Clinical and genomic characterization of KRAS G13X non-small cell lung carcinoma

Abstract

Background KRAS mutations (KRASm)represent the most common oncogenic drivers in non–small cell lung cancer (NSCLC). However, molecular features and clinical implications of the less common, codon 13 mutations (KRAS G13X) remain poorly characterized. We conducted a retrospective study to characterize KRAS G13X-positive NSCLC. Methods We reviewed patients’ charts with KRASm NSCLC treated at University of Iowa Health Care. Based on intent of therapy, patients were assigned to curative-intent (CI) or palliative-intent (PI) cohorts. Clinicopathologic data, co-mutation profiles, and outcomes were assessed. Results A total of 108 CI and 100 PI patients were included. KRAS G13X accounted for ~10% of KRASm NSCLC. KRAS G13X tumors were enriched for STK11, KEAP1, NFE2L2, and TSC1/2 co-mutations. In the CI cohort, KRAS G13X had the lowest 12-month disease-free survival (DFS) (41%), though KRAS subtype was not independently prognostic. Poor performance status, stage III disease, delayed treatment initiation, and not having ATM co-mutations were associated with inferior DFS. TET2 alterations were associated with worse overall survival (OS). In the PI cohort, KRAS G13X had the lowest 12-month progression-free survival (PFS) (17%) and OS (27%) compared to other KRAS alterations. On multivariable analysis, STK11, TERT, and TSC1/2 alterations remained independently associated with worse survival, while KRAS G13X and G12D tended to exhibit poorer OS. Conclusions KRAS G13X mutations represent a small but clinically meaningful subset of NSCLC defined by a distinctive co-mutation pattern. Outcomes appear driven predominantly by co-mutations. Combinational therapeutic strategies addressing these vulnerabilities can help improve outcomes.