Prognostic and predictive effects of TP53 co-mutation in patients with EGFR -mutated non-small cell lung cancer (NSCLC)
Abstract
Introduction TP53 mutations are common in non-small cell lung cancer (NSCLC) and have been reported as prognostic of poor outcome. The impact of TP53 co-mutations in epidermal growth factor receptor (EGFR)-mutated NSCLC is unclear.Materials and methods Tissue from 105 patients with EGFR-mutated NSCLC at Princess Margaret Cancer Centre was analyzed by next-generation or Sanger sequencing to determine TP53 mutational status. Associations between TP53 status and baseline patient and tumor characteristics, treatments and outcomes (relapse-free survival [RFS] after surgical resection, overall survival [OS], overall response rate [ORR] and progression-free survival [PFS] on EGFR tyrosine kinase inhibitors [TKIs]), were investigated.Results Dual TP53/EGFR mutations were found in 43/105 patients (41%). Among 76 patients who underwent surgical resection, neither RFS (HR 0.99, CI 0.56-1.75, p=0.96) nor OS (HR 1.39, CI 0.70-2.77; p=0.35) was associated with TP53 status. Sixty patients (24 TP53 MUT; 36 TP53 WT) received first-generation EGFR TKIs for advanced disease. ORR was not significantly different (TP53 MUT 54%, WT 66%, p=0.42). There was a non-significant trend towards shorter PFS on EGFR TKIs with TP53 mutation (HR 1.74, CI 0.98-3.10, p=0.06). When limited to TP53 missense mutations (n=17), PFS was significantly shorter (HR 1.91, CI 1.01-3.60, p=0.04). Among 11 evaluable patients treated with T790M inhibitors, ORR was not significantly different (TP53 MUT 3/3 [100%], WT 7/8 [88%]).Conclusions Patients with dual TP53/EGFR mutations, especially missense mutations, had marginally lower response rates and shorter PFS when treated with EGFR TKI therapy. Larger datasets are required to validate these observations.
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Multiple clinical studies have identified TP53 co-alterations as a negative prognostic marker in EGFR-mutant LUAD and a consistent predictor of worse clinical outcomes following EGFR TKI therapy.
“In keeping with a more complex genomic landscape and a larger burden of clonal or sub-clonal co-drivers, multiple clinical studies have identified TP53 co-alterations as a negative prognostic marker in EGFR-mutant LUAD and a consistent predictor of worse clinical outcomes following EGFR TKI therapy72, 73, 111–116.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [115]
PIK3CA co-mutations do not appear to affect response rates to first- or second-line EGFR TKI therapy.
“do not appear to impact response rates and progression-free survival with first or second line EGFR TKI therapy73, 115, 123”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [115]
In vitro, PIK3CA mutations that co-occur enhance invasion and migration of cells.
“In vitro, co-occurring PIK3CA mutations promote cellular invasion and migration”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [115]
Some in vivo studies link co-occurring PIK3CA mutations to poorer overall survival.
“in vivo they are associated with worse overall survival in some studies”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [115]
PIK3CA co-mutations do not appear to affect progression-free survival with first- or second-line EGFR TKI therapy.
“do not appear to impact response rates and progression-free survival with first or second line EGFR TKI therapy73, 115, 123”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [115]
Evidence also indicates that TP53 co-mutations worsen outcomes on third-generation mutant-selective EGFR TKIs in patients with acquired EGFR T790M.
“there is further evidence that they adversely impact clinical outcomes with the third generation, mutant-selective EGFR TKIs, in patients whose tumors have acquired the EGFRT790M gatekeeper mutation72, 115.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [115]
Across studies, TP53 co-mutations predict shorter PFS when first- or second-generation EGFR TKIs are given upfront.
“TP53 co-mutations have consistently been associated with shorter progression-free survival following upfront treatment with 1st or 2nd generation EGFR TKIs”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [115]
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- Authors
- Labbé, C., Cabanero, M., Korpanty, G. J., Tomasini, P., Doherty, M. K., Mascaux, C., Jao, K., Pitcher, B., Wang, R., Pintilie, M., Leighl, N. B., Feld, R., Liu, G., Bradbury, P. A., Kamel-Reid, S., Tsao, M.-S., & Shepherd, F. A.
- Affiliations
- University Health Network (CA)
- Queen's University (CA)
- Aix-Marseille Université (FR)
- Sunnybrook Health Science Centre (CA)
- Hôpital du Sacré-Cœur de Montréal (CA)
- Corresponding author
- Labbé, Catherine
- Korpanty, Grzegorz J.
- Tomasini, Pascale
- Doherty, Mark K.
- Mascaux, Céline
- Jao, Kevin
- Pitcher, Bethany
- Wang, Rick
- Pintilie, Melania
- Leighl, Natasha B.
- Feld, Ronald
- Liu, Geoffrey
- Bradbury, Penelope Ann
- Tsao, Ming-Sound
- Shepherd, Frances A.
- ORCID
- Venue
- Lung Cancer
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 111
- Pages
- 23-29
- ISSN
- 0169-5002 (ISSN-L)
- OpenAlex
- W2655216406
- Cited by
- 230
- References
- 7
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 14 · 2023: 33 · 2022: 37 · 2021: 35 · 2020: 44 · 2019: 23 · 2018: 17 · 2017: 2
- FWCI
- 19.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Lung Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- TP53 mutation, EGFR mutation, non-small cell lung cancer, EGFR tyrosine kinase inhibitors, progression-free survival, overall response rate, prognostic factors, predictive biomarkers, TP53 missense mutations, relapse-free survival, overall survival, EGFR-mutant non-small cell lung cancer
- MeSH terms
- Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Combined Modality Therapy, Exons, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Neoplasm Staging, Neoplasms, Prognosis, Survival Analysis, Tumor Suppressor Protein p53, Treatment Outcome, Safety Management, Kaplan-Meier Estimate, ErbB Receptors
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