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

Cancer. 2005 May 1;103(9):1770-7. doi: 10.1002/cncr.20970.


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.

MeSH terms

  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Drug Synergism
  • ErbB Receptors / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lymph Nodes / pathology
  • Neoplasm Invasiveness / pathology
  • Neoplasm Staging
  • Prognosis
  • Receptor, ErbB-2 / metabolism*
  • Receptor, ErbB-3 / metabolism*
  • Receptor, ErbB-4
  • Survival Rate


  • Biomarkers, Tumor
  • ERBB4 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Receptor, ErbB-4