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

Vollständiger Abstract

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Background KRAS mutations (KRAS m )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 KRAS m 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 KRAS m 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.