title: EGFR and HER2 genomic gain in recurrent non-small cell lung cancer after surgery: impact on outcome to treatment with gefitinib and association with EGFR and KRAS mutations in a Japanese cohort.
abstract: BACKGROUND
  Sensitivity to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and frequency of activation mutations in EGFR is lower in Caucasian than Asian non small-cell lung cancer (NSCLC) patients. Increased EGFR gene copy numbers evaluated by fluorescence in situ hybridization (FISH) has been reported as predictor of clinical benefit from EGFR-TKIs in Caucasian NSCLC patients. This study was carried out to verify whether EGFR FISH had similar performance in Japanese patients.
  
  
  METHODS
  A cohort of 44 Japanese patients with recurrent NSCLC after surgery was treated with gefitinib 250 mg daily. The cohort included 48% females and 52% never-smokers; 73% had prior chemotherapy and 57% had stage III-IV at the time of surgery. Adenocarcinoma was the most common histology (86%). FISH was performed using the EGFR/Chromosome Enumeration Probe 7 and PathVysion DNA probes (Abbott Molecular). Specimens were classified as FISH positive when showing gene amplification or high polysomy (> or = 4 copies of the gene in > or = 40% of tumor cells). Tumor response to gefitinib was assessed by RECIST for 33 patients with measurable diseases.
  
  
  RESULTS
  Twenty-nine tumors (66%) were EGFR FISH+ and 23 (53%) were HER2 FISH+. Overall response rate was 52%, representing 65% of EGFR FISH+ patients and 29% of EGFR FISH- patients (p = 0.0777). Survival was not impacted by the EGFR FISH (p = 0.9395) or the HER2 FISH (p = 0.0671) status. EGFR FISH+ was significantly associated with HER2 FISH+ (p = 0.015) and presence of EGFR mutation (p = 0.0060). EGFR mutation significantly correlated with response (p < 0.0001) and survival after gefitinib (p = 0.0204). EGFR and HER2 FISH status were not associated with KRAS mutation.
  
  
  CONCLUSIONS
  Frequency of EGFR FISH+ status was higher and its predictive power for TKI sensitivity was lower in this Japanese cohort than in Western NSCLC cohorts. These findings support differences in the mechanisms of EGFR pathway activation in NSCLC between Asian and Caucasian populations. Confirmation of these results in larger cohorts is warranted.
authors.affiliation: University of Colorado Cancer Center, Department of Medicine and Pathology, Aurora, CO 80045, USA.
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.forename: Yashushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kosaka
authors.forename: Eiji
authors.initials: E
authors.lastname: Nakajima
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Xavier
authors.forename: Margaret
authors.initials: M
authors.lastname: Skokan
authors.forename: Chan
authors.initials: C
authors.lastname: Zeng
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D015331:Cohort Studies; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D018734:Genes, erbB-2; D011905:Genes, ras; D016678:Genome; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007564:Japan; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011336:Probability; D011379:Prognosis; D011799:Quinazolines / Q000627:therapeutic use*; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib