Since phase III studies on the combination of fulvestrant + CDK4/6i in metastatic BC resistant to aromatase inhibitor alone demonstrated a median PFS within the range of 11.2–20.5 months and a median OS of 34.8–46.7 months [23,24,25], the CDK4/6i rechallenge does not represent a viable clinical option. Here, CDK4 is linked to breast cancer.