A. Schneeweiss (Heidelberg, Germany)

Universitätsklinikum und Deutsches Krebsforschungszentrum

Author Of 1 Presentation

 Conference Calendar
Proffered Paper session 1 Proffered paper

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)

Presentation Number
2O
Lecture Time
15:03 - 15:13
Speakers
Session Name
Proffered Paper session 1
Room
Channel 2
Date
Fri, 07.05.2021
Time
14:15 - 15:30

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.

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Author Of 4 Presentations

 On-Demand ePoster Display

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.

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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

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

*OR/HR (nP vs P groups) in multivariate model **interaction test (BACH1 high/HIF1α high by nP arm) p value, multivariate model.

 .

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.

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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.

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

* adjusted for tumor stage, nodal status, tumor grade, Ki67, TILs and carboplatin use.

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.

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98P - Final results from AVANTI, a multicentre German observational study of 1st-line bevacizumab (BEV) + chemotherapy (CT) in >2000 patients (pts) with advanced breast cancer (aBC)

Abstract

Background

In Europe, BEV is approved in combination with paclitaxel (PAC) or capecitabine (CAP) as 1st-line therapy for HER2-negative aBC. AVANTI (ML22452) assessed safety, effectiveness and pt-reported outcomes (EORTC QLQ-C30) with these regimens in German routine oncology practice.

Methods

Eligible pts had HER2-negative aBC, no BEV contraindications and had received no prior CT for aBC. CT schedule, diagnostics and follow-up visits were at the physician’s discretion. Data were collected for 1 y after starting BEV, then every 6 mo for 1.5 y (max follow-up: 2.5 y). Treatment satisfaction was rated by pts and physicians. Subgroup analysis was prespecified in clinically relevant subgroups, including triple-negative breast cancer (TNBC).

Results

Between 1 Nov 2009 and 30 Apr 2016, 2065 eligible pts at 346 centres received ≥1 dose of BEV with PAC (n=1821) or CAP (n=295); 51 switched CT and were analysed in both subgroups. Data cut-off for the final analysis was 3 Feb 2020. Median age was 60 y, 21% had TNBC, 56% prior (neo)adjuvant CT and 29% de novo metastatic disease. Pts receiving BEV + CAP were less likely to have de novo disease and more likely to have TNBC, age ≥60 y and prior CT and endocrine therapy (ET). The median treatment duration was 6.0 mo (95% CI 5.6–6.3) for BEV and 4.2 mo (4.0–4.2) for CT. Overall (complete or partial) response rate was 49% (95% CI 46–51%). Median PFS was 12.6 (95% CI 11.9–13.2) mo (12.8 with BEV + PAC, 10.5 with BEV + CAP); median OS was 23.9 (22.2–25.1) mo. PFS and OS were worse in pts with TNBC, prior CT or prior ET (Table). Grade 3/4 AEs were reported in 27% of pts and led to treatment discontinuation in 15%. Treatment satisfaction was rated as good or better by 304/394 (77%) responding pts at week 54 and in 1393/2065 pts (67%) by physicians across the study.

Subgroup PFS OS
Median, mo HR (95% CI) Median, mo HR (95% CI)
Baseline hypertension Hypertensive v normotensive 13.6 v 11.9 0.88 (0.77–1.00) 25.1 v 23.2 0.88 (0.76–1.01)
TNBCa Yes v no 10.3 v 12.9 1.44 (1.24–1.67) 16.8 v 25.2 1.53 (1.30–1.80)
Age ≥60 v <60 y 12.8 v 12.3 1.09 (0.96–1.23) 21.9 v 25.4 1.26 (1.11–1.44)
Metastatic sites ≥3 v <3 11.6 v 12.8 1.06 (0.88–1.28) 19.3 v 24.9 1.15 (0.96–1.39)
Prior anthracycline/ taxane Yes v no 11.5 v 14.3 1.32 (1.16–1.50) 20.8 v 27.4 1.25 (1.09–1.43)
Prior ET Yes v no 10.7 v 13.2 1.56 (1.33–1.82) 17.6 v 25.1 1.56 (1.33–1.82)

aUnknown in 127 pts. CI = confidence interval; HR = hazard ratio; OS = overall survival; PFS = progression-free survival.

Conclusions

Final results from AVANTI show median PFS of 12.6 mo and a safety profile consistent with phase III experience.

Clinical trial identification

ML22452, 13th May 2015.

Editorial acknowledgement

Medical writing assistance: Jennifer Kelly (Medi-Kelsey Ltd.).

Legal entity responsible for the study

Roche Pharma AG.

Funding

Roche Pharma AG.

Disclosure

V. Mueller: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Teva; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy: Hexal; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: ClinSol; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Tesaro; Honoraria (self), Advisory/Consultancy: Nektar; Research grant/Funding (institution): Genentech. O. Hoffmann: Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Eisai; Honoraria (self), Travel/Accommodation/Expenses: Amgen; Honoraria (self): Riemser Pharma; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Hexal. A-K. Sommer: Full/Part-time employment: Roche Pharma AG; Shareholder/Stockholder/Stock options: Roche. A. Schneeweiss: Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Lilly; Research grant/Funding (institution): AbbVie. All other authors have declared no conflicts of interest.

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