title: HER-2/neu gene amplification in relation to expression of HER2 and HER3 proteins in patients with esophageal adenocarcinoma.
abstract: BACKGROUND
  Human epidermal growth factor receptor 2 (HER2) is a therapeutic target in patients with esophageal adenocarcinoma (EAC), with gene amplification used as a selection criterion for treatment, although to the authors' knowledge the concordance between amplification and HER2 protein expression remains undefined in EAC. Furthermore, the association between HER2 and its interacting partner, human epidermal growth factor receptor 3 (HER3), is unknown yet appears to be of potential therapeutic relevance.
  
  
  METHODS
  Patients with untreated EACs (N = 673) were analyzed for HER2 amplification and polysomy 17 by fluorescence in situ hybridization in parallel with immunohistochemistry (IHC) (IHC scores of 0-1+, 2+, and 3+). Amplification was defined as HER2/CEP17 ≥ 2. HER3 expression by IHC was analyzed in randomly selected cases (n = 224). IHC and fluorescence in situ hybridization results were compared using least squares linear regression.
  
  
  RESULTS
  Overall, 17% of the EACs (116 of 673 EACs) were HER2-amplified with an amplification frequency that was highest among IHC3+ cases (89%) and declined among IHC2+ cases (13%) and IHC0 to IHC1+ cases (4%). Among HER2-amplified cases, the level of amplification increased linearly with HER2 membranous expression (HER2/CEP17 ratio: 7.9 in IHC3+ and 5.5 in IHC2+ vs 2.8 in IHC0 to IHC1+ [P < .0001]), with 14% of amplified tumors demonstrating absent/faint expression (IHC0 to IHC1+). Polysomy 17 was not found to be associated with HER2 expression. Cytoplasmic HER3 expression was detected in 87% of tumors (195 of 224 tumors) and was found to be significantly associated with better differentiation (P < .0001). Stepwise increases in HER3 expression were associated with higher HER2 expression levels (P = .0019).
  
  
  CONCLUSIONS
  Levels of HER2 protein expression and amplification were found to be linearly associated and highly concordant. Among amplified tumors with absent/faint expression, the level of amplification was low. Frequent expression of HER3 suggests its relevance as a therapeutic target, and its significant association with HER2 supports ongoing efforts to inhibit HER2/HER3 in patients with EAC.
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Harry H
authors.initials: HH
authors.lastname: Yoon
authors.forename: William R
authors.initials: WR
authors.lastname: Sukov
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Sattler
authors.forename: Anne E
authors.initials: AE
authors.lastname: Wiktor
authors.forename: Robert B
authors.initials: RB
authors.lastname: Diasio
authors.forename: Tsung-Teh
authors.initials: TT
authors.lastname: Wu
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D000368:Aged; D004938:Esophageal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D020893:Receptor, ErbB-3 / Q000032:analysis*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C508053:ERBB2 protein, human
keywords: ERBB2; HER2 expression; HER2 gene amplification; HER3/ERBB3; concordance; esophageal adenocarcinoma; esophageal cancer; esophagogastric cancer; fluorescence in situ hybridization; human epidermal growth factor receptor 2 (HER2)