<i>KRAS</i> ^G12C Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma.

Abstract

<i>KRAS</i> ^G12C is the most common <i>KRAS</i> mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of <i>KRAS</i> ^G12C inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected <i>KRAS</i> ^G12C-mutant lung adenocarcinoma. 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 <i>KRAS</i> wild-type (<i>KRAS</i> ^wt), G12C (<i>KRAS</i> ^G12C), or non-G12C (<i>KRAS</i> ^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. In total, 604 patients were included: 374 <i>KRAS</i> ^wt (62%), 95 <i>KRAS</i> ^G12C (16%), and 135 <i>KRAS</i> ^other (22%). Three-year DFS was not different between <i>KRAS</i>-mutant and <i>KRAS</i> ^wt tumors. However, 3-year DFS was worse in patients with <i>KRAS</i> ^G12C than <i>KRAS</i> ^other tumors (log-rank <i>P</i> = 0.029). <i>KRAS</i> ^G12C tumors had more lymphovascular invasion (51% vs. 37%; <i>P</i> = 0.032) and higher tumor mutation burden [median (interquartile range), 7.0 (5.3-10.8) vs. 6.1 (3.5-9.7); <i>P</i> = 0.021], compared with <i>KRAS</i> ^other tumors. <i>KRAS</i> ^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. <i>KRAS</i> ^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 <i>KRAS</i>-mutant tumors. We identified a high-risk group for whom <i>KRAS</i> ^G12C inhibitors may be investigated to improve survival.