Clinical Impact of PI3K/BRAF Mutations in RAS Wild Metastatic Colorectal Cancer: Meta-analysis Results.

BACKGROUND: Understanding the molecular mechanisms of colorectal cancer has evolved during the last decade ushering the era of personalized medicine. Alteration of BRAF and PI3K is common in colorectal cancer, and can affect several signaling pathways including EGFR (epidermal growth factor receptor). The aim of this meta-analysis is to evaluate the clinical role of PI3K and BRAF mutations in patients with KRAS wild-type metastatic colorectal cancer (MCRC) receiving an EGFR monoclonal antibody (anti-EGFR) inhibitor as first-line therapy.

METHODS: A literature search was performed to identify studies exploring the association between PI3K/BRAF mutations and clinical outcomes of KRAS wild-type mCRC patients treated with anti-EGFR as a first-line therapy. The primary clinical outcome was overall response rate (ORR). The secondary outcomes included progression-free survival (PFS) and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed-effect model or random effect model according to heterogeneity between studies.

RESULTS: Ten studies with 1470 mCRC patients (357 for PI3K studies and 1113 from BRAF studies) met selection criteria. We observed a trend towards lower ORR in patients with PI3K mutations (3 studies, 357 patients; ORR = 14.3% in mutant-type PI3K vs. 52.4% in wild-type PIK3CA [95% CI - 0.12-0.02]; P = 0.13). Patients with mutant-type PI3K have significant shorter PFS (3 studies, 357 patients, 3.8 vs. 4.15 months, HR = 1.36; [95% CI 1.04-1.77]; P = 0.02]), and OS (3 studies, 357 patients, 14.17 vs. 16.3 months, HR = 1.50; [95% CI 1.14-1.97]; P = 0.004) compared to those with wild PI3K. For BRAF, patients with mutant type have significantly lower ORR (7 studies, 1113 patients; ORR = 33% vs. 39%; [95% CI - 0.16-0.01]; P = 0.03), shorter PFS (5 studies, 814 patients, 3.9 vs. 5.7 months, HR = 1.72; [95% CI 1.47-2.01]; P = 0.00001), and shorter OS (4 studies, 766 pts., 9.1 vs. 18.9 months, HR = 1.22; [95% CI 1.04-1.44]; P = 0.01) compared to those with wild-type.

CONCLUSION: This analysis suggests that patients with mCRC and either PI3K or BRAF mutation may have a lower response and worse outcome when treated with anti-EGFR in the first line. Given their worse outcome, routine testing for BRAF and PI3K mutational status should be considered. Novel therapeutic approaches are needed for patients with mutations in BRAF or PI3K.