Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer

Background: Activating mutations in KRAS have been suggested as potential predictive and prognostic biomarkers. However, the prognostic impact of specific point mutations remains less clear. This study assessed the prognostic impact of specific KRAS mutations on survival for patients with colorectal cancer. Methods: Retrospective review of patients KRAS typed for advanced and recurrent colorectal cancer between 2010 and 2015 in a UK Cancer Network. Results: We evaluated the impact of KRAS genotype in 392 patients. Mutated KRAS was detected in 42.9% of tumours. KRAS mutations were more common in moderate vs well-differentiated tumours. On multivariate analysis, primary tumour T stage (HR 2.77 (1.54-4.98), P = 0.001), N stage (HR 1.51 (1.01-2.26), P = 0.04), curative intent surgery (HR 0.51 (0.34-0.76), P = 0.001), tumour grade (HR 0.44 (0.30-0.65), P = 0.001) and KRAS mutation (1.54 (1.23-2.12), P = 0.005) were all predictive of overall survival. Patients with KRAS codon 12 mutations had worse overall survival (HR 1.76 (95% CI 1.27-2.43), P = 0.001). Among the five most common codon 12 mutations, only p.G12C (HR 2.21 (1.15-4.25), P = 0.01) and p.G12V (HR 1.69 (1.08-2.62), P = 0.02) were predictive of overall survival. Conclusions: For patients with colorectal cancer, p.G12C and p.G12V mutations in codon 12 were independently associated with worse overall survival after diagnosis.