ESR1 and breast cancer: It is well established that CDK4/6 inhibitors target the cyclin D/CDK/retinoblastoma signaling pathway, inducing cell cycle arrest, decreasing cell viability and causing tumor shrinkage.34 As the cyclin D/CDK complex is activated downstream of estrogen signaling, the combination of CDK4/6 inhibitors with standard endocrine therapies is a rational approach to elicit synergistic antitumor activity in estrogen receptor (ER)-positive breast cancer.