title: Prognostic value of acquired resistance-related molecules in Japanese patients with NSCLC treated with an EGFR-TKI.
abstract: BACKGROUND
  Most patients with lung cancer experience relapse, although epidermal growth factor receptor (EGFR) of tyrosine kinase inhibitor (TKI) has an astounding effect on tumors with EGFR-activating mutations. It is therefore critical to determine the mechanisms of resistance against agents and the prognostic value of acquired resistance-related molecules to EGFR-TKI.
  
  
  METHODS
  Tumor specimens were obtained from 19 matched specimens before and after treatment with gefitinib. A retrospective multi-institutional study analyzed the correlation between patients' survival and acquired resistance-related molecules in non-small cell lung cancer (NSCLC) samples, that possessed sensitive EGFR mutations (7 cases: exon 19 deletion, and 12 cases: exon 21 point mutation). The status of the epidermal growth factor receptor (EGFR) and KRAS genes were investigated by polymerase chain reaction (PCR)-based analyses. Real-time PCR assays were also used to evaluate MET gene amplification. The expression of hepatocyte growth factor (HGF) and changes in the epithelial-mesenchymal transition (EMT) status including the expression of E-cadherin and γ-catenin as epithelial markers, and those of vimentin and fibronectin as mesenchymal markers, were evaluated by immunohistochemistry.
  
  
  RESULTS
  Eight of the gefitinib refractory tumors exhibited a secondary threonine-to-methionine mutation at codon 790 in EGFR (T790M). All of the tumors had wild type KRAS gene expression. No MET amplification was detected in any of the samples. A strong expression of HGF was detected in eight of the specimens at post-treatment. A change in the EMT status between pre-and post-treatment was found in five cases. The 5-year survival rate of patients with and without T790M was 86.7% and 13.3%, respectively (p=0.020). The 5-year overall survival (OS) rate for patients with overexpresion and for those with weak expression of HGF was 75.0% and 22.2%, respectively (p=0.259). In addition, the 5-year OS rate for patients with unchanged and changed EMT status was 83.3% and 40.0%, respectively (p=0.123).
  
  
  CONCLUSIONS
  The current results showed that the presence of T790M is associated with favorable survival. On the other hand, the patients with weak HGF expression and EMT change tend to have a poor survival. The current patients' selection might be changed by discrimination of acquired resistance-related molecules in patients with NSCLC treated with an EGFR-TKI.
authors.affiliation: Second Department of Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan. hidetaka@med.uoeh-u.ac.jp
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Uramoto
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kondo
authors.forename: Seiki
authors.initials: S
authors.lastname: Hasegawa
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Tanaka
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005091:Exons; D005260:Female; D000077156:Gefitinib; D005784:Gene Amplification; D015870:Gene Expression; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007564:Japan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D012189:Retrospective Studies
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib