The development of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors for the treatment of hormone receptor-positive advanced breast cancer was based on preclinical studies that identified a dependence of HR+ breast cancer on CDK4 and CDK6 signaling as well as a synergistic effect from targeting the ER, cyclin-D-CDK4/6-Rb pathway [2]. This evidence concerns the gene ESR1 and breast carcinoma.