Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis

Abstract

Background: The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non-small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments.

Methods: Eligible studies were identified by searching the online databases PubMed, Embase, Medline, The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.

Results: In total, 15 studies with 1342 patients were included for final analysis. Overall, concurrent TP53 mutation was associated with unfavorable progression-free survival (PFS) (HR = 1.88, 95%CI: 1.59-2.23, p < 0.001, I² = 0.0%, P = 0.792) and overall survival (OS) (HR = 1.92, 95%CI: 1.55-2.38, p < 0.001, I² = 0.0%, P = 0.515). Subgroup analysis based on type of targeted therapy (EGFR-TKIs or ALK-TKIs, pathological type of cancer (adenocarcinoma only or all NSCLC subtypes) and line of treatment (first-line only or all lines) all showed that TP53 mutations was associated with shorter survivals of patients with EGFR-TKIs or ALK-TKIs treatments. Particularly, in patients with first-line EGFR-TKIs treatment, significantly poorer prognosis was observed in patients with TP53 concurrent mutations (pooled HR for PFS: 1.69, 95% CI 1.25-2.27, P < 0.001, I² = 0.0%, P = 0.473; pooled HR for OS: 1.94, 95% CI 1.36-2.76, P < 0.001, I² = 0.0%, P = 0.484). Begg's funnel plots and Egger's tests indicated no significant publication bias in this study.

Conclusions: This meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced NSCLC.

Keywords: Anaplastic lymphoma kinase; Epidermal growth factor receptor; Non-small-cell lung cancer; Tumor protein 53; Tyrosine kinase inhibitors.

Fig. 1

Flow diagram of included studies for this meta-analysis

Fig. 2

Forest plots of pooled HRs of overall PFS and OS between the wild type and the TP53 mutation patients with advanced NSCLC (a) PFS; (b) OS. Abbreviations: HR hazard ratio, TP53 tumor protein p53, PFS progression-free survival, OS overall survival, NSCLC non-small cell lung cancer

Fig. 3

Forest plots of pooled HRs of PFS and OS between the wild type and the TP53 mutation patients based on TKIs therapy (a) PFS; (b) OS. Abbreviations: HR hazard ratio, PFS progression-free survival, OS overall survival, TP53 tumor protein 53, TKI tyrosine kinase inhibitor, EGFR epidermal growth factor receptor, ALK anaplastic lymphoma kinase

Fig. 4

Forest plots of pooled HRs of PFS and OS between the wild type and the TP53 mutation patients based on histopathological type of tumor (ADC or all NSCLC subtypes (a) PFS; (b) OS. Abbreviations: HR hazard ratio, PFS progression-free survival, OS overall survival, TP53 tumor protein 53, TKI tyrosine kinase inhibitor, ALK anaplastic lymphoma kinase, ADC adenocarcinoma, NSCLC non-small cell lung cancer

Fig. 5

Forest plots of pooled HRs of PFS and OS between the wild type and the TP53 mutation patients based on line of treatment (first line or all lines) (a) PFS; (b) OS. Abbreviations: HR hazard ratio, PFS progression-free survival, OS overall survival, TP53 tumor protein 53

Fig. 6

Forest plots of pooled HRs of PFS and OS between the wild type and the TP53 mutation in patients with EGFR-TKIs treatment (a) subgroup analysis for pooled HR of PFS based on pathological type (b) subgroup analysis for pooled HR of OS based on pathological type. Abbreviations: HR hazard ratio, PFS progression-free survival, OS overall survival, EGFR epidermal growth factor receptor, TKI tyrosine kinase inhibitor, ADC adenocarcinoma, NSCLC non-small cell lung cancer

Fig. 7

Begg’s funnel plots for publication bias of (a) overall PFS (b) overall OS. Abbreviations: PFS progression-free survival, OS overall survival Abbreviations: PFS progression-free survival, OS overall survival