title: Detection of the T790M mutation of EGFR in plasma of advanced non-small cell lung cancer patients with acquired resistance to tyrosine kinase inhibitors (West Japan oncology group 8014LTR study).
abstract: BACKGROUND
  Next-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to overcome resistance to earlier generations of such drugs mediated by a secondary T790M mutation of EGFR, but the performance of a second tumor biopsy to assess T790M mutation status can be problematic.
  
  
  METHODS
  We developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance.
  
  
  RESULTS
  A total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites fluid from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. TKI-sensitizing and T790M mutations were detected in plasma of 120 (46.2%) and 75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients with plasma positive for TKI-sensitizing mutations. For the 41 patients with paired samples obtained after acquisition of EGFR-TKI resistance, the concordance for mutation detection by ddPCR in plasma compared with tumor tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations and 65.9% for T790M.
  
  
  CONCLUSIONS
  Noninvasive genotyping by ddPCR with cell-free DNA extracted from plasma is a promising approach to the detection of gene mutations during targeted treatment.
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Takahama
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Internal Medicine, Division of Respirology, Neurology, and Rheumatology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Azuma
authors.affiliation: Department of Thoracic Oncology, Aichi Cancer Center, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Hida
authors.affiliation: Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Hirabayashi
authors.affiliation: Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Oguri
authors.affiliation: Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Respiratory Oncology, Iizuka Hospital, Fukuoka, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ebi
authors.affiliation: Department of Respiratory Medicine and Oncology, Gifu Municipal Hospital, Gifu, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sawa
authors.affiliation: Department of Pulmonary Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Bessho
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Hyogo, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Tachihara
authors.affiliation: Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Akamatsu
authors.affiliation: Division of Hematology, Rheumatology, and Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Bandoh
authors.affiliation: Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Himeji
authors.affiliation: Department of Surgery, Tokyo Medical University, Tokyo, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ohira
authors.affiliation: Department of Cancer Information Research, National Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Shimokawa
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001201:Ascites; D001706:Biopsy; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002474:Cell-Free System; D004273:DNA, Neoplasm / Q000097:blood; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010996:Pleural Effusion; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004273:DNA, Neoplasm; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases
keywords: T790M; cell-free DNA; epidermal growth factor receptor (EGFR); mutation; non–small cell lung cancer