Questions: 1. What is the role of trastuzumab in the treatment of women with HER2/neu-overexpressing metastatic breast cancer? 2. What are the most effective methods of assessing HER2/neu status? Perspectives: Trastuzumab (Herceptin®) is a monoclonal antibody approved for use in Canada since August 1999. The Breast Cancer Disease Site Group (DSG) of Cancer Care Ontario's Practice Guidelines Initiative examined the role of trastuzumab in the treatment of women with HER2/neu-overexpressing metastatic breast cancer. The DSG also reviewed the methods of assessing HER2/neu status. Methodology: A systematic review of the published literature was combined with a consensus process around the interpretation of the evidence in the context of conventional practice. Results: Trastuzumab has activity in metastatic breast cancer, demonstrated by tumour response rates of 12%-23% when the drug was given as a single agent in 1 randomised trial and in 2 phase II studies. Adding trastuzumab (T) to first-line chemotherapy (C) - either paclitaxel, or anthracycline plus cyclophosphamide - improved median time-to-progression (7.2 months with T+C vs. 4.5 months with C, p < 0.0001). 1-year survival rate (79% with T+C vs. 68% with C, p < 0.01), and median overall survival rate (25.4 months for T+C vs. 20.9 months for C alone). Class III or IV cardiac dysfunction was reported in 5% of patients treated with trastuzumab as a single agent, 3% treated with trastuzumab plus cisplatin, 4% treated with trastuzumab plus paclitaxel, and 19% treated with trastuzumab plus anthracycline plus cyclophosphamide. Many methods of assessing HER2/neu are possible. For evaluation of HER2/neu status in the clinical setting, immunohistochemistry or fluorescent in-situ hybridisation (FISH) are most commonly performed. Opinions of the Breast Cancer Disease Site Group: At present, there is insufficient evidence on which to base firm clinical recommendations. Based on data from uncontrolled studies, trastuzumab as a single agent appears to be a reasonable treatment alternative in women whose tumours overexpress HER2/neu (defined as moderate-to-strong complete membrane staining in at least 10% of the neoplastic cells, by immunohistochemistry) and whose cancer has progressed following treatment with anthracyclines or taxanes. Paclitaxel plus trastuzumab has been compared with paclitaxel alone in a randomised trial and could be considered a reasonable treatment alternative for women being considered for paclitaxel therapy. The need for reliable and reproducible methods of assessing HER2/neu status to optimally identify patients most likely to respond to Herceptin® therapy is urgent. At present, technical and clinical validation of many of the currently used methodologies is lacking. Pending validation studies, the group's recommendation is that HER2/neu status be determined using standardised immunohistochemical methodologies. Indeterminate cases by immunohistochemistry should be further evaluated by FISH or quantitative polymerase chain reaction.