Incidence and outcomes of atrial arrhythmia with cyclin dependent kinase 4/6 inhibitors in hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancer

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are increasingly used in hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer, yet emerging data suggest potential cardiotoxicity, including atrial arrhythmias (AA). Understanding incidence and outcomes of AA is essential as indications for CDK4/6 inhibitors expand. OBJECTIVES: To evaluate the incidence of new-onset AA and associated outcomes in patients with HR+/HER2- breast cancer treated with CDK4/6 inhibitors. METHODS: We conducted a retrospective cohort study of patients who received CDK4/6 inhibitors for HR+/HER2- breast cancer at Mayo Clinic from 2015 to 2024. The primary outcome was incidence of AA (atrial fibrillation, atrial flutter, or atrial tachycardia). Secondary outcomes included cerebrovascular events and all-cause mortality. Fine-Gray subdistribution hazard models and Cox regression models were used to assess risk factors for AA and all-cause mortality, respectively. RESULTS: Among 2773 patients, 59% received palbociclib, 28% abemaciclib, and 14% ribociclib. New-onset AA occurred in 42, cumulative incidence at 5 years of 2.1% (95% CI 1.5-2.8%). No significant differences in 5-year AA incidence were observed between agents: 1.5% (95% CI 0.7-2.8%), 2.3 (95% CI 1.6-3.2%), 1.0 (95% CI 0.3-2.6%) (p = 0.49). Multivariable analysis identified age at treatment as the only independent predictor of AA (HR 1.07, 95% CI 1.04-1.09, p < 0.001). New-onset AA was associated with increased mortality (HR 1.56, 95% CI 1.10-2.20, p = 0.012). CONCLUSIONS: Patients who receive CDK4/6 inhibitors for breast cancer experience a low but measurable risk of new-onset atrial arrhythmias. There was no significant difference in new-onset AA risk between agents. Prospective studies are needed to define mechanisms and guide monitoring strategies.