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Clinical Trial
. 2025 Feb 3;8(2):e2461639.
doi: 10.1001/jamanetworkopen.2024.61639.

Genetic Alterations, Therapy Response, and Survival Among Patients With Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial

Lisa Richters  1   2 , Oleg Gluz  3   4   5 , Nana Weber-Lassalle  1   2 , Matthias Christgen  6 , Heinz Haverkamp  7   8 , Sherko Kuemmel  3   9   10 , Mohamad Kayali  1   2 , Ronald E Kates  3 , Eva-Maria Grischke  11 , Janine Altmüller  12   13   14 , Helmut Forstbauer  15 , Holger Thiele  12 , Michael Braun  16 , Mathias Warm  17 , Anna Ossowski  12 , Rachel Wuerstlein  3   18 , Corinna Ernst  1   2 , Monika Graeser  3   4   19 , Sabine C Linn  20   21   22 , Ulrike Nitz  3 , Jan Hauke  1   2 , Hans Heinrich Kreipe  6 , Rita K Schmutzler  1   2 , Eric Hahnen  1   2 , Nadia Harbeck  3   18
Affiliations
Clinical Trial

Genetic Alterations, Therapy Response, and Survival Among Patients With Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial

Lisa Richters et al. JAMA Netw Open. .

Abstract

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 <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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Richters reported receiving personal fees and nonfinancial support from AstraZeneca outside the submitted work. Dr Gluz reported receiving grants from Celgene and nonfinancial support from Teva during the conduct of the study. In addition, Dr Gluz reported receiving personal fees from Roche, AstraZeneca, Gilead, MSD, Novartis, Pfizer, Lilly, Exact Science, Agendia, and Daiichi-Sankyo outside the submitted work. Dr Gluz also reported serving as co-director of the West German Study Group (WSG). Prof Kuemmel reported receiving personal fees for consulting or advisory board service from Novartis, Pfizer, Lilly Roche, AstraZeneca, Hologic, MSD Oncology, Agendia, Gilead, Sonoscape, Daiichi-Sankyo, Pink DiGA, Stemline, and Exact Science during the conduct of the study. In addition, Prof Kuemmel reported receiving travel support from Roche and Daiichi-Sankyo and having an uncompensated relationship with WSG outside the submitted work. Prof Wuerstlein reported receiving personal fees from Agendia, Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, Exact Sciences, Gilead, Hexal, Lilly, MSD, Nanostring, Novartis, Onkowissen, Paxman, Palleos, Pfizer, Pierre Fabre, PINK, Roche, Seagen, Sidekick, Stemline, Teva, Veracyte, Viatris, and Wiley during the conduct of the study. In addition, Prof Wuerstlein reported receiving grants from SPCC and personal fees from FOMF, Aurikamed, Clinsol, Pomme Med, IMED, MCI, MediSeminar, Medicultus, H+O Communications, Streamed Up, AGO, PINK!, Coach, WSG, Junge Erwachsene mit Krebs, and Brustkrebs Deutschland eV outside the submitted work. Prof Linn reported receiving institutional unrestricted research grants from AstraZeneca, Eurocept Pharmaceuticals, Roche, Agendia, GlaxoSmithKline (GSK), Gilead, and Novartis and an educational grant from Daiichi-Sankyo outside the submitted work. In addition, Prof Linn reported receiving nonfinancial support in the form of study drugs from AstraZeneca, Roche, GSK, and Novartis and diagnostic tests from Agilent and Agendia; and serving on advisory boards for AstraZeneca and Agendia (compensation paid to institute) and for Cergentis (uncompensated) outside the submitted work. Prof Linn also reported having a patent issued (EP4141127: Method for Assessing Homologous Recombination Deficiency in Ovarian Cancer Cells). Dr Hauke reported receiving grants from German Cancer Aid outside the submitted work. Prof Schmutzler reported receiving grants from the German Breast Group during the conduct of the study. Prof Harbeck reported receiving personal fees from AstraZeneca, Daiichi-Sankyo, Gilead, Lilly, Novartis, MSD, Pierre Fabre, Pfizer, Sandoz, and Seagen and having minority ownership in WSG outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Pathologic Complete Response (pCR) Rate According to BRCA1/2–Tumor Pathogenic Variant (tPV) Status Overall and in Both Treatment Groups
OR indicates odds ratio; WT, wild type.
Figure 2.
Figure 2.. Survival According to BRCA1/2–Tumor Pathogenic Variant (tPV) Status and Treatment Group
WT indicates wild type.
Figure 3.
Figure 3.. Effect of Pathologic Complete Response (pCR) on Survival in the BRCA1/2–Wild Type (WT) and BRCA1/2–Tumor Pathogenic Variant (tPV) Cohorts
See this image and copyright information in PMC

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