Recent development of next-generation endocrine therapies (e.g. selective estrogen receptor degraders (SERDs); third-generation aromatase inhibitors (AI) and targeted therapies (e.g., CDK4/6, PI3K, and mTOR inhibitors)) as well as antibody drugs conjugates (ADC, eg. T-DXd and SG) showed promising results with meaningful improvements in survival for patients with metastatic HR + HER2 − BC. This evidence concerns the gene ESR1 and breast cancer.