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

ABSTRACT

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.