C. Denkert (Marburg, Germany)
Philipps-University MarburgAuthor Of 3 Presentations
Immunohistochemistry: The new IHC “low” categories (ER, HER2⋯.) and androgen receptor testing (ID 23)
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.
95MO - Characteristics of patients with brain metastases from HER2-positive breast cancer (ID 267)
Abstract
Background
About 40% of patients with a metastatic HER2+ breast cancer (BC) develop brain metastases (BM). A better understanding of clinical features of patients with HER2+ BC with BM is required.
Methods
A total of 2948 patients of the Brain Metastases in Breast Cancer (BMBC) Registry were available for this analysis, 1311 of them had a HER2+ subtype.
Results
Patients with a HER2+ BC and BM were,compared to HER2- patients, slightly younger at BC diagnosis (median 52 vs 53 years, p<0.001) and BM diagnosis (median 55 vs 58 years, p<0.001), had a higher pathological complete response rate after neoadjuvant chemotherapy (21.5 vs 12.2%, p=0.002), higher tumor grading (G3 59.5 vs 56.5%, p<0.001) and had less common extracranial metastases (ECM) at BM diagnosis (77.7 vs 80.0%, p<0.001). HER2+ patients had significantly more often BM in the posterior fossa (57.9 vs 49.0%, p<0.001) but less common leptomeningeal metastases (LM) (9.3 vs 19.1%, p<0.001). Hormone-receptor-positive HER2+ patients were younger at BC diagnosis (median 50 vs 53 years, p=0.03), had a smaller initial BC (<5cm: 78.4 vs 66.3%, p=0.002), a lower grading of the primary tumor (G1/G2: 46.1 vs 29.9%, p<0.001) and more often LM (11.3 vs 6.8%, p=0.007). The median overall survival (OS) in all HER2+ patients was 13.2 months (95% CI 11.4-14.4). The following factors were associated with a worse OS (multivariate analysis): older age (≥60 vs <60 years: Hazard Ratio [HR] 1.63, p<0.001), lower performance status (ECOG 2-4 vs 0-1: HR 1.58, p<0.001), greater number of BM (2-3 vs 1 BM: HR 1.36; ≥4 vs 1 BM: HR 1.53, p=0.003; overall p=0.012), BM in fossa anterior (HR 1.71, p<0.001), LM (HR 1.62, p=0.027), BM with neurological symptoms at diagnosis (HR 1.38, p=0.029), ECM at diagnosis of BM (HR 1.44, p=0.02) and the absence of targeted therapy (HR 0.625, p=0.001). Although progression-free survival did not differ in HER2+ patients according to hormone-receptor status, a significantly better OS could be observed for hormonereceptor-positive patients (median 14.3 vs 10.9 months, p=0.027).
Conclusions
The performed analysis identified factors associated with prognosis of HER2+ patients with BM. Further research is needed to understand the factors determining the longer survival of HER2+ hormonereceptor-positive patients.
Legal entity responsible for the study
German Breast Group Forschungs GmbH.
Funding
Has not received any funding.
Disclosure
I. Witzel: Honoraria (institution): Amgen; Honoraria (institution): AstraZeneca; Honoraria (institution): MSD; Honoraria (institution): Novartis; Honoraria (institution): Pierrre Fabre Pharma; Honoraria (institution): Pfizer; Honoraria (institution): Roche; Honoraria (institution): Sanofi-Pfizer. 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. S. Loibl: Honoraria (institution), honoraria for lectures and ad boards paid to institute: AbbVie; Honoraria (institution), honoraria 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), honoraria 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. V. Mueller: Advisory/Consultancy: Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Tesaro and Nektar; Speaker Bureau/Expert testimony: Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seagen and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Tesaro, Nektar; Honoraria (institution): Novartis, Roche, Seattle Genetics, Genentech. All other authors have declared no conflicts of interest.
Presenter Of 1 Presentation
Immunohistochemistry: The new IHC “low” categories (ER, HER2⋯.) and androgen receptor testing (ID 23)
Moderator Of 1 Session
Author Of 3 Presentations
- 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.