Co-mutation landscape and prognostic impact of genomic complexity in EGFR-mutant non-small cell lung cancer.

Abstract

Methods: Clinical and genomic data of patients with EGFR-mutant NSCLC were collected from publicly available cBioPortal cohorts. Cohort composition, stage availability, recurrent co-mutations, and study-origin heterogeneity were evaluated. Patients harboring EGFR Del19 or L858R mutations and available survival information were included for survival analyses. Genomic landscapes were analyzed using a standardized Del19/L858R survival cohort. Survival outcomes were evaluated using Kaplan-Meier curves and Cox regression models, including sensitivity analyses adjusted for study origin and available tumor stage. Co-mutation burden and TP53/ATM-defined DDR-related alterations were further assessed as exploratory prognostic features.

Results: A total of 1,024 EGFR-mutant NSCLC patients were identified. Among them, 844 patients harbored Del19 or L858R mutations. Among the 844 patients with EGFR Del19 or L858R mutations, 820 had complete survival information and were included in survival analyses (Del19, n = 429; L858R, n = 391). An apparent OS difference was observed between Del19 and L858R tumors in the pooled cBioPortal cohort; however, this association was attenuated after accounting for study-origin heterogeneity and was therefore interpreted as exploratory. TP53 mutation was the most robust adverse prognostic factor and remained independently associated with inferior survival after adjustment for study origin. PIK3CA mutation also remained associated with poorer OS in the study-origin-adjusted model, whereas EGFR subtype and CDKN2A mutation were not retained as independent prognostic factors after accounting for study-level heterogeneity. Increasing co-mutation burden was associated with progressively shorter OS. TP53/ATM-defined DDR-related alterations were associated with inferior OS in exploratory analysis, but this result was largely driven by TP53 because ATM-only alterations were rare and not significantly associated with OS.

Conclusion: Our study demonstrates that prognosis in EGFR-mutant NSCLC is strongly influenced by broader genomic context, particularly TP53 mutation and overall co-mutation burden. EGFR subtype-specific survival differences and TP53/ATM-defined DDR-related findings should be interpreted cautiously because of study-origin heterogeneity, incomplete clinical annotation, and the limited DDR gene definition.