title: Adverse prognostic impact of intratumor heterogeneous HER2 gene amplification in patients with esophageal adenocarcinoma.
abstract: OBJECTIVE
  There is increasing recognition of the existence of intratumoral heterogeneity of the human epidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. We determined the frequency and prognostic impact of heterogeneous HER2 gene amplification and polysomy 17 in patients with esophageal adenocarcinoma (EAC).
  
  
  METHODS
  HER2 amplification (by fluorescence in situ hybridization) was examined in surgical EAC specimens (n = 675). HER2 heterogeneity was defined according to consensus guidelines as gene amplification (HER2/CEP17 ratio ≥ 2.0) in more than 5% but less than 50% of cancer cells. No patient received neoadjuvant or HER2-targeted therapy. Cox models were used to assess disease-specific survival (DSS) and overall survival (OS).
  
  
  RESULTS
  Overall, 117 EACs (17%) demonstrated HER2 amplification, of which 20 (17%) showed HER2 heterogeneity. All HER2-heterogeneous tumors were amplified. Among HER2-amplified tumors, heterogeneous tumors had significantly higher frequency of poor histologic grade and polysomy 17. In multivariable models that included number of metastatic lymph nodes, grade, tumor stage, and polysomy 17, only HER2 heterogeneity and node number were prognostic among HER2-amplified tumors, with heterogeneity showing worse DSS (hazard ratio, 2.04; 95% CI, 1.09 to 3.79; P = .025) and OS (P = .026). Among HER2-nonamplified EACs, polysomy 17 was independently associated with worse DSS (P = .012) and OS (P = .023).
  
  
  CONCLUSIONS
  Among HER2-amplified EACs, 17% show HER2 heterogeneity, which independently predicts for worse cancer-specific death. Among HER2-nonamplified EACs, polysomy 17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and determination of benefit from HER2-targeted therapy.
authors.affiliation: MHS, Mayo Clinic Comprehensive Cancer Center, 200 First St SW, Rochester, MN 55905, USA. yoon.harry@mayo.edu
authors.forename: Harry H
authors.initials: HH
authors.lastname: Yoon
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.forename: William R
authors.initials: WR
authors.lastname: Sukov
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lewis
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Sattler
authors.forename: Anne E
authors.initials: AE
authors.lastname: Wiktor
authors.forename: Tsung-Teh
authors.initials: TT
authors.lastname: Wu
authors.forename: Robert B
authors.initials: RB
authors.lastname: Diasio
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D000328:Adult; D000368:Aged; D000782:Aneuploidy; D002869:Chromosome Aberrations; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000601:surgery; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008869:Microtubule-Associated Proteins; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010750:Phosphoproteins / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: C502822:Cep170 protein, human; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins