Mutations in exon 8 of TP53 are associated with shorter survival in patients with advanced lung cancer

Liu, Yutao; Xu, Fang; Wang, Yübo; Wu, Qingchen; Wang, Buhai; Yao, Yanwen; Han‐Zhang, Han; Ye, Junyi; Zhang, Lu; Zhang, Zhe; Liu, Jing; Zhu, Liangjun; Guo, Renhua

doi:10.3892/ol.2019.10625

Cited by 13 publications

(11 citation statements)

References 54 publications

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“…These results, in agreement with those reported by Kim et al [7], suggest a negative predictive role of TP53 mutation in all lines of therapy and in relation to all TKIs. Furthermore, our results are consistent with a recent study that found that TP53 mutations in exon 8 are associated with shorter OS of patients receiving a TKI as a first line treatment [27].…”

Section: Discussionsupporting

confidence: 93%

Concomitant TP53 Mutation Confers Worse Prognosis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Treated with TKIs

Canale

Petracci

Delmonte

et al. 2020

JCM

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Background: Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths worldwide. Epidermal Growth Factor Receptor (EGFR)-mutated patients usually benefit from TKIs treatment, but a significant portion show unresponsiveness due to primary resistance mechanisms. We investigated the role of TP53 mutations in predicting survival and response to EGFR-TKIs in EGFR-mutated NSCLC patients, to confirm, on an independent case series, our previous results. Methods: An independent retrospective cohort study was conducted, on a case series of 136 EGFR-mutated NSCLC patients receiving first or second generation TKIs as a first line therapy, and a smaller fraction of patients who acquired the T790M resistance mutation and were treated with third generation TKIs in the second or further line of treatment. TP53 mutations were evaluated in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) of the patients. Results: Forty-two patients (30.9%) showed a TP53 mutation. Considered together, TP53 mutations had no significant impact on time-to-event endpoints. Considering the different TP53 mutations separately, exon 8 mutations confirmed their negative effect on PFS (HR 3.16, 95% 1.59-6.28, p = 0.001). In patients who developed the T790M resistance mutation, treated with third generation TKIs, the TP53 exon 8 mutations predicted worse PFS (even though not statistically significant), and OS (HR 4.86, 95% CI: 1.25-18.90, p = 0.023). Conclusions: TP53 exon 8 mutations confirmed their negative prognostic impact in patients treated with first and second generation TKIs and demonstrated a role in affecting clinical outcome in patients treated with third generation TKIs.

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Section: Discussionsupporting

confidence: 93%

Concomitant TP53 Mutation Confers Worse Prognosis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Treated with TKIs

Canale

Petracci

Delmonte

et al. 2020

JCM

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“…Later, we confirmed our results in an independent case series of EGFR-mutated patients (HR for PFS 3.16, 95% CI 1.59-6.28, p = 0.001) [115]. These results were confirmed in a larger case series of NSCLC patients, where TP53 exon 8 mutations were able to predict the prognosis of EGFR-mutated patients, independently of the received treatment [116]. These results were not confirmed by the abovementioned study, which found that TP53 in exon 8 were not predictors for PFS compared with mutations in other exons (13 months vs. 13.1 months, p = 0.2) [112].…”

Section: Tp53 Mutations In Egfr-positive Nsclc: Clinical Significancesupporting

confidence: 86%

The Role of TP53 Mutations in EGFR-Mutated Non-Small-Cell Lung Cancer: Clinical Significance and Implications for Therapy

Canale

Andrikou

Priano

et al. 2022

Cancers

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Non-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Oncogene-addicted patients usually benefit from targeted therapy, but primary and acquired resistance mechanisms inevitably occur. Tumor protein 53 (TP53) gene is the most frequently mutated gene in cancer, including NSCLC. TP53 mutations are able to induce carcinogenesis, tumor development and resistance to therapy, influencing patient prognosis and responsiveness to therapy. TP53 mutants present in different forms, suggesting that different gene alterations confer specific acquired protein functions. In recent years, many associations between different TP53 mutations and responses to Epidermal Growth Factor Receptor (EGFR) targeted therapy in NSCLC patients have been found. In this review, we discuss the current landscape concerning the role of TP53 mutants to guide primary and acquired resistance to Tyrosine-Kinase Inhibitors (TKIs) EGFR-directed, investigating the possible mechanisms of TP53 mutants within the cellular compartments. We also discuss the role of the TP53 mutations in predicting the response to targeted therapy with EGFR-TKIs, as a possible biomarker to guide patient stratification for treatment.

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“…In addition, 18.3% of the cases tested by NGS carried tumor-mutations in non- EGFR genes classified currently as non-actionable, such as TP53, SMAD4, FBXW7, CTNNB1 and NOTCH1. However, pathogenic variants in these genes were considered to have prognostic or predictive significances for NSCLC patients [ 21 , 22 ]. For the 7.2% of the cases tested by NGS without finding any of tier 1 and tier 2 mutations in neither EGFR nor non -EGFR genes, but we think tier 3 variants (variants of unknown clinical significance-VUS, not reported) found in these cases might represent potentially useful biomarkers for monitoring cancer treatment effects via liquid biopsy.…”

Section: Discussionmentioning

confidence: 99%

Mutation Spectrum of EGFR From 21,324 Chinese Patients With Non-Small Cell Lung Cancer (NSCLC) Successfully Tested by Multiple Methods in a CAP-Accredited Laboratory

Mao

Zhao

et al. 2021

Pathol. Oncol. Res.

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Genotyping epidermal growth factor receptor (EGFR) gene in patients with advanced non-small cell lung cancers (NSCLC) is essential for identifying those patients who may benefit from targeted therapies. Systemically evaluating EGFR mutation detection rates of different methods currently used in clinical setting will provide valuable information to clinicians and laboratory scientists who take care of NSCLC patients. This study retrospectively reviewed the EGFR data obtained in our laboratory in last 10 years. A total of 21,324 NSCLC cases successfully underwent EGFR genotyping for clinical therapeutic purpose, including 5,244 cases tested by Sanger sequencing, 13,329 cases tested by real-time PCR, and 2,751 tested by next-generation sequencing (NGS). The average EGFR mutation rate was 45.1%, with 40.3% identified by Sanger sequencing, 46.5% by real-time PCR and 47.5% by NGS. Of these cases with EGFR mutations identified, 93.3% of them harbored a single EGFR mutation (92.1% with 19del or L858R, and 7.9% with uncommon mutations) and 6.7% harbored complex EGFR mutations. Of the 72 distinct EGFR variants identified in this study, 15 of them (single or complex EGFR mutations) were newly identified in NSCLC. For these cases with EGFR mutations tested by NGS, 65.3% of them also carried tumor-related variants in some non-EGFR genes and about one third of them were considered candidates of targeted drugs. NGS method showed advantages over Sanger sequencing and real-time PCR not only by providing the highest mutation detection rate of EGFR but also by identifying actionable non-EGFR mutations with targeted drugs in clinical setting.

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Mutations in exon 8 of TP53 are associated with shorter survival in patients with advanced lung cancer

Cited by 13 publications

References 54 publications

Concomitant TP53 Mutation Confers Worse Prognosis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Treated with TKIs

Concomitant TP53 Mutation Confers Worse Prognosis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Treated with TKIs

The Role of TP53 Mutations in EGFR-Mutated Non-Small-Cell Lung Cancer: Clinical Significance and Implications for Therapy

Mutation Spectrum of EGFR From 21,324 Chinese Patients With Non-Small Cell Lung Cancer (NSCLC) Successfully Tested by Multiple Methods in a CAP-Accredited Laboratory

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