title: MET FISH-positive status predicts short progression-free survival and overall survival after gefitinib treatment in lung adenocarcinoma with EGFR mutation.
abstract: BACKGROUND
  Lung adenocarcinoma patients with EGFR gene mutations have shown a dramatic response to gefitinib. However, drug resistance eventually emerges which limits the mean duration of response. With that in view, we examined the correlations between MET gene status as assessed by fluorescence in situ hybridization (FISH) with overall survival (OS) and progression-free survival (PFS) in adenocarcinoma patients with EGFR gene mutations who had received gefitinib therapy.
  
  
  METHODS
  We evaluated 35 lung cancer samples with EGFR mutation from adenocarcinoma patients who had received gefitinib. Gene copy numbers (GCNs) and amplification of MET gene before gefitinib therapy was examined by FISH. MET protein expression was also evaluated by immunohistochemistry (IHC).
  
  
  RESULTS
  FISH assessment showed that of the 35 adenocarcinoma samples, 10 patients (29%) exhibited high polysomy (5 copies≦mean MET per cell) and 1 patient (3%) exhibited amplification (2≦MET gene (red)/CEP7q (green) per cell). IHC evaluation of MET protein expression could not confirm MET high polysomy status. The Eleven patients with MET FISH positivity had significantly shorter progression-free survival (PFS) and overall survival (OS) than the 24 patients who were MET FISH-negative (PFS: p = 0.001 and OS: p = 0.03). Median PFS and OS with MET FISH-positivity were 7.6 months and 16.8 months, respectively, whereas PFS and OS with MET FISH-negativity were 15.9 months and 33.0 months, respectively. Univariate analysis revealed that MET FISH-positivity was the most significant independent factor associated with a high risk of progression and death (hazard ratio, 3.83 (p = 0.0008) and 2.25 (p = 0.03), respectively).
  
  
  CONCLUSIONS
  Using FISH analysis to detect high polysomy and amplification of MET gene may be useful in predicting shortened PFS and OS after Gefitinib treatment in lung adenocarcinoma. The correlation between MET gene status and clinical outcomes for EGFR-TKI should be further evaluated using large scale samples.
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. r-noro@nms.ac.jp.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Noro
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. mseike@nms.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Seike
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. zoufenfei@hotmail.com.
authors.forename: Fenfei
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. soeno-c@nms.ac.jp.
authors.forename: Chie
authors.initials: C
authors.lastname: Soeno
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. kuniko-m@nms.ac.jp.
authors.forename: Kuniko
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. tetsu629@nms.ac.jp.
authors.forename: Teppei
authors.initials: T
authors.lastname: Sugano
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. nobu-829@nms.ac.jp.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Nishijima
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. s7062@nms.ac.jp.
authors.forename: Masaru
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. kazu-k@nms.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kitamura
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. say-cos@nms.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kosaihira
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. yminegishi@nms.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Minegishi
authors.affiliation: Department of Clinical Oncology, Tokyo Medical University Hospital, Tokyo, Japan. ay1004@tokyo-med.ac.jp.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. kkubota@nms.ac.jp.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. agemma@nms.ac.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Gemma
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage
chemical_list: D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib