RB1 and breast cancer: Palbociclib is a reversible, small-molecule CDK4/6-I and was the first-in class to show meaningful clinical activity in ER-positive BC both in preclinical and clinical studies.12,13 Palbociclib showed a highly specific activity against CDK4 and CDK6, with a half maximal inhibitory concentration (IC50) of 11 and 15 nanomol/Litre (nM/L), respectively.14 In addition, it demonstrated antiproliferative activity against RB-positive tumor cells in vitro, inducing an exclusive G1 arrest with a concomitant reduction of phospho-Ser780/Ser795 on the Rb protein.