The innovative use of CDK4 and CDK6 inhibitors in combination with hormone therapy (HT) as a treatment for estrogen receptor positive/human epidermal growth factor receptor-2 negative (ESR+/HER2−) metastatic breast cancer (BC) patientsis safe and successful in term of response rate (RR), progression-free survival (PFS), and overall survival (OS). The gene discussed is ESR1; the disease is breast cancer.