Predictive value of PIK3CA mutations for response to CDK4/6 inhibitors in hormone receptor-positive, HER2-negative metastatic breast cancer: A systematic review and meta-analysis.

Abstract

e13025 Background: Hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common subtype of breast cancer. Currently, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors combined with hormone therapy are the standard treatment for patients with HR+/HER2- metastatic breast cancer. However, it is still unknown whether there are patients who are better candidates for CDK4/6 inhibitors or if there are any predictive biomarkers of response. Methods: To evaluate the association between Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) mutation status and treatment response to CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer. Methods. We extensively searched the PubMed, Web of Science, Cochrane Library, and Google Scholar databases for articles published from January 1990 to December 2024. Studies were included if they assessed the impact of PIK3CA on the clinical outcomes of HR+/HER2- metastatic breast cancer treated with CDK4/6 inhibitors. The primary outcome of our study was progression-free survival (PFS), and the secondary outcomes included overall survival (OS) and objective response rate (ORR). Results: Seven studies – involving 2221 women with HR+/HER2- metastatic breast cancer – were systematically analysed. The pooled results showed that patients with PIK3CA mutation had significantly poorer PFS than those with PIK3CA wild-type (hazard ratio (HR): 1.47; 95% confidence interval (CI): 1.22 – 1.77; p<0.0001). Similarly, PIK3CA mutation was associated with significantly poorer OS than PIK3CA wild-type (HR: 1.42; 95% CI: 1.06 – 1.89; p = 0.02). ORR was only reported in one study, with the results of that study showing that the ORR was higher in patients with wild-type PIK3CA than in patients with PIK3CA alteration (53/180 (29%) vs. 13/85 (15%). Conclusions: In summary, PIK3CA mutation correlates with poor PFS and OS in patients with HR+/HER2- metastatic breast cancer receiving CDK4/6 inhibitors. Therefore, PIK3CA mutation status should be considered as a potential predictive biomarker of resistance to CDK4/6 inhibitors. PIK3CA mutations are associated with poorer outcomes in HR+/HER2− metastatic breast cancer treated with CDK4/6 inhibitors, including shorter progression-free and overall survival. These findings highlight PIK3CA as a potential predictive biomarker for resistance to CDK4/6 inhibitors, likely due to activation of the PI3K/AKT/mTOR pathway. Integrating PIK3CA mutation status into treatment planning may guide personalised approaches, including alternative or combination therapies to overcome resistance. Future prospective studies are needed to validate these results and explore strategies to mitigate the impact of PIK3CA-mediated resistance.