A meta-analysis of eight clinical trials, encompassing 4,580 patients, reveals that cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, when combined with endocrine therapy, significantly improve progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR-positive), HER2-negative advanced breast cancer. The findings, published on NCBI, underscore the clinical benefit of this combination as a salvage treatment option.
Improved Survival Outcomes
The analysis showed a significantly longer duration of PFS in the CDK4/6 inhibitor group compared to the control group (hazard ratio, 0.55; 95% CI, 0.51–0.60; P<0.00001). Treatment with CDK4/6 inhibitors plus endocrine therapy also resulted in longer OS than endocrine therapy alone (hazard ratio, 0.79; 95% CI, 0.66–0.96; P=0.01). These results indicate a substantial clinical benefit for patients receiving the combination therapy.
Safety Profile and Adverse Events
The meta-analysis also assessed the adverse event profiles of the treatments. A notable rise in bone marrow suppression, especially neutropenia and leukopenia, was observed with the CDK4/6 inhibitor combination (RR =32.04; 95% CI, 17.14–59.90 and RR =30.65; 95% CI, 16.51–56.91, respectively). However, the analysis did not find a significant increase in gastrointestinal toxicity.
Background and Rationale
Breast cancer, particularly the luminal subtypes, often relies on endocrine therapy as a primary treatment. However, resistance to endocrine therapy can develop, necessitating alternative approaches. CDK4/6 inhibitors target the cyclin D1-CDK4/6-Rb pathway, which is frequently dysregulated in breast cancer, promoting cell proliferation. By inhibiting this pathway, these drugs offer a new avenue for managing advanced breast cancer.
Study Details and Methodology
The meta-analysis included randomized clinical trials evaluating CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) in combination with endocrine therapy. The Cochrane Risk of Bias Tool was used to assess the risk of bias in each study. Heterogeneity across studies was evaluated using the Cochrane Q value and I² statistics. Fixed and random effect models were employed based on heterogeneity analysis to pool hazard ratios and risk ratios.
Implications and Future Directions
The findings support the use of CDK4/6 inhibitors in combination with endocrine therapy for advanced breast cancer, demonstrating significant improvements in PFS and OS. While bone marrow suppression is a notable adverse event, it is generally manageable. Further research is needed to identify biomarkers that can predict which patients will benefit most from these agents and to evaluate the long-term efficacy and safety of CDK4/6 inhibitors in different breast cancer subtypes and treatment settings. Longer follow-up is essential to fully evaluate the OS improvement of CDK4/6 inhibitors for advanced breast cancer patients.
