In estrogen receptor (ER)+ and HER2+ breast cancer, the most common mechanism of abnormal activation of the PAM pathway is PIK3CA mutation, accounting for 47% of cases of the ER+/HER2− (luminal A) subtype, 33% of the ER+/HER2+ (luminal B) subtype, 23%–39% of the ER-/HER2+ subtype and 8–25% of the triple-negative breast cancer (TNBC) subtype [33,34,36]. The gene discussed is ESR1; the disease is breast cancer.