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<p>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, <i>n</i> = 71) and GeparSepto (dual HER2 blockade and randomization for paclitaxel vs. nab-paclitaxel, <i>n</i> = 293) were analyzed by targeted next generation sequencing of hot spot regions of 17 genes. Mutations in <i>TP53</i> (47.3%) and <i>PIK3CA</i> (23.9%) were most prevalent. <i>EGFR, KRAS, NRAS, HRAS</i> were combined to the MAPK module with 2.5% harboring mutations. In GeparSepto, the pCR rate was significantly lower in <i>PIK3CA</i>-mutant vs wild-type (wt) tumors (47.7% vs. 66.7%; <i>p</i> = 0.009). In patients treated with nab-paclitaxel, pCR rates were significantly lower in <i>PIK3CA</i>-mutated tumors compared to wt-tumors (38.7% vs. 72.0%; <i>p</i> = 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 <i>PIK3CA</i>-wt cohort (<i>p</i> = 0.339). In HER2+ breast cancer, <i>PIK3CA</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月14日

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  • 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

摘要

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.