PIK3CA mutations are present in high frequency in malignant breast tumors revealing its transcendence in the biology of breast cancer. In the other hand, pathological complete response (pCR) after neoadjuvant anti-HER2 targeted therapy in estrogen receptor-positive patients is a controversial endpoint of efficacy due to the lack of correlation with long-term outcomes. In a recent paper, Loibl et al. report that PIK3CA mutations are associated to lower pCR rates, conferring resistance to neoadjuvant anti-HER2 targeted therapy in hormone receptors-positive/HER2 positive breast cancers. This and prior reports raise some questions about what is the better therapeutic strategy in HER2+/ER+ tumors bearing PIK3CA mutations and its prognostic value since PI3K pathway have high relevance in the escape of hormonal dependence in estrogen-positive tumors. Recent in vitro and in vivo studies suggest the benefit of targeting the PI3K pathway, HER2 and hormonal receptors in breast cancer instead HER2 as sole target.