Several mechanisms of endocrine resistance have been implicated in HR + mBC settings, including: (1) mutations in the gene coding for ERα expressed in breast cancer cells, ESR1; (2) amplification of growth receptors, including FGFR1, HER2, EGFR, and IGF1R; (3) activation of phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mTOR pathway; (4) alterations of key cell cycle checkpoints, including hyperphosphorylation of tumor suppressor protein, and amplification/mutation of CDK4; and (5) enhanced levels of basal autophagy. The gene discussed is PIK3CA; the disease is breast carcinoma.