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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 blocka...

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Main Authors: Mackelenbergh, Marion Tina van (Author) , Pfarr, Nicole (Author) , Weber, Karsten (Author) , Untch, Michael (Author) , Solbach, Christine (Author) , Schneeweiss, Andreas (Author) , Jank, Paul (Author) , Blohmer, Jens (Author) , Treue, Denise (Author) , Schmatloch, Sabine (Author) , Lehmann, Annika (Author) , Hanusch, Claus (Author) , Link, Theresa (Author) , Sers, Christine (Author) , Bjelic-Radisic, Vesna (Author) , Hummel, Michael (Author) , Huober, Jens (Author) , Schmitt, Wolfgang D. (Author) , Fasching, Peter A. (Author) , Aktas, Bahriye (Author) , Rhiem, Kerstin (Author) , Reinisch, Mattea (Author) , Nekljudova, Valentina (Author) , Denkert, Carsten (Author) , Loibl, Sibylle (Author)
Format: Article (Journal)
Language:English
Published: 14 April 2026
In: npj Breast cancer
Year: 2026, Volume: 12, Pages: 1-9
ISSN:2374-4677
DOI:10.1038/s41523-026-00948-7
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41523-026-00948-7
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41523-026-00948-7
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Author Notes:Marion T. Van Mackelenbergh, Nicole Pfarr, Karsten Weber, Michael Untch, Christine Solbach, Andreas Schneeweiss, Paul Jank, Jens Blohmer, Denise Treue, Sabine Schmatloch, Annika Lehmann, Claus Hanusch, Theresa Link, Christine Sers, Vesna Bjelic-Radisic, Michael Hummel, Jens Huober, Wolfgang D. Schmitt, Peter A. Fasching, Bahriye Aktas, Kerstin Rhiem, Mattea Reinisch, Valentina Nekljudova, Carsten Denkert & Sibylle Loibl
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Summary: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.
Item Description:Gesehen am 05.05.2026
Physical Description:Online Resource
ISSN:2374-4677
DOI:10.1038/s41523-026-00948-7

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