Dataset Information

Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer.

ABSTRACT: Epidermal growth factor receptor (EGFR) mutations are the second most common oncogenic driver event in non-small cell lung cancer (NSCLC). Classical activating mutations (exon 19 deletions and the L858R point mutation) comprise the vast majority of EGFR mutations and are well defined as strong predictors for good clinical response to EGFR tyrosine kinase inhibitors (EGFRi). However, low frequency mutations including point mutations, deletions, insertions and duplications occur within exons 18-25 of the EGFR gene in NSCLC and are associated with poorer responses to EGFRi. Despite an increased uptake of more sensitive detection methods to identify rare EGFR mutations in patients, our understanding of the biology of these rare EGFR mutations is poor compared to classical mutations. In particular, clinical data focused on these mutations is lacking due to their rarity and challenges in trial recruitment, resulting in an absence of effective treatment strategies for many low frequency EGFR mutations. In this review, we describe the structural and mechanistic features of rare EGFR mutations in NSCLC and discuss the preclinical and clinical evidence for EGFRi response for individual rare EGFR mutations. We also discuss EGFRi sensitivity for complex EGFR mutations, and conclude by offering a perspective on the outstanding questions and future steps required to make advances in the treatment of NSCLC patients that harbour rare EGFR mutations.

SUBMITTER: Harrison PT

PROVIDER: S-EPMC7083237 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer.

Harrison Peter T PT Vyse Simon S Huang Paul H PH

Seminars in cancer biology 20190925

Epidermal growth factor receptor (EGFR) mutations are the second most common oncogenic driver event in non-small cell lung cancer (NSCLC). Classical activating mutations (exon 19 deletions and the L858R point mutation) comprise the vast majority of EGFR mutations and are well defined as strong predictors for good clinical response to EGFR tyrosine kinase inhibitors (EGFRi). However, low frequency mutations including point mutations, deletions, insertions and duplications occur within exons 18-25 ...[more]

PMID: 31562956

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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

Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer.

Publications

Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer.

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