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

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.