Prognostic Value of KRAS Mutations in Stage III Colon Cancer: Post-Hoc Analyses of the Petacc8 Phase III Trial

Abstract

Introduction: The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined the prognostic impact of KRAS mutations in stage III patients receiving adjuvant FOLFOX +/‐ cetuximab from the PETACC8 Phase III trial. Methods: KRAS exon2 mutations were examined in BRAF wild type tumors from patients enrolled in the PETACC8 trial. Because no effect from adjuvant cetuximab was reported, tumors from both study arms were pooled for analysis. Association between time to recurrence (TTR) and Disease‐free survival (DFS) and KRAS mutation type was evaluated using Cox proportional hazard model. Results: KRAS mutations were found in 638/1657 tumors. KRAS mutations in codon 12 (HR: 1.67; 95% confidence interval [CI] [1.35‐2.04]; P < 0.001) but not in codon 13 (HR: 1.23; 95% confidence interval [CI] [0.85‐1.79]; P = 0.26) were significantly associated with shorter TTR as compared to patients with KRAS/BRAF wild‐type tumors, independently of other covariates. Taking anatomic sites into account, the impact of KRAS mutations on TTR was only found for distal tumors (n = 1043; 692 wild type; 351 mutated) with an increased risk of relapse (HR: 1.96; 95% confidence interval [CI] [1.51‐2.56]; P < 0.0001) for KRAS codon 12 mutated tumors and a trend for codon 13 (HR: 1.59; 95% confidence interval [CI] [1.00‐2.56]; P = 0.051). Similar results were found for DFS. Conclusion: KRAS exon 2 mutations are independent predictors of TTR for patients with stage III distal CC receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider tumor location and KRAS mutations as important stratification factors.