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Fukui T, Mamesaya N, Takahashi T, Kishi K, Yoshizawa T, Tokito T, Azuma K, Morikawa K, Igawa S, Okuma Y, Yamanaka Y, Hosokawa S, Kasai T, Masubuchi K, Nakamichi S, Aga M, Sasaki J, Kada A, Saito AM, Naoki K, Okamoto H, Thoracic Oncology Research Group (TORG). A Prospective Phase II Trial of First-Line Osimertinib for Patients With EGFR Mutation-Positive NSCLC and Poor Performance Status (OPEN/TORG2040). J Thorac Oncol 2025; 20:665-675. [PMID: 39755169 DOI: 10.1016/j.jtho.2024.12.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 12/16/2024] [Accepted: 12/28/2024] [Indexed: 01/06/2025]
Abstract
INTRODUCTION Osimertinib is the first-line treatment for patients with NSCLC who have EGFR mutations and favorable performance status (PS). Despite the increasing clinical data on osimertinib, evidence for its use in patients with impaired PS remains limited. Therefore, a multicenter phase II trial (OPEN/TORG2040) was conducted to evaluate the efficacy and safety of first-line osimertinib treatment in patients with EGFR mutation-positive NSCLC and a poor PS. METHODS Patients with previously untreated advanced NSCLC harboring EGFR-sensitizing mutations and PS of 2 to 4 were enrolled. Osimertinib (80 mg once daily) was orally administered to eligible patients. The primary end point was objective response rate. The secondary end points were disease control rate, PS improvement rate, patient-reported outcomes, and safety. RESULTS Between February 2021 and February 2022, 30 patients with poor PS (22 with a PS of 2, six with a PS of 3, and two with a PS of 4) were enrolled. The median age was 75 (range, 41-92) years, and 18 patients had brain metastases. The objective response rate was 63.3% (90% confidence interval, 46.7%-77.9%; one-sided, p = 0.033). Disease control and PS improvement rates were 93.3% and 63.3%, respectively. Global health status/QoL also improved. Median progression-free and overall survival were 8.0 and 25.4 months, respectively. Eight patients (26.7%) experienced serious adverse events leading to discontinuation, and six (20.0%) experienced interstitial lung disease. CONCLUSIONS This prospective study confirmed the efficacy of first-line osimertinib treatment in patients with EGFR mutation-positive NSCLC and poor PS, highlighting the need for interstitial lung disease risk management. TRIAL REGISTRATION NUMBER Japan Registry of Clinical Trials Identifier: jRCTs041200100.
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Affiliation(s)
- Tomoya Fukui
- Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan; Department of Respiratory Medicine, Shonan Kamakura General Hospital, Kanagawa, Japan.
| | - Nobuaki Mamesaya
- Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | | | - Kazuma Kishi
- Department of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan
| | - Takahiro Yoshizawa
- Department of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan
| | - Takaaki Tokito
- Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Koichi Azuma
- Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Kei Morikawa
- Division of Respiratory Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Satoshi Igawa
- Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan
| | - Yusuke Okuma
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yuta Yamanaka
- Department of Thoracic Oncology, Kansai Medical University Hospital, Osaka, Japan
| | - Shinobu Hosokawa
- Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan
| | - Takashi Kasai
- Division of Thoracic Oncology, Tochigi Cancer Center, Tochigi, Japan
| | - Ken Masubuchi
- Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Gunma, Japan
| | - Shinji Nakamichi
- Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Masaharu Aga
- Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan
| | - Jiichiro Sasaki
- Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Kanagawa, Japan
| | - Akiko Kada
- Clinical Research Center, NHO Nagoya Medical Center, Aichi, Japan
| | - Akiko M Saito
- Clinical Research Center, NHO Nagoya Medical Center, Aichi, Japan
| | - Katsuhiko Naoki
- Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan
| | - Hiroaki Okamoto
- Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan
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Tomita Y, Yoshida N, Ishikawa H, Otani T, Kobayashi R, Hashimoto H, Hirose R, Dohi O, Inoue K, Morinaga Y, Itoh Y. Prevalence of gastric cancer following colorectal endoscopic submucosal dissection for lesions more than 20 mm: A retrospective analysis. DEN OPEN 2025; 5:e70042. [PMID: 39697613 PMCID: PMC11653160 DOI: 10.1002/deo2.70042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/19/2024] [Accepted: 11/22/2024] [Indexed: 12/20/2024]
Abstract
OBJECTIVES Colorectal endoscopic submucosal dissection (ESD) for large tumors is spreading worldwide. Gastric cancer (GC) sometimes occurs after colorectal ESD. However, its status including frequency and risk factors have not been examined well. In this study, we analyzed the detailed status of GC after colorectal ESD. METHODS This was a single-center retrospective study. Patients receiving colorectal ESD between 2010 and 2018 were reviewed. All patients were recommended to receive esophagogastroduodenoscopy (EGD) for screening. Finally, 436 patients receiving EGD, who underwent colorectal ESD for lesions of ≥20 mm were analyzed. The primary outcome was the GC rate after colorectal ESD, including intramucosal cancer. As a control, we compared it to the GC rate in matched Japanese national cancer registry data. The secondary outcome was risk factors for developing GC. RESULTS The mean age was 66.9 ± 10.6 and 55.3% were males. The GC rate was 5.96% (26/436) with a median observation period of 27 months. It was significantly higher than the mean GC rate in the diagnosed age calculated with the cancer registry (0.26%, observed value/expected value ratio [95% confidence interval]: 22.20 [14.50-32.53], p < 0.01). The comparison between cases with and without GC showed that significant risk factors were male (p = 0.02) and smokers (p < 0.01) and their GC rates were 8.3% and 10.9%. Also, in the limited cases, Helicobacter pylori infection (past and present) and atrophic gastritis were significant and their GC rates were 11.1% and 11.6%. CONCLUSION The GC rate was high after resecting colorectal tumors of ≥20 mm, suggesting the necessity of EGD.
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Affiliation(s)
- Yuri Tomita
- Department of GastroenterologyKoseikai Takeda HospitalKyotoJapan
| | - Naohisa Yoshida
- Department of Molecular Gastroenterology and HepatologyKyoto Prefectural University of MedicineGraduate School of Medical ScienceKyotoJapan
| | - Hideki Ishikawa
- Department of Molecular‐Targeting PreventionKyoto Prefectural University of MedicineGraduate School of Medical ScienceKyotoJapan
| | - Takahiro Otani
- Department of Public HealthNagoya City UniversityGraduate School of Medical SciencesAichiJapan
| | - Reo Kobayashi
- Department of Molecular Gastroenterology and HepatologyKyoto Prefectural University of MedicineGraduate School of Medical ScienceKyotoJapan
| | - Hikaru Hashimoto
- Department of GastroenterologyOsaka General Hospital of West Japan Railway CompanyOsakaJapan
| | - Ryohei Hirose
- Department of Molecular Gastroenterology and HepatologyKyoto Prefectural University of MedicineGraduate School of Medical ScienceKyotoJapan
| | - Osamu Dohi
- Department of Molecular Gastroenterology and HepatologyKyoto Prefectural University of MedicineGraduate School of Medical ScienceKyotoJapan
| | - Ken Inoue
- Department of Molecular Gastroenterology and HepatologyKyoto Prefectural University of MedicineGraduate School of Medical ScienceKyotoJapan
| | - Yukiko Morinaga
- Department of Surgical PathologyKyoto Prefectural University of MedicineGraduate School of Medical ScienceKyotoJapan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and HepatologyKyoto Prefectural University of MedicineGraduate School of Medical ScienceKyotoJapan
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Fukui T, Sasaki J, Igawa S, Kada A, Saito TI, Kogure Y, Okamoto H, Naoki K. Rationale and protocol design of a phase II study of first-line osimertinib treatment for patients with poor performance status and EGFR mutation-positive non-small cell lung cancer (OPEN/TORG2040). BMC Cancer 2022; 22:1314. [PMID: 36522630 PMCID: PMC9753257 DOI: 10.1186/s12885-022-10409-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Cancer chemotherapy indications for patients with poor performance status and advanced lung cancer are limited. Molecular targeted drugs, including epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors, can be used in patients with poor performance status owing to their high efficacy and safety. The third-generation EGFR-tyrosine kinase inhibitor osimertinib has demonstrated effectiveness in the initial treatment of advanced EGFR mutation-positive non-small cell lung cancer in patients with good performance status; however, no evidence exists of the drug's effectiveness in patients with poor performance status in a prospective study. We designed a study that aims to investigate the efficacy and safety of first-line osimertinib treatment in patients with advanced non-small cell lung cancer harboring sensitive EGFR mutations and with poor performance status. METHODS The OPEN/TORG2040 study is a multicenter, single-arm, phase II trial for patients with unresectable, advanced EGFR mutation-positive non-small cell lung cancer with a poor performance status (≥ 2). Eligible patients will receive osimertinib until disease progression or unacceptable toxicity. The primary endpoint is the objective response rate of the first-line osimertinib treatment. Considering a threshold value of 45%, expected value of 70% for objective response rate, one-sided significance level of 5%, statistical power of 80%, and ineligible patients, the sample size was set to 30. The secondary endpoints are disease control rate, performance status improvement rate, and safety and patient-reported outcomes using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Quality of Life Questionnaire and Lung Cancer 13. Time to treatment failure, progression-free survival, and overall survival will also be assessed. DISCUSSION Our study can determine the clinical benefits of osimertinib treatment in patients with poor performance status, since the clinical outcomes of patients with EGFR mutation-positive non-small cell lung cancer with poor performance status treated with this drug as a first-line treatment have not been sufficiently evaluated. TRIAL REGISTRATION Japan Registry of Clinical Trials: jRCTs041200100 (registration date: February 12, 2021).
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Affiliation(s)
- Tomoya Fukui
- grid.410786.c0000 0000 9206 2938Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Jiichiro Sasaki
- grid.410786.c0000 0000 9206 2938Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Kanagawa, Japan
| | - Satoshi Igawa
- grid.410786.c0000 0000 9206 2938Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
| | - Akiko Kada
- grid.410840.90000 0004 0378 7902Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan
| | - Toshiki I. Saito
- grid.410840.90000 0004 0378 7902Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan
| | - Yoshihito Kogure
- grid.410840.90000 0004 0378 7902Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center, Aichi, Japan
| | - Hiroaki Okamoto
- grid.417366.10000 0004 0377 5418Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen’s Hospital, Kanagawa, Japan
| | - Katsuhiko Naoki
- grid.410786.c0000 0000 9206 2938Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
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Ng WW, Lin CC, Cheng CY, Jiang JS, Kao SJ, Yeh DY. Real-world outcomes of first- and second-generation tyrosine kinase inhibitors first-line in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer: A retrospective observational cohort study. PLoS One 2021; 16:e0253335. [PMID: 34166400 PMCID: PMC8224855 DOI: 10.1371/journal.pone.0253335] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 06/02/2021] [Indexed: 11/18/2022] Open
Abstract
The sequencing of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) remains a matter of controversy. This cohort study analyzed the overall survival (OS) and progression-free survival (PFS) of afatinib compared with erlotinib and gefitinib first-line. EGFRm+, advanced NSCLC patients treated with either afatinib, erlotinib or gefitinib were retrospectively analyzed. A total of 107 patients were included. There was no statistically significant difference in PFS among the 3 groups. In the ≥ 60 years age group, the afatinib group had longer survival compared to the gefitinib group (p = 0.01). Median OS were 19.1, 22.9, and 35.6 months for gefitinib, erlotinib, and afatinib groups, respectively, with statistical significance between the gefitinib and afatinib groups (p = 0.009). Patients on afatinib also had longer median OS than erlotinib and gefitinib pooled together (35.5 versus 21.4 months; hazard ratio = 0.54, p = 0.016), despite similar median PFS. In conclusion, afatinib is a better choice compared to gefitinib or erlotinib for EGFRm+ patients. The OS obtained with afatinib is just 3 months shorter than osimertinib in the FLAURA trial. Direct comparison studies with osimertinib are still needed to determine optimal sequencing.
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Affiliation(s)
- Wei-Wei Ng
- Division of Chest Medicine, Department of Internal Medicine, Shin Kong Wu-Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Chen-Chun Lin
- Division of Chest Medicine, Department of Internal Medicine, Shin Kong Wu-Ho-Su Memorial Hospital, Taipei, Taiwan
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Ching-Yuan Cheng
- Division of Chest Medicine, Department of Internal Medicine, Shin Kong Wu-Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Jiunn-Song Jiang
- Division of Chest Medicine, Department of Internal Medicine, Shin Kong Wu-Ho-Su Memorial Hospital, Taipei, Taiwan
- School of Respiratory Therapy, Taipei Medical University, Taipei, Taiwan
| | - Shang-Jyh Kao
- Division of Chest Medicine, Department of Internal Medicine, Shin Kong Wu-Ho-Su Memorial Hospital, Taipei, Taiwan
- School of Respiratory Therapy, Taipei Medical University, Taipei, Taiwan
| | - Diana Yuwung Yeh
- Division of Chest Medicine, Department of Internal Medicine, Shin Kong Wu-Ho-Su Memorial Hospital, Taipei, Taiwan
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
- * E-mail:
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Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB, Bernicker EH, Colasacco C, Dacic S, Hirsch FR, Kerr K, Kwiatkowski DJ, Ladanyi M, Nowak JA, Sholl L, Temple-Smolkin R, Solomon B, Souter LH, Thunnissen E, Tsao MS, Ventura CB, Wynes MW, Yatabe Y. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med 2018; 142:321-346. [PMID: 29355391 DOI: 10.5858/arpa.2017-0388-cp] [Citation(s) in RCA: 573] [Impact Index Per Article: 81.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
CONTEXT - In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE - To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. DESIGN - The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. RESULTS - Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. CONCLUSIONS - The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients; the inclusion of additional genes ( ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels; immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing; use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors; and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain.
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Affiliation(s)
- Neal I Lindeman
- From the Departments of Pathology (Drs Lindeman and Sholl) and Medicine (Dr Kwiatkowski), Brigham and Women's Hospital, Boston, Massachusetts; the Cancer Center (Dr Bernicker) and the Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas (Dr Cagle); the Department of Pathology, University of Colorado School of Medicine, Denver (Dr Aisner); the Diagnostic and Molecular Pathology Laboratory (Dr Arcila) and the Molecular Diagnostics Service (Dr Ladanyi), Memorial Sloan Kettering Cancer Center, New York, New York; the Department of Pathology & Medicine, Pulmonary, Critical Care and Sleep Medicine, New York, New York (Dr Beasley); the Pathology and Laboratory Quality Center, College of American Pathologists, Northfield, Illinois (Mss Colasacco and Ventura); the Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Dacic); the Department of Medicine and Pathology, University of Colorado, Denver (Dr Hirsch); the Department of Pathology, University of Aberdeen, Aberdeen, Scotland (Dr Kerr); the Department of Molecular Pathology, Roswell Park Cancer Institute, Buffalo, New York (Dr Nowak); the Clinical and Scientific Affairs Division, Association for Molecular Pathology, Bethesda, Maryland (Dr Temple-Smolkin); the Molecular Therapeutics and Biomarkers Laboratory, Peter Maccallum Cancer Center, Melbourne, Australia (Dr Solomon); the Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands (Dr Thunnissen); the Department of Laboratory Medicine and Pathobiology, Princess Margaret Cancer Center, Toronto, Ontario, Canada (Dr Tsao); Scientific Affairs, International Association for the Study of Lung Cancer, Aurora, Colorado (Dr Wynes); and the Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan (Dr Yatabe). Dr Souter is in private practice in Wellanport, Ontario, Canada
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Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB, Bernicker EH, Colasacco C, Dacic S, Hirsch FR, Kerr K, Kwiatkowski DJ, Ladanyi M, Nowak JA, Sholl L, Temple-Smolkin R, Solomon B, Souter LH, Thunnissen E, Tsao MS, Ventura CB, Wynes MW, Yatabe Y. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Thorac Oncol 2018; 13:323-358. [PMID: 29396253 DOI: 10.1016/j.jtho.2017.12.001] [Citation(s) in RCA: 357] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2017] [Indexed: 12/15/2022]
Abstract
CONTEXT In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. DESIGN The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. RESULTS Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. CONCLUSIONS The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients; the inclusion of additional genes (ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels; immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing; use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors; and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain.
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Affiliation(s)
- Neal I Lindeman
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
| | - Philip T Cagle
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas
| | - Dara L Aisner
- Department of Pathology, University of Colorado School of Medicine, Denver, New York
| | - Maria E Arcila
- Diagnostic and Molecular Pathology Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mary Beth Beasley
- Department of Pathology & Medicine, Pulmonary, Critical Care and Sleep Medicine, New York, New York
| | | | - Carol Colasacco
- Pathology and Laboratory Quality Center, College of American Pathologists, Northfield, Illinois
| | - Sanja Dacic
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Fred R Hirsch
- Department of Medicine and Pathology, University of Colorado, Denver, New York
| | - Keith Kerr
- Department of Pathology, University of Aberdeen, Aberdeen, Scotland
| | | | - Marc Ladanyi
- Molecular Diagnostics Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jan A Nowak
- Department of Molecular Pathology, Roswell Park Cancer Institute, Buffalo, New York
| | - Lynette Sholl
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Robyn Temple-Smolkin
- Clinical and Scientific Affairs Division, Association for Molecular Pathology, Bethesda, Maryland
| | - Benjamin Solomon
- Molecular Therapeutics and Biomarkers Laboratory, Peter Maccallum Cancer Center, Melbourne, Australia
| | | | - Erik Thunnissen
- Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands
| | - Ming S Tsao
- Department of Laboratory Medicine and Pathobiology, Princess Margaret Cancer Center, Toronto, Ontario, Canada
| | - Christina B Ventura
- Pathology and Laboratory Quality Center, College of American Pathologists, Northfield, Illinois
| | - Murry W Wynes
- Scientific Affairs, International Association for the Study of Lung Cancer, Aurora, Colorado
| | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
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Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB, Bernicker EH, Colasacco C, Dacic S, Hirsch FR, Kerr K, Kwiatkowski DJ, Ladanyi M, Nowak JA, Sholl L, Temple-Smolkin R, Solomon B, Souter LH, Thunnissen E, Tsao MS, Ventura CB, Wynes MW, Yatabe Y. Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Mol Diagn 2018; 20:129-159. [PMID: 29398453 DOI: 10.1016/j.jmoldx.2017.11.004] [Citation(s) in RCA: 248] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2017] [Indexed: 02/07/2023] Open
Abstract
CONTEXT In 2013, an evidence-based guideline was published by the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology to set standards for the molecular analysis of lung cancers to guide treatment decisions with targeted inhibitors. New evidence has prompted an evaluation of additional laboratory technologies, targetable genes, patient populations, and tumor types for testing. OBJECTIVE To systematically review and update the 2013 guideline to affirm its validity; to assess the evidence of new genetic discoveries, technologies, and therapies; and to issue an evidence-based update. DESIGN The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel to develop an evidence-based guideline to help define the key questions and literature search terms, review abstracts and full articles, and draft recommendations. RESULTS Eighteen new recommendations were drafted. The panel also updated 3 recommendations from the 2013 guideline. CONCLUSIONS The 2013 guideline was largely reaffirmed with updated recommendations to allow testing of cytology samples, require improved assay sensitivity, and recommend against the use of immunohistochemistry for EGFR testing. Key new recommendations include ROS1 testing for all adenocarcinoma patients; the inclusion of additional genes (ERBB2, MET, BRAF, KRAS, and RET) for laboratories that perform next-generation sequencing panels; immunohistochemistry as an alternative to fluorescence in situ hybridization for ALK and/or ROS1 testing; use of 5% sensitivity assays for EGFR T790M mutations in patients with secondary resistance to EGFR inhibitors; and the use of cell-free DNA to "rule in" targetable mutations when tissue is limited or hard to obtain.
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Affiliation(s)
- Neal I Lindeman
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
| | - Philip T Cagle
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas
| | - Dara L Aisner
- Department of Pathology, University of Colorado School of Medicine, Denver, Colorado
| | - Maria E Arcila
- Diagnostic and Molecular Pathology Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mary Beth Beasley
- Department of Pathology & Medicine, Pulmonary, Critical Care and Sleep Medicine, New York, New York
| | - Eric H Bernicker
- Cancer Research Program, Houston Methodist Research Institute, Houston, Texas
| | - Carol Colasacco
- Pathology and Laboratory Quality Center, College of American Pathologists, Northfield, Illinois
| | - Sanja Dacic
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Fred R Hirsch
- Department of Medicine and Pathology, University of Colorado, Denver, Colorado
| | - Keith Kerr
- Department of Pathology, University of Aberdeen, Aberdeen, Scotland
| | | | - Marc Ladanyi
- Molecular Diagnostics Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jan A Nowak
- Department of Molecular Pathology, Roswell Park Cancer Institute, Buffalo, New York
| | - Lynette Sholl
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Robyn Temple-Smolkin
- Clinical and Scientific Affairs Division, Association for Molecular Pathology, Bethesda, Maryland
| | - Benjamin Solomon
- Molecular Therapeutics and Biomarkers Laboratory, Peter Maccallum Cancer Center, Melbourne, Australia
| | | | - Erik Thunnissen
- Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
| | - Ming S Tsao
- Department of Laboratory Medicine and Pathobiology, Princess Margaret Cancer Center, Toronto, Ontario, Canada
| | - Christina B Ventura
- Pathology and Laboratory Quality Center, College of American Pathologists, Northfield, Illinois
| | - Murry W Wynes
- Scientific Affairs, International Association for the Study of Lung Cancer, Aurora, Colorado
| | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan
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Yuan N, Zhang X, Cao Y, Jiang X, Zhao S, Feng Y, Fan Y, Lu Z, Gao H. Contrast-enhanced computerized tomography combined with a targeted nanoparticle contrast agent for screening for early-phase non-small cell lung cancer. Exp Ther Med 2017; 14:5063-5068. [PMID: 29201215 DOI: 10.3892/etm.2017.5140] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 05/11/2017] [Indexed: 12/13/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is a major cause of morbidity and mortality, and patients with NSCLC are frequently diagnosed at an advanced stage. This is primarily due to a lack of advanced and sensitive protocols for the detection of early stage NSCLC. Therefore, methods for the accurate diagnosis of early stage NSCLC are urgently required to improve survival rates. The present study investigated the use of contrast-enhanced computerized tomography (CECT) combined with a targeted nanoparticle contrast agent (TNCA) to diagnose early-stage NSCLC in a mice xenograft model. The TNCA used was lenvatinib, a multi-target tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor β, proto-oncogene tyrosine-protein kinase receptor Ret and mast/stem cell growth factor receptor Kit. Xenograft NSCLC mice were established and used to analyze the efficacy of CECT-TNCA compared with CT scanning alone. The TNCA was inhaled with the use of an atomizer. The results demonstrated that CECT-TNCA improved the sensitivity of the diagnosis of early stage NSCLC. In addition, imaging using the TNCA enabled the visualization of nodules in the lung in mice with early stage NSCLC. In addition, lung nodule signal enhancement was increased in CECT-TNCA compared with CT, suggesting a high accurate accumulation of the TNCA in tumor nodules. Mice diagnosed with early stage NSCLC exhibited a higher eradication rate of NSCLC after treatment with cisplatin compared with mice with advanced stage NSCLC. These data indicate that the sensitivity and accuracy of CT imaging for the diagnosis of early stage NSCLC was improved through combination with the liposome-encapsulated TNCA.
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Affiliation(s)
- Ninglu Yuan
- Department of Radiology, The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050011, P.R. China
| | - Xiaohe Zhang
- Department of Cardiothoracic Surgery, The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050011, P.R. China
| | - Yonghui Cao
- Department of Radiology, The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050011, P.R. China
| | - Xiaojie Jiang
- Department of Computerized Tomography, The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050011, P.R. China
| | - Si Zhao
- Department of Radiology, The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050011, P.R. China
| | - Yingying Feng
- Department of Radiology, The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050011, P.R. China
| | - Yimeng Fan
- Department of Computerized Tomography, The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050011, P.R. China
| | - Zhitao Lu
- Department of Radiology, The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050011, P.R. China
| | - Hongmei Gao
- Department of Radiology, The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050011, P.R. China
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Lung cancer mutation profile of EGFR, ALK, and KRAS: Meta-analysis and comparison of never and ever smokers. Lung Cancer 2016; 102:122-134. [DOI: 10.1016/j.lungcan.2016.10.010] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 10/15/2016] [Accepted: 10/24/2016] [Indexed: 02/07/2023]
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Comparison of clinical outcomes of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations after tyrosine kinase inhibitors treatment: a meta-analysis. Eur J Clin Pharmacol 2016; 72:1-11. [PMID: 26490356 DOI: 10.1007/s00228-015-1966-0] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 10/13/2015] [Indexed: 10/22/2022]
Abstract
PURPOSE Exon 19 deletion and exon 21 L858R mutation were the most common epidermal growth factor receptor (EGFR) mutations. We examined the clinical impact of these two mutations in patients with non-small-cell lung cancer (NSCLC) after EGFR tyrosine kinase inhibitor (TKI) treatment. METHODS The outcomes of interest were progression-free survival (PFS), overall survival (OS) and objective response rates (ORR), network meta-analysis and direct meta-analysis were conducted to calculate the efficacy of EGFR-TKIs between these two mutations. We also investigated the association between EGFR mutation types and clinical characteristics. RESULTS A total of 4835 patients from 26 trials were assessed. EGFR-TKIs, compared with chemotherapy, significantly prolonged PFS and OS in both exon 19 deletion and exon 21 L858R mutation based on 8 trials. Network meta-analysis revealed that treatment with EGFR-TKIs had greater benefit in exon 19 deletion than in exon 21 L858R mutation. Furthermore, direct meta-analysis from 12 studies showed the similar result; patients with exon 19 deletion had a significantly longer PFS compared with exon 21 L858R mutation (HR, 0.69; 95 % CI, 0.57–0.82; P < 0.001). There were also greater benefit on OS (HR, 0.61; 95 % CI, 0.43–0.86; P = 0.005) and higher ORR (OR, 2.14; 95 % CI, 1.63–2.81; P < 0.001). Additionally, we found that a significant association between the type of mutation and age (P < 0.001) or smoking status (P = 0.022), but no other significant differences were detected in sex, histologic subtype and performance status between these two mutations. CONCLUSIONS Patients with NSCLC and EGFR exon 19 deletion had a longer PFS, OS and higher response rates after EGFR-TKI therapy compared with exon 21 L858R mutation.
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Early evaluation of targeted therapy effectiveness in non-small cell lung cancer by dynamic contrast-enhanced CT. Clin Transl Oncol 2015; 18:47-57. [DOI: 10.1007/s12094-015-1335-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 06/20/2015] [Indexed: 10/23/2022]
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12
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Liu YT, Hao XZ, Li JL, Hu XS, Wang Y, Wang ZP, Wang HY, Wang B, Han XH, Zhang XR, Shi YK. Survival of patients with advanced lung adenocarcinoma before and after approved use of gefitinib in China. Thorac Cancer 2015; 6:636-42. [PMID: 26445613 PMCID: PMC4567010 DOI: 10.1111/1759-7714.12267] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 03/29/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND To compare the overall survival (OS) of patients with advanced lung adenocarcinoma in China before and after the approved use of gefitinib, and analyze clinical factors that may affect OS. METHODS Clinical data of 558 patients with advanced lung adenocarcinoma who received chemotherapy from January 2002 to December 2010 were retrospectively analyzed. According to the matched-pair case-control study design, 255 patients who only received chemotherapy and 255 patients who received gefitinib treatment after its approval were stringently matched by age, gender, and smoking history and enrolled in the study. Clinical factors including age, gender, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status (PS), tumor stage, organ metastasis, and the number of prior chemotherapies were analyzed to determine their correlations with OS. RESULTS The median survival time (MST) of the 510 enrolled patients with advanced lung adenocarcinoma was 22.8 months. The MST of the patients who received gefitinib treatment was significantly longer than that of patients who did not receive gefitinib treatment (33.5 vs. 14.1 months, P < 0.001). The OS in patients who received gefitinib treatment was significantly longer than in patients who did not receive gefitinib treatment in almost all clinical factor-based subgroups, including age, gender, smoking history, ECOG PS 0-1, tumor stage, the presence or absence of lung, pleural, bone, brain, adrenal gland and liver metastasis, and the number of prior chemotherapies (all P < 0.001), except in the ECOG PS ≥2 subgroup. CONCLUSIONS Gefitinib treatment significantly improved the survival of patients with advanced lung adenocarcinoma in China.
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Affiliation(s)
- Yu-Tao Liu
- Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing, China
| | - Xue-Zhi Hao
- Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing, China
| | - Jun-Ling Li
- Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing, China
| | - Xing-Sheng Hu
- Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing, China
| | - Yan Wang
- Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing, China
| | - Zi-Ping Wang
- Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing, China
| | - Hong-Yu Wang
- Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing, China
| | - Bin Wang
- Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing, China
| | - Xiao-Hong Han
- Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing, China
| | - Xiang-Ru Zhang
- Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing, China
| | - Yuan-Kai Shi
- Department of Medical Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs Beijing, China
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Chen L, Chen R, Zhu Z, Zhang Y, Wen Z, Li Y, Li X, Luo Y, Ma L, Lin S, Chen X. Predictive factors associated with gefitinib response in patients with advanced non-small-cell lung cancer (NSCLC). Chin J Cancer Res 2014; 26:466-70. [PMID: 25232221 DOI: 10.3978/j.issn.1000-9604.2014.08.09] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 08/10/2014] [Indexed: 11/14/2022] Open
Abstract
PURPOSE A number of different clinical characteristics have been reported to singly correlate with therapeutic activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced non-small-cell lung cancer (NSCLC). This study aimed to identify predictive factors associated with prognostic benefits of gefitinib. PATIENTS AND METHODS EGFR gene typing in 33 advanced NSCLC patients received gefitinib (250 mg/day) were analyzed with mutant-enriched PCR assay. Gefitinib response was evaluated with potential predictive factors retrospectively. RESULTS The overall objective response rate (ORR) and median progression-free survival (PFS) in the 33 patients treated by gefitinib were 45.5% and 3.0 (2.0-4.0) months. The ORR and median PFS in EGFR gene mutation patients were significantly higher/longer than those in EGFR gene wild-type patients (P<0.01). Similarly, the ORR and median PFS in non-smoker patients were significantly higher/longer than those in smoker patients (P<0.05, P<0.01, respectively). However, no difference for ORR and median PFS occurred between male and female patients. Logistic multivariate analysis showed that only EGFR mutated gene was significantly associated with the ORR (P<0.01). Both EGFR mutated gene and non-smoker were the major factors that contributed to PFS (P<0.05). CONCLUSIONS EGFR mutated gene and non-smoker status are potential predictors for gefitinib response in NSCLC patients.
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Affiliation(s)
- Lian Chen
- 1 Southern Medical University, Guangzhou 510515, China ; 2 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China ; 3 Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China ; 4 Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Rui Chen
- 1 Southern Medical University, Guangzhou 510515, China ; 2 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China ; 3 Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China ; 4 Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Zhe Zhu
- 1 Southern Medical University, Guangzhou 510515, China ; 2 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China ; 3 Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China ; 4 Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Yichen Zhang
- 1 Southern Medical University, Guangzhou 510515, China ; 2 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China ; 3 Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China ; 4 Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Zhengwei Wen
- 1 Southern Medical University, Guangzhou 510515, China ; 2 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China ; 3 Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China ; 4 Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Yun Li
- 1 Southern Medical University, Guangzhou 510515, China ; 2 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China ; 3 Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China ; 4 Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Xiaoming Li
- 1 Southern Medical University, Guangzhou 510515, China ; 2 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China ; 3 Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China ; 4 Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Yuwen Luo
- 1 Southern Medical University, Guangzhou 510515, China ; 2 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China ; 3 Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China ; 4 Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Liyu Ma
- 1 Southern Medical University, Guangzhou 510515, China ; 2 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China ; 3 Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China ; 4 Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Shuguang Lin
- 1 Southern Medical University, Guangzhou 510515, China ; 2 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China ; 3 Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China ; 4 Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Xin Chen
- 1 Southern Medical University, Guangzhou 510515, China ; 2 Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China ; 3 Department of Respiratory Diseases, SUN Yat-sen Memorial Hospital, SUN Yat-sen University, Guangzhou 510120, China ; 4 Department of Respiratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
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PharmGKB summary: very important pharmacogene information for the epidermal growth factor receptor. Pharmacogenet Genomics 2014; 23:636-42. [PMID: 23962910 DOI: 10.1097/fpc.0b013e3283655091] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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15
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Kaira R, Kaira K, Shukuya T, Kenmotsu H, Ono A, Murakami H, Tsuya A, Nakamura Y, Naito T, Endo M, Yamamoto N, Takahashi T. Long-term survival of more than 3 years among patients with advanced non-small cell lung cancer treated with chemotherapy. World J Respirol 2013; 3:110-115. [DOI: 10.5320/wjr.v3.i3.110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 09/12/2013] [Accepted: 10/12/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the prognostic factors of long-term survival of more than 3 years in patients with advanced non-small cell lung cancer (NSCLC).
METHODS: We retrospectively analyzed the records of 474 patients with advanced IIIB/IV NSCLC who received chemotherapy as initial treatment between September 2002 and March 2007.
RESULTS: The median survival time (MST) was 12.5 mo and the 3 year and 5 year survival rates were 14.6% and 5.3%, respectively. Long-term survival of more than 3 and 5 years was observed in 65 and 16 patients, respectively. The MST for the 65 patients was 61.5 mo (range, 60.1-81.0 mo). In the 474 patients, a good performance status (PS), female sex, non-smoking status and adenocarcinoma histology were significantly associated with a favorable outcome. Furthermore, female sex, a good PS, non-smoking status and adenocarcinoma histology were significantly correlated with long-term survival of more than 3 years and most of these patients (89.2%, 58/65) received epidermal growth factor receptor-tyrosine kinase inhibitors as any line treatment. Survival analysis of long-term survivors showed that a PS of 0 was an independent prognostic factor for predicting favorable outcomes.
CONCLUSION: Our results suggest that a good PS and adenocarcinoma histology play an important role in long-term survival of more than 3 years. A PS of 0 was an independent prognostic factor for predicting favorable outcomes in patients with advanced NSCLC who survived for more than 3 years.
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Martin P, Owen SP, Leighl NB. Gefitinib: re-emerging from the shadows. Lung Cancer Manag 2013. [DOI: 10.2217/lmt.13.42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
SUMMARY In the past decade, the identification of mutations in the EGFR gene and the sensitivity of activating mutations to EGF receptor–tyrosine kinase inhibitors has improved survival in a subset of non-small-cell lung cancer patients. Over 70% of patients with EGFR mutations have a response to gefitinib therapy. Gefitinib, a first-generation EGF receptor–tyrosine kinase inhibitor, is well tolerated and continues to be widely used. However, eventually most patients develop resistance to gefitinib. This article reviews the pharmacology of gefitinib and summarizes the clinical trials that have resulted in its current day indications.
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Affiliation(s)
- Petra Martin
- Division of Medical Oncology, Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, ON, Canada
| | - Scott P Owen
- Division of Medical Oncology, Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, ON, Canada
| | - Natasha B Leighl
- Division of Medical Oncology, Princess Margaret Hospital/University Health Network, University of Toronto, Toronto, ON, Canada
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Sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors in males, smokers, and non-adenocarcinoma lung cancer in patients with EGFR mutations. Int J Biol Markers 2013; 28:249-58. [PMID: 23873621 DOI: 10.5301/jbm.5000039] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2013] [Indexed: 11/20/2022]
Abstract
INTRODUCTION The demographical/clinical characteristics of being Asian, having an adenocarcinoma, being female, and being a "never-smoker" are regarded as favorable predictors for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) efficacy in non-small cell lung cancer (NSCLC) with unknown EGFR gene status. In this study, we examined the effects of the supposedly unfavorable clinical variables in EGFR-mutant patients. METHOD In total, 159 EGFR-mutant NSCLC patients' clinical features were correlated with progression-free survival (PFS), response rate (RR), and overall survival (OS). Multivariate analysis of clinical characteristics was performed using the Cox and logistic regression methods. RESULT There were 90 females (56.6%), 112 never-smokers (70.4%), and 153 patients with adenocarcinomas (96.2%). All patients were treated with EGFR-TKI, and 52.8% received TKI in a first-line setting. The median PFS of patients receiving first-line TKI was similar, regardless of gender (males vs females: 9.1 vs 9.7 months, p=0.793), smoking status (never-smokers vs smokers: 9.9 vs 9.1 months, p=0.570), or histology (adenocarcinoma vs non-adenocarcinoma: 9.7 vs 9.2 months, p=0.644). OS curves of first-line TKI-treated patients were also not associated with gender (p=0.722), smoking status (p=0.579), or histology (p=0.480). Similar results of PFS and OS were obtained for patients who received TKI beyond first-line. Multivariate analysis indicated that none of these clinical factors was an independent predictor of survival. CONCLUSIONS The supposedly 'favorable' clinical factors of female gender, non-smoking status, and adenocarcinoma were not independent predictive factors for PFS or OS in this population of EGFR-mutant NSCLC patients.
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18
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Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M, College of American Pathologists International Association for the Study of Lung Cancer and Association for Molecular Pathology. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn 2013; 15:415-53. [PMID: 23562183 DOI: 10.1016/j.jmoldx.2013.03.001] [Citation(s) in RCA: 352] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Accepted: 02/12/2013] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. PARTICIPANTS Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. EVIDENCE Three unbiased literature searches of electronic databases were performed to capture published articles from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. EVIDENCE was formally graded for each recommendation. CONSENSUS PROCESS Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). CONCLUSIONS The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
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Affiliation(s)
- Neal I Lindeman
- Department of Pathology, Brigham & Women's Hospital, Boston, MA 02115-6110, USA.
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Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol 2013; 8:823-59. [PMID: 23552377 PMCID: PMC4159960 DOI: 10.1097/jto.0b013e318290868f] [Citation(s) in RCA: 624] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To establish evidence-based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. PARTICIPANTS Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. EVIDENCE Three unbiased literature searches of electronic databases were performed to capture articles published published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. CONSENSUS PROCESS Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). CONCLUSIONS The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
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Affiliation(s)
- Neal I Lindeman
- Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts 02115-6110, USA.
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Zheng CX, Gu ZH, Han B, Zhang RX, Pan CM, Xiang Y, Rong XJ, Chen X, Li QY, Wan HY. Whole-exome sequencing to identify novel somatic mutations in squamous cell lung cancers. Int J Oncol 2013; 43:755-64. [PMID: 23799614 DOI: 10.3892/ijo.2013.1991] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Accepted: 05/08/2013] [Indexed: 11/06/2022] Open
Abstract
Squamous cell lung cancer is a major histotype of non-small cell lung cancer (NSCLC) that is distinct from lung adenocarcinoma. We used whole-exome sequencing to identify novel non-synonymous somatic mutations in squamous cell lung cancer. We identified 101 single-nucleotide variants (SNVs) including 77 non-synonymous SNVs (67 missense and 10 nonsense mutations) and 11 INDELs causing frameshifts. We also found four SNVs located within splicing sites. We verified 62 of the SNVs (51 missense, 10 nonsense and 1 splicing-site mutation) and 10 of the INDELs as somatic mutations in lung cancer tissue. Sixteen of the mutated genes were also mutated in at least one patient with a different type of lung cancer in the Catalogue of Somatic Mutation in Cancer (COSMIC) database. Four genes (LPHN2, TP53, MYH2 and TGM2) were mutated in approximately 10% of the samples in the COSMIC database. We identified two missense mutations in C10orf137 and MS4A3 that also occurred in other solid-tumor tissues in the COSMIC database. We found another somatic mutation in EP300 that was mutated in 4.2% of the 2,020 solid-tumor samples in the COSMIC database. Taken together, our results implicate TP53, EP300, LPHN2, C10orf137, MYH2, TGM2 and MS4A3 as potential driver genes of squamous cell lung cancer.
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Affiliation(s)
- Cui-Xia Zheng
- Department of Respiration, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China
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Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med 2013; 137:828-60. [PMID: 23551194 PMCID: PMC4162344 DOI: 10.5858/arpa.2012-0720-oa] [Citation(s) in RCA: 335] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVE To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. PARTICIPANTS Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. EVIDENCE Three unbiased literature searches of electronic databases were performed to capture articles published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. CONSENSUS PROCESS Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). CONCLUSIONS The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.
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Affiliation(s)
- Neal I Lindeman
- Department of Pathology, Brigham & Women's Hospital, Boston, MA 02115-6110, USA.
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Singh N, Aggarwal AN, Behera D. Management of advanced lung cancer in resource-constrained settings: a perspective from India. Expert Rev Anticancer Ther 2012; 12:1479-1495. [PMID: 23249112 DOI: 10.1586/era.12.119] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Advanced lung cancer (LC) is an important cause of cancer-related morbidity and mortality in resource-constrained settings (RCSs). Cytological/pathological confirmation of diagnosis of LC is essential prior to treatment initiation for ruling out mimickers such as pulmonary tuberculosis. Accurate staging is necessary for optimal management, and investigations should be prioritized based on availability and cost-effectiveness. Platinum-based doublet chemotherapy remains the standard of care for advanced LC. Cost of therapy, lack of medical insurance and frequency of visits are important determinants of treatment regimen. EGF receptor mutation testing may not be readily available in RCSs and chemotherapy should be preferred for unselected patients with advanced non-small-cell lung cancer. Generic drugs may be more affordable than innovator brands. Treatment efficacy should be assessed with traditional end points (survival and objective response rates) as well as those relevant to RCSs (quality of life, toxicity profile and healthcare facility utilization). Issues related to LC treatment in first- and subsequent-line settings in RCSs are discussed in detail in this evidence-based review.
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Affiliation(s)
- Navneet Singh
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India.
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Predictive Risk Factors for Mediastinal Lymph Node Metastasis in Clinical Stage IA Non–Small-Cell Lung Cancer Patients. J Thorac Oncol 2012; 7:1246-51. [DOI: 10.1097/jto.0b013e31825871de] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Zhang XH, Li C, Dai CF, Zhou BS. Epidermal growth factor receptor mutations and their correlation with epidermal growth factor receptor-tyrosine kinase inhibitor therapy and association with the characteristics of patients with non-small-cell lung cancer: A meta-analysis. Thorac Cancer 2011; 2:101-108. [PMID: 27755824 DOI: 10.1111/j.1759-7714.2011.00051.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Many studies have demonstrated that epidermal growth factor receptor (EGFR) mutation is associated with the response to therapy with single agent EGFR-tyrosine kinase inhibitors (EGFR-TKI) in non-small cell lung cancer (NSCLC) patients, but the extent of the effect is varied. We carried out a meta-analysis to assess the association between EGFR mutation and the efficacy of EGFR-TKI therapy and the independent predictor of EGFR mutation in order to identify who would be likely to benefit from this kind of therapy. METHODS All literature relating to EGFR mutation and EGFR-TKI therapy was researched and carefully selected. Related variables were abstracted and the pooled odds ratio calculated after a heterogeneity test with the software, State 10. Publication bias was evaluated at the same time. RESULTS Seventeen studies were included according to the selection criteria. We found a statistically significant higher probability of response in patients with an EGFR mutation versus wild-type (19.33, 95% CI, 13.61-27.46, P < 0.0001). Furthermore, the pooled odds ration of susceptibility to EGFR mutation among female patients compared with male patients was 3.01 (95% confidence interval (CI), 2.34-3.88 P < 0.0001), adenocarcinoma patients compared with non-adenocarcinoma patients was 5.40 (95% CI, 2.55-11.40 P < 0.0001), and non-smoker patients compared smoker patients was 19.33 (95% CI:,13.61-27.46 P < 0.0001). The publication bias analysis had no statistically significant results. CONCLUSION Female, adenocarcinoma and non-smoker are independent predictors for the EGFR mutation. Efficacy of EGFR-TKI therapy favors patients with an EGFR mutation. Without the gene mutational analysis, patients selected for EGFR-TKI therapy should be female non-smokers with adenocarcinoma.
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Affiliation(s)
- Xiao-Hang Zhang
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, China Department of Seven-Yeared Clinical Medicine, China Medical University, Shenyang, China
| | - Cheng Li
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, China Department of Seven-Yeared Clinical Medicine, China Medical University, Shenyang, China
| | - Chen-Fei Dai
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, China Department of Seven-Yeared Clinical Medicine, China Medical University, Shenyang, China
| | - Bao-Sen Zhou
- Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, China Department of Seven-Yeared Clinical Medicine, China Medical University, Shenyang, China
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Yano T, Haro A, Shikada Y, Maruyama R, Maehara Y. Non-small cell lung cancer in never smokers as a representative 'non-smoking-associated lung cancer': epidemiology and clinical features. Int J Clin Oncol 2011; 16:287-93. [PMID: 21562939 DOI: 10.1007/s10147-010-0160-8] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2010] [Indexed: 01/28/2023]
Abstract
Recent interest in lung cancer without a history of tobacco smoking has led to the classification of a distinct disease entity of 'non-smoking-associated lung cancer'. In this review article, we have made an overview of the recent literature concerning both the epidemiology and clinical features of lung cancer in never smokers, and have brought 'non-smoking-associated lung cancer' into relief. The etiology of lung cancer in never smokers remains indefinite although many putative risk factors have been described including secondhand smoking, occupational exposures, pre-existing lung diseases, diet, estrogen exposure, etc. Non-small cell lung cancer (NSCLC) in never smokers is clinically characterized by an increased incidence in females and a higher occurrence of adenocarcinoma in comparison to NSCLC in ever smokers in both surgical patients and non-resectable advanced-stage patients. Furthermore, the prognosis of never-smoking NSCLC is better than that of smoking-related NSCLC in both surgical patients and non-resectable advanced-stage patients. Recently recognized novel gene mutations such as EGFR (epidermal growth factor receptor) mutations are largely limited to never smokers or light smokers, and the expression of this gene is responsible for the clinical efficacy of gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor. NSCLC with the EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion gene is also more likely to occur in never smokers and in those with adenocarcinoma histology, and is expected to benefit from ALK inhibitors. In consideration of the future increase in never-smoking NSCLC or 'non-smoking-associated lung cancer', both clinical trials and investigations are needed.
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Affiliation(s)
- Tokujiro Yano
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.
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Wu JY, Shih JY, Chen KY, Yang CH, Yu CJ, Yang PC. Gefitinib therapy in patients with advanced non-small cell lung cancer with or without testing for epidermal growth factor receptor (EGFR) mutations. Medicine (Baltimore) 2011; 90:159-167. [PMID: 21512416 DOI: 10.1097/md.0b013e31821a16f4] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Gefitinib is effective in treating advanced non-small cell lung cancer (NSCLC), especially in Asian patients in whom the prevalence of epidermal growth factor receptor (EGFR) mutation was high. We analyzed our gefitinib treatment use in patients for advanced NSCLC to study the influence of clinical factors on the treatment outcomes in a tertiary referral medical center in Taiwan. Clinical data and EGFR mutational status of the tumors were collected. A total of 907 patients received gefitinib for advanced NSCLC: 466 patients (51.4%) underwent testing for EGFR mutations, and the other 441 patients did not. In the 466 patients who were tested for EGFR mutations, 272 (58.4%) had EGFR mutations, and an EGFR mutation was a prominent factor for objective response to gefitinib (67.3% vs. 18.3% in wildtype EGFR, p < 0.001). In the 441 patients who did not receive EGFR mutation sequencing, nonsmoker status, female sex, and adenocarcinoma cell type were predictors for better gefitinib response (p < 0.005). We found that testing for EGFR mutations was helpful in NSCLC patients in Taiwan to guide the use of gefitinib. In patients with positive activating EGFR mutations, gefitinib efficacy was prominent and significant. Therefore, analysis for EGFR mutation should be advocated. In those patients who have unknown EGFR mutation status, demographic and histopathology characteristics can be relied on to judge the potential efficacy of gefitinib use.
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Affiliation(s)
- Jenn-Yu Wu
- From Department of Internal Medicine (JYW), National Taiwan University Hospital Yun-Lin Branch, Yun-Lin; Department of Internal Medicine (JYS, KYC, CJY, PCY) and Department of Oncology (CHY), National Taiwan University Hospital, Taipei, Taiwan
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Domingo G, Perez CA, Velez M, Cudris J, Raez LE, Santos ES. EGF receptor in lung cancer: a successful story of targeted therapy. Expert Rev Anticancer Ther 2011; 10:1577-87. [PMID: 20942629 DOI: 10.1586/era.10.141] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Lung cancer research has incorporated molecular medicine into the management of this disease during the last 5 years. Several novel tumorigenesis pathways associated with lung cancer development and proliferation have been discovered and further developed as targets. The idea behind this is to deliver individualized therapy for each patient based on his/her tumor phenotype, which may involve the overexpression or lack of certain proteins, receptors, mutations and other factors. To date, many of these characteristics have been shown to have a potential role as prognostic or predictive biomarkers, with most of the available data being obtained from retrospective analyses, various laboratory platforms, and data sets used for comparison. However, well-designed prospective randomized clinical trials are underway to validate the significance and future role of these novel biomarkers, allowing us to sort out the best personalized management for an individual with lung cancer diagnosis. Nevertheless, one of these features, the EGF receptor (EGFR) gene mutation, has emerged as a prognostic and strongly predictive biomarker when EGFR inhibition is used as a therapy for tumors that harbor the mutation. Our article displays the most recently developed data related to this biomarker and what have we learned based on the analyses of clinical trials that have studied different agents in the clinical arena.
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Affiliation(s)
- Gelenis Domingo
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1475 NW 12th Avenue, D8-4, Miami, FL 33136, USA
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Azzoli CG, Baker S, Temin S, Pao W, Aliff T, Brahmer J, Johnson DH, Laskin JL, Masters G, Milton D, Nordquist L, Pfister DG, Piantadosi S, Schiller JH, Smith R, Smith TJ, Strawn JR, Trent D, Giaccone G. [American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2010; 13:171-89. [PMID: 20681066 PMCID: PMC6136061 DOI: 10.3779/j.issn.1009-3419.2010.03.15] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
本文旨在为Ⅳ期非小细胞肺癌患者的治疗提供更新版推荐。本文资料检索源自2002年以来公布的相关随机试验文献。此指南范围限于化疗与生物治疗。更新委员会对这些文献进行了总结并提供了推荐更新。162篇文献符合标准被纳入参考。本推荐基于可改善总生存期的治疗方法。仅改善无进展生存期的治疗方法推动了对毒性及生存质量的监测。对于体力状态评分为0分或1分患者的一线治疗，可推荐以铂类为基础的细胞毒性药物的两药联用。对铂类治疗有禁忌的患者，可采用非铂类细胞毒性两药联合。对于体力状态评分为2分的患者，单一细胞毒性药物即可。对于疾病进展或经过4个周期的治疗仍对治疗无反应的患者，应停止一线细胞毒性化疗。即使在6个周期后患者对治疗仍有反应，亦应停止两药细胞毒性化疗。对于伴有明确的表皮生长因子受体（epidermal growth factor receptor, EGFR）突变的患者，可推荐一线采用吉非替尼治疗；对于EGFR突变为阴性或不明确的患者，细胞毒性化疗更佳。除具有特定临床特征的患者外，可推荐贝伐单抗与卡铂-紫杉醇联用。对于通过免疫组化证实EGFR阳性的肿瘤患者，可推荐西妥昔单抗与顺铂-长春瑞滨联用。多西紫杉醇、厄洛替尼、吉非替尼或培美曲塞被推荐作为二线治疗。对于未曾接受过厄洛替尼或吉非替尼治疗的患者，可推荐厄洛替尼作为三线治疗。现有数据不足以推荐常规三线采用细胞毒性药物。已有的证据也不足以推荐常规应用分子标记物选择化疗。
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Wang F, Zhang Y, Zhao H, Chen L, Shi YX, Zhang L. Validation of a clinical prognostic model in Chinese patients with metastatic and advanced pretreated non-small cell lung cancer treated with gefitinib. Med Oncol 2010; 28:331-5. [PMID: 20204544 DOI: 10.1007/s12032-010-9451-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2010] [Accepted: 02/09/2010] [Indexed: 10/19/2022]
Abstract
A clinical prognostic model derived from BR.21 trial was established by Florescu et al., which helped to identify a small group of patients with non-small cell lung cancer (NSCLC) who might be less likely to benefit from erlotinib therapy. Whether the prognostic model derived from Caucasian patients treated with erlotinib will be applied to Asian patients treated with gefitinib is still an open question. We reviewed a multi-center clinical trial of Chinese patients with NSCLC treated with gefitinib. The data were collected and analyzed according to the prognostic model reported by Florescu et al. One hundred and nineteen patients were included in the validation study. Twenty-eight patients, 61 patients, 27 patients, and 3 patients were classified into the Low Risk (LR) group, Intermediate Low Risk (ILR) group, Intermediate High Risk/High Risk (IHR/HR) group, respectively. The median overall survival of LR group was not reached, ILR and IHR/HR group was 8.9 months and 4.5 months, respectively. There was a significant difference in overall survival between LR group versus ILR group and IHR/HR group (P = 0.0003 and 0.0001, respectively). While IHR/HR group appeared to have less survival benefit than ILR group, the difference was not statistically significant (P = 0.148). The result has shown a similar effect as that seen by Florescu et al. in differentiating patient risk groups. Our study provides the potential evidence that the prognostic model might be applied to Asian patients with NSCLC treated with gefitinib and helps clinicians to select patients for gefitinib therapy and stratify patients within second-line clinical trials.
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Affiliation(s)
- Fenghua Wang
- State Key Laboratory of Oncology in Southern China & Department of Medical Oncology, Cancer Center, Sun Yat-sen University, 510060 Guangzhou, Guangdong Province, China.
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Azzoli CG, Baker S, Temin S, Pao W, Aliff T, Brahmer J, Johnson DH, Laskin JL, Masters G, Milton D, Nordquist L, Pfister DG, Piantadosi S, Schiller JH, Smith R, Smith TJ, Strawn JR, Trent D, Giaccone G. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009; 27:6251-66. [PMID: 19917871 DOI: 10.1200/jco.2009.23.5622] [Citation(s) in RCA: 571] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The purpose of this article is to provide updated recommendations for the treatment of patients with stage IV non-small-cell lung cancer. A literature search identified relevant randomized trials published since 2002. The scope of the guideline was narrowed to chemotherapy and biologic therapy. An Update Committee reviewed the literature and made updated recommendations. One hundred sixty-two publications met the inclusion criteria. Recommendations were based on treatment strategies that improve overall survival. Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life. For first-line therapy in patients with performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For patients with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with carboplatin-paclitaxel, except for patients with certain clinical characteristics. Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs. Data are insufficient to recommend routine use of molecular markers to select chemotherapy.
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Affiliation(s)
- Christopher G Azzoli
- American Society of Clinical Oncology, 2318 Mill Rd, Suite 800, Alexandria, VA 22314, USA
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Park SH, Ha SY, Lee JI, Lee H, Sim H, Kim YS, Hong J, Park J, Cho EK, Shin DB, Lee JH. Epidermal growth factor receptor mutations and the clinical outcome in male smokers with squamous cell carcinoma of lung. J Korean Med Sci 2009; 24:448-52. [PMID: 19543508 PMCID: PMC2698191 DOI: 10.3346/jkms.2009.24.3.448] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2007] [Accepted: 07/27/2008] [Indexed: 11/30/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) have been reported to be related to certain clinical characteristics (i.e., female, non-smokers with adenocarcinoma) and gefitinib responsiveness. This exploratory analysis was performed to determine the incidence of EGFR mutations in male smokers with squamous cell carcinoma, who were treated with EGFR tyrosine kinase inhibitor, gefitinib. Sixty-nine Korean NSCLC patients were treated with gefitinib in a prospective study. For a subset of 20 male patients with squamous cell carcinoma and a history of smoking, pretreatment tumor tissue samples were obtained and analyzed for EGFR mutations (exons 18 to 21). EGFR mutations were found in 3 (15%) patients, including in-frame deletions within exon 19 (n=2) and L858R missence mutation in exon 21 (n=1). These 3 patients with EGFR mutations responded to gefitinib, whereas only one of remaining 17 patients with wild-type EGFR achieved clinical response. Trend toward longer progression-free (5.8 vs. 2.4 months; P=0.07) was noted in patients with EGFR mutations compared to those with wild-type EGFR. Although male smokers with squamous cell carcinoma have not been considered ideal candidates for gefitinib treatment, significant incidence of EGFR mutations was observed. The molecular markers should be considered to predict clinical benefits from gefitinib.
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Affiliation(s)
- Se Hoon Park
- Department of Medicine, Sungkyunkwan University Samsung Medical Center, Seoul, Korea
| | - Seung Yeon Ha
- Department of Pathology, Gachon University Gil Medical Center, Incheon, Korea
- Korea Lung Tissue Bank, Seoul, Korea
| | - Jae-Ik Lee
- Department of Thoracic Surgery, Gachon University Gil Medical Center, Incheon, Korea
| | - Hyewon Lee
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Hoyong Sim
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Young Saing Kim
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Junshik Hong
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Jinny Park
- Department of Medicine, Sungkyunkwan University Samsung Medical Center, Seoul, Korea
| | - Eun Kyung Cho
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Dong Bok Shin
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Jae Hoon Lee
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
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Carlson JJ, Garrison LP, Ramsey SD, Veenstra DL. Epidermal growth factor receptor genomic variation in NSCLC patients receiving tyrosine kinase inhibitor therapy: a systematic review and meta-analysis. J Cancer Res Clin Oncol 2009; 135:1483-93. [PMID: 19430813 DOI: 10.1007/s00432-009-0595-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2008] [Accepted: 04/22/2009] [Indexed: 11/30/2022]
Abstract
INTRODUCTION The objective of this analysis was to examine the relationship between genomic variation and health outcomes in studies performed in non-small cell lung cancer (NSCLC) patients treated with single agent epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) using a systematic review with statistical pooling of data. METHODS We performed a systematic search of the literature using the MEDLINE, BIOSIS, and EMABASE databases from July 1997 to July 2007. Eligible studies were evaluated for quality and clinical, methodological, and statistical heterogeneity. Abstracted data judged to be sufficiently homogenous were pooled using a fixed effect model. RESULTS We found a statistically significant higher probability of tumor response (according to the RECIST criteria) for patients with EGFR mutations versus wild type (5.92, 95% CI 4.91-7.13) and patients with high- versus low EGFR protein expression (2.71, 95% CI 1.72-4.29). EGFR mutation and high EGFR protein expression were associated with significantly improved survival over the wild type and low protein expression groups (0.36, 95% CI 0.29-0.46 and 0.59, 95% CI 0.44-0.81), respectively. Last, there was a significant difference in EGFR-TKI treatment effect in the high EGFR gene copy number and high EGFR protein expression groups (0.72, 95% CI 0.57-0.92 and 0.53, 95% CI 0.35-0.80). CONCLUSION In conclusion, EGFR mutation and protein expression status may provide useful clinical information in terms of the likelihood of tumor response and disease prognosis. EGFR gene copy number and to a lesser extent, EGFR protein expression status, appear to be promising biomarkers for predicting a survival benefit with EGFR-TKI therapy in second line NSCLC, but further evidence is needed.
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Affiliation(s)
- Josh John Carlson
- Pharmaceutical Outcomes Research and Policy Program, School of Pharmacy, University of Washington, Seattle, WA 98195, USA.
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Jae Park M, Lee J, Hong JY, Choi MK, Yi JH, Lee SJ, Oh SJ, Ahn JS, Park K, Ahn MJ. Prognostic model to predict outcomes in nonsmall cell lung cancer patients treated with gefitinib as a salvage treatment. Cancer 2009; 115:1518-30. [DOI: 10.1002/cncr.24151] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Hida T, Ogawa S, Park JC, Park JY, Shimizu J, Horio Y, Yoshida K. Gefitinib for the treatment of non-small-cell lung cancer. Expert Rev Anticancer Ther 2009; 9:17-35. [PMID: 19105704 DOI: 10.1586/14737140.9.1.17] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Gefitinib is an orally bioavailable, EGF receptor tyrosine kinase inhibitor and was the first targeted drug to be approved for non-small-cell lung cancer (NSCLC). Identification of objective tumor regressions with gefitinib in NSCLC patients has resulted in intense, worldwide clinical and basic research directed toward finding the optimal use of gefitinib in NSCLC. A recent large international Phase III study (IRESSA NSCLC Trial Evaluating Response and Survival Against Taxotere [INTEREST]) comparing gefitinib and docetaxel in unselected pretreated patients showed equivalent survival with better tolerability and quality of life. In addition, a Phase III study (WJTOG0203) evaluating gefitinib as sequential therapy after platinum-doublet chemotherapy showed the improved progression-free survival time. Furthermore, a large-scale randomized study (IRESSA Pan-Asia study [IPASS]) comparing gefitinib monotherapy with carboplatin/paclitaxel for previously untreated patients with adenocarcinoma who were never- or light-smokers showed an improved progression-free survival time in the gefitinib arm. A smaller Phase III study of pretreated Japanese patients (V-15-32) also demonstrated no difference in overall survival compared with docetaxel, with a statistically greater overall response rate. Somatic mutations in the EGFR gene, the target of gefitinib, were associated with dramatic and durable regressions in patients with NSCLC. Currently, investigators are trying to determine the optimal approach to select patients for treatment with gefitinib. This article aims to briefly summarize the profile of gefitinib, EGFR mutations, landmark trials with gefitinib and, also, ongoing trials that may herald an era of individualized therapy in at least some NSCLC patients.
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Affiliation(s)
- Toyoaki Hida
- Department of Thoracic Oncology, Aichi Cancer Center Hospital, Kanokoden, Chikusa-ku, Nagoya, Japan.
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Morinaga R, Okamoto I, Fujita Y, Arao T, Sekijima M, Nishio K, Ito H, Fukuoka M, Kadota JI, Nakagawa K. Association of epidermal growth factor receptor (EGFR) gene mutations with EGFR amplification in advanced non-small cell lung cancer. Cancer Sci 2008; 99:2455-60. [PMID: 18957054 PMCID: PMC11158508 DOI: 10.1111/j.1349-7006.2008.00962.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2008] [Revised: 08/05/2008] [Accepted: 08/06/2008] [Indexed: 12/25/2022] Open
Abstract
Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Increased EGFR copy number has also been associated with sensitivity to these drugs. However, given that it is often difficult to obtain sufficient amounts of tumor tissue for genetic analysis from patients with advanced NSCLC, the relationship between these two types of EGFR alterations has remained unclear. We have now evaluated EGFR mutation status both by direct sequencing and with a high-sensitivity assay, the Scorpion-amplification-refractory mutation system, and have determined EGFR copy number by fluorescence in situ hybridization (FISH) analysis in paired tumor specimens obtained from 100 consecutive patients with advanced NSCLC treated with chemotherapy. EGFR mutations or FISH positivity (EGFR amplification or high polysomy) were apparent in 18% (18/100) and 32% (32/100) of patients, respectively. The Scorpion-amplification-refractory mutation system was more sensitive than direct sequencing for the detection of EGFR mutations. Furthermore, EGFR mutations were associated with EGFR amplification (P = 0.009) but not with FISH positivity (P = 0.266). Our results therefore suggest the existence of a significant association between EGFR mutation and EGFR amplification in patients with advanced NSCLC.
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Affiliation(s)
- Ryotaro Morinaga
- Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan
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Hotta K, Kiura K, Takigawa N, Fujiwara Y, Tabata M, Ueoka H, Tanimoto M. Association of the benefit from gefitinib monotherapy with smoking status in Japanese patients with non-small-cell lung cancer. Lung Cancer 2008; 62:236-41. [DOI: 10.1016/j.lungcan.2008.03.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2008] [Revised: 03/11/2008] [Accepted: 03/12/2008] [Indexed: 11/15/2022]
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A population-based study of gefitinib in patients with non-small cell lung cancer. Med Oncol 2008; 26:222-7. [PMID: 18975151 DOI: 10.1007/s12032-008-9110-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2008] [Accepted: 10/13/2008] [Indexed: 10/21/2022]
Abstract
Survival data for non-small cell lung cancer is typically reported from clinical trials that include patients fit enough to meet treatment criteria. The denominator of all patients from which the gefitinib-treated population is derived has rarely been reported and the impact of gefitinib on population-based outcomes is difficult to measure. We have retrospectively reviewed data of 626 patients who received gefitinib in Ibaraki Prefecture (with a population of 3 million) in Japan from July 2002 until September 2007. Overall response rate was found to 30.8%, and the median survival time was 8.0 months (95% confidence interval: 7.0-9.0 months). Female gender, good PS, and adenocarcinoma were significantly associated with prolonged survival. Adverse events were generally mild and were mostly skin reactions and diarrhea. Our population-based study has generated similar results to those previously reported in published clinical trials, which had restrictive criteria for eligible patients.
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Ishikawa N, Hattori N, Yokoyama A, Tanaka S, Nishino R, Yoshioka K, Ohshimo S, Fujitaka K, Ohnishi H, Hamada H, Arihiro K, Kohno N. Usefulness of monitoring the circulating Krebs von den Lungen-6 levels to predict the clinical outcome of patients with advanced nonsmall cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. Int J Cancer 2008; 122:2612-20. [PMID: 18324627 DOI: 10.1002/ijc.23411] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Krebs von den Lungen-6 (KL-6) is a high molecular weight glycoprotein classified in the category of human MUC1 mucin. KL-6 has been reported to serve as a sensitive marker for interstitial pneumonia; however, recent studies have suggested that it can also be used as a tumor marker as its origin shows. To further elucidate the clinicopathological significance of circulating KL-6 in lung cancer, we monitored the circulating KL-6 levels in advanced nonsmall cell lung cancer (NSCLC) patients and analyzed the association between these levels and the clinical outcome of EGFR-TKI treatment. The pretreatment levels of circulating KL-6 were found to be significantly higher in progressive disease (PD) patients than disease-controlled (partial response (PR) and stable disease (SD)) patients. Multivariate analyses revealed the circulating KL-6 level to be an independent prognostic factor for overall survival as well as progression-free survival. In addition to these observations, we found that changes in circulating KL-6 levels at 2 weeks after the start of EGFR-TKI treatment from the baseline could quite precisely discriminate PD cases from PR or SD patients and the clinical outcome of EGFR-TKI in NSCLC patients. These results indicate that the monitoring of circulating KL-6 levels in NSCLC patients is effective for both selecting patients to be treated with EGFR-TKI and predicting the clinical outcome of EGFR-TKI. In addition, the findings suggest that the circulating KL-6 level could be used as a clinically relevant biomarker in patients with NSCLC, particularly those who are candidates for EGFR-TKI treatment.
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Affiliation(s)
- Nobuhisa Ishikawa
- Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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Mutations in the epidermal growth factor receptor gene and effects of EGFR-tyrosine kinase inhibitors on lung cancers. Gen Thorac Cardiovasc Surg 2008; 56:97-103. [PMID: 18340507 DOI: 10.1007/s11748-007-0193-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2007] [Indexed: 01/28/2023]
Abstract
Epidermal growth factor receptor (EGFR) gene mutations are frequent in lung cancer arising in patients of Asian ethnicity, female sex, nonsmokers, and adenocarcinoma histology. About 70% of the patients with EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib, whereas only 10% of those without the mutations do so. Therefore, EGFR mutation is being recognized as one of the most reliable predictive factors for treatment using EGFR-TKIs. Another important issue in clinical practice is the fatal interstitial lung disease (ILD) that can develop in patients with gefitinib treatment, especially Asian patients. A nested case-control study recently conducted in Japan identified some risk factors that cause ILD, including age > or = 55 years, a history of smoking, preexisting ILD, poor performance status, short duration since diagnosis of lung cancer, reduced extent of normal lung on computed tomography, and concurrent cardiac disease. About half of the acquired resistance to EGFR-TKIs that almost always occurs during the course of treatment is caused by a secondary mutation at codon 790 (T790M). EGFR-TKIs are not universally effective for treating lung cancers but are effective in patients with particular genotypes. Therefore, patients who would benefit from EGFR-TKIs therapy should be concentrated in clinical trials. Based on this concept, Phase III clinical trials comparing gefitinib monotherapy with standard platinum-based chemotherapy are currently ongoing for patients with EGFR mutations and lung cancer.
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Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 2007; 98:1817-24. [PMID: 17888036 PMCID: PMC11159145 DOI: 10.1111/j.1349-7006.2007.00607.x] [Citation(s) in RCA: 467] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2007] [Revised: 07/29/2007] [Accepted: 07/31/2007] [Indexed: 01/03/2023] Open
Abstract
Recent discovery of mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma greatly stimulated biomarker research on predictive factors for EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib. Although patients with activating mutations of the EGFR generally respond to EGFR TKIs very well, it is natural to assume that there is no sole determinant, considering great complexity and redundancy of the EGFR pathway. Subsequently, roles of different types of EGFR mutations or mutations of genes that are members of the EGFR pathway such as KRAS and HER2 have been evaluated. In this review, we summarize the recent findings about how mutations of the EGFR and related genes affect sensitivity to EFGR-TKIs. We also discuss molecular mechanisms of acquired resistance to EGFR-TKIs that is almost inevitable in EGFR-TKI therapy. The door for genotype-based treatment of lung cancer is beginning to open, and through these efforts, it will be possible to slow the progression of lung cancer and eventually, to decrease mortality from lung cancer.
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Affiliation(s)
- Tetsuya Mitsudomi
- Department of Thoracic Surgery, Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
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Costa DB, Kobayashi S, Tenen DG, Huberman MS. Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers. Lung Cancer 2007; 58:95-103. [PMID: 17610986 PMCID: PMC2551312 DOI: 10.1016/j.lungcan.2007.05.017] [Citation(s) in RCA: 135] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2007] [Revised: 05/16/2007] [Accepted: 05/23/2007] [Indexed: 11/25/2022]
Abstract
PURPOSE Epidermal growth factor receptor (EGFR) mutations have been found in the majority of gefitinib-responsive non-small cell lung cancer (NSCLC) patients from retrospective studies. We sought to compile the available phase II and prospective trials of this EGFR tyrosine kinase inhibitor (TKI) to better understand the efficacy and safety of selecting patients to receive gefitinib based on their genotype. DESIGN We searched published trials involving EGFR-mutant patients and gefitinib. Five reports were identified (published between June 2006 and April 2007) in which gefitinib was given in a prospective manner to EGFR mutation positive patients at a dose of 250mg/day. Responses were determined by RECIST and toxicities by NCI-CTC. RESULTS A total of 101 patients were pooled from these studies. Fifty-nine received gefitinib as their first line of therapy and 42 after having received chemotherapy. The combined rate of complete and partial response (CR+PR) in the 99 measured patients was 80.8% (80/99) and only 7.1% (7/99) had progressive disease as best response. The response rate (CR+PR) for exon 19 deletion and L858R patients were 80.3% (53/66) and 81.8% (27/33), respectively. The median progression-free survival ranged from 7.7 to 12.9 months. Overall survival had not been reached in 4/5 reports and was 15.4 months in one of them. Gefitinib administration was safe (<50% of patients developed grades 1-2 skin rash or diarrhea) and interstitial lung disease was only reported in two patients (2%), without deaths. CONCLUSIONS Gefitinib monotherapy leads to objective responses in most patients with EGFR mutations. Both L858R and deletion 19 mutations derived similar clinical benefits. Small molecule TKIs are the new treatment paradigm for EGFR-mutant NSCLC.
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Affiliation(s)
- Daniel B Costa
- Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Av., Rabb 430, Boston, MA 02215, USA.
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News and Views. Clin Pharmacol Ther 2007. [DOI: 10.1038/sj.clpt.6100252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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