7.3.1　CDK4/6 Inhibitor

In ER+breast cancer，estrogen stimulates excessive activation of growth signaling pathways in tumor cells.Downstream of the estrogen receptor（ER），the activity of the Cyclin D1-CDK4/6 complex is increased，resulting in a loss of control of the cell cycle and excessive proliferation of tumor cells.By selectively inhibiting CDK4/6，CDK4/6 inhibitors prevent tumor cells from passing through the G1 phase-S phase checkpoint，blocking cell cycle progression，thereby inhibiting tumor cell proliferation.Second，CDK4/6 inhibitors have a synergistic effect with endocrine therapy，blocking the upstream and downstream components of the ER pathway and inhibiting tumor cell proliferation.CDK4/6 inhibitors combined with endocrine therapy achieve stronger and longer-lasting cell cycle arrest than endocrine monotherapy，inducing cell death and tumor shrinkage.CDK4/6 is the confluence of multiple intracellular signaling pathways in HR+breast cancer，and CDK4/6 inhibitors help prevent endocrine resistance.(https://www.daowen.com)

In recent years，CDK4/6 inhibitors palbociclib，ribociclib，and abemaciclib have been studied in advanced hormone receptor-positive/HER-2 negative postmenopausal breast cancer.It has been shown that its combination with aromatase inhibitor or fulvestrant can significantly prolong PFS in patients.CDK4/6 inhibitors can inhibit the binding of CDK4/6 to Cyclin D1，and the latter can phosphorylate Rb（a tumor suppressor gene），leading to the disappearance of Rb's tumor suppressor effect，and the cells enter the cell cycle to proliferate and divide.In the PALOMA-2 clinical study，patients receiving anastrozole or letrozole as part of（new）adjuvant therapy，if there is a disease progression after 12 months of completion of adjuvant therapy，letrozole plus pasuccini and single drug compared with letrozole，the median PFS was extended from 14.5 months to 24.8 months（P＜0.000001，HR=0.58）；whereas in the PALOMA-3 clinical study，paboxini was combined with fulvestrant median PFS was prolonged by approximately 5 months compared with fluvix group（9.5 months vs 4.6 months，HR=0.46，P＜0.0001）.Subsequently，the Monalissa series of studies and the Monarch series of studies also confirmed that Ribsini and Bomasini have similar effects.In the［GS1-04］PALLET study，the study of clinical and antiproliferative effects of letrozole+piperazine in neoadjuvant therapy was compared.After 14 weeks of letrozole combined with piperacillin in the treatment of ER+breast cancer，it was possible to significantly predict the proliferation of malignant cells by evaluating Ki67，but it could not improve the clinical remission rate in essence.Simultaneous reduction in cell dying may also reduce the rate of tumor shrinkage.It can be said that the era of CDK4/6 inhibitors has arrived.