PIK3CA mutations predict HER2-targeted therapy resistance in primary HER2-positive breast cancer: post hoc analyses of GeparTrio and GeparSepto

In primary HER2-positive breast cancer, the association of tumor mutations and efficacy of HER2-targeted therapy is not clear. Post hoc analyses of 364 samples from HER2-positive tumors of two neoadjuvant trials in Germany, GeparTrio (no anti-HER2 treatment; n=71) and GeparSepto (dual HER2 blockade and randomization to paclitaxel versus nab-paclitaxel; n=293) investigated the impact of mutations in 17 cancer genes on response to neoadjuvant chemotherapy. Mutations in TP53 (47.3%) and PIK3CA (23.9%) were most prevalent. EGFR, KRAS, NRAS, and HRAS were combined to the MAPK module with 2.5% harboring mutations. In GeparSepto, the pCR rate was significantly lower in PIK3CA mutant versus wild-type tumors (47.7% versus 66.7%; p=0.009). In patients treated with nab-paclitaxel, pCR rates were significantly lower in PIK3CA mutated versus wild-type tumors (38.7% versus 72.0%; p=0.001). In GeparTrio, the pCR rate was 27.3% in the PIK3CA mutated cohort compared to 16.3% in the PIK3CA wild-type cohort. The authors conclude that in HER2-positive breast cancer, PIK3CA mutations were significantly associated with reduced response to dual HER2 blockade; which was not observed in GeparTrio without anti-HER2 therapy.