Prevalence of the epidermal growth factor receptor mutations in lung adenocarcinoma patients from the Middle East region

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Abstract

Lung cancer remains a major cause of cancer mortality with a 5-year survival in advanced stages around 4%. Platinum-based chemotherapy was routinely used as the standard of care in patients with advanced nonsmall cell lung cancer, but it is being progressively replaced by targeted molecular therapy. One of the molecular aberrations harbored by lung adenocarcinoma is the epidermal growth factor receptor (EGFR). A large ethnic variation has been reported in the prevalence of EGFR mutations in patients with lung adenocarcinoma. Data regarding its prevalence from the Middle East area remains limited. This paper aims at reviewing the data available for the prevalence of this mutation in the Middle Eastern patient population and comparing it with other reported series.

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Most cited references 38

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The blockade of immune checkpoints in cancer immunotherapy.

Drew M Pardoll (2012)

Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.

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EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

W Pao, V. Miller, M Zakowski … (2004)

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.

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Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers.

Hisayuki Shigematsu, Li. Lin, Takao Takahashi … (2005)

Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. We sequenced exons 18-21 of the EGFR TK domain from genomic DNA isolated from 617 non-small-cell lung cancers (NSCLCs) and 524 normal lung tissue samples from the same patients and 36 neuroendocrine lung tumors collected from patients in Japan, Taiwan, the United States, and Australia and from 243 other epithelial cancers. Mutation status was compared with clinicopathologic features and with the presence of mutations in KRAS, a gene in the EGFR signaling pathway that is also frequently mutated in lung cancers. All statistical tests were two sided. We detected a total of 134 EGFR TK domain mutations in 130 (21%) of the 617 NSCLCs but not in any of the other carcinomas, nor in nonmalignant lung tissue from the same patients. In NSCLC patients, EGFR TK domain mutations were statistically significantly more frequent in never smokers than ever smokers (51% versus 10%), in adenocarcinomas versus cancer of other histologies (40% versus 3%), in patients of East Asian ethnicity versus other ethnicities (30% versus 8%), and in females versus males (42% versus 14%; all P < .001). EGFR TK domain mutation status was not associated with patient age at diagnosis, clinical stage, the presence of bronchioloalveolar histologic features, or overall survival. The EGFR TK domain mutations we detected were of three common types: in-frame deletions in exon 19, single missense mutations in exon 21, and in-frame duplications/insertions in exon 20. Rare missense mutations were also detected in exons 18, 20, and 21. KRAS gene mutations were present in 50 (8%) of the 617 NSCLCs but not in any tumors with an EGFR TK domain mutation. Mutations in either the EGFR TK domain or the KRAS gene can lead to lung cancer pathogenesis. EGFR TK domain mutations are the first molecular change known to occur specifically in never smokers.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Thorac Med

Journal ID (iso-abbrev): Ann Thorac Med

Journal ID (publisher-id): ATM

Title: Annals of Thoracic Medicine

Publisher: Wolters Kluwer - Medknow (India )

ISSN (Print): 1817-1737

ISSN (Electronic): 1998-3557

Publication date (Print): Jul-Sep 2019

Volume: 14

Issue: 3

Pages: 173-178

Affiliations

[1] Department of Internal Medicine, Division of Hematology and Oncology, American University of Beirut, Beirut, Lebanon

Author notes

Address for correspondence: Dr. Arafat Hussein Tfayli, American University of Beirut Medical Center, Naef K. Basile Cancer Institute, 11-0236, Riad El Solh, 1107 2020, Beirut, Lebanon. E-mail: at35@ 123456aub.edu.lb

Article

Publisher ID: ATM-14-173

DOI: 10.4103/atm.ATM_344_18

PMC ID: 6611202

SO-VID: a992699c-6ef8-4e98-938f-1a1c72b8d17b

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This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

History

Date received : 29 November 2018

Date accepted : 02 February 2019

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Prevalence of the epidermal growth factor receptor mutations in lung adenocarcinoma patients from the Middle East region

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Most cited references 38

The blockade of immune checkpoints in cancer immunotherapy.

EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers.

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Cited by 7