Prognostic Value of KRAS Exon 3 and Exon 4 Mutations in Colorectal Cancer Patients

Background: The clinical significance of KRAS exon 3/4 mutations in colorectal cancer (CRC) remains unclear. We aimed to assess the prognostic value of KRAS exons 3 and 4 mutations to determine the necessity for their testing. Methods: KRAS mutations in exon 2/3/4 were evaluated in 1816 stage I-IV patients with colorectal adenocarcinoma. Results: The mutation rates of KRAS and KRAS exons 2, 3, and 4 were 49.0%, 43.0%, 1.9%, and 4.1%, respectively. Univariate survival analysis showed that patients with exon 3 mutation had worse overall survival (OS) compared to those with KRAS exon 2 mutation or wild-type KRAS (P = 0.044, and P = 0.001). Meanwhile, there was no difference in survival between patients with wild-type KRAS and with exon 4 mutation (P = 0.128). In multivariate analysis, KRAS mutations in exon 3 and 2 were both independent factors for worse OS (Exon 3, P = 0.032, HR = 1.861, 95% CI: 1.021-3.391; Exon 2, P = 0.049, HR = 1.298, 95% CI: 1.002-1.682). Among the patients with KRAS exon 2 mutations, those that had mutations in codon 13 had significantly worse prognosis than those with wild-type KRAS (P = 0.001) or KRAS codon 12 mutations (P = 0.003). Conclusions: In KRAS-mutated CRC, exon 3 mutations predict the worst prognosis, while exon 4 mutations predict the best prognosis. Among KRAS exon 2 mutated patients, codon 13 mutations predict worse prognosis than codon 12 mutations. Mutations of different KRAS exons should be analyzed separately.