EGFR mutation subtype modifies the clinical impact of TP53 functional loss on brain metastasis and survival in lung cancer

Background: Brain metastasis (BM) is common in EGFR-mutant non-small cell lung cancer (NSCLC). Exon 19 deletion (Ex19del) and L858R, the two predominant EGFR sensitizing mutations, differ in biological behavior, therapeutic response, and CNS relapse patterns. TP53 is the most frequent co-mutation in EGFR-mutant disease, has been associated with increased metastatic potential and CNS progression, but its subtype-specific effects in the BM setting remain unclear. We examined whether TP53 functional loss differentially influences BM risk and post-BM survival in EGFR subtypes. Methods: We analyzed NSCLC patients from MSK-IMPACT cohort and GENIE BPC cohort. Aim 1 (BM risk): time-to-BM Cox models evaluated associations of EGFR subtype, TP53 status, and their interaction with BM at presentation and BM during follow-up, adjusting for demographics, smoking, and stage. Aim 2 (post-BM prognosis): Among patients with radiographically confirmed BM or CNS, overall survival (OS) from BM diagnosis was evaluated using multivariable Cox models adjusting for BM timing, local intracranial therapy, systemic treatment generation, and extracranial metastatic burden. Results: Among 152 patients, time-to-BM analyses similarly showed shorter BM-free survival for TP53 functional loss (adjusted HR=1.65, P=0.11). Among 836 patients with BM, TP53 functional loss predicted worse OS (adjusted HR=1.97, P=0.05), and this adverse effect differed markedly by EGFR L858R and Ex19del subtype (interaction P=0.047). In Ex19del tumors, TP53 loss had a modest association with poorer OS, whereas in L858R tumors it was strongly associated with worse outcomes (median OS 34.7 vs 48.2 months). Results were consistent across cohorts and robust to exclusion of low-VAF TP53 variants. Conclusions: TP53 functional loss has distinct clinical implications across EGFR mutation subtypes, conferring both higher risk of brain metastasis and significantly worse post-BM survival in L858R compared with Ex19del disease. These findings reveal important subtype-specific heterogeneity within EGFR-mutant NSCLC and support integrating TP53 status into BM risk assessment and management strategies.