Update on HER-2 as a target for cancer therapy: herceptin in the clinical setting

Herceptin is the first therapy for breast cancer which targets an oncogene product. This humanized antibody to HER-2 has been shown to have activity as a single agent in a phase II trial of heavily pre-treated patients with advanced breast cancer and, in phase III studies, its use with chemotherapy is associated with higher response rates, longer time to progression and improved survival when compared with chemotherapy alone. Retrospective analysis of data from these pivotal trials suggests that attributable benefit of herceptin is greater in those patients who express HER-2 at the highest levels, that is 3+ expression by immunohistochemistry. Further analysis also implies that cases which are positive for HER-2 by fluorescent in situ hybridization may also benefit from treatment regardless of whether they express HER-2 at the 2+ or 3+ level. Use of herceptin as first-line therapy for metastatic disease in early studies suggest that response rates and clinical benefit rate similar to chemotherapy may be achievable and that survival using this sequential approach may not be compromized. Other combinations of herceptin and chemotherapy have been investigated with phase II data suggesting considerable activity with weekly taxol and when combined with navelbine. The non-linear pharmacokinetics of herceptin suggest that, as doses increased, half-life increases and may be feasible on a 3-weekly schedule. The role of herceptin in the adjuvant setting in the management of breast cancer will be tested in randomized studies of patients who express HER-2 at the highest levels; two of these studies have already begun.