Abstract
Background
We investigated the impact of factors that influence TP53 mutations on the efficacy of EGFR-tyrosine kinase inhibitors and potential treatment
strategies.
Materials and Methods
Tumor samples were collected to screen gene mutations by next-generation sequencing,
as well as the patients’ baseline characteristics. The overall response to treatment
with TKIs was evaluated based on interval computed tomography scans at each follow-up
time point. A Fisher's exact test and log-rank test were used to determine the statistical
differences in this study.
Results
A total of 1134 clinical samples were collected from NSCLC patients, and TP53mut was identified in 644 cases and EGFRmut in 622 cases. A low frequency of TP53mut or more than 50% EGFR co-mutation rate were related to the prognosis of TKI-treated patients. In addition,
TP53mut in the region outside of the DB domain had the strongest correlation with TKI resistance,
whereas various types of mutations in the DB domain only had an impact on PFS. A grouping
study of EGFR-TKI-based treatment revealed that EGFR-TKIs with chemotherapy were associated
with more significant survival benefits for patients with prognostic TP53mut, whereas EGFR-TKI therapy was favorable for TP53wt patients. Furthermore, TP53mut could shorten the time to the relapse of postoperative patients, who will also likely
respond well to EGFR-TKIs with chemotherapy.
Conclusion
Various characteristics of TP53mut affect the prognosis of TKI-treated patients to varying degrees. EGFR-TKIs with chemotherapy
were benefit for patients’ survival with prognostic TP53mut, which provides an important reference for treatment management of EGFRmut patients.
Keywords
Abbreviations:
TP53mut (TP53 mutation), EGFRmut (EGFR mutation), EGFR-TKIs (EGFR-tyrosine kinase inhibitors), PFS (progression-free survival), OS (overall survival), NSCLC (Non-small cell lung cancer), ORR (the objectiveresponse rate), DCR (disease control rate), NGS (next-generation sequencing), CR (complete response), PR (partial response), SD (stable disease), PD (progressive disease), RFS (Relapse-Free Survival)To read this article in full you will need to make a payment
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References
- Oncogenic driver mutations in non-small cell lung cancer: Past, present and future.J. Clin. Oncol. 2021; 12: 217
- Relationship between EGFR Mutations and Pathological Classification and Specimen of Lung Adenocarcinoma.Chin J Cancer. 2017; 20: 382-388
- Postoperative adjuvant egfr-tkis for resected egfr-mutant nsclc—opportunities and obstacles.Ann Transl Med. 2021; 9 (-586): 586
- Adjuvant egfr-tkis for patients with resected egfr-mutant non-small cell lung cancer: a meta-analysis of 1,283 patients.Front. Oncol. 2021; 11629394
- Osimertinib in patients with advanced epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer: rationale, evidence and place in therapy.Ther Adv Med Oncol. 2017; 9: 387-404
- Targeted therapy in advanced non-small cell lung cancer: current advances and future trends.J Hemato Oncol. 2021; 14: 1-20
- Concurrent TP53 mutations predict poor outcomes of EGFR-TKI treatments in Chinese patients with advanced NSCLC.Cancer Manag Res. 2019; 11: 5665
- Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors.Clin Cancer Res. 2017; 23: 2195-2202
- Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: Correlation with clinical outcomes.Lung cancer. 2017; 106: 17-21
- Twenty years of p53 research: structural and functional aspects of the p53 protein.Oncogene. 1999; 18: 7621-7636
- Exploring the multiple roles of guardian of the genome: P53, Egypt.J. Med. Hum. Genet. 2020; 21: 1-23
- Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies.Cancer Gene Ther. 2011; 18: 2-11
- Interaction of the p53 DNA-binding domain with its n-terminal extension modulates the stability of the p53 tetramer.J. Mol. Biol. 2011; 409: 358-368
- Understanding the function–structure and function–mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.Proc. Natl. Acad. Sci. 2003; 100: 8424-8429
- Integrated analysis of TP53 gene and pathway alterations in the cancer genome atlas.Cell Rep. 2019; 28: 1370-1384
- TP53 mutations as potential prognostic markers for specific cancers: analysis of data from The Cancer Genome Atlas and the International Agency for Research on Cancer TP53 Database.J. Cancer Res. Clin. Oncol. 2019; 145: 625-636
- Arsenic trioxide rescues structural p53 mutations through a cryptic allosteric site.Cancer cell. 2021; 39: 225-239
- Mutation hotspots in the p53 gene in tumors of different origin: correlation with evolutionary conservation and signs of positive selection.Biochim. Biophys. Acta, Gene Struct. Expression. 2004; 1679: 95-106
- Heterogeneity of TP53 Mutations and P53 protein residual function in cancer: does it matter?.Front. Oncol. 2020; 10: 593383
- Why are there hotspot mutations in the TP53 gene in human cancers?.Cell Death Differ. 2018; 25: 154-160
- Mutational hotspots in the TP53gene and, possibly, other tumor suppressors evolve by positive selection.Biol. Direct. 2006; 1: 1-9
- A, Functional impact of p53 hotspot mutantions on tumor development and therapy responses in the Eµ-myc mouse lymphoma model.Cancer Res. 2011; 71: 240
- Targeted next generation sequencing in Chinese colorectal cancer patients guided anti-EGFR treatment and facilitated precision cancer medicine.Oncotarget. 2017; 8105072
- Genomic signature of driver genes identified by target next-generation sequencing in Chinese non-small cell lung cancer.Oncologist. 2019; 24: e1070-e1081
- Targeted next-generation sequencing for cancer-associated gene mutation and copy number detection in 206 patients with non–small-cell lung cancer.Bioengineered. 2021; 12: 791-802
- Revised RECIST guideline version 1.1: what oncologists want to know and what radiologists need to know.Am. J. Roentgenol. 2010; 195: 281-289
- RECIST criteria and clinical practice, Nowotwory.J. Oncol. 2021; 71: 319-320
- TP53 mutations and survival in squamous-cell carcinoma of the head and neck.N. Engl. J. Med. 2007; 357: 2552-2561
- Statistical notes for clinical researchers: x2 test and Fisher's exact test.Restor. Dent. Endod. 2017; 42: 152-155
- The clinical viewpoint: definitions, limitations of RECIST, practical considerations of measurement.Clin. Cancer Res. 2013; 19: 2629-2636
- Preoperative identification of clinicopathological prognostic factors for relapse-free survival in clinical N1 non-small cell lung cancer: a retrospective single center-based study.J. Cardiothora. Surg. 2020; 15: 1-9
- TP53 mutations in human cancers: origins, consequences, and clinical use, Cold Spring Harbor Perspect.Biol. 2010; 2a001008
- Putting p53 in context.Cell. 2017; 170: 1062-1078
- Elevated expression of p53 gain-of-function mutation R175H in endometrial cancer cells can increase the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway.Mol. Cancer. 2009; 8: 1-7
- Concurrent TP53 mutations facilitate resistance evolution in EGFR mutant lung adenocarcinoma.J. Thorac. Oncol. 2022; 17 (S1556-0864(22)00141-1): 779-792
- The clinical efficacy of combinatorial therapy of EGFR-TKI and crizotinib in overcoming MET amplification-mediated resistance from prior EGFR-TKI therapy.Lung Cancer. 2020; 146: 165-173
- Mutations in the p53 tumor suppressor gene: important milestones at the various steps of tumorigenesis.Genes cancer. 2011; 2: 466-474
- Correlation of tumor mutational burden (TMB) with CDKN2A and TP53 mutation in HPV-negative head and neck squamous cell carcinoma (HNSCC).Am. J. Clin. Oncol. 2020; 2020 (-6552): 6552
- Mutant p53 as a guardian of the cancer cell.Cell Death Differ. 2019; 26: 199-212
- ATRIP protects progenitor cells against DNA damage in vivo.Cell Death Dis. 2020; 11: 1-12
- Mechanisms of DNA damage, repair, and mutagenesis.Environ. Mol. Mutagen. 2017; 58: 235-263
- P2. 01-44 Prognostic Value of TP53 Hot exon mutation in patients with advanced Non-Small Cell Lung Cancer (NSCLC).J. Thorac. Oncol. 2018; 13: S681-S682
- Combination strategies based on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for cancer patients: pooled analysis and subgroup analysis of efficacy and safety.Medicine. 2019; 98: e14135
- Combination strategies using EGFR-TKi in NSCLC therapy: learning from the gap between pre-clinical results and clinical outcomes.Int. J. Biol. Sci. 2018; 14: 204
- Development of EGFR TKIs and options to manage resistance of third-generation EGFR TKI osimertinib: conventional ways and immune checkpoint inhibitors.Front. Oncol. 2020; 10: 277
Article info
Publication history
Published online: August 14, 2022
Accepted:
August 4,
2022
Received in revised form:
June 26,
2022
Received:
February 17,
2022
Identification
Copyright
© 2022 Published by Elsevier Inc.
