Co-overexpression of HER2/HER3 is a predictor of impaired survival in breast cancer patients

Breast. 2014 Oct;23(5):637-43. doi: 10.1016/j.breast.2014.06.011. Epub 2014 Jul 10.


Background: Recently, HER3-expression was postulated as independent risk factor for metastatic spread. Therefore, we investigated the role of HER3 expression as prognostic marker in metastatic breast cancer patients.

Methods: Patients of different breast cancer subtypes diagnosed with metastatic disease (visceral and/or brain metastases) were identified from a breast cancer database. Tissue samples of the respective primary tumors were retrieved, and immunohistochemical staining for estrogen-receptor, progesterone-receptor, HER2, and HER3 was performed. In HER2 equivocal and selected HER3 positive cases, subsequent fluorescent in situ hybridization (FISH) analysis was performed.

Results: Tissue specimens of 110 patients were available for this analysis. 21% had strong, complete, membranous HER3 staining of at least 10% of all tumor cells; HER3 protein expression was not associated with HER3 gene amplification. HER2/HER3 co-overexpression was observed in 12/110 (11%) specimens and HER3-overexpression showed a statistically significant association with HER2-overexpression (p = 0.02). No correlation was observed for HER3-overexpression and overall survival (OS), time to diagnosis of brain metastases, and incidence of brain metastases. Still, in patients with HER3 overexpression, a higher rate of 'brain only' metastatic behavior was observed (p = 0.042). In the HER2-positive subgroup, HER3-overexpression was significantly associated with shorter OS from diagnosis of metastatic disease (median 17 vs. 35 months; p = 0.04; log rank test).

Conclusions: HER2/HER3 co-overexpression is significantly associated with impaired OS from diagnosis of metastatic disease in patients with HER2-positive metastatic breast cancer. Co-inhibition of HER2 and HER3 or the inhibition of HER2/HER3 hetero-dimerization may improve clinical outcome in this subgroup.

Keywords: Breast cancer; HER2-positive; HER3; Trastuzumab.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Brain Neoplasms / mortality*
  • Brain Neoplasms / secondary*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Digestive System Neoplasms / mortality*
  • Digestive System Neoplasms / secondary*
  • Female
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Middle Aged
  • Prognosis
  • Receptor, ErbB-2 / metabolism*
  • Receptor, ErbB-3 / metabolism*
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Retrospective Studies
  • Survival Analysis


  • Receptors, Estrogen
  • Receptors, Progesterone
  • ERBB2 protein, human
  • ERBB3 protein, human
  • Receptor, ErbB-2
  • Receptor, ErbB-3