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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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          Most cited references 26

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          Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.

          Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib. Copyright 2004 Massachusetts Medical Society
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            Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.

            Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer. In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group. Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.) 2009 Massachusetts Medical Society
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              EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.

              Receptor tyrosine kinase genes were sequenced in non-small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib.
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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
                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

                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

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                Figures: 1, Tables: 3, Pages: 10
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                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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