Genetic Alterations, Therapy Response, and Survival Among Patients With Triple-Negative Breast Cancer
Authors: Lisa Richters, Oleg Gluz, Nana Weber-Lassalle, Matthias Christgen, Heinz Haverkamp, Sherko Kuemmel, Mohamad Kayali, Ronald E. Kates, Eva-Maria Grischke, Janine Altmüller, Helmut Forstbauer, Holger Thiele, Michael Braun, Mathias Warm, Anna Ossowski, Rachel Wuerstlein, Corinna Ernst, Monika Graeser, Sabine C. Linn, Ulrike Nitz, Jan Hauke, Hans Heinrich Kreipe, Rita K. Schmutzler, Eric Hahnen, Nadia Harbeck
Journal: JAMA Network Open (2025)

Importance Subgroup definitions for possible deescalation of neoadjuvant cancer treatment are urgently needed in clinical practice. Objective To investigate the effect of BRCA1 and/or BRCA2 tumor pathogenic variants (tPVs) by comparing 2 deescalated neoadjuvant regimens (nab-paclitaxel plus either carboplatin or gemcitabine) on pathologic complete response (pCR), invasive disease–free survival (IDFS), and overall survival (OS) of patients with early-stage triple-negative breast cancer (TNBC). Design, Setting, and Participants This was a preplanned secondary analysis of a phase 2 prospective randomized clinical trial (ADAPT-TN) conducted by the West German Study Group (WSG) at 45 sites in Germany between June 2013 and February 2015. The trial enrolled patients with noninflammatory early-stage TNBC (clinical tumor size ≥1 cm; estrogen receptor and progesterone receptor expression &amp;amp;lt;1%; and ERBB2 negative). DNA samples from pretreatment biopsies were obtained. Genetic analysis was performed between January 2018 and March 2020. Final data analyses took place in September 2023. Exposure Patients were randomized to 12 weeks of treatment with nab-paclitaxel plus either carboplatin or gemcitabine; omission of otherwise mandatory anthracycline-containing chemotherapy was allowed in the case of pCR. tPVs in 20 cancer-associated genes, including BRCA1 and BRCA2 , were analyzed using a customized gene panel. Main Outcomes and Measures The prevalence of BRCA1 and/or BRCA2 tPVs and their effect on pCR rate, IDFS, and OS were evaluated using logistic and Cox proportional hazards regression. Results Of the 307 patients with DNA samples from pretreatment biopsies available, tumor next-generation sequencing analyses were successful for 266 patients. The 266 patients included in this analysis were female, with a median age of 51 years (range, 26-76 years). A total of 162 patients (60.9%) had a clinical tumor size of 2 cm or greater, and 70 (26.3%) had clinical node-positive disease. BRCA1 and/or BRCA2 tPVs were detected in 42 patients (15.8%). The highest pCR rate among patients with BRCA1 and/or BRCA2 tPVs was seen in the nab-paclitaxel plus carboplatin group (9 of 14 patients [64.3%]) compared with the nab-paclitaxel plus gemcitabine group (10 of 28 [35.7%]) (odds ratio, 3.24 [95% CI, 0.85-12.36]; P = .08); the highest numeric 5-year IDFS and OS rates (84.4% and 92.9%, respectively) were seen in the nab-paclitaxel plus carboplatin group. Conclusions and Relevance In this secondary analysis of the WSG-ADAPT-TN randomized clinical trial on tPVs, deescalated nab-paclitaxel plus carboplatin was superior to nab-paclitaxel plus gemcitabine, particularly in patients with BRCA1 and/or BRCA2 tPVs. These findings suggest that BRCA1 and/or BRCA2 tPV status could be a candidate marker for a deescalation strategy in early-stage TNBC; however, prospective validation of survival outcomes in larger cohorts with differentiation between germline and somatic pathogenic variants is necessary. Trial Registration ClinicalTrials.gov Identifier: NCT01815242