Tumor mutations predict HER2-targeted therapy resistance in primary HER2-positive breast cancer

Van Mackelenbergh MT, Pfarr N, Weber K, Untch M, Solbach C, Schneeweiss A, Jank P, Blohmer J, Treue D, Schmatloch S, Lehmann A, Hanusch C, Link T, Sers C, Bjelic-Radisic V, Hummel M, Huober J, Schmitt WD, Fasching PA, Aktas B, Rhiem K, Reinisch M, Nekljudova V, Denkert C, Loibl S (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 12

Article Number: 59

Journal Issue: 1

DOI: 10.1038/s41523-026-00948-7

Abstract

The presented study investigated the relevance of mutations in 17 cancer genes and response to neoadjuvant chemotherapy in two clinical cohorts of HER2+ breast cancer. 364 samples from HER2+ tumors of the neoadjuvant studies GeparTrio (no anti-HER2 treatment, n = 71) and GeparSepto (dual HER2 blockade and randomization for paclitaxel vs. nab-paclitaxel, n = 293) were analyzed by targeted next generation sequencing of hot spot regions of 17 genes. Mutations in TP53 (47.3%) and PIK3CA (23.9%) were most prevalent. EGFR, KRAS, NRAS, HRAS were combined to the MAPK module with 2.5% harboring mutations. In GeparSepto, the pCR rate was significantly lower in PIK3CA-mutant vs wild-type (wt) tumors (47.7% vs. 66.7%; p = 0.009). In patients treated with nab-paclitaxel, pCR rates were significantly lower in PIK3CA-mutated tumors compared to wt-tumors (38.7% vs. 72.0%; p = 0.001). In the GeparTrio cohort without neoadjuvant anti-HER2 therapy the pCR rate was 27.3% in the mutant cohort compared to 16.3% in the PIK3CA-wt cohort (p = 0.339). In HER2+ breast cancer, PIK3CA mutations were significantly associated with reduced response to dual HER2 blockade with pertuzumab+trastuzumab as well as reduced response to nab-paclitaxel. This reduction was not observed in GeparTrio without anti-HER2 therapy.

Involved external institutions

Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) GBG Forschungs GmbH (German Breast Group) Germany (DE) Universitätsklinikum Gießen und Marburg (UKGM) Germany (DE) Universitätsklinikum Leipzig Germany (DE) Universitätsklinikum Köln Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Universitätsklinikum Heidelberg Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Elisabeth-Krankenhaus Germany (DE) Rotkreuzklinikum München Germany (DE) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) HELIOS Kliniken Germany (DE) Kantonsspital St.Gallen Switzerland (CH) Technische Universität München (TUM) Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE)

How to cite

APA:

Van Mackelenbergh, M.T., Pfarr, N., Weber, K., Untch, M., Solbach, C., Schneeweiss, A.,... Loibl, S. (2026). Tumor mutations predict HER2-targeted therapy resistance in primary HER2-positive breast cancer. npj Breast Cancer, 12(1). https://doi.org/10.1038/s41523-026-00948-7

MLA:

Van Mackelenbergh, Marion T., et al. "Tumor mutations predict HER2-targeted therapy resistance in primary HER2-positive breast cancer." npj Breast Cancer 12.1 (2026).

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