Infectious Complications of Cyclin-Dependent Kinases 4 and 6 Inhibitors in Patients With Hormone Receptor-Positive Metastatic Breast Cancer: A Systematic Review and Meta-analysis

Abstract Aim: The combination of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors plus endocrine therapy (ET) improved the survival outcomes and became standard of care in the treatment of metastatic hormone-positive breast cancer. However, these combinations increased the risk of neutropenia compared with ET alone. While the infection-related mortalities did not seem to be increased, the exact risk of infections with CDK 4/6 inhibitor and ET combinations is relatively understudied. Therefore, we performed a meta-analysis of CDK 4/6 inhibitor clinical trials to assess the infection risk of adding CDK4/6 inhibitors to ET.Material and Method: We systemically searched the PubMed database for relevant clinical trials. For each study, all grades and grade 3 or higher infections, upper respiratory tract infections (URTI), urinary tract infections (UTI), pneumonia and febrile neutropenia rates were recorded, whenever available. The hazard ratios (HR) with %95 confidence intervals (CI) of infection risk were calculated via the generic inverse-variance method with a random-effects model.Results: Nine eligible studies were included in the analyses (MONALEESA-2,3,7, MONARCH-2,3, MONARCH plus, PALOMA-1,2,3). In the meta-analysis of these studies, CDK 4/6 inhibitors plus ET arms were associated with increased all grades infections (HR: 1.77 95% CI: 1.56-2.01 p<0.00001), grade 3 or higher infections, (HR: 1.77, %95 CI:1.28-2.43 p=0.0005), UTIs (HR:1.59 %95 CI: 1.19-2.12 p=0.43), and febrile neutropenia (HR:4.28 %95 CI:1.73-10.62 p=0.002) Conclusion: In this meta-analysis, we observed that adding CDK4/6 inhibitors to ET significantly increased all grades and grade 3 or higher infections, UTIs. We propose that a close vigilance for infections is required for metastatic breast cancer patients using CDK 4/6 inhibitors.