We made very interesting and thought-provoking observations: first, patients with HR + /HER2− BC with PIK3CA-gain/mut have worse outcome, independently of the most relevant clinico-pathological characteristics; second, PIK3CA mutations and CN gain might hold different prognostic effects in luminal A and luminal B BC; third, although very preliminary, our data from pan-cancer cell lines and PDX suggest that response to alpelisib might be influenced by PIK3CA CN gain. The gene discussed is PIK3CA; the disease is cancer.