Tumor mutations predict HER2-targeted therapy resistance in primary HER2-positive breast cancer
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.
Authors
- Denise Treue (ORCID: https://orcid.org/0000-0002-0657-5505)
- Christine Sers (ORCID: https://orcid.org/0000-0002-6219-1514)
- Wolfgang Schmitt (ORCID: https://orcid.org/0000-0002-7870-138X)
- Christine Solbach (ORCID: https://orcid.org/0000-0001-8284-3199)
- Michael Hummel (ORCID: https://orcid.org/0000-0001-6717-605X)
- Claus Hanusch
- Paul Jank (ORCID: https://orcid.org/0000-0001-7076-0476)
- Nicole Pfarr (ORCID: https://orcid.org/0000-0002-5977-5375)
- Annika Lehmann (ORCID: https://orcid.org/0000-0001-9424-5882)
- Sabine Schmatloch (ORCID: https://orcid.org/0000-0002-0131-7515)
- Andreas Schneeweiss
- Sibylle Loibl
- Kerstin Rhiem
- Jens Blohmer
- Karsten Weber
- Marion T. Van Mackelenbergh
- Michael Untch
- Valentina Nekljudova
- Theresa Link
- Vesna Bjelic-Radisic
- Mattea Reinisch
- Bahriye Aktas
- Carsten Denkert
- Jens Huober
- Peter A. Fasching
Institutions
- Goethe University Frankfurt (DE)
- Witten/Herdecke University (DE)
- Philipps University of Marburg (DE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Kantonsspital St. Gallen (CH)
- University Hospital Heidelberg (DE)
- Humboldt-Universität zu Berlin (DE)
- Marienkrankenhaus Kassel (DE)
- National Center for Tumor Diseases (DE)
- University Hospital Schleswig-Holstein (DE)
- Helios Universitätsklinikum Wuppertal (DE)
- University Hospital Leipzig (DE)
- German Breast group (DE)
- University Hospital Frankfurt (DE)
- Helios Kliniken (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Rotkreuzklinikum München (DE)
- Centrum für Integrierte Onkologie (DE)
- Nord-Ostdeutsche Gesellschaft für Gynäkologische Onkologie (DE)
- Comprehensive Cancer Center Erlangen (DE)
- University Hospital Cologne (DE)
- Helios Hospital Berlin-Buch (DE)
- University Medical Centre Mannheim (DE)
- University Hospital Carl Gustav Carus (DE)
- Technical University of Munich (DE)
- Freie Universität Berlin (DE)
- Technische Universität Dresden (DE)
- Charité - Universitätsmedizin Berlin (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- npj Breast Cancer
- Published
- 2026-04-14
- DOI
- https://doi.org/10.1038/s41523-026-00948-7
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutschen Konsortium für Translationale Krebsforschung