Impact of PIK3CA Mutations on the Clinical Benefits of CDK 4/6 Inhibitors in HR+/HER2- Advanced Breast Cancer: An Updated Pairwise and Network Meta-Analysis

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have revolutionized the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer. However, identifying reliable biomarkers and determining overall survival (OS) outcomes for CDK4/6i remains challenging. Methods: We conducted a systematic review and updated pairwise meta-analysis of randomized controlled trials to evaluate the clinical benefits and biomarker interactions of CDK4/6i in HR+ and HER2- advanced breast cancer. Hazard ratio (HR) and 95% confidence interval (CI) were calculated for progression-free survival (PFS) and OS across different clinical settings. Additionally, a network meta-analysis was performed to assess the comparative efficacy of different CDK4/6i in specific populations using ranking probabilities. Results: CDK4/6i significantly improved PFS (HR 0.55, 95% CI 0.52-0.59) and OS (HR 0.80, 95% CI 0.74-0.86) in patients with HR+/HER2- advanced breast cancer. Sensitivity analyses confirmed the robustness of these findings. Subgroup and meta-regression analyses demonstrated consistent clinical benefits across different lines of therapy, endocrine therapy categories, patient characteristics, and follow-up durations. However, PIK3CA mutation status emerged as a potential CDK4/6i efficacy modifier, particularly among patients who were endocrine therapy-naïve for advanced disease (First-line treatment: p for interaction = 0.03; received prior treatment, p = 0.68). The network meta-analysis suggested comparable overall efficacy among CDK4/6i. However, ribociclib may offer a slight OS advantage over palbociclib in first-line treatment, with ranking probabilities varying by specific clinical settings. Conclusions: This updated meta-analysis further validates the OS benefit of CDK4/6i in HR+/HER2- advanced breast cancer. The influence of PIK3CA mutation status on CDK4/6i efficacy appears more pronounced in endocrine therapy-naïve patients rather than those receiving later-line therapy. While currently approved CDK4/6 inhibitors exhibit similar efficacy overall, their ranking probabilities vary depending on individual clinical contexts. These findings highlight the need for further investigation into the modifying effects of PIK3CA status and specific CDK4/6i to optimize treatment strategies in HR+/HER2- advanced breast cancer.