Dataset Information

Concurrent Driver Gene Mutations as Negative Predictive Factors in Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.

ABSTRACT: BACKGROUND:Tyrosine kinase inhibitors (TKIs) are clinically effective in non-small cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) oncogene mutations. Genetic factors, other than EGFR sensitive mutations, that allow prognosis of TKI treatment remain undefined. METHODS:We retrospectively screened 423 consecutive patients with advanced NSCLC and EGFR 19del or 21L858R mutations. A total of 71 patients whose progression-free survivals (PFS) were shorter than 6?months or longer than 24?months were included and stratified into separate groups. Genetic background discrepancy was analysed in the two groups using next generation sequencing (NGS). FINDINGS:Sensitive EGFR mutations of 19del or 21L858R were detected by NGS in all patients; the 21L858R mutation was the major type. The most frequent accompanying somatic mutations were TP53, RB1, MAP2K. ALK fusion, MET amplification, and BRAF V600E were found only in the short PFS group. Concurrent pretreament T790?M mutation was found in both groups, but was proportionally higher in the short PFS group. In the short PFS group, patients had significantly more driver gene mutations than in long PFS group (P?=?0·018). The numbers of concomitant somatic mutations, EGFR pathway-related mutations, and tumor mutation burden (TMB) were not significantly different between the two groups. INTERPRETATION:Co-occuring driver gene mutations were negative predictive factors of TKI therapy in EGFR-mutated patients. This study highlights the importance of exploring co-occuring genomic alterations before initiation of EGFR-TKIs.

SUBMITTER: Chen M

PROVIDER: S-EPMC6491938 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Concurrent Driver Gene Mutations as Negative Predictive Factors in Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.

Chen Minjiang M Xu Yan Y Zhao Jing J Zhong Wei W Zhang Li L Bi Yalan Y Wang Mengzhao M

EBioMedicine 20190314

<h4>Background</h4>Tyrosine kinase inhibitors (TKIs) are clinically effective in non-small cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) oncogene mutations. Genetic factors, other than EGFR sensitive mutations, that allow prognosis of TKI treatment remain undefined.<h4>Methods</h4>We retrospectively screened 423 consecutive patients with advanced NSCLC and EGFR 19del or 21L858R mutations. A total of 71 patients whose progression-free survivals (PFS) were sh ...[more]

PMID: 30878600

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Project description:BackgroundIdentification of variable epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer (NSCLC) is important for the selection of appropriate targeted therapies. This meta-analysis was conducted to provide a worldwide overview of EGFR mutation and submutation (specifically exon 19 deletions, exon 21 L858R substitutions, and others) prevalence, and identify important covariates that influence EGFR mutation status in patients with advanced NSCLC to address this clinical data gap.MethodsEmbase® and MEDLINE® in Ovid were searched for studies published between 2004 and 2019 with cohorts of ≥ 50 adults with EGFR mutations, focusing on stage III/IV NSCLC (≤ 20% of patients with stage I/II NSCLC). Linear mixed-effects models were fitted to EGFR mutation endpoints using logistic transformation (logit), assuming a binomial distribution. The model included terms for an intercept reflecting European studies and further additive terms for other continents. EGFR submutations examined were exon 19 deletions, exon 21 L858R substitutions, and others.ResultsOf 3969 abstracts screened, 57 studies were included in the overall EGFR mutation analysis and 74 were included in the submutation analysis relative to the overall EGFR mutation population (Europe, n = 12; Asia, n = 51; North America, n = 5; Central America, n = 1; South America, n = 1; Oceania, n = 1; Global, n = 3). The final overall EGFR mutations model estimated Asian and European prevalence of 49.1% and 12.8%, respectively, and included an additive covariate for the proportion of male patients in a study. There were no significant covariates in the submutation analyses. Most submutations were actionable: exon 19 deletions (49.2% [Asia]; 48.4% [Europe]); exon 21 L858R substitutions (41.1% [Asia]; 29.9% [Europe]).ConclusionsAlthough EGFR mutation prevalence was higher in Asian than Western countries, data support worldwide testing for EGFR overall and submutations to inform appropriate targeted treatment decisions.

Project description:BackgroundEpidermal growth factor receptor (EGFR) and BRAF are 2 driver genes in non-small cell lung cancer (NSCLC) which are normally mutually exclusive. It has been previously reported that the existence of BRAF V600E in EGFR-mutated NSCLC patients could cause resistance to EGFR tyrosine kinase inhibitors (TKIs), but the influence of other BRAF actionable mutations on resistance to EGFR-TKIs has not yet been investigated. Understanding the coexistence of EGFR and BRAF actionable mutations in Chinese NSCLC patients may be essential for further treatment and prognostic prediction.MethodsA total of 127 Chinese NSCLC patients harboring EGFR and BRAF co-mutations were enrolled in this study. We analyzed the mutation profiles of these patients through next-generation sequencing (NGS). We explored the associations between somatic mutations and patient characteristics, including tumor stage and age, among others.ResultsThe frequency of EGFR and BRAF co-mutation was 0.91% in Chinese NSCLC patients, compared with 0.97% in Western NSCLC patients (cBioPortal). Among the 127 patients with both EGFR and BRAF mutations, 93 of them harbored clinically significant mutations. The remaining 34 patients were found to have mutations of uncertain significance of either EGFR or BRAF. TP53 was the most frequently mutated gene in BRAF and EGFR co-mutation patients, accounting for around 58% (N=54/93). MET active mutations (amplification and exon 14 skipping) accounted for 12% (N=11/93). Approximately 18% of patients (N=17/93) with significant EGFR mutations were detected to have fusions/rearrangements of the BRAF gene. BRAF fusion was more likely detected in EGFR exon19del patients compared with non-exon19del patients (P value =0.015). In addition, EGFR T790M, the most TKI-resistant mutation, was not found in any patient with BRAF fusion/rearrangement.ConclusionsThis study is the first to show different subtypes of EGFR and BRAF co-mutations in Chinese NSCLC patients. The prognosis of EGFR-TKI treatment may vary according to different BRAF actionable mutations. Aside from BRAF V600E, class II/III and BRAF fusions were found, which provides clues for investigating the resistance mechanisms of EGFR-TKIs in the future.

Dataset Information

Concurrent Driver Gene Mutations as Negative Predictive Factors in Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.

Publications

Concurrent Driver Gene Mutations as Negative Predictive Factors in Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.

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