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

<b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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, <i>PIK3CA</i> mutation status emerged as a potential CDK4/6i efficacy modifier, particularly among patients who were endocrine therapy-naïve for advanced disease (First-line treatment: <i>p</i> for interaction = 0.03; received prior treatment, <i>p</i> = 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. <b>Conclusions:</b> This updated meta-analysis further validates the OS benefit of CDK4/6i in HR+/HER2- advanced breast cancer. The influence of <i>PIK3CA</i> 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 <i>PIK3CA</i> status and specific CDK4/6i to optimize treatment strategies in HR+/HER2- advanced breast cancer.