Predictive Biomarkers and Personalized Medicine KRASCodon 12 and 13Mutations inRelation toDisease-Free Survival in BRAF–Wild-Type Stage III Colon Cancers from an Adjuvant Chemotherapy Trial (N0147 Alliance)

Purpose:We examined the prognostic impact of specific KRASmutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF–wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive. Experimental Design: The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478BRAF–wild-type tumors. BecauseKRASmutations in codon12 (n1⁄4 779) or 13 (n1⁄4 220) were not predictive of adjuvant cetuximab benefit, study armswere pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models. Results:KRASmutations in codon12 (multivariateHR, 1.52; 95%confidence interval, CI, 1.28–1.80;P< 0.0001) or codon 13 (multivariate HR, 1.36; 95% CI, 1.04–1.77; P1⁄4 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P < 0.0001), proximal tumor site (P < 0.0001), low grade, age, and sex, whereas codon 13mutationswere associatedwith proximal site (P < 0.0001). Conclusion: KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRASmutations in both codons in the progression of this malignancy in the adjuvant setting. Clin Cancer Res; 20(11); 3033–43. 2014 AACR.