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

Abstract

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. 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 or 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. Nine trials were selected (QUASAR 2, PETACC-8, N0147, CALGB-89803, NSABP-C07, NSABP-C08, PETACC-3, QUASAR, MOSAIC) including a total of 10 893 patients. In the primary meta-analysis, KRAS mutation was associated with poor DFS (pooled hazard ratio [HR] = 1.36, 95% confidence interval [CI] = 1.15 to 1.61, P < .001) and OS (pooled HR = 1.27, 95% CI = 1.03 to 1.55, P = .03) and BRAF mutation was also associated with poor DFS (pooled HR = 1.33, 95% CI = 1.00 to 1.78, P = .05) and OS (pooled HR = 1.49, 95% CI = 1.31 to 1.70, P < .001). The effect of the mutations on outcome was enhanced in the MSI-adjusted subgroup for both the KRAS mutation (pooled HR for DFS = 1.43, 95% CI = 1.15 to 1.79, P = .001; and pooled HR for OS = 1.33, 95% CI = 1.03 to 1.71, P = .03) and the BRAF mutation (pooled HR for DFS = 1.59, 95% CI = 1.22 to 2.07, P = .001; and pooled HR for OS = 1.67, 95% CI = 1.37 to 2.04, P < .001). The interaction between BRAF and MSI adjustment was statistically significant for DFS (Pinteraction = .02). This interaction was even more pronounced in the DFS-OS multivariate meta-analysis. 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.