title: Co-overexpression of HER2/HER3 is a predictor of impaired survival in breast cancer patients.
abstract: 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.
authors.affiliation: Institute of Neurology, Medical University of Vienna, Austria; Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Berghoff
authors.affiliation: Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria; Department of Medicine I, Clinical Division of Medical Oncology, Medical University of Vienna, Austria. Electronic address: rupert.bartsch@meduniwien.ac.at.
authors.forename: Rupert
authors.initials: R
authors.lastname: Bartsch
authors.affiliation: Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria; Department of Medicine I, Clinical Division of Medical Oncology, Medical University of Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Preusser
authors.affiliation: Institute of Neurology, Medical University of Vienna, Austria; Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.
authors.forename: Gerda
authors.initials: G
authors.lastname: Ricken
authors.affiliation: Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria; Department of Medicine I, Clinical Division of Medical Oncology, Medical University of Vienna, Austria.
authors.forename: Guenther G
authors.initials: GG
authors.lastname: Steger
authors.affiliation: Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria; Department of Pathology, Medical University of Vienna, Austria.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Bago-Horvath
authors.affiliation: Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria; Department of Pathology, Medical University of Vienna, Austria.
authors.forename: Margareta
authors.initials: M
authors.lastname: Rudas
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
authors.forename: Berthold
authors.initials: B
authors.lastname: Streubel
authors.affiliation: Department of Surgery, Medical University of Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Dubsky
authors.affiliation: Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria; Department of Surgery, Medical University of Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Gnant
authors.affiliation: Department of Surgery, Medical University of Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Fitzal
authors.affiliation: Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria; Department of Medicine I, Clinical Division of Medical Oncology, Medical University of Vienna, Austria.
authors.forename: Christoph C
authors.initials: CC
authors.lastname: Zielinski
authors.affiliation: Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria; Department of Pathology, Medical University of Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000401:mortality* / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D004067:Digestive System Neoplasms / Q000401:mortality* / Q000556:secondary*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D016019:Survival Analysis
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: Breast cancer; HER2-positive; HER3; Trastuzumab