title: Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients.
abstract: OBJECTIVE
  In non-small-cell lung cancer (NSCLC), response to tyrosine kinase inhibitors (TKIs) is significantly associated with the presence of increased copy number and/or activating mutations of the epidermal growth factor receptor gene (EGFR). Preclinical data indicate that HER2, a member of the EGFR family, could enhance TKI sensitivity.
  
  
  METHODS
  HER2 gene copy numbers per cell were evaluated by fluorescent in situ hybridization (FISH) in 102 NSCLC patients treated with gefitinib, and previously evaluated for EGFR status by FISH, immunohistochemistry, and presence of mutations.
  
  
  RESULTS
  Patients with HER2 high copy number (high polysomy and gene amplification [HER2 FISH positive]) represented 22.8% of patients, and compared with patients with no or low gain (HER2 FISH negative), had significantly better objective response (OR, 34.8% v 6.4%; P = .001), disease control rate (DCR, 56.5% v 33.3%; P = .04), time to progression (TTP, 9.05 v 2.7 months; P = .02), and a trend toward longer overall survival (OS, 20.8 v 8.4 months; P = .056). HER2 protein expression investigated by immunohistochemistry was positive in only five of 72 (7%) patients analyzed and all 89 patients tested by DNA sequencing were negative for mutations in HER2 exon 20. Patients with HER2 FISH-positive tumors displaying increased expression of EGFR protein, gene gain, or mutations (EGFR positive) had a significantly better OR, DCR, TTP, and OS than patients negative for both receptors.
  
  
  CONCLUSIONS
  Increased copy number of the HER2 gene is associated with gefitinib sensitivity in EGFR-positive patients, supporting use of HER2 FISH analysis for selection of patients for TKI therapy.
authors.affiliation: University of Colorado Cancer Center, Department of Medicine and Pathology, Aurora, CO 80010, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Shigematsu
authors.forename: Irene
authors.initials: I
authors.lastname: Domenichini
authors.forename: Stefania
authors.initials: S
authors.lastname: Bartolini
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Ceresoli
authors.forename: Elisa
authors.initials: E
authors.lastname: Rossi
authors.forename: Vienna
authors.initials: V
authors.lastname: Ludovini
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gregorc
authors.forename: Luca
authors.initials: L
authors.lastname: Toschi
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Lucio
authors.initials: L
authors.lastname: Crino
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000097:blood*; D000077156:Gefitinib; D018628:Gene Dosage; D020869:Gene Expression Profiling; D018734:Genes, erbB-2; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib