remunerated activity/ies: MSD Merck; Honoraria (institution), Non-remunerated activity/ies: Mundipharma; Honoraria (institution), Non-remunerated activity/ies: Myriad Genetics; Honoraria (self), Non-remunerated activity/ies: Odonate; Honoraria (institution), Non-remunerated activity/ies: Pfizer; Honoraria (self): PUMA Biotechnology; Honoraria (institution), Non-remunerated activity/ies: Roche; Honoraria (institution), Non-remunerated activity/ies: Sanofi Aventis Deutschland GmbH; Honoraria (institution), Non-remunerated activity/ies: Teva; Honoraria (institution), Non-remunerated activity/ies: Novartis; Honoraria (institution): Pierre Fabre and Seattle Genetics; Honoraria (institution), Non-remunerated activity/ies: Clovis Oncology. S. Loibl: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Honoraria (institution): SeaGen; Research grant/Funding (institution): Immunomedics/Gilead Sciences Inc.; Honoraria (institution): Prime/Medscape; Honoraria (institution): Eirgenix; Research grant/Funding (self), Research grant/Funding (institution): DSI; Honoraria (institution): BMS; Honoraria (institution): Merck; Honoraria (institution): Puma; Speaker Bureau/Expert testimony: Chugai; Licensing/Royalties, patent pending: EP14153692.0-Immunsignature in TNBC. All other authors have declared no conflicts of interest.
- J. Leichsenring (Heidelberg, Germany)
- V. Vladimirova (Neu-Isenburg, Germany)
- C. Solbach (Frankfurt am Main, Germany)
- T. Karn (Frankfurt am Main, Germany)
- B. Ataseven (München and Essen, Germany)
- B. Sinn (Berlin, Germany)
- J. Barinoff (Berlin, Germany)
- V. Mueller (Hamburg, Germany)
- J. Blohmer (Berlin, Germany)
- C. Schem (Hamburg, Germany)
- K. Engels (Neuss, Germany)
- F. Marmé (Mannheim, Germany)
- A. Fissler-Eckhoff (Wiesbaden, Germany)
- P. Fasching (Erlangen, Germany)
- E. Stickeler (Aachen, Germany)
- M. Van Mackelenbergh (Kiel, Germany)
- C. Denkert (Marburg, Germany)
- A. Stenzinger (Heidelberg, Germany)
- S. Loibl (Neu-Isenburg, Germany)
- S. Gröschel (Heidelberg, Germany)
28P - EVI1 expression in early-stage breast cancer patients treated with neoadjuvant chemotherapy
Abstract
Background
Overexpression of the proto-oncogene EVI1 has been implicated as a prognostic factor in breast cancer (BC), particularly triple-negative BC (TNBC). The purpose of this study was to investigate frequency and clinical relevance of EVI1 expression in newly diagnosed BC treated with neoadjuvant chemotherapy.
Methods
EVI1 expression was determined by immunohistochemistry in pretherapeutic biopsies of BC patients treated with anthracycline/taxane based neoadjuvant chemotherapy within the GeparTrio trial. EVI1 expression was analyzed as a continuous variable and dichotomized into low or high based on median expression. Logistic regression and Cox proportional hazard models were used to correlate EVI1 expression with pathological complete response (pCR) and survival outcome, respectively. Disease-free survival (DFS) and overall survival (OS) rates according to EVI1 dichotomized expression were estimated with Kaplan-Maier curves with log-rank p-values.
Results
Of the 993 tumors with evaluable EVI1, 50.8% were HR+/HER2-, 15% HR+/HER2+, 9.8% HR-/HER2+, and 24.5% TNBC. Median EVI1 H-score was 112.16 (range 0.5-291.4). High EVI1 expression was more frequently observed in HR+/HER2- (52%) and TNBC (25%) compared to 13% in HR+/HER2+ and 10% in HR-/HER2+ and was significantly associated with smaller tumor size (cT1-2, p=0.004) in HR+/HER- BC. Elevated EVI1 levels were not significantly associated with therapy response and survival in the overall cohort. However, TNBC patients with high EVI1 showed a trend towards higher pCR rates compared to low EVI1 group (37.7% vs 27.5%, p=0.072; odds ratio 1.60 (95%CI 0.90-2.85, p=0.110) and numerically better survival (DFS: HR=0.77 [95%CI 0.48-1.23], log-rank p=0.271); OS: (HR=0.76 [95% 0.44-1.31], log-rank p=0.314).
Conclusions
EVI1 did neither influence response to neoadjuvant therapy nor patient survival in the overall cohort. TNBC patients with elevated EVI1 expression showed numerically better pCR and improved survival. Further analyses are needed to verify our findings, especially in the pathological work-up of newly diagnosed TNBC patients.
Clinical trial identification
NCT00544765; NCT00544765.
Legal entity responsible for the study
GBG Forschungs GmbH.
Funding
Has not received any funding.
Disclosure
B. Ataseven: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self): AstraZeneca; Honoraria (self): Clovis; Non-remunerated activity/ies: PharmaMar; Honoraria (self), Non-remunerated activity/ies: Tesaro/GSK; Honoraria (self): MSD; Honoraria (self): Celgene; Honoraria (self): Amgen. V. Mueller: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Seagen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Genentech; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Celgene; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self): Teva; Honoraria (self): Janssen-Cilag; Advisory/Consultancy: Hexal; Advisory/Consultancy: Nektar. J-U. Blohmer: Honoraria (self), Research grant/Funding (institution): Sysmex; Research grant/Funding (institution): Somatex; Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): SonoScape. F. Marmé: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Clovis; Honoraria (self): GSK/Tesaro; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Roche; Honoraria (self): Celgene; Honoraria (self): Seagen; Honoraria (self): Myriad; Honoraria (self): PharmaMar; Honoraria (self): Eisai; Honoraria (self): Janssen-Cilag. P.A. Fasching: Honoraria (self): Novartis; Research grant/Funding (institution): Biontech; Honoraria (self): Pfizer; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Merck Sharp & Dohme; Research grant/Funding (institution): Cepheid; Honoraria (self): Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Seattle Genetics; Honoraria (self): Roche; Honoraria (self): Hexal. M. van Mackelenbergh: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Genomic Health; Honoraria (self): Mylan; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Roche. C. Denkert: Research grant/Funding (institution), Oncobiome project: European Commission H2020; Research grant/Funding (institution), INTEGRATE-TN project: German Cancer Aid Translational Oncology; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): MSD Oncology; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Molecular Health; Research grant/Funding (institution): Myriad; Honoraria (self): Merck; Shareholder/Stockholder/Stock options, Cofounder/shareholder until 2016: Sividon diagnostics; Licensing/Royalties, patent royalties: VMScope digital pathology software; Licensing/Royalties, patent pending: WO2020109570A1 - cancer immunotherapy; Licensing/Royalties, patent issued: WO2015114146A1 and WO2010076322A1- therapy response. A. Stenzinger: Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: AGCT; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Illumina; Advisory/Consultancy, Speaker Bureau/Expert testimony: Janssen; Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Seattle Genetics; Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Advisory/Consultancy, Speaker Bureau/Expert testimony: Thermo Fisher; Research grant/Funding (institution): Chugai. S. Loibl: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Honoraria (institution): SeaGen; Research grant/Funding (institution): Immunomedics/Gilead Sciences Inc.; Honoraria (institution): Prime/Medscape; Honoraria (institution): Eirgenix; Research grant/Funding (self), Research grant/Funding (institution): DSI; Honoraria (institution): BMS; Honoraria (institution): Merck; Honoraria (institution): Puma; Speaker Bureau/Expert testimony: Chugai; Licensing/Royalties, patent pending: EP14153692.0-Immunsignature in TNBC. All other authors have declared no conflicts of interest.
- S. Labidi-Galy (Geneva, Switzerland)
- A. Schneeweiss (Heidelberg, Germany)
- H. Sinn (Heidelberg, Germany)
- J. Blohmer (Berlin, Germany)
- L. Romanens (Geneva, Switzerland)
- D. Zahm (Gera, Germany)
- J. Huober (Ulm, Germany)
- D. Dohnal (Düsseldorf, Germany)
- T. Link (Dresden, Germany)
- C. Hanusch (München, Germany)
- C. Jackisch (Offenbach, Germany)
- P. Fasching (Erlangen, Germany)
- C. Solbach (Frankfurt am Main, Germany)
- K. Rhiem (Köln, Germany)
- C. Denkert (Marburg, Germany)
- K. Weber (Neu-Isenburg, Germany)
- B. Lederer (Neu-Isenburg, Germany)
- M. Untch (Berlin, Germany)
- S. Loibl (Neu-Isenburg, Germany)
- J. Furlanetto (Neu-Isenburg, Germany)
66P - Baseline menopausal status, Ki-67 and stromal tumor-infiltrating lymphocytes (TILs) and association with outcome in triple-negative breast cancer (TNBC): exploratory analysis in GeparSixto
Abstract
Background
Several trials confirmed a survival benefit from temporary menopause during or after chemotherapy (CT) for patients with estrogen receptor-negative early BC. We investigated the impact of menopause on TNBC outcome after neoadjuvant CT (NACT).
Methods
GeparSixto evaluated the addition of carboplatin to anthracycline-taxane-based NACT. We aimed to determine the impact of menopausal status on continuous Ki-67 and TILs from baseline biopsies in all patients, and according to germline (g)BRCA1 status. TILs and gBRCA status were centrally assessed. Secondary objectives were the impact of age (≤40 vs >40 years) on baseline Ki-67 and TILs in all patients and according to gBRCA1 status, baseline menopausal status and age on pathological complete response (pCR, ypT0 ypN0), disease-free survival (DFS) and distant disease-free survival (DDFS) according to pCR.
Results
43/315 included patients had a gBRCA1 mutation (14.8%); mean Ki-67 was higher in ≤40 compared to >40 years (63.9 vs 57.9%, p=0.045) and in pre- compared to postmenopausal patients (63.1 vs 53.9%, t-test p=0.001). Mean TILs did not differ according to age (38.4 vs 33.5%, p=0.126) or menopausal status (35.9 vs 33.0%, p=0.311). There was no difference in Ki-67 or TILs according to age and menopausal status in gBRCA1 carriers. pCR rate was higher in women ≤40 years (55.4 vs 44.4%) and premenopausal (50.5 vs 36.6%). For multivariate analysis for DFS refer to the below table. Neither young age nor premenopausal status at baseline predicted for DFS. In non-pCR patients, premenopausal status at baseline but not age ≤40 years was associated with a higher relapse risk (Table). Similar results were obtained for DDFS. * adjusted for tumor stage, nodal status, tumor grade, Ki67, TILs and carboplatin use.
pCR (ypT0 ypN0) OR (95% CI)* p-value 5-year DFS rate (N=315) HR (95% CI)* p-value 5-year DFS rate in non-pCR (N=173) HR (95% CI)* p-value 5-year DFS rate in pCR (N=142) HR (95% CI)* p-value Age >40 years (N=232) 41.4% 1 74.9% 1 62.7% 1 91.7% 1 ≤40 years (N=83) 55.4% 1.47 (0.85-2.55) 0.167 81.2% 0.87 (0.48-1.55) 0.631 68.8% 0.83 (0.43-1.61) 0.583 91.6% 1.11 (0.26-4.68) 0.890 Menopausal status Postmenopausal (N=123) 36.6% 1 78.4% 1 70.2% 1 92.3% 1 Premenopausal (N=192) 50.5% 1.54 (0.92-2.57) 0.101 75.3% 1.49 (0.88-2.52) 0.137 58.8% 1.79 (1.01-3.18) 0.046 91.4% 1.16 (0.26-5.20) 0.849
Conclusions
In patients with early TNBC, premenopausal compared to postmenopausal status is associated with a higher cancer cell proliferation at baseline and a higher risk of relapse in case of no pCR.
Legal entity responsible for the study
GBG.
Funding
Has not received any funding.
Disclosure
S.I. Labidi-Galy: Honoraria (self): AstraZeneca; Honoraria (institution): Novimmune. A. Schneeweiss: Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses, Research Grant, Travel expenses, Medical writing grant: Celgene; Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses, Expert testimony, Research Grant, Travel expenses: Roche; Honoraria (institution), Research Grant: AbbVie; Honoraria (self), Expert testimony, Honoraria: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses, Honoraria, Travel expenses: Pfizer; Honoraria (self), Honoraria: Novartis; Honoraria (self), Honoraria: MSD; Honoraria (self), Honoraria: Tesaro; Honoraria (self), Honoraria: Lilly. J-U. Blohmer: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self), Honoraria (institution): Sysmex; Honoraria (self): Roche; Honoraria (self): Pierre Fabre. J. Huober: Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): AbbVie; Honoraria (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Celgene; Honoraria (self): Roche; Travel/Accommodation/Expenses: Daiichi; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pfizer; Honoraria (institution): Novartis; Honoraria (institution): Hexal. T. Link: Honoraria (self): Teva; Honoraria (self): Tesaro; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Amgen; Honoraria (self): Clovis; Honoraria (self): Celgene; Honoraria (self): Lilly; Honoraria (self): Myriad. C. Hanusch: Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self): Lilly. C. Jackisch: Honoraria (self): Celgene. P.A. Fasching: Honoraria (self): Novartis; Honoraria (institution): Biontech; Honoraria (self): Pfizer; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Merck Sharp & Dohme; Honoraria (institution): Cepheid; Honoraria (self): Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Seattle Genetics; Honoraria (self): Roche; Honoraria (self): Hexal. K.E. Rhiem: Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): MSD. C. Denkert: Honoraria (institution), Oncobiome project: European Commission H2020; Honoraria (institution), INTEGRATE-TN project: German Cancer Aid Translational Oncology; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): MSD Oncology; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Molecular Health; Honoraria (institution): Myriad; Honoraria (self): Merck; Shareholder/Stockholder/Stock options, Cofounder/shareholder until 2016: Sividon diagnostics; Licensing/Royalties: VMScope digital pathology software; Licensing/Royalties: WO2020109570A1 - cancer immunotherapy; Licensing/Royalties: WO2015114146A1 and WO2010076322A1- therapy response. M. Untch: Honoraria (institution), All fees to the institution/employer: AbbVie; Honoraria (institution), All fees to the institution/employer: Amgen GmbH; Honoraria (institution), All fees to the institution/employer: AstraZeneca; Honoraria (institution), All fees to the institution/employer: BMS; Honoraria (institution), All fees to the institution/employer: Celgene GmbH; Honoraria (institution), All fees to the institution/employer: Daiichi Sankyo; Honoraria (institution), All fees to the institution/employer: Eisai GmbH; Honoraria (institution), All fees to the institution/employer: Lilly Deutschland; Honoraria (institution), All fees to the institution/employer: Lilly Int.; Honoraria (institution), All fees to the institution/employer: MSD Merck; Honoraria (institution), All fees to the institution/employer: Mundipharma; Honoraria (institution), All fees to the institution/employer: Myriad Genetics; Honoraria (institution): Odonate; Honoraria (institution), All fees to the institution/employer: Pfizer GmbH; Honoraria (institution): PUMA Biotechnology; Honoraria (institution), All fees to the institution/employer: Roche Pharma AG; Honoraria (institution), All fees to the institution/employer: Sanofi Aventis Deutschland GmbH; Honoraria (institution), All fees to the institution/employer: TEVA Pharmaceuticals Ind Ltd.; Honoraria (institution), All fees to the institution/employer: Novartis; Honoraria (institution), All fees to the institution/employer: Pierre Fabre, Clovis Oncology, Seatlle Genetics. S. Loibl: Honoraria (institution), honorario for lectures and ad boards paid to institute: AbbVie; Honoraria (institution), honorario for lectures and ad boards paid to institute: Celgene; Honoraria (institution), honorarium for lectures paid to institute: PriME/Medscape; Honoraria (self), lecture: Chugai; Honoraria (self), Honoraria (institution), honorario paid to institute: Daiichi Sankyo; Honoraria (institution), honorarium for ad boards paid to institute: Lilly; Honoraria (institution), advisor honorarium paid to institute: BMS; Honoraria (institution), advisor honorarium paid to institute: Puma; Honoraria (institution), paid to institute: Immunomedics; Honoraria (institution), honorarium for lectures and ad boards paid to institute: AstraZeneca; Honoraria (institution), honorarium for lectures and ad boards paid to institute: Pierre Fabre; Honoraria (institution), honorarium for lectures and ad boards paid to institute: Merck; Honoraria (institution), advisor honorarium paid to institute: EirGenix; Honoraria (institution), honorarium for lectures and ad boards paid to institute: Amgen; Honoraria (institution), honorarium for lectures and ad boards paid to institute: Novartis; Honoraria (institution), honorarium for lectures and ad boards paid to institute: Pfizer; Honoraria (institution), grant and honorarium paid to institute: Roche; Honoraria (institution), paid to institute: Seagen; Licensing/Royalties, Immunsignature in TNBC: EP14153692.0. All other authors have declared no conflicts of interest.
108P - Epigenetic regulation of the putative breast cancer metastasis suppressor gene SCN4B
Abstract
Background
Breast cancer is still the leading cause of cancer deaths in women worldwide. While SCN4B is considered to be a novel metastasis suppressor gene in breast cancer, very little is known about its epigenetic regulation – in particular its downregulation in cancer tissue. In this study we explored SCN4B epigenetic regulation by promotor methylation and histone deacetylation and the clinical properties of breast tumors showing loss of SCN4B.
Methods
After performing methylation analysis of the SCN4B promotor region with data obtained from the TCGA data base, SCN4B methylation and expression levels were investigated in breast cancer cell lines by pyrosequencing and qPCR, respectively. Next, cell lines were treated with methyltransferase inhibitor 5-azacytidine (AZA) and histone deacetylase inhibitor trichostatin A (TSA) to investigate possible re-expression of SCN4B. To study clinical properties, a tissue micro array (TMA) containing 420 breast cancer samples (Bavarian breast cancer cohort) was stained with a SCN4B antibody and evaluated using IRS classification.
Results
TCGA data clearly showed higher SCN4B methylation levels in breast cancer tissues compared to normal tissue (p < 0.001) as well as lower SCN4B mRNA expression (p < 0.001) in cancer – with moderate correlation between the two. Concordantly, breast cancer cell lines showed high promotor methylation levels. After AZA and TSA treatment, cell lines exhibited increased SCN4B mRNA expression up to 200-fold. TMA staining showed significantly longer metastasis- and local recurrence-free survival for tumors retaining SCN4B protein expression, as well as correlations between SCN4B protein expression and several clinicopathological parameters such as molecular subtype where loss of SCN4B was particularly substantial in triple negative breast cancer (TNBC). Interestingly, Ki67 was inversely correlated (p < 0.01) with SCN4B expression.
Conclusions
Our findings indicate that SCN4B is a novel metastasis suppressor gene that is epigenetically downregulated in breast cancer, especially in TNBC. Interfering with the cellular signaling pathways normally suppressed by SCN4B may open new avenues to treat triple negative breast cancer.
Legal entity responsible for the study
The authors.
Funding
European Union (Horizon 2020).
Disclosure
All authors have declared no conflicts of interest.