Introduction: Advances in molecular biology have led to the identification of potential markers of prognostic and therapeutic importance in human cancers. HER-2 testing and targeted therapy now represents a critical cornerstone in the management of breast cancer. The objectives of the current study were to determine the frequency and prognostic significance of HER-3 over-expression and HER-4 over-expression by invasive breast cancer.
Methods: Tissue microarrays were constructed using clinically annotated formalin-fixed and paraffin-embedded tumor samples from 4046 patients diagnosed with invasive breast carcinoma with a median 12.5 years of follow-up. Type 1 growth factor receptor family members HER-1, HER-2, HER-3, and HER-4 expression levels were determined by immunohistochemistry, and HER-2 status was further resolved by fluorescent in-situ hybridization. The study cohort was randomly divided and analyzed as a core data set and a validation data set.
Results: HER-3 over-expression was identified in 10.0% of tumors and was a significant marker of reduced patient breast cancer-specific survival on univariate analysis (P = 1.32 × 10−5). Furthermore, in tumors with normal expression levels of HER-1 and HER-2, the overexpression of HER-3 had a significant negative prognostic effect on disease-specific survival (HR: 1.541, 95% CI: 1.166–2.036, P = 2.37 × 10−3) independent of patient age at diagnosis, Estrogen receptor status, tumor grade, tumor size, nodal status, and the presence of lymphatic or vascular invasion by cancer. HER-4 overexpression was identified in 78.2% of breast cancers and was not a significant marker of patient survival (P = 0.214). Results of all statistical tests were positively confirmed in the validation data set analysis.
Conclusions: HER-3 status is an important prognostic marker of disease-specific survival in patients with invasive breast cancer. Accordingly, evaluation of the HER-3 expression level may identify a subset of patients with a poor disease prognosis, and who could undergo further evaluation for the efficacy of HER-3 targeted anticancer agents.
Type 1 growth factor receptor family members HER-1, HER-2, HER-3, and HER-4 expression levels were determined utilizing tissue microarrays constructed of tumor samples from 4046 patients diagnosed with invasive breast cancer. HER-3 overexpression was identified in 10.0% of tumors and was a significant marker of reduced patient breast cancer-specific survival on univariate and multivariate analysis. Supplemental digital content is available in the article.
From the *Department of Surgery, St. Paul's Hospital, University of British Columbia, Vancouver, Canada; †Department of Anatomical Pathology, University of British Columbia, Vancouver, Canada; ‡Genetic Pathology Evaluation Centre, Vancouver Coastal Health Research Institute, British Columbia Cancer Agency, and University of British Columbia, Vancouver, Canada; §Department of Radiation Oncology, British Columbia Cancer Agency, Vancouver, Canada; ¶Centre for Applied and Translational Genomics, Vancouver, Canada; ∥Department of Pathology, British Columbia Cancer Agency, Vancouver, Canada; and British Columbia Breast Cancer outcomes Unit.
Supported by Michael Smith Foundation for Health Research (MSFHR).
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.annalsofsurgery.com).
Reprints: Sam M. Wiseman, MD, FRCSC, Department of Surgery, St. Paul's Hospital, University of British Columbia, C303–1081 Burrard Street, Vancouver, BC, Canada, V6Z 1Y6. E-mail: firstname.lastname@example.org.