Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer: A Secondary Analysis of the GeparOcto Randomized Clinical Trial

Esther Pohl-Rescigno; Jan Hauke; Sibylle Loibl; Volker Möbus; Carsten Denkert; Peter A Fasching; Mohamad Kayali; Corinna Ernst; Nana Weber-Lassalle; Claus Hanusch; Hans Tesch; Volkmar Müller; Janine Altmüller; Holger Thiele; Michael Untch; Kristina Lübbe; Peter Nürnberg; Kerstin Rhiem; Jenny Furlanetto; Bianca Lederer; Christian Jackisch; Valentina Nekljudova; Rita K Schmutzler; Andreas Schneeweiss; Eric Hahnen

doi:10.1001/jamaoncol.2020.0007

. 2020 Mar 12;6(5):1–5. doi: 10.1001/jamaoncol.2020.0007

Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer

A Secondary Analysis of the GeparOcto Randomized Clinical Trial

Esther Pohl-Rescigno ¹, Jan Hauke ¹, Sibylle Loibl ², Volker Möbus ³, Carsten Denkert ⁴, Peter A Fasching ⁵, Mohamad Kayali ¹, Corinna Ernst ¹, Nana Weber-Lassalle ¹, Claus Hanusch ⁶, Hans Tesch ⁷, Volkmar Müller ⁸, Janine Altmüller ^9,¹⁰, Holger Thiele ⁹, Michael Untch ¹¹, Kristina Lübbe ¹², Peter Nürnberg ^9,^10,¹³, Kerstin Rhiem ¹, Jenny Furlanetto ², Bianca Lederer ², Christian Jackisch ¹⁴, Valentina Nekljudova ², Rita K Schmutzler ¹, Andreas Schneeweiss ¹⁵, Eric Hahnen ^1,^✉

¹Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany

²German Breast Group, Neu-Isenburg, Germany

³Department of Medicine II, Hematology and Oncology, University of Frankfurt, Frankfurt, Germany

⁴Institut für Pathologie, Philipps-Universität Marburg und Universitätsklinikum Marburg, Marburg, Germany

⁵Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany

⁶Rotkreuzklinikum München, Frauenklinik, Munich, Germany

⁷Hämatologisch-Onkologische Gemeinschaftspraxis, Frankfurt, Germany

⁸Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg, Germany

⁹Cologne Center for Genomics, University of Cologne, Cologne, Germany

¹⁰Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

¹¹Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin, Germany

¹²Breast Center, Diakovere Henriettenstift, Hannover, Germany

¹³Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany

¹⁴Sana Klinikum Offenbach GmbH, Offenbach, Germany

¹⁵National Center for Tumor Diseases, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany

Accepted for Publication: December 16, 2019.

^✉

Corresponding Author: Eric Hahnen, PhD, University Hospital Cologne, Kerpener Straße 34, 50931 Cologne, Germany (eric.hahnen@uk-koeln.de).

Published Online: March 12, 2020. doi:10.1001/jamaoncol.2020.0007

Author Contributions: Drs Lederer and Nekljudova had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Pohl-Rescigno, Loibl, Möbus, Fasching, Hanusch, Untch, Jackisch, Nekljudova, Schmutzler, Schneeweiss, Hahnen.

Acquisition, analysis, or interpretation of data: Pohl-Rescigno, Hauke, Loibl, Möbus, Denkert, Fasching, Kayali, Ernst, Weber-Lassalle, Tesch, Müller, Altmüller, Thiele, Untch, Lübbe, Nürnberg, Rhiem, Furlanetto, Lederer, Jackisch, Nekljudova, Schmutzler, Schneeweiss, Hahnen.

Drafting of the manuscript: Pohl-Rescigno, Hauke, Untch, Lederer, Schmutzler, Schneeweiss, Hahnen.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Lederer, Nekljudova.

Obtained funding: Loibl, Möbus, Schmutzler, Hahnen.

Administrative, technical, or material support: Pohl-Rescigno, Loibl, Möbus, Denkert, Fasching, Kayali, Weber-Lassalle, Tesch, Altmüller, Thiele, Nürnberg, Rhiem, Lederer, Jackisch, Schmutzler, Schneeweiss, Hahnen.

Study supervision: Pohl-Rescigno, Loibl, Möbus, Untch, Lübbe, Nekljudova, Schmutzler, Schneeweiss, Hahnen.

Conflict of Interest Disclosures: Dr Loibl reported receiving grants for the GeparOcto Study from Roche, Amgen, and Teva Pharmaceutical Industries during the conduct of the study; grants and honoraria for lectures and advisory boards paid to institution from AbbVie, Amgen, AstraZeneca, Celgene, Novartis, Pfizer, and Roche; honoraria for lectures and advisory boards paid to institution from Seattle Genetics and Samsung; honoraria for lectures paid to institution from PRIME/Medscape; personal fees from Chugai; grants from Teva and Vifor Pharma; grants and honoraria paid to institution from Daiichi Sankyo; honoraria for advisory boards paid to institution from Lilly; and advisor fees paid to institution from Eirgenix outside the submitted work; in addition, Dr Loibl reported a pending patent to EP14153692.0. Dr Möbus received honoraria and lecture fees from Amgen, AstraZeneca, Celgene, Myelo Therapeutics, Novartis, Roche, and Clovis outside the submitted work. Dr Denkert reported grants from GBG Forschungs GmbH during the conduct of the study; grants for advisory or consultancy roles from MSD Oncology, Amgen, and Daiichi Sankyo; honoraria from Teva Pharmaceutical Industries, Novartis, Pfizer, Roche, and Amgen; and holding stock and other ownership interests with Sividon Diagnostics outside the submitted work; and patents, royalties, and intellectual property from VMscope digital pathology software (patent applications for EP18209672 [cancer immunotherapy] and EP20150702464 [therapy response]). Dr Fasching reported receiving grants and personal fees from Novartis, Amgen, and Celgene; grants from BioNTech and Cepheid; personal fees from Roche, Pfizer, Celgene, Daiichi Sankyo, Teva Pharmaceutical Industries, AstraZeneca, Merck Sharp & Dohme, Myelo Therapeutics, Macrogenics, Eisai, Puma, and Lilly during the conduct of the study. Dr Hanusch reported receiving grants for advisory or consultancy roles from Roche, Pfizer, Novartis, and AstraZeneca and honoraria from Roche, Pfizer, Genentech, AstraZeneca, Novartis, Eisai, Lilly, Celgene, and Amgen outside the submitted work. Dr Tesch reported receiving honoraria, travel grants, and grants for advisory or consultancy role from Novartis and Roche outside the submitted work. Dr Müller reported receiving grants, payment to institution for clinical trials, speaker honoraria, and consultancy honoraria from Roche and Pfizer; payment to institution for clinical trials, research grant to institution, speaker honoraria, and consultancy honoraria from Novartis; consultancy honoraria from Amgen, AstraZeneca, Genomic Health, Pierre Fabre, Merck Sharp & Dohme, Lilly; speaker and consultancy honoraria from Daiichi Sankyo, Eisai, Teva Pharmaceutical Industries, Tesaro, Hexal, and Novartis; speaker honoraria from Celgene; consultancy honoraria and payment to institution for clinical trials from Nektar; and research support from Novartis, Roche, Seattle Genetics, and Genentech outside the submitted work. Dr Untch reported serving on advisory boards for Amgen, Myriad Genetics, Celgene, and Roche and receiving travel support from Celgene and Roche during the conduct of the study; serving on advisory boards and receiving travel support for AbbVie, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Janssen, Cilag, Johnson & Johnson, Lilly, Merck Sharp & Dohme, Mundipharma, Odonate Therapeutics, and Pfizer; serving on advisory boards for Riemser, Sanofi-Aventis, and Teva Pharmaceutical Industries; and receiving honoraria from AbbVie, AdBoard, Amgen, AstraZeneca, Celgene, Clovis, Daiichi Sankyo, Eisai, Lilly, Merck Sharp & Dohme, Myriad Genetics, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche, Sanofi-Aventis, and Teva Pharmaceutical Industries outside the submitted work. Dr Lübbe reported receiving payment for documentation of patient data from the German Breast Group during the conduct of the study; receiving grants for advisory or consultancy from Roche and Novartis; and receiving honoraria from Pfizer, Lilly, and Genomic Health outside the submitted work. Dr Rhiem reported receiving personal fees from AstraZeneca, Pfizer, and Tesaro outside the submitted work. Dr Jackisch reported receiving travel grants from Bristol-Myers Squibb and Amgen and personal fees from Roche and AstraZeneca outside the submitted work. Drs Schmutzler and Hahnen reported receiving honoraria from AstraZeneca outside the submitted work. Dr Schneeweiss reported receiving research grants from Roche and Celgene; honoraria from Amgen, AstraZeneca, Celgene, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Tesaro; and medical writing grants from Roche outside the submitted work. No other disclosures were reported.

Funding/Support: The GeparOcto study was supported by Roche, Amgen, Teva Pharmaceutical Industries, and Vifor Pharma (no grant numbers applicable). Support for research and genetic analyses was provided by the Koeln Fortune Program, Faculty of Medicine, University of Cologne, Germany.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We are thankful to all patients who participated in this study.

^✉

Corresponding author.

PMCID: PMC7068666 PMID: 32163106

This secondary analysis of a randomized clinical trial assesses treatment outcomes in women with different biological types of breast cancer according to germline variant status of BRCA1/2 and non-BRCA1/2 breast cancer predisposition genes.

Key Points

Question

Is germline variant status of BRCA1/2 and non-BRCA1/2 breast cancer predisposition genes associated with higher response rates in patients enrolled in the GeparOcto trial?

Findings

In this secondary analysis of 914 patients included in a randomized clinical trial, women with triple-negative breast cancer with BRCA1/2 variants benefited most from both treatment regimens (paclitaxel and nonpegylated liposomal doxorubicin plus carboplatin, 74.3%; epirubicin, paclitaxel, and cyclophosphamide, 64.7%). A positive BRCA1/2 variant status also was associated with higher response rates in ERBB2-negative, hormone receptor–positive breast cancer.

Meaning

Effective chemotherapy for BRCA1/2-mutated triple-negative breast cancer is commonly suggested to be platinum based; sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide appears to also be effective in these patients, though with a lower point estimate. Patients with ERBB2-negative, hormone receptor–positive breast cancer may benefit from BRCA1/2 testing prior to treatment.

Abstract

Importance

The GeparOcto randomized clinical trial compared the efficacy of 2 neoadjuvant breast cancer (BC) treatment regimens: sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) vs weekly paclitaxel and nonpegylated liposomal doxorubicin (PM) in patients with different biological BC subtypes. Patients with triple-negative BC (TNBC) randomized to the PM arm received additional carboplatin (PMCb). Overall, no difference in pathologic complete response (pCR) rates was observed between study arms. It remained elusive whether the germline variant status of BRCA1/2 and further BC predisposition genes are associated with treatment outcome.

Objective

To determine treatment outcome for BC according to germline variant status.

Design, Setting, and Participants

This retrospective biomarker study is a secondary analysis of the GeparOcto multicenter prospective randomized clinical trial conducted between December 2014 and June 2016. Genetic analyses assessing for variants in BRCA1/2 and 16 other BC predisposition genes in 914 of 945 women were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany, from August 2017 through December 2018.

Main Outcomes and Measures

Proportion of patients who achieved pCR (ypT0/is ypN0 definition) after neoadjuvant treatment according to germline variant status.

Results

In the study sample of 914 women with different BC subtypes with a mean (range) age at BC diagnosis of 48 (21-76) years, overall higher pCR rates were observed in patients with BRCA1/2 variants than in patients without (60.4% vs 46.7%; odds ratio [OR], 1.74; 95% CI, 1.13-2.68; P = .01); variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response. Patients with TNBC with BRCA1/2 variants achieved highest pCR rates. In the TNBC subgroup, a positive BRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0% without BRCA1/2 variant; OR, 3.26; 95% CI, 1.44-7.39; P = .005) and the iddEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P = .04). A positive BRCA1/2 variant status was also associated with elevated pCR rates in patients with ERBB2-negative, hormone receptor–positive BC (31.8% vs 11.9%; OR, 3.44; 95% CI, 1.22-9.72; P = .02).

Conclusions and Relevance

Effective chemotherapy for BRCA1/2-mutated TNBC is commonly suggested to be platinum based. With a pCR rate of 64.7%, iddEPC may also be effective in these patients, though further prospective studies are needed. The elevated pCR rate in BRCA1/2-mutated ERBB2-negative, hormone receptor–positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start.

Trial Registration

ClinicalTrials.gov Identifier: NCT02125344

Introduction

The GeparOcto randomized clinical trial¹ compared the efficacy of treatment with a sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide–based chemotherapy regimen (iddEPC) vs a weekly paclitaxel plus nonpegylated liposomal doxorubicin regimen (PM) in 945 patients with different biological subtypes of breast cancer (BC). The study cohort included 403 patients with triple-negative BC (TNBC), 382 patients with ERBB2-positive BC, and 160 patients with ERBB2-negative, estrogen receptor–positive or progesterone receptor–positive (hormone receptor [HR]–positive) BC and histologically verified lymph node involvement. Patients with TNBC randomized to the PM arm received additional carboplatin (PMCb) based on previous results.² Patients with ERBB2-positive BC received additional trastuzumab and pertuzumab in both study arms (trial protocol in Supplement 1; eFigure in Supplement 2). No overall difference in pathologic complete response (pCR) rates was observed between study arms (iddEPC arm, 48.3%; PM[Cb] arm, 48.0%; ypT0/is ypN0 definition).¹ It was concluded that sequential iddEPC appeared more feasible than PM(Cb) owing to elevated nonhematologic adverse effects and lower adherence to treatment with PM(Cb).¹

In particular, TNBC is associated with a hereditary cause, and germline variant screening of unselected patients with TNBC revealed a high BRCA1/2 variant prevalence.^2,3 BRCA1/2 genes are critical in the homologous recombination repair of DNA double-strand breaks. Many of the other genes involved in homologous recombination repair are now recognized to also contribute to hereditary BC risk. Heterozygous germline inactivation of these genes may be accompanied by a somatic inactivation of the second allele, resulting in a homologous recombination deficiency and limited DNA repair capacity of the tumor cell.⁴ This functional role in DNA repair may be exploited in the treatment of homologous recombination–deficient cancers with drugs that challenge the DNA repair machinery, such as epirubicin, cyclophosphamide, doxorubicin, and carboplatin, which were used in the GeparOcto trial.¹ These data prompted us to conduct this retrospective biomarker study of patients enrolled in the GeparOcto trial to determine treatment efficacies according to germline variant status overall, by treatment arm, and by tumor subtype.

Methods

Of the 945 patients enrolled in the original GeparOcto investigation, 914 (96.7%) were successfully analyzed for germline (g) variants in BRCA1/2 and 16 further BC predisposition genes (Figure 1; eMethods in Supplement 2). All patients provided written informed consent for trial participation and translational research. The Ethics Committee of the University of Cologne (07-048) granted ethical approval for genetic analyses. Pearson χ² test was used to compare pCR rates between groups. Univariate logistic regression analyses were performed to estimate odds ratio (OR) and 95% CIs. Interaction was assessed using the Breslow-Day test; P values less than .05 were considered statistically significant. Analyses were performed with SPSS statistical software version 25 (IBM Corp). This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Figure 1. — Between December 2014 and June 2016, 1204 patients were screened for eligibility, 961 patients were randomized at 57 sites, 945 started treatment (intention-to-treat population), and 938 underwent surgery.¹ Of these 938 patients, 24 patients were not included in this secondary analysis because no DNA sample was available. BC indicates breast cancer; CONSORT, Consolidated Standards of Reporting Trials; HR, hormone receptor; iddEPC, intense dose-dense epirubicin, paclitaxel, and cyclophosphamide; PM(Cb), paclitaxel and nonpegylated liposomal doxorubicin with or without carboplatin; TNBC, triple-negative BC.

Results

In the subgroup of 914 patients included in this investigation, the mean (range) age at BC diagnosis was 48 (21-76) years. Overall pCR rates were similar to those observed in the original investigation (iddEPC arm: 48.3%; PM[Cb] arm: 47.9%; OR, 0.99; 95% CI, 0.76-1.28; P = .91; ypT0/is ypN0 definition; eTable 1 in Supplement 2). Of the 914 patients, 96 (10.5%) carried pathogenic gBRCA1/2 variants (Figure 2A; eTable 2 in Supplement 2). Irrespective of the treatment arm and subtype, patients with gBRCA1/2 variants had higher pCR rates compared with patients without gBRCA1/2 variants (60.4% vs 46.7%; OR, 1.74; 95% CI, 1.13-2.68; P = .01; eTable 1 in Supplement 2); interaction between gBRCA1/2 variant and study arm was not significant (P = .11).

The gBRCA1/2 variant prevalence as well as the pCR rates were highly different when analyzed by biological tumor subtypes. As expected from the GeparSixto trial,² a high gBRCA1/2 variant prevalence was observed in patients with TNBC (69 of 393 [17.6%]; Figure 2A; eTable 2 in Supplement 2). Irrespective of the treatment arm, patients with TNBC and gBRCA1/2 variants achieved higher pCR rates compared with patients with TNBC without gBRCA1/2 variants (69.6% vs 46.0%; OR, 2.69; 95% CI, 1.54-4.69; P = .001; Figure 2C; eTable 1 in Supplement 2). For TNBC, a positive gBRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0%; OR, 3.26; 95% CI, 1.44-7.39; P = .005) and the iddEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P = .04; Figure 2C; eTable 1 in Supplement 2). Differences between treatment arms were not significant (74.3% vs 64.7%; OR, 1.58; 95% CI, 0.56-4.43; P = .39; Figure 2C). Interaction between gBRCA1/2 variant and study arm was not significant (P = .51).

In ERBB2-positive BC, a low gBRCA1/2 variant prevalence was suggested.⁵ Five gBRCA1/2 variant carriers (5 of 365 [1.4%]; Figure 2A; eTable 2 in Supplement 2) were present in this subgroup; therefore, we refrained from calculating ORs according to gBRCA1/2 variant status. Overall, pCR rates of approximately 60% were observed in ERBB2-positive BC (eTable 1 in Supplement 2).

In ERBB2-negative, HR-positive BC, a high gBRCA1/2 variant prevalence was observed (22 of 156 [14.1%]; Figure 2A; eTable 2 in Supplement 2). Irrespective of the treatment arm, a positive gBRCA1/2 variant status was associated with a higher pCR rate (31.8% vs 11.9%; OR, 3.44; 95% CI, 1.22-9.72; P = .02; Figure 2D, eTable 1 in Supplement 2); interaction between gBRCA1/2 variant and study arm was not significant (P = .44).

It is currently unknown whether variants in additional, non-BRCA1/2 BC predisposition genes are associated with chemotherapy response. Among the 818 patients without gBRCA1/2 variants, 76 patients (9.3%) carried at least 1 variant in the 16 non-BRCA1/2 genes (Figure 2B; eTable 2 in Supplement 2). The overall variant prevalence was mainly driven by the ATM, CHEK2, FANCM, and PALB2 BC predisposition genes,^6,7 and a high variant prevalence was found in all 3 biological subgroups (Figure 2B). In accordance with previous studies, variants in the FANCM and PALB2 genes are associated with TNBC, while variants in the ATM and CHEK2 genes are associated with ERBB2-positive and ERBB2-negative, HR-positive BC^7,8 (eTable 2 in Supplement 2). Patients without pathogenic gBRCA1/2 variants but germline variants in non-BRCA1/2 genes achieved pCR rates comparable to patients without any variant (eTable 1 in Supplement 2); however, gene-specific effects cannot be excluded.

Discussion

Patients with gBRCA1/2 variants benefited most from both treatment regimens, while variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response. Especially following the studies by Byrski et al⁹ and most recently the Triple Negative Trial by Tutt et al,¹⁰ effective chemotherapy of gBRCA1/2-mutated TNBC is suggested to be platinum based, a result that was also confirmed in our investigation. In gBRCA1/2-mutated TNBC, we demonstrate that iddEPC appears to be also effective, though with a pCR rate approximately 10 percentage points lower than that observed in the PMCb arm. It remains elusive whether this difference is associated with survival outcome. However, our study was not powered to compare PM(Cb) vs iddEPC treatment efficacies specifically in patients with gBRCA1/2-mutated BC; larger prospective studies are required to address this question. Of further interest is the high gBRCA1/2 variant prevalence in ERBB2-negative, HR-positive BC along with the elevated pCR rate of gBRCA1/2 variant carriers compared to noncarriers. Although the subgroup of patients with ERBB2-negative, HR-positive BC was small in our study (n = 156), we suggest that patients with ERBB2-negative, HR-positive BC may benefit from BRCA1/2 testing prior to treatment start.

Limitations

The study did have a limitation. It was not powered to compare PM(Cb) vs iddEPC treatment efficacies in patients with gBRCA1/2-mutated BC.

Conclusions

Effective chemotherapy for gBRCA1/2-mutated TNBC is commonly suggested to be platinum based. With a pCR rate of 64.7%, we demonstrate that iddEPC appears to be also effective in these patients and may be considered in future prospective studies. The elevated pCR rate in gBRCA1/2-mutated ERBB2-negative, HR-positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start.

Supplement 1.

Trial Protocol

Click here for additional data file.^{(366.1KB, pdf)}

Supplement 2.

eMethods

eFigure. GeparOcto study design

eTable 1. Pathological complete response (pCR) rates (ypT0/is ypN0 definition) according to germline (g) variant status (BRCA1/2 and non-BRCA1/2 breast cancer predisposition genes), overall and by treatment arm

eTable 2. Prevalence of germline variants in BRCA1/2 and 16 non-BRCA1/2 genes in 914 breast cancer patients

eReferences

Click here for additional data file.^{(241.4KB, pdf)}

Supplement 3.

Data Sharing Statement

Click here for additional data file.^{(18.5KB, pdf)}

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

Click here for additional data file.^{(366.1KB, pdf)}

Supplement 2.

eMethods

eFigure. GeparOcto study design

eTable 2. Prevalence of germline variants in BRCA1/2 and 16 non-BRCA1/2 genes in 914 breast cancer patients

eReferences

Click here for additional data file.^{(241.4KB, pdf)}

Supplement 3.

Data Sharing Statement

Click here for additional data file.^{(18.5KB, pdf)}

[cbr200001r1] 1.Schneeweiss A, Möbus V, Tesch H, et al. . Intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for neoadjuvant treatment of high-risk early breast cancer (GeparOcto-GBG 84): a randomised phase III trial. Eur J Cancer. 2019;106:181-192. doi: 10.1016/j.ejca.2018.10.015 [DOI] [PubMed] [Google Scholar]

[cbr200001r2] 2.Hahnen E, Lederer B, Hauke J, et al. . Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto randomized clinical trial. JAMA Oncol. 2017;3(10):1378-1385. doi: 10.1001/jamaoncol.2017.1007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr200001r3] 3.Hahnen E, Hauke J, Engel C, Neidhardt G, Rhiem K, Schmutzler RK. Germline mutations in triple-negative breast cancer. Breast Care (Basel). 2017;12(1):15-19. doi: 10.1159/000455999 [DOI] [PMC free article] [PubMed] [Google Scholar]

[cbr200001r4] 4.Severson TM, Peeters J, Majewski I, et al. . BRCA1-like signature in triple negative breast cancer: molecular and clinical characterization reveals subgroups with therapeutic potential. Mol Oncol. 2015;9(8):1528-1538. doi: 10.1016/j.molonc.2015.04.011 [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Association of Germline Variant Status With Therapy Response in High-risk Early-Stage Breast Cancer

Esther Pohl-Rescigno, PhD

Jan Hauke, PhD

Sibylle Loibl, MD

Volker Möbus, MD

Carsten Denkert, MD

Peter A Fasching, MD

Mohamad Kayali, BSc

Corinna Ernst, MSc

Nana Weber-Lassalle, MSc

Claus Hanusch, MD

Hans Tesch, MD

Volkmar Müller, MD

Janine Altmüller, MD

Holger Thiele, MD

Michael Untch, MD

Kristina Lübbe, MD

Peter Nürnberg, PhD

Kerstin Rhiem, MD

Jenny Furlanetto, MD

Bianca Lederer, PhD

Christian Jackisch, MD

Valentina Nekljudova, PhD

Rita K Schmutzler, MD

Andreas Schneeweiss, MD

Eric Hahnen, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Figure 1. CONSORT Flow Diagram.

Results

Figure 2. Germline Variant Prevalence and Pathologic Complete Response (pCR) Rates According to Variant Status and Study Arm.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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