Biologic therapy involves the delivery of a systemic agent that can be specifically targeted toward a unique cellular feature, often a component of a cell surface receptor. Over the last decade, the approach to systemic therapy in breast cancer has been revolutionized by the development and efficacious application of biologic agents. Rapid translation of laboratory data to the clinic has resulted in meaningful differences in patient outcomes.
Three biologic therapies—trastuzumab, lapatinib, and bevacizumab—are now approved for use in patients with breast cancer. Preclinical and clinical data supporting the use of these agents are the focus of this chapter.
Human epidermal growth factor receptor 2 (ErbB2/HER-2) is a 185-kd transmembrane protein overexpressed in 20% to 25% of breast cancer patients and correlated with adverse survival outcomes.1-3 Trastuzumab, a humanized monoclonal antibody to HER-2, was developed to antagonize the role of HER-2 in the progression of breast tumors. After preclinical studies demonstrated growth inhibition in breast cancer cell lines and xenograft models,4,5 phase I data revealed a favorable safety profile.6,7 Efficacy trials were subsequently initiated.
Use in Patients with Metastatic Disease
In 1996, Baselga et al6 reported the results of a phase II study assessing the efficacy of trastuzumab as a single agent in the treatment of HER-2-overexpressing metastatic breast cancer. Forty-six patients received a loading dose of trastuzumab followed by 10 weekly doses. One complete remission and 4 partial remissions were seen (11.6%) in this heavily pretreated group.6 Pegram et al7 subsequently reported the results of a similar phase II clinical trial evaluating the combination of trastuzumab and cisplatin. Thirty-nine patients with HER-2 overexpression (2+ or 3+ by immunohistochemistry [IHC]) and progressive metastatic disease on standard therapy received a loading dose followed by 8 weekly doses of trastuzumab. Those without disease progression could continue treatment with maintenance cisplatin and trastuzumab until disease progression or unacceptable toxicity. The toxicity profile seen in this trial was comparable to historical controls treated with cisplatin alone. Almost half of the patients did not progress during the study period, and a quarter had a partial response lasting a median of 5.1 months. As in the first trial, no immunologic adverse events were noted, and pharmacokinetic analysis showed no drug interaction.7 Two hundred and twenty-two patients from multiple continents were accrued to another trial evaluating response rates to weekly trastuzumab (until disease progression) in HER-2-overexpressing metastatic breast cancer patients. The overall response rate was 22% (8 complete responses) and median time to progression was 9.1 months, despite the fact that greater than 60% of the patients had received prior chemotherapy for metastatic disease. Patients with higher levels of HER-2 overexpression (3+ vs 2+) were noted to have more favorable responses to trastuzumab. Only 14% (n = 29) of patients experienced severe adverse events thought to possibly be related to study drug, several occurring in ...