Commentary: can circulating HER-2 extracellular domain predict response to trastuzumab in HER-2-negative breast cancer?

Human epidermal growth factor receptor 2 (HER-2) is one of four members of the type I family of tyrosine kinase growth factor receptors. Other members of this family include the epidermal growth factor receptor (EGFR, HER1), HER-3, and HER-4. These proteins are localized to the cell membrane. Their structure includes an intracellular cytoplasmic domain that exhibits tyrosine kinase activity (except HER-3), a transmembrane domain, and an extracellular domain (ECD). The ECDs of EGFR, HER-3, and HER-4 contain binding sites for multiple ligands. No ligand has been identified for HER-2. Phosphorylation of HER proteins results in activation of critical signal transduction pathways involved in mammalian cell growth. In cancer cells, amplification or otherwise overexpression of HER-2 has been associated with unregulated cell proliferation, invasion, and metastases. The HER-2 gene is amplified in 20%–25% of invasive breast cancers. Survival rates are worse in patients whose tumors carry the HER-2 gene amplification than in patients whose tumors express normal levels of HER-2. Expression of the truncated form of HER-2 has been associated with yet a worse prognosis compared with expression of the whole HER-2 protein. The HER-2 gene copy number can be determined by fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH). For FISH assays using chromosome 17 (CEP17) as a control, a HER-2/ CEP17 ratio 2.2 is considered positive. For FISH assays that do not include CEP17 as a control, at least six copies of the HER-2 gene should be identified for a tumor to be considered HER-2 positive. A tumor is considered HER-2 positive using immunohistochemistry (IHC) if at least 30% of the cells exhibit complete membrane staining. All patients with breast cancer should have their tumors tested for HER-2 expression by either IHC or FISH/CISH to determine eligibility for HER-2–directed therapy [1]. The initial clinical trials of trastuzumab monoclonal antibody therapy (Herceptin ; Genentech, South San Francisco, CA) relied on IHC testing of HER-2 expression in breast cancer tissue using the antibodies 4D5 and CB11. Based on retrospective analyses of archived tissue from patients treated with trastuzumab in clinical trials, the U.S. Food and Drug Administration approved several IHC and FISH assays for selecting breast cancer patients for HER2–targeted therapy. Although FISH is highly accurate and more reproducible than IHC, both assays are commonly used in the clinic. All laboratories offering HER-2 testing for patient care should follow the guidelines published by the American Society of Clinical Oncology and the College of American Pathologists [1]. It is hoped that these guidelines will improve the accuracy of HER-2 testing in breast cancer and allow proper patient selection for HER-2–targeted therapy.