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.