Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial.
Eric Hahnen,Bianca Lederer,Jan Hauke,Sibylle Loibl,Sandra Kröber,Andreas Schneeweiss,Carsten Denkert,Peter A. Fasching,Peter A. Fasching,Jens Uwe Blohmer,Christian Jackisch,Stefan Paepke,Bernd Gerber,Sherko Kümmel,Christian Schem,Guido Neidhardt,Jens Huober,Kerstin Rhiem,SD Costa,Janine Altmüller,Claus Hanusch,Holger Thiele,Volkmar Müller,Peter Nürnberg,Thomas Karn,Valentina Nekljudova,Michael Untch,Gunter von Minckwitz,Rita K. Schmutzler +28 more
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TLDR
Evidence is provided that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline, taxane, and bevacizumab increases pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC).Abstract:
Importance The GeparSixto trial provided evidence that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline, taxane, and bevacizumab increases pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Whether BRCA1 and BRCA2 germline mutation status affects treatment outcome remains elusive. Objective To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC. Design, Setting, and Participants This secondary analysis of a randomized clinical trial used archived DNA samples and cancer family history of 315 patients with TNBC enrolled between August 1, 2011, and December 31, 2012, in the GeparSixto trial. In all, 291 participants (92.4%) were included in this multicenter prospective investigation. DNA samples were analyzed for germline mutations in BRCA1, BRCA2, and 16 other cancer predisposition genes. The pCR rates between the carboplatin and noncarboplatin arms were compared. Genetic analyses were performed at the Center for Familial Breast and Ovarian Cancer in Cologne, Germany; data analysis, November 1 through December 31, 2015. Main Outcomes and Measures Proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status. For pCR rates, the ypT0/is ypN0 definition was used as a primary end point. Results Of the 291 patients with TNBC, all were women; the mean (SD) age was 48 (11) years. The pCR rate in the carboplatin group was 56.8% (83 of 146) and 41.4% (60 of 145) in the noncarboplatin group (odds ratio [OR], 1.87; 95% CI, 1.17-2.97; P = .009). Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients (17.2%). In the noncarboplatin arm, the pCR rate was 66.7% (16 of 24) for patients with BRCA1 and BRCA2 mutations and 36.4% (44 of 121) for patients without (OR, 3.50; 95% CI, 1.39-8.84; P = .008). The high pCR rate observed in BRCA1 and BRCA2 mutation carriers (16 of 24 [66.7%]) was not increased further by adding carboplatin (17 of 26 [65.4%]). In contrast, carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations: 66 of the 120 patients (55%) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients (36.4%) in the noncarboplatin arm (OR, 2.14; 95% CI, 1.28-3.58; P = .004). Patients without pathogenic BRCA1 and BRCA2 alterations showed elevated disease-free survival rates when carboplatin was added (without carboplatin, 73.5%; 95% CI, 64.1%-80.8% vs with carboplatin, 85.3%; 95% CI, 77.0%-90.8%; hazard ratio, 0.53; 95% CI, 0.29-0.96; P = .04). Conclusions and Relevance Under the nonstandard GeparSixto polychemotherapy regimen, patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin. Trial Registration clinicaltrials.gov Identifier:NCT01426880read more
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Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
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TL;DR: This work seeks to review the most recent efforts to classify TNBC based on the comprehensive profiling of tumors for cellular composition and molecular features to help improve risk stratification of patients, guide treatment decisions and surveillance, and help identify new targets for drug development.
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Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial
Sibylle Loibl,Joyce O'Shaughnessy,Michael Untch,William M. Sikov,Hope S. Rugo,Mark D. McKee,Jens Huober,Mehra Golshan,Gunter von Minckwitz,David Maag,Danielle Sullivan,Norman Wolmark,Kristi McIntyre,Jose Juan Ponce Lorenzo,Otto Metzger Filho,Priya Rastogi,W. Fraser Symmans,Xuan Liu,Charles E. Geyer +18 more
TL;DR: The proportion of patients who achieved a pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving pac litaxel alone.
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A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study
S. Loibl,Michael Untch,Nicole Burchardi,J Huober,Bruno Valentin Sinn,J-U Blohmer,EM Grischke,Jenny Furlanetto,Hans Tesch,Claus Hanusch,Knut Engels,Mahdi Rezai,C. Jackisch,Wolfgang D. Schmitt,G. von Minckwitz,Jörg Thomalla,S Kümmel,Beate Rautenberg,PA Fasching,Karsten Weber,K Rhiem,Carsten Denkert,Andreas Schneeweiss +22 more
TL;DR: The results suggest that the addition of durvalumab to anthracycline/taxane based NACT increases pCR rate particularly in patients treated with durvalUMab alone prior to start of chemotherapy.
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Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: A systematic review and meta-analysis
Francesca Poggio,Francesca Poggio,Marco Bruzzone,Marcello Ceppi,Noam Pondé,G. La Valle,L. Del Mastro,E. de Azambuja,Matteo Lambertini +8 more
TL;DR: In TNBC patients, platinum-based neoadjuvant chemotherapy is associated with significantly increased pCR rates at the cost of worse hematological toxicities, with no increased risk of grade 3 and 4 neuropathy.
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TL;DR: In this paper, the authors compared the three most commonly used definitions of pathological complete response (ypT0 ypN0, ypT0/is ypNs0, and ypTsN0/IsYPN0) for their association with EFS and overall survival in clinical trials of neoadjuvant treatment of breast cancer.
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