Beyond trastuzumab: new treatment options for HER2-positive breast cancer.

HER2-positive tumors comprise 15% to 20% of all breast cancers (BC) and are associated with worse clinical outcomes [Slamon et al., Science 1987;235:177-82]. Trastuzumab is a humanized monoclonal antibody designed to target the extracellular domain of the HER2 receptor, and is the foundation of care of women with early and advanced HER2-positive BC. However, a significant proportion of patients with this type of BC display either primary or secondary resistance to trastuzumab. Therefore, in an effort to overcome such resistance and further improve the outcome of patients with HER2-positive disease, several new anti-HER2 agents are currently being developed. These include small molecules that inhibit the HER2 tyrosine kinase activity (lapatinib, neratinib), monoclonal antibodies directed at other epitopes of the HER2 extracellular domain (pertuzumab), antibody-drug conjugates (trastuzumab-DMl), and heat shock protein 90 inhibitors (tanespimycin). A great deal of interest has been generated by recent data from the randomized neo-adjuvant studies NeoALTTO and NeoSphere, which have shown that dual blockade of the HER2 receptor with anti-HER2 agents is significantly superior to using one agent alone. If these results are validated in larger ongoing and planned phase III studies in early BC, they could lead to a paradigm shift in treatment strategy. Therefore, to avoid unnecessary toxicities and costs, it is critical to intensify the research for biomarkers that can identify those patients most likely to benefit from specific targeted therapies.