Breast cancer in the 21st century: neu opportunities and neu challenges

Recent advances in the understanding of the molecular and genetic alterations underlying breast cancer development and progression have provided the opportunity to develop novel therapeutic strategies for this disease. None of these developments has had a greater recent impact on clinicians and pathologists than the recognition of the importance of the HER-2/neu (c-erbB-2) oncogene. Located on chromosome 17, this gene encodes a 185 kD transmembrane glycoprotein with tyrosine kinase activity that functions as a growth factor receptor. Amplification or overexpression of HER-2/neu is seen in approximately 20 to 30% of invasive breast cancers and this has been considered to be an adverse prognostic factor in many studies. However, recent interest in HER-2/neu has largely been focused on its role as a potential target for breast cancer treatment. In particular, recognition of the role of HER-2/neu in breast cancer growth led to the development of a humanized monoclonal antibody directed against the HER-2/neu protein as a therapeutic agent (Herceptin). Clinical studies have further suggested that HER-2/neu status can provide important information regarding sensitivity to certain forms of conventional systemic therapy, particularly anthracyclines. As a result of these developments, there has been increasing demand for pathologists to perform assays for HER-2/neu on current and archived breast cancer specimens. Immunohistochemistry and fluorescence in situ hybridization have emerged as the most viable assays for evaluation of HER-2/neu in routine clinical practice. However, each of these methods has its advantages and disadvantages. Determining the relative merits of these assays and developing clinically meaningful and reproducible systems to report the results are challenges pathologists must now address. The development of a therapeutic agent that directly targets a protein involved in a growth-signaling pathway represents a new paradigm in breast cancer treatment. Therapeutic strategies that target other molecules involved in breast cancer development and progression are on the horizon. It is crucial that pathologists become aware of these advances and assume a pivotal role in the development and application of assays to evaluate these new molecular targets.