Effects of concurrent TP53 mutations on the efficacy and prognosis of targeted therapy for advanced EGFR mutant lung adenocarcinoma

How concurrent TP53 mutations affect targeted therapy of advanced Epidermal Growth Factor Receptor (EGFR) mutant lung adenocarcinoma remains controversial, particularly the deep classification of TP53 mutations.This study retrospectively analyzed the clinical data of advanced EGFR mutant lung adenocarcinoma patients treated with EGFR-tyrosine kinase inhibitors (TKIs) in the First Affiliated Hospital of Soochow University. The survival rates were compared using Log-rank tests. Potential prognostic factors were identified using multivariate Cox hazard regression models.Total 156 advanced lung adenocarcinoma patients treated with EGFR-TKIs were included in this study. Multivariate analysis showed that male [hazard rate (HR): 1.537, 95% confidence interval (CI): 1.055-2.240, P = 0.025], brain metastasis (HR: 1.707, 95%CI: 1.086-2.682, P = 0.020) and concurrent TP53 mutations (HR: 1.569, 95%CI: 1.051-2.341, P = 0.028) were independent negative predictors of progression-free survival (PFS). EGFR L858R mutations (HR: 2.475, 95%CI: 1.443-4.248, p = 0.001), smoking history (HR: 2.530, 95%CI: 1.352-4.733, P = 0.004) and concurrent TP53 mutations (HR: 2.326, 95%CI: 1.283-4.218, P = 0.005) were associated with worse survival. Further analysis revealed that mutations in TP53 exons 4, 5 and 8 (P<0.05), missense mutations (P = 0.006) and nondisruptive mutations (P<0.001) were associated with shorter PFS, whereas mutations in TP53 exons 5 and 7 (P<0.05), missense mutations and non-missense mutations (P = 0.006; P = 0.007), disruptive mutations and nondisruptive mutations (P = 0.013; P = 0.013) were all associated with poorer survival times. In addition, the PFS and overall survival (OS) of nondisruptive mutations in exon 7 were worse than those in other exons (P = 0.041; P<0.001).Concurrent TP53 mutations conferred worse EGFR-TKIs efficacy and prognosis in advanced EGFR mutant lung adenocarcinoma and the effects of different TP53 mutation types were heterogeneous.