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).
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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: email@example.com.