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.

Genomic landscape and prognosis of patients with TP53-mutated non-small cell lung cancer

“…Impacting carcinogenicity, co-mutations have become the core determinants in molecular and clinical heterogeneity of oncogene-driven NSCLC (14). TP53-MUT could be found in 30-72% of EGFR-mutated NSCLCs and 25-56% of ALK-positive NSCLCs (15). And EGFR mutation could be found in 10% of NSCLCs with TP53-MUT (16).…”

Longitudinal therapy monitoring of ALK-positive lung cancer by combined copy number and targeted mutation profiling of cell-free DNA

“…Moreover, t-MAD scores correlate with established molecular features of higher risk, i.e. with the presence of TP53 mutations and the EML4-ALK variant 3, which themselves portend worse survival, both in carefully controlled retrospective [ 5 , [54] , [55] , [56] ] and prospective trials [57] . While the EML4-ALK variant does not change during the disease, TP53 mutations do emerge under treatment, and their appearance is a marker of increased risk [6] .…”

Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer

“…12 Concomitant TP53 mutations may also have the potential to affect alectinib treatment efficacy, having been previously associated with unfavorable outcomes in patients with advanced ALK-positive NSCLC receiving ALK inhibitors. [17][18][19] The potential utility of blood-based nextgeneration sequencing (NGS) to detect these molecular factors is unclear.…”