Esther Pohl-Rescigno1, Jan Hauke1, Sibylle Loibl2, Volker Möbus3, Carsten Denkert4, Peter A Fasching5, Mohamad Kayali1, Corinna Ernst1, Nana Weber-Lassalle1, Claus Hanusch6, Hans Tesch7, Volkmar Müller8, Janine Altmüller9,10, Holger Thiele9, Michael Untch11, Kristina Lübbe12, Peter Nürnberg9,10,13, Kerstin Rhiem1, Jenny Furlanetto2, Bianca Lederer2, Christian Jackisch14, Valentina Nekljudova2, Rita K Schmutzler1, Andreas Schneeweiss15, Eric Hahnen1. 1. Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany. 2. German Breast Group, Neu-Isenburg, Germany. 3. Department of Medicine II, Hematology and Oncology, University of Frankfurt, Frankfurt, Germany. 4. Institut für Pathologie, Philipps-Universität Marburg und Universitätsklinikum Marburg, Marburg, Germany. 5. Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany. 6. Rotkreuzklinikum München, Frauenklinik, Munich, Germany. 7. Hämatologisch-Onkologische Gemeinschaftspraxis, Frankfurt, Germany. 8. Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg, Germany. 9. Cologne Center for Genomics, University of Cologne, Cologne, Germany. 10. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. 11. Department of Gynecology and Obstetrics, Helios Klinikum Berlin-Buch, Berlin, Germany. 12. Breast Center, Diakovere Henriettenstift, Hannover, Germany. 13. Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases, University of Cologne, Cologne, Germany. 14. Sana Klinikum Offenbach GmbH, Offenbach, Germany. 15. National Center for Tumor Diseases, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany.
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.
RCT Entities:
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.
Authors: Cynthia Villarreal-Garza; Ana S Ferrigno; Alejandro Aranda-Gutierrez; Paul H Frankel; Nora H Ruel; Alan Fonseca; Steven Narod; Yanin Chavarri-Guerra; Erika Sifuentes; Maria Cristina Magallanes-Hoyos; Josef Herzog; Danielle Castillo; Rosa M Alvarez-Gomez; Alejandro Mohar-Betancourt; Jeffrey N Weitzel Journal: Cancer Res Commun Date: 2021-12-08
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Authors: Hans Tesch; Volkmar Müller; Achim Wöckel; Johannes Ettl; Erik Belleville; Florian Schütz; Andreas Hartkopf; Marc Thill; Jens Huober; Peter A Fasching; Hans-Christian Kolberg; Carla E Schulmeyer; Manfred Welslau; Friedrich Overkamp; Tanja N Fehm; Michael P Lux; Andreas Schneeweiss; Diana Lüftner; Wolfgang Janni Journal: Geburtshilfe Frauenheilkd Date: 2020-11-06 Impact factor: 2.915