Safety and Feasibility of Radiation Therapy Combined with CDK 4/6 Inhibitors in the Management of Advanced Breast Cancer

SIMPLE SUMMARY: CDK4/6 inhibitors target cell proliferation resulting in toxicity, mainly bone marrow suppression manifesting as neutropenia. Radiation therapy (RT), widely used in breast cancer patients, may enhance myelotoxicity, and no consensus guidelines exist to guide practice when both treatments are to be instantiated. Since the risks of combination therapy are not well studied, many radiation and medical oncologists prefer to suspend CDK4/6i during RT. Nonetheless, a significant challenge that limits the efficacy of CDK4/6i treatment is the occurrence of acquired resistance that leads to the progression of metastatic disease. Thus, we performed a retrospective analysis of advanced breast cancer patients treated in a tertiary cancer center with RT sequentially or concomitantly to ribociclib, palbociclib, or abemaciclib. No excessive toxicities were observed after the addition of radiotherapy to systemic treatment. Our results may help to optimize multimodality treatment in a large population of patients with advanced breast cancer. ABSTRACT: The addition of CDK4/6 inhibitors to endocrine therapy in advanced hormone receptor-positive HER2-negative breast cancer has led to practice-changing improvements in overall survival. However, data concerning the safety of CDK4/6i combination with radiotherapy (RT) are conflicting. A retrospective evaluation of 288 advanced breast cancer patients (pts) treated with CDK4/6i was performed, and 100 pts also received RT. Forty-six pts received 63 RT courses concurrently and fifty-four sequentially before CDK4/6i initiation (76 RT courses). Neutropenia was common (79%) and more frequent during and after concurrent RT than sequential RT (86% vs. 76%); however, CDK4/6i dose reduction rates were similar. In patients treated with CDK4/6i alone, the dose reduction rate was 42% (79 pts) versus 38% with combined therapy, and 5% discontinued treatment due to toxicity in the combined group. The risk of CDK4/6i dose reduction was correlated with neutropenia grade, RT performed within the first two CDK4/6i cycles, and more than one concurrent RT; a tendency was observed in concurrent bone irradiation. However, on multivariate regression analysis, only ECOG 1 performance status and severe neutropenia at the beginning of the second cycle were found to be associated with a higher risk of CDK4/6i dose reduction. This largest single-center experience published to date confirmed the acceptable safety profile of the CDK4/6i and RT combination without a significantly increased toxicity compared with CDK4/6i alone. However, one might delay RT for the first two CDK4/6i cycles, when myelotoxic AE are most common.