AbstractPurpose:

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.