title: HER2 Amplification and HER2 Mutation Are Distinct Molecular Targets in Lung Cancers.
abstract: BACKGROUND
  Human epidermal growth factor receptor 2 gene (HER2 [also known as ERBB2]) alterations have been identified as oncogenic drivers and potential therapeutic targets in lung cancers. The molecular associations of HER2 gene amplification, mutation, and HER2 protein overexpression in lung cancers have not been distinctly defined. To explore these associations, Memorial Sloan Kettering Cancer Center and the University of Colorado combined their data on HER2 alterations in lung cancers.
  
  
  METHODS
  Tumor specimens from 175 patients with lung adenocarcinomas and no prior targeted therapy were evaluated for the presence of HER2 amplification and mutation and HER2 protein overexpression. Amplification was assessed by fluorescence in situ hybridization (FISH) and defined as an HER2-to-chromosome enumeration probe 17 ratio of at least 2.0. Mutation was assessed by fragment analysis, mass spectrometry genotyping, and Sanger sequencing. Overexpression was assessed by immunohistochemical (IHC) staining. The frequencies of HER2 amplification and mutation and HER2 overexpression were calculated and their overlap examined.
  
  
  RESULTS
  HER2 amplification was detected by FISH in 5 of 175 cases (3%). HER2 mutation was detected in 4 of 148 specimens (3%), including three identical 12-base pair insertions (p.A775_G776insYVMA) and a 9-base pair insertion, all in exon 20. None of the HER2-mutant cases was amplified. HER2 overexpression (2+ or 3+) on IHC staining was not detected in the 25 specimens available for testing, and negative IHC staining correlated with the negative results according to FISH.
  
  
  CONCLUSIONS
  HER2 mutations are not associated with HER2 amplification, thus suggesting a distinct entity and therapeutic target. HER2-positive lung cancer may not be an adequate term, and patient cohorts for the study of HER2-targeted agents should be defined by the specific HER2 alteration present.
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA; Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address: lib1@mskcc.org.
authors.forename: Bob T
authors.initials: BT
authors.lastname: Li
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Dara S
authors.initials: DS
authors.lastname: Ross
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Dara L
authors.initials: DL
authors.lastname: Aisner
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Chaft
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Meier
authors.initials: M
authors.lastname: Hsu
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Severine L
authors.initials: SL
authors.lastname: Kako
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.affiliation: Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA.
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Molecular Diagnostics Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: Amplification; HER2; Lung cancer; Mutation; Overexpression