title: HER2 expression and markers of phosphoinositide-3-kinase pathway activation define a favorable subgroup of metastatic pulmonary adenocarcinomas.
abstract: OBJECTIVE
  Pulmonary adenocarcinomas (ADC) can be sub-grouped based on dominant oncogenic drivers. EGFR mutations define an entity of metastatic ADC with favorable prognosis and high susceptibility to EGFR tyrosine kinase inhibition. In contrast, the clinical impact of additional ERBB family members in ADC is less defined. To this end we prospectively studied HER2 expression, gene amplification, and mutation in relation to outcome of patients with advanced or metastatic ADC.
  
  
  METHODS
  Diagnostic tumor biopsies from 193 sequential patients with stage III/IV ADC were prospectively studied for HER2 expression by immunohistochemistry (IHC). Cases with IHC scores 2+ or 3+ were analyzed by HER2 chromogenic in situ hybridization (CISH), and sequencing of HER2 exons 20 and 23. Additional prospectively determined biomarkers included PTEN, cMET, pAKT, and pERK expression, KRAS, EGFR, BRAF and PIK3CA mutations, and ALK fluorescence ISH (FISH).
  
  
  CONCLUSIONS
  HER2-IHC was feasible in 176 (91.2%) cases. Of 53 (30%) cases with IHC scores 2+/3+, 45 (85%) could be studied by CISH and 34 (64%) by sequencing. The lower number of HER2-mutational analyses resulted from exhaustion of tumor tissue and DNA following mutational analysis of KRAS, EGFR, BRAF and PIK3CA. HER2 amplification was detected in 4 cases (2.3%), while no mutation was found. HER2 expression correlated with expression of pAKT and cMET. Expression of HER2 and pAKT was associated with favorable overall survival in stage IV disease. HER2-expressing ADC more frequently harbored KRAS mutations, while HER2 expression was absent in all 4 cases with BRAF mutation. HER2-IHC was not predictive of HER2 gene amplification or mutation, which both were rare events in prospectively studied patients with advanced or metastatic ADC. Expression of HER2 and pAKT define a population of patients with stage IV ADC with a distinct disease course, who could benefit from specifically tailored pharmacotherapies.
authors.affiliation: Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Reis
authors.affiliation: Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany; German Cancer Research Center, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Herold
authors.affiliation: Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Ting
authors.affiliation: Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Worm
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Huber
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: D C
authors.initials: DC
authors.lastname: Christoph
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany; Division of Thoracic Oncology, Ruhrlandklinik, West German Lung Center, University Hospital Essen, 45239 Essen, Germany.
authors.forename: W E
authors.initials: WE
authors.lastname: Eberhardt
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Kostbade
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kasper
authors.affiliation: Division of Thoracic Surgery, Ruhrlandklinik, West German Lung Center, University Hospital Essen, 45239 Essen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Stamatis
authors.affiliation: Division of Thoracic Surgery, Ruhrlandklinik, West German Lung Center, University Hospital Essen, 45239 Essen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Welter
authors.affiliation: Division of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital Essen, 45239 Essen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Darwiche
authors.affiliation: Division of Interventional Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital Essen, 45239 Essen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Karpf-Wissel
authors.affiliation: Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Theegarten
authors.affiliation: Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: K W
authors.initials: KW
authors.lastname: Schmid
authors.affiliation: German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany; Division of Thoracic Oncology, Ruhrlandklinik, West German Lung Center, University Hospital Essen, 45239 Essen, Germany. Electronic address: martin.schuler@uk-essen.de.
authors.forename: M
authors.initials: M
authors.lastname: Schuler
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wiesweg
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: Biomarker; HER2; Lung adenocarcinoma; NSCLC; PI3K; Prospective study