ESR1 and neoplasm: ESR1 mutations in the ligand-binding domain of ER lead to constitutive activity in model systems4 and have been detected in 15–20% of patients with metastatic ER + endocrine resistance BC5–10; up to 40% of patients have been reported to have ESR1-mutated circulating tumour (ct) DNA.11 Other potential mechanisms of resistance to endocrine therapy include the activation of signalling pathways such as the PI3K/mTOR pathway.12