The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study

SIMPLE SUMMARY: In this multicentre study of 1117 patients with stage I–IV non-squamous non-small cell lung carcinoma (NSCLC), we investigated associations between KRAS and clinical characteristics and survival. We investigated survival among the following groups of patients: those with no KRAS mutations (wild type) versus those with mutated tumours, those with KRAS wild type versus KRAS G12C versus KRAS non-G12C mutated tumours and among patients with different KRAS mutation subtypes. We also grouped KRAS mutated patients according to mutation preference for the Raf, PI3K/Akt and RalGDS/Ral intracellular signalling pathways and investigated whether there were differences in survival according to their preference for these pathways. We found that the proportion of KRAS mutated patients and frequency of KRAS mutation subtypes in our study is consistent with other studies of non-Asian patients with NSCLC. In multivariable analyses, we found no significant differences in the time to disease progression or overall survival within any of the analysed groups. ABSTRACT: Background: due to emerging therapeutics targeting KRAS G12C and previous reports with conflicting results regarding the prognostic impact of KRAS and KRAS G12C in non-small cell lung cancer (NSCLC), we aimed to investigate the frequency of KRAS mutations and their associations with clinical characteristics and outcome. Since mutation subtypes have different preferences for downstream pathways, we also aimed to investigate whether there were differences in outcome according to mutation preference for the Raf, PI3K/Akt, or RalGDS/Ral pathways. Methods: retrospectively, clinicopathological data from 1233 stage I–IV non-squamous NSCLC patients with known KRAS status were reviewed. KRAS’ associations with clinical characteristics were analysed. Progression free survival (PFS) and overall survival (OS) were assessed for the following groups: KRAS wild type (wt) versus mutated, KRAS wt versus KRAS G12C versus KRAS non-G12C, among KRAS mutation subtypes and among mutation subtypes grouped according to preference for downstream pathways. Results: a total of 1117 patients were included; 38% had KRAS mutated tumours, 17% had G12C. Among KRAS mutated, G12C was the most frequent mutation in former/current smokers (45%) and G12D in never smokers (46%). There were no significant differences in survival according to KRAS status, G12C status, among KRAS mutation subtypes or mutation preference for downstream pathways. Conclusion: KRAS status or KRAS mutation subtype did not have any significant influence on PFS or OS.