[Biological, preclinical and clinical aspects of the association between radiation therapy and CDK4/6 inhibitors]. / Aspects biologiques, précliniques et cliniques de l'association de radiothérapie et d'inhibiteur de CDK 4/6.

ABSTRACT

Several clinical studies have shown that CDK4/6 inhibitors (CDK4/6i) improve survival in patients with metastatic or locally advanced HR-positive, HER-2-negative breast cancer (BC). The aim of this review was to synthesize the biological, preclinical and clinical aspects of the treatment of BC with CDK4/6i, with a focus on the combination of CDK4/6i and radiotherapy. The DNA damage induced after exposure of cells to ionizing radiation activates control pathways that inhibit cell progression in the G1 and G2 phases and induce a transient delay in progression in the S phase. These checkpoints are in particular mediated by cyclin-dependent kinases (CDK) 4/6 activated by cyclin D1. Several preclinical studies have shown that CDK4/6i could be used as radiosensitizers in non-small cell lung cancer, medulloblastoma, brainstem glioma and breast cancer. CDK4/6 inhibition also protected against radiation-induced intestinal toxicities by inducing redistribution of quiescent intestinal progenitor cells, making them less radiosensitive. Clinical data on the combination of CDK inhibitors and radiotherapy for both locoregional and metastatic irradiation are based on retrospective data. Nevertheless, the most optimal therapeutic sequence would be radiotherapy followed by palbociclib. Pending prospective clinical trials, the concomitant combination of the two treatments should be done under close supervision.