Universität zu Köln

Richters, Lisa ORCID: 0000-0002-9233-5291, Gluz, Oleg ORCID: 0000-0001-6019-7544, Weber-Lassalle, Nana ORCID: 0009-0000-7014-5721, Christgen, Matthias, Haverkamp, Heinz ORCID: 0000-0001-6895-4132, Kuemmel, Sherko, Kayali, Mohamad ORCID: 0000-0003-2092-5695, Kates, Ronald E., Grischke, Eva-Maria, Altmüller, Janine ORCID: 0000-0003-4372-1521, Forstbauer, Helmut, Thiele, Holger ORCID: 0000-0003-4495-4597, Braun, Michael, Warm, Mathias, Ossowski, Anna, Wuerstlein, Rachel, Ernst, Corinna ORCID: 0000-0001-7756-8815, Graeser, Monika, Linn, Sabine C., Nitz, Ulrike, Hauke, Jan ORCID: 0000-0001-8236-4075, Kreipe, Hans Heinrich, Schmutzler, Rita K. ORCID: 0000-0001-8160-4348, Hahnen, Eric ORCID: 0000-0002-1152-8367 and Harbeck, Nadia (2025). Genetic Alterations, Therapy Response, and Survival Among Patients With Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Network Open, 8 (2). pp. 1-15. JAMA Network Open. ISSN 2574-3805

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Abstract

[Artikel-Nr. e2461639] 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

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Richters, Lisa UNSPECIFIED https://orcid.org/0000-0002-9233-5291 UNSPECIFIED Gluz, Oleg UNSPECIFIED https://orcid.org/0000-0001-6019-7544 UNSPECIFIED Weber-Lassalle, Nana UNSPECIFIED https://orcid.org/0009-0000-7014-5721 UNSPECIFIED Christgen, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Haverkamp, Heinz UNSPECIFIED https://orcid.org/0000-0001-6895-4132 UNSPECIFIED Kuemmel, Sherko UNSPECIFIED UNSPECIFIED UNSPECIFIED Kayali, Mohamad UNSPECIFIED https://orcid.org/0000-0003-2092-5695 UNSPECIFIED Kates, Ronald E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Grischke, Eva-Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmüller, Janine UNSPECIFIED https://orcid.org/0000-0003-4372-1521 UNSPECIFIED Forstbauer, Helmut UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED https://orcid.org/0000-0003-4495-4597 UNSPECIFIED Braun, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Warm, Mathias UNSPECIFIED UNSPECIFIED UNSPECIFIED Ossowski, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Wuerstlein, Rachel UNSPECIFIED UNSPECIFIED UNSPECIFIED Ernst, Corinna UNSPECIFIED https://orcid.org/0000-0001-7756-8815 UNSPECIFIED Graeser, Monika UNSPECIFIED UNSPECIFIED UNSPECIFIED Linn, Sabine C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nitz, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED Hauke, Jan UNSPECIFIED https://orcid.org/0000-0001-8236-4075 UNSPECIFIED Kreipe, Hans Heinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmutzler, Rita K. UNSPECIFIED https://orcid.org/0000-0001-8160-4348 UNSPECIFIED Hahnen, Eric UNSPECIFIED https://orcid.org/0000-0002-1152-8367 UNSPECIFIED Harbeck, Nadia UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-797629
Identification Number:	10.1001/jamanetworkopen.2024.61639
Journal or Publication Title:	JAMA Network Open
Volume:	8
Number:	2
Page Range:	pp. 1-15
Number of Pages:	1
Date:	26 February 2025
Publisher:	JAMA Network Open
ISSN:	2574-3805
Language:	English
Faculty:	Central Institutions / Interdisciplinary Research Centers Faculty of Medicine
Divisions:	Cologne Center for Genomics Faculty of Medicine > Frauenheilkunde > Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe Faculty of Medicine > Medizinische Statistik und Bioinformatik Faculty of Medicine > Sonstiges > Centrum für integrierte Onkologie (CIO)
Subjects:	Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/79762