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, I 2 = 0.0%, P = 0.792) and overall survival (OS) (HR = 1.92, 95%CI: 1.55-2.38, p < 0.001, I 2 = 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, I 2 = 0.0%, P = 0.473; pooled HR for OS: 1.94, 95% CI 1.36-2.76, P < 0.001, I 2 = 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.

Purpose: The study investigated the impact of TP53 mutations on the clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors (TKIs) in Chinese patients with advanced or recurrent non-small-cell lung cancer (NSCLC). Patients and methods: Tissues from 163 NSCLC patients at the Affiliated Hospital of Qingdao University were analyzed by next-generation sequencing (NGS) to determine the mutational status of EGFR and concurrent genetic alterations. TP53 mutations were evaluated in relation to baseline patient characteristics and treatment outcomes (progression-free survival [PFS], overall survival [OS], objective response rate [ORR] and disease control rate [DCR]). Results: Among 163 patients with advanced NSCLC, 77 were identified as EGFR-mutant (47.2%). Six patients who did not receive TKI treatment were excluded. Among the remaining 71 patients with EGFR genetic alterations, the frequency of pathogenic TP53 mutations was 60.6% (43/71), while other concurrent mutations were rare events. Markedly shorter median PFS (mPFS) (6.5 versus 14.0 months, P =0.025) and median OS (mOS) (28.0 versus 52.0 months, P =0.023) were observed in TP53-mut patients than in TP53-wt controls. The overall DCR and ORR of TP53-mutant patients were both lower than those of the TP53-wt cases (DCR: 76.7% versus 89.3%, P =0.160; ORR: 25% versus 28%, P =0.374). Differences in prognosis were significant, especially in the subgroup of patients with TP53 non-missense mutations, non-disruptive mutations, mutations in exon 6, mutations in exon 7 and mutations in the non-DBD region among all TP53 mutations. Conclusion: TP53 mutations reduce responsiveness to TKIs and worsen the prognosis of EGFR-mutant NSCLC patients, especially for those with non-missense mutations and non-disruptive mutations, as well as mutations in exon 6, exon 7 and non-DBD region, thus acting as an independent predictor of poor outcome in advanced NSCLC patients treated with first-generation TKI therapy. Our study also suggests that TP53 mutation might be involved in primary resistance to EGFR-TKIs in Chinese NSCLC patients.

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