Distinct Role of TP53 Co-mutations in Different EGFR Subtypes Mediating the Response to EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer.

TP53 co-mutations are closely associated with poor outcomes in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Our study aimed to explore whether TP53 co-mutations affect survival and response to EGFR tyrosine kinase inhibitors (TKIs) in patients with different EGFR subtypes. We retrospectively analyzed 240 NSCLC with EGFR mutation (MT) from the First Affiliated Hospital of Sun Yat-sen University. The effects of TP53 co-mutations on the response to EGFR TKIs were evaluated in EGFR-mutant patients. Among various EGFR-mutant subtypes, patients with EGFRL858R/TP53MT exhibited significantly worse progression-free survival (PFS) than those without TP53 co-mutations (7.9 months vs. 19.8 months, HR = 1.53, 95% CI: 1.03-2.28, P = .032), whereas a similar trend did not reappear in subgroups of EGFR19del (P = .730) and EGFRothers (P = .495). Specifically, patients with EGFRL858R/TP53MT who were treated with second-generation TKIs exhibited worse PFS than those without TP53 co-mutations. TP53 co-mutations were identified as the only independent risk factor for PFS by multivariate analysis. Moreover, TP53 co-mutations mediated the acquisition of resistance in patients harboring EGFRL858R, and concomitant mutations in additional tumor suppressor genes (TSGs) (RB1, NF1, ARID1A, and BRCA1) represented a subgroup characterized by an aggressive disease phenotype with worse PFS. TP53 co-mutations are associated with poor survival and may cooperate with other genomic events to facilitate resistance in NSCLC harboring EGFRL858R. Sequential therapeutic interventions beyond EGFR-TKIs monotherapy may extend the survival of patients with EGFRL858R/TP53MT.