Management of hepatotoxicity associated with CDK4/6 inhibitors and rechallenge strategies in metastatic hormone-positive, HER2-NEGATIVE BREAST CANCER.

Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy have significantly improved clinical outcomes in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR + /HER2-) metastatic breast cancer. Hepatotoxicity is a known class-related adverse event that may interrupt or modify treatment. However, real-world evidence on its incidence, risk factors, and management strategies-particularly rechallenge approaches-remains limited. This study aimed to evaluate the frequency and clinical characteristics of CDK4/6 inhibitor-associated hepatotoxicity, to identify risk factors, and to assess the outcomes and safety of rechallenge following liver injury.

Methods: This retrospective multicenter study included 544 patients with HR+ /HER2- metastatic breast cancer who were treated with ribociclib or palbociclib between January 2017 and July 2024 in oncology centers across Turkey. Abemaciclib was not included due to reimbursement limitations during the study period. Patient characteristics, comorbidities, concomitant medications, and herbal or dietary supplement use were recorded. Liver function tests and viral hepatitis serologies were analyzed. Hepatotoxicity was graded using the Common Terminology Criteria for Adverse Events (CTCAE v5.0), and causality was assessed with the Roussel Uclaf Causality Assessment Method (RUCAM). Management strategies-including dose interruption, dose reduction, switching to another CDK4/6 inhibitor, and outcomes of rechallenge were evaluated.

Results: Hepatotoxicity occurred in 10.5% of patients, most commonly in a hepatocellular pattern. Ribociclib was the most frequently used agent. Younger age, herbal supplement use, and hepatitis B carrier status were significantly associated with increased risk of hepatotoxicity. All hepatotoxic events were managed conservatively. None of the patients developed acute liver failure or required invasive evaluation. Dose reduction or switching to the alternate agent was attempted in most patients after enzyme normalization and was successful in the majority, with no recurrence of severe hepatotoxicity.

Conclusion: CDK4/6 inhibitor-related hepatotoxicity is manageable with careful monitoring and individualized strategies. Timely dose interruption, switching agents, or cautious rechallenge allowed most patients to resume therapy safely. These findings support the continued use of CDK4/6 inhibitors in eligible patients, even after hepatotoxicity events.