KRAS G12C Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma.

ABSTRACT

PURPOSE: KRAS G12C is the most common KRAS mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of KRAS G12C inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected KRAS G12C-mutant lung adenocarcinoma. EXPERIMENTAL DESIGN: Patients who underwent resection of stage I-III lung adenocarcinoma and next-generation sequencing (NGS) were evaluated. Exclusion criteria were receipt of induction therapy, incomplete resection, and low-quality NGS. Mutations were classified as KRAS wild-type (KRAS wt), G12C (KRAS G12C), or non-G12C (KRAS other). DFS was compared between groups using the log-rank test; factors associated with DFS were assessed using Cox regression. Mutual exclusivity and cooccurrence, tumor clonality, and mutational signatures were assessed. RESULTS: In total, 604 patients were included 374 KRAS wt (62%), 95 KRAS G12C (16%), and 135 KRAS other (22%). Three-year DFS was not different between KRAS-mutant and KRAS wt tumors. However, 3-year DFS was worse in patients with KRAS G12C than KRAS other tumors (log-rank P = 0.029). KRAS G12C tumors had more lymphovascular invasion (51% vs. 37%; P = 0.032) and higher tumor mutation burden [median (interquartile range), 7.0 (5.3-10.8) vs. 6.1 (3.5-9.7); P = 0.021], compared with KRAS other tumors. KRAS G12C mutation was independently associated with worse DFS on multivariable analysis. Our DFS findings were externally validated in an independent The Cancer Genome Atlas cohort. CONCLUSIONS: KRAS G12C mutations are associated with worse DFS after complete resection of stage I-III lung adenocarcinoma. These tumors harbor more aggressive clinicopathologic and genomic features than other KRAS-mutant tumors. We identified a high-risk group for whom KRAS G12C inhibitors may be investigated to improve survival.