KRAS and BRAF mutations modify adjuvant chemotherapy outcomes in early stage colorectal cancer

KRAS and BRAF^V600E mutations are established biomarkers in metastatic colorectal cancer (CRC), but their predictive roles in early-stage disease remain uncertain. We aimed to determine whether KRAS and BRAF^V600E mutations modify the association between adjuvant chemotherapy regimen and survival in stage III and high-risk stage II CRC. We analyzed patients who underwent curative resection and molecular profiling for KRAS and BRAF^V600E. Adjuvant chemotherapy was classified as fluoropyrimidine monotherapy (5FU) or oxaliplatin-based therapy (Ox+). Propensity score overlap weighting addressed non-randomized treatment allocation. Weighted Cox models assessed recurrence-free survival (RFS) and overall survival (OS), including tests for treatment-by-mutation interaction. Among treated patients (n = 853), a global interaction test indicated a differential association between regimens and survival by mutation status (OS, p = 0.007; RFS p = 0.049). Ox+ was associated with improved survival in patients with KRAS-mutated tumors (OS HR = 0.68, 95% CI, 0.47-0.98), and a less favorable outcome in BRAF-mutated tumors (OS HR = 2.58, 95% CI, 1.16-5.77) compared with 5FU. Outcomes were similar between Ox+ and 5FU in double wild-type (KRAS and BRAF wild-type) tumors (OS HR = 1.11, 95% CI, 0.82-1.50). These findings suggest molecular heterogeneity in treatment associations that may inform adjuvant therapy selection.