title: Coexpression of the type 1 growth factor receptor family members HER-1, HER-2, and HER-3 has a synergistic negative prognostic effect on breast carcinoma survival.
abstract: BACKGROUND
  The clinical significance of coexpression of type 1 growth factor receptor (T1GFR) family members remains largely unknown. The objective of the current study was to determine the frequency and the possible prognostic effect of coexpression of HER-1, HER-2, HER-3, and HER-4 by breast carcinoma.
  
  
  METHODS
  Tissue microarrays were constructed using clinically annotated formalin-fixed, paraffin-embedded tumor samples from 242 patients with invasive breast carcinomas with a median 15-year follow-up. The levels of TIGFR family members (HER-1-HER-4) were measured by immunohistochemistry. K-means clustering algorithm, as well as univariate (Kaplan-Meier, log-rank test) and multivariate (Cox regression) survival analyses were applied to the data set.
  
  
  RESULTS
  Using univariate analysis, expression of HER-1, HER-2, and HER-3, but not HER-4, was significantly associated with decreased patient disease-specific survival (P < 0.05). Kaplan-Meier survival analysis showed that coexpression of >/= 2 of HER-1, HER-2, and HER-3 in any combination was associated with reduced patient disease-specific survival compared with single marker expression or no expression (35% vs. 65% vs. 78% 10-year survival rates, P = 0.001). Using multivariate analysis, expression of >/= 2 of HER-1, HER-2, and HER-3 was independent of lymph node status and tumor size.
  
  
  CONCLUSIONS
  In a cohort of patients with breast carcinoma, the authors observed T1GFR family member coexpression (HER-1, HER-2, and HER-3) to have a negative synergistic effect on patient outcome, independent of tumor size or lymph node status. Thus, coexpression of T1GFR family members identified a subset of patients with a poor disease prognosis who may potentially benefit from therapy simultaneously targeting several T1GFR family members.
authors.affiliation: Genetic Pathology Evaluation Center at the Prostate Research Center of Vancouver General Hospital & British Columbia Cancer Agency, Vancouver, British Columbia, Canada. smwiseman@providencehealth.bc.ca
authors.forename: Sam M
authors.initials: SM
authors.lastname: Wiseman
authors.forename: Nikita
authors.initials: N
authors.lastname: Makretsov
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
authors.forename: Blake
authors.initials: B
authors.lastname: Gilks
authors.forename: Erika
authors.initials: E
authors.lastname: Yorida
authors.forename: Maggie
authors.initials: M
authors.lastname: Cheang
authors.forename: Dmitry
authors.initials: D
authors.lastname: Turbin
authors.forename: Karen
authors.initials: K
authors.lastname: Gelmon
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D066247:Receptor, ErbB-4; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C587689:ERBB4 protein, human