RB1 mutations have been detected in the ctDNA of breast cancer patients resistant to CDK4/6 inhibitors, with an estimated frequency of 5%.383 Ectopic overexpression of cyclin E1 (CCNE1) and cyclin E2 (CCNE2) can also result in resistance to antioestrogen and palbociclib monotherapy through activation of CDK2.384 In addition to cell cycle alterations, overexpression or mutation in upstream proteins, including AKT1, KRAS/HRAS/NRAS, ERBB2, and FGFR2, have also been observed as potential resistance mechanisms. This evidence concerns the gene CDK4 and breast cancer.