Trastuzumab is not the first monoclonal antibody to be used as an anti-tumor agent, but it may be the most publicized. In about one third of breast cancers, the human epidermal growth factor receptor (HER2) gene is overexpressed, which encodes the growth factor receptor that is targeted by trastuzumab. Given the current modest beneficial effects of standard chemotherapy in patients with metastatic breast cancer, any agent that can improve survival in even a small portion of patients is eagerly anticipated. Phase I and II trials of trastuzumab have already shown some benefits. Slamon and colleagues report the results of a larger, randomized phase III trial of usual chemotherapy versus chemotherapy plus trastuzumab in patients with metastatic breast cancer.
Women with overexpression of the HER2 receptor were identified by immunohisto-chemical staining of tumor specimens. A total of 469 women were enrolled in the study. The trastuzumab group was followed for a median length of 40 weeks. Because of their decreased survival, follow-up was shorter in the usual chemotherapy group (median length: 25 weeks).
The usual chemotherapy consisted of an anthracycline (e.g., doxorubicin) plus cyclophosphamide, or paclitaxel alone in patients who had already received an anthracycline earlier in the course of their breast cancer treatment. Patients who were randomly assigned to the trastuzumab group received an intravenous loading dose and then smaller infusions until there was evidence of disease progression. In any patient with disease progression during the study, an option to enter an open-label study of trastuzumab was offered; two thirds of such patients elected to transfer.
Several benefits were noted in patients who received trastuzumab in addition to usual chemotherapy. Median survival increased from 20.3 to 25.1 months, there was a higher rate of overall response and a longer duration of response. Trastuzumab use was also associated with a longer time to disease progression, a significantly lower death rate at one year and a 20 percent reduction in the risk of death. Patients with a higher degree of HER2 overexpression benefited more from the addition of trastuzumab.
The most significant adverse effect identified in patients who received trastuzumab was an increased incidence of cardiotoxicity. The highest rate of cardiac dysfunction (27 percent) occurred in the subgroup that received trastuzumab, cyclophosphamide and an anthracycline. Although cardiotoxicity could be severe and possibly life-threatening, symptoms generally improved with standard medical care. The possibility of this side effect should be weighed against trastuzumab's potential clinical benefit.
The authors concluded that, when added to conventional chemotherapy, trastuzumab improved survival for the subset of metastatic breast cancer patients that overexpresses the HER2 gene.