KRAS and BRAF Mutations in Stage II/III Colon Cancer: A Systematic Review and Meta-Analysis

Background: KRAS and BRAF mutations are well-established predictive and prognostic factors in metastatic colorectal cancer, however their impact in the adjuvant setting has not yet been established. Methods: We performed a meta-analysis of adjuvant phase III trials in patients with stage II and III colon cancer with available data on the impact of KRAS/BRAF mutations on both disease-free survival (DFS) and overall survival (OS). Trials were subgrouped based on whether adjustment for microsatellite instability (MSI) was performed and the subgroup effect was analyzed through a meta-regression. To increase the precision of the estimates, a joint DFS/OS (so-called 'multivariate') meta-analysis was performed. All statistical tests were 2-sided. Results: Nine trials were selected (QUASAR 2, PETACC-8, N0147, CALGB-89803, NSABP-C07, NSABP-C08, PETACC-3, QUASAR, MOSAIC) including a total of 10893 patients. In the primary meta-analysis, KRAS mutation was associated with poor DFS (pooled HR = 1.36, 95% CI = 1.15-1.61, P < .001) and OS (pooled HR = 1.27, 95% CI = 1.03-1.55, P = .03) and BRAF mutation was also associated with poor DFS (pooled HR = 1.33, 95% CI = 1.00-1.78, P = .05) and OS (pooled HR = 1.49, 95% CI = 1.31-1.70, P < .001). MSI adjustment enhanced the effect of the mutations on outcome in the MSI-adjusted subgroup for both the KRAS mutation (pooled HR for DFS = 1.43, 95% CI = 1.15-1.79, P = .001; and pooled HR for OS = 1.33, 95% CI = 1.03-1.71, P = .03) and the BRAF mutation (pooled HR for DFS = 1.59, 95% CI = 1.22-2.07, P = .001; and pooled HR for OS = 1.67, 95% CI = 1.37-2.04, P < .001). The interaction between BRAF and MSI adjustment was statistically significant for DFS (P interaction = 0.02). This interaction was even more pronounced in the DFS/OS multivariate meta-analysis. Conclusions: Both KRAS and BRAF mutations were statistically significantly associated with both DFS and OS, with the mutation effect being enhanced by MSI adjustment. Effective adjuvant treatment for microsatellite stable BRAF or KRAS-mutated colon cancer represents an unmet clinical need and exploring the use of recently available BRAF and KRAS inhibitors in this setting would be highly desirable