title: Thymidylate synthase gene amplification predicts pemetrexed resistance in patients with advanced non-small cell lung cancer.
abstract: BACKGROUND
  Thymidylate synthase (TYMS) expression in lung cancer tissue affects the therapeutic efficacy of pemetrexed (PMT). TYMS protein expression is primarily assessed using immunohistochemistry (IHC), but this method is not suitable for accurate quantitative analysis. It is not known whether the analysis of TYMS gene copy number using fluorescence in situ hybridization (FISH) is a useful method for assessment of TYMS expression.
  
  
  METHODS
  The participants were patients with chemo-naïve advanced NSCLC treated with PMT plus carboplatin (CBDCA) in prospective clinical phase II study. TYMS expression was evaluated in 40 patients by gene copy number and protein expression using FISH and IHC. Therapeutic efficacy was evaluated by investigating the response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
  
  
  RESULTS
  TYMS gene amplification was detected in 8 patients (32 %) among 25 patients who could be evaluated for TYMS gene copy number. There were no patients with complete or partial response in the TYMS amplified group. RR and DCR were lower in the TYMS amplified group compared with the TYMS unamplified group (0 versus 35.3 %, p = 0.0539, 62.5 versus 94.1 %, p = 0.0443). PFS and OS were reduced in the TYMS amplified group. The analysis of TYMS gene copy number had higher sensitivity and specificity compared with TYMS protein expression (76.2 versus 50.0 %, 75.0 versus 66.7 %).
  
  
  CONCLUSIONS
  The analysis of TYMS gene copy number is more suitable than TYMS protein expression for assessment of TYMS expression. TYMS gene amplification predicts outcome of patients receiving PMT with advanced NSCLC.
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, 30-1, Oyaguchi-Kamichou, Itabashi-ku, Tokyo, 173-8610, Japan. shimizu.tetsuo@nihon-u.ac.jp.
authors.forename: T
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, 30-1, Oyaguchi-Kamichou, Itabashi-ku, Tokyo, 173-8610, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, 30-1, Oyaguchi-Kamichou, Itabashi-ku, Tokyo, 173-8610, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, 30-1, Oyaguchi-Kamichou, Itabashi-ku, Tokyo, 173-8610, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hashimoto
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed / Q000008:administration & dosage*; D011379:Prognosis; D013940:Thymidylate Synthase / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D000068437:Pemetrexed; C000600377:TYMS protein, human; D013940:Thymidylate Synthase
keywords: Fluorescence in situ hybridization; Gene amplification; Immunohistochemistry; Pemetrexed; Thymidylate synthase