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

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2020 Apr 18

PMID 32299384

Citations 67

Authors

Kang Qin

Helei Hou

Yu Liang

Xiaochun Zhang

Affiliations

Soon will be listed here.

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

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References

Levine A . p53, the cellular gatekeeper for growth and division. Cell. 1997; 88(3):323-31. DOI: 10.1016/s0092-8674(00)81871-1. View

Rho J, Choi Y, Ryoo B, Na I, Yang S, Kim C . p53 enhances gefitinib-induced growth inhibition and apoptosis by regulation of Fas in non-small cell lung cancer. Cancer Res. 2007; 67(3):1163-9. DOI: 10.1158/0008-5472.CAN-06-2037. View

Karachaliou N, Pilotto S, Lazzari C, Bria E, de Marinis F, Rosell R . Cellular and molecular biology of small cell lung cancer: an overview. Transl Lung Cancer Res. 2016; 5(1):2-15. PMC: 4758976. DOI: 10.3978/j.issn.2218-6751.2016.01.02. View

Yu Y, Ou Q, Wu X, Bao H, Ding Y, Shao Y . Concomitant resistance mechanisms to multiple tyrosine kinase inhibitors in ALK-positive non-small cell lung cancer. Lung Cancer. 2019; 127:19-24. DOI: 10.1016/j.lungcan.2018.11.024. View

Lin J, Riely G, Shaw A . Targeting ALK: Precision Medicine Takes on Drug Resistance. Cancer Discov. 2017; 7(2):137-155. PMC: 5296241. DOI: 10.1158/2159-8290.CD-16-1123. View

Lovly C, Iyengar P, Gainor J . Managing Resistance to EFGR- and ALK-Targeted Therapies. Am Soc Clin Oncol Educ Book. 2017; 37:607-618. PMC: 10183098. DOI: 10.1200/EDBK_176251. View

Canale M, Petracci E, Delmonte A, Chiadini E, Dazzi C, Papi M . Impact of Mutations on Outcome in -Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors. Clin Cancer Res. 2016; 23(9):2195-2202. DOI: 10.1158/1078-0432.CCR-16-0966. View

Rachiglio A, Fenizia F, Piccirillo M, Galetta D, Crino L, Vincenzi B . The Presence of Concomitant Mutations Affects the Activity of EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) Patients. Cancers (Basel). 2019; 11(3). PMC: 6468673. DOI: 10.3390/cancers11030341. View

Russo A, Perez D, Gunasekaran M, Scilla K, Lapidus R, Cooper B . Liquid biopsy tracking of lung tumor evolutions over time. Expert Rev Mol Diagn. 2019; 19(12):1099-1108. DOI: 10.1080/14737159.2020.1680287. View

10.

Hou H, Zhu H, Zhao H, Yan W, Wang Y, Jiang M . Comprehensive Molecular Characterization of Young Chinese Patients with Lung Adenocarcinoma Identified a Distinctive Genetic Profile. Oncologist. 2018; 23(9):1008-1015. PMC: 6192606. DOI: 10.1634/theoncologist.2017-0629. View

11.

Halvorsen A, Silwal-Pandit L, Meza-Zepeda L, Vodak D, Vu P, Sagerup C . TP53 Mutation Spectrum in Smokers and Never Smoking Lung Cancer Patients. Front Genet. 2016; 7:85. PMC: 4863128. DOI: 10.3389/fgene.2016.00085. View

12.

Offin M, Chan J, Tenet M, Rizvi H, Shen R, Riely G . Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical Outcomes. J Thorac Oncol. 2019; 14(10):1784-1793. PMC: 6764905. DOI: 10.1016/j.jtho.2019.06.002. View

13.

Fenizia F, De Luca A, Pasquale R, Sacco A, Forgione L, Lambiase M . EGFR mutations in lung cancer: from tissue testing to liquid biopsy. Future Oncol. 2015; 11(11):1611-23. DOI: 10.2217/fon.15.23. View

14.

Moher D, Liberati A, Tetzlaff J, Altman D . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6(7):e1000097. PMC: 2707599. DOI: 10.1371/journal.pmed.1000097. View

15.

Herbst R, Baas P, Kim D, Felip E, Perez-Gracia J, Han J . Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2015; 387(10027):1540-1550. DOI: 10.1016/S0140-6736(15)01281-7. View

16.

Christopoulos P, Dietz S, Kirchner M, Volckmar A, Endris V, Neumann O . Detection of TP53 Mutations in Tissue or Liquid Rebiopsies at Progression Identifies ALK+ Lung Cancer Patients with Poor Survival. Cancers (Basel). 2019; 11(1). PMC: 6356563. DOI: 10.3390/cancers11010124. View

17.

Stang A . Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010; 25(9):603-5. DOI: 10.1007/s10654-010-9491-z. View

18.

Aisner D, Sholl L, Berry L, Rossi M, Chen H, Fujimoto J . The Impact of Smoking and TP53 Mutations in Lung Adenocarcinoma Patients with Targetable Mutations-The Lung Cancer Mutation Consortium (LCMC2). Clin Cancer Res. 2017; 24(5):1038-1047. PMC: 7008001. DOI: 10.1158/1078-0432.CCR-17-2289. View

19.

Begg C, Mazumdar M . Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994; 50(4):1088-101. View

20.

Yu H, Arcila M, Rekhtman N, Sima C, Zakowski M, Pao W . Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013; 19(8):2240-7. PMC: 3630270. DOI: 10.1158/1078-0432.CCR-12-2246. View