The addition of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (e.g. palbociclib, ribociclib, abemaciclib) to endocrine therapy (e.g. tamoxifen, aromatase inhibitors, fulvestrant) has transformed the treatment landscape for patients with advanced/metastatic estrogen receptor positive (ER+) breast cancer [1–3]. The gene discussed is ESR1; the disease is breast cancer.