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      Molecular Epidemiology of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung Cancer of Adenocarcinoma Histology – Mainland China Subset Analysis of the PIONEER study

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          Abstract

          Epidermal growth factor receptor (EGFR) mutations are the strongest response predictors to EGFR tyrosine kinase inhibitors (TKI) therapy, but knowledge of the EGFR mutation frequency on lung adenocarcinoma is still limited to retrospective studies. The PIONEER study (NCT01185314) is a prospective molecular epidemiology study in Asian patients with newly diagnosed advanced lung adenocarcinoma, aiming to prospectively analyze EGFR mutation status in IIIB/IV treatment-naïve lung adenocarcinomas in Asia. We report the mainland China subset results. Eligible patients (≥20 yrs old, IIIB/IV adenocarcinoma and treatment-naïve) were registered in 17 hospitals in mainland China. EGFR was tested for mutations by amplification refractory mutation system using biopsy samples. Demographic and clinical characteristics were collected for subgroup analyses. A total of 747 patients were registered. Successful EGFR mutation analysis was performed in 741, with an overall mutation rate of 50.2%. The EGFR active mutation rate is 48.0% (with 1.3% of combined active and resistance mutations). Tobacco use (>30 pack-year vs. 0–10 pack-year, OR 0.27, 95%CI: 0.17–0.42) and regional lymph nodes involvement (N3 vs. N0, OR 0.47, 95%CI: 0.29–0.76) were independent predictors of EGFR mutation in multivariate analysis. However, even in regular smokers, the EGFR mutation frequency was 35.3%. The EGFR mutation frequency was similar between diverse biopsy sites and techniques. The overall EGFR mutation frequency of the mainland China subset was 50.2%, independently associated with the intensity of tobacco use and regional lymph nodes involvement. The relatively high frequency of EGFR mutations in the mainland China subset suggest that any effort to obtain tissue sample for EGFR mutation testing should be encouraged.

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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.

          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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            Global cancer statistics

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              Non-small-cell lung cancer.

              In the decade since the last Lancet Seminar on lung cancer there have been advances in many aspects of the classification, diagnosis, and treatment of non-small-cell lung cancer (NSCLC). An international panel of experts has been brought together to focus on changes in the epidemiology and pathological classification of NSCLC, the role of CT screening and other techniques that could allow earlier diagnosis and more effective treatment of the disease, and the recently introduced seventh edition of the TNM classification and its relation to other prognostic factors such as biological markers. We also describe advances in treatment that have seen the introduction of a new generation of chemotherapy agents, a proven advantage to adjuvant chemotherapy after complete resection for specific stage groups, new techniques for the planning and administration of radiotherapy, and new surgical approaches to assess and reduce the risks of surgical treatment. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                23 November 2015
                2015
                : 10
                : 11
                : e0143515
                Affiliations
                [1 ]Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, No.17 Panjiayuan Nanli, Chaoyang District, Beijing (100021), China
                [2 ]Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing (1011429), China
                [3 ]Department of Respiration Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing (100005), China
                [4 ]Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou (450008), Henan Province, China
                [5 ]Department of Medical Oncology, Guangzhou Chest Hospital, Guangzhou (510095), Guangdong Province, China
                [6 ]Cancer Center, Union Hospital, Tongji Medical College HuaZhong University of Science and Technology, Wuhan (430030), Hubei Province, China
                [7 ]Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang (050035), Hebei Province, China
                [8 ]Department of Medical Oncology, The 309th Hospital of Chinese People’s Liberation Army, Beijing (100091), China
                [9 ]Department of Medical Oncology, Nanfang Hospital, Southern Medical University, Guangzhou (510515), Guangdong Province, China
                [10 ]Department of Respiration Medicine, Chinese People’s Liberation Army General Hospital, Beijing (100853), China
                [11 ]Department of Medical Oncology, Liaoning Cancer Hospital, Shenyang (110042), Liaoning Province, China
                [12 ]Department of Medical Oncology, Sichuan Cancer Hospital, Chengdu (610041), Sichuan Province, China
                [13 ]Department of Medical Oncology, Qilu Hospital, Shandong University, Jinan (250012), Shandong Province, China
                [14 ]Department of Medical Oncology, The First Hospital of China Medical University, Shenyang (110001), Liaoning Province, China
                [15 ]Department of Medical Oncology, Shandong Cancer Hospital, Jinan (250117), Shandong Province, China
                [16 ]Department of Respiration Medicine, Peking University First Hospital, Beijing (100034), China
                [17 ]Department of Medical Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian (116011), Liaoning Province, China
                University of Central Florida, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YKS. Performed the experiments: YKS JLL SCZ MZW SJY NL GW WL GQL KCC LAC MZZ PY XWW YPL QSG LGN JWL XHH. Analyzed the data: YKS JLL SCZ MZW SJY NL GW WL GQL KCC LAC MZZ PY XWW YPL QSG LGN JWL XHH. Contributed reagents/materials/analysis tools: YKS JLL SCZ MZW SJY NL GW WL GQL KCC LAC MZZ PY XWW YPL QSG LGN JWL XHH. Wrote the paper: YKS JLL SCZ MZW SJY NL GW WL GQL KCC LAC MZZ PY XWW YPL QSG LGN JWL XHH.

                Article
                PONE-D-15-14510
                10.1371/journal.pone.0143515
                4657882
                26599344
                14a47179-c741-4dcc-b012-d3939d929f5d
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 16 April 2015
                : 5 November 2015
                Page count
                Figures: 1, Tables: 3, Pages: 10
                Funding
                This study was funded by AstraZeneca and partly supported by Chinese National Major Project for New Drug Innovation (2008ZX09312, 2012ZX09303012-001) and Research Special Fund for Public Welfare Industry of Health (200902002-1).
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                All relevant data are within the paper and its Supporting Information files.

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