Professor of Medicine and Director, Breast
Oncology and Clinical Trials Education,
University of California, San Francisco, Helen
Diller Family Comprehensive Cancer Center,
San Francisco, CA;
Trastuzumab-derivative of maytansine-1 (trastuzumab emtansine; T-DM1) is a novel antibody-drug conjugate that combines an antibody targeted specifically to HER2- overexpressing cancer cells with maytansine, a potent cytotoxic agent. In comparison with lapatinib and capecitabine in patients with trastuzumab-resistant HER2+ advanced breast cancer, treatment with T-DM1 resulted in improved progression-free and overall survival, with a superior safety profile. Ongoing clinical trials are investigating T-DM1-based therapy in combination with other chemotherapy agents, with other targeted agents, and as treatment for early-stage HER2+ breast cancer and other malignancies.
Between 20% and 25% of all breast cancers overexpress the HER2/neu receptor or have amplification of the HER2 (ErbB2) gene, with about half also expressing the estrogen receptor. Before the introduction of targeted therapy, HER2-expressing (HER2+) breast cancers were associated with a high risk of short-term recurrence and shorter overall survival (OS).1,2 Trastuzumab, a humanized monoclonal antibody targeting the HER2/neu receptor, was approved by the FDA in 1998 for the treatment of HER2+ metastatic breast cancer (mBC),3,4 and in 2006 for the treatment of early-stage disease. In the advanced-disease setting, trastuzumab administered as monotherapy exerts a modest antitumor effect but has marked synergistic antiproliferative effects when combined with cytotoxic agents.5-7
Although trastuzumab combined with chemotherapy has become the standard of care for the treatment of HER2+ mBC, up to 50% of patients present with de novo resistance.8 Progression-free survival (PFS) following treatment with trastuzumab combined with taxane-based chemotherapy is only about 1 year.9,10 PFS can be extended to about 18 months with the addition of pertuzumab, a novel HER2-targeted antibody approved in this setting by the FDA in June 2012.11 Chemotherapy combined with trastuzumab in the early-stage setting has significantly improved disease-free survival (DFS) and OS; however, relapses continue to occur even years after initial treatment.6,7,12 In addition, improved OS in both early- and late-stage disease with trastuzumab has been seen only when the antibody is given in combination with chemotherapy, and hence, concomitant chemotherapy toxicity.