Targeted therapies in breast cancer

Targeted therapeutic agents in breast cancer are representing a larger proportion of new drugs entering clinical testing. Carcinogenesis is a multistep process characterized by genetic alterations that influence key cellular pathways involved in growth and development. Therefore, there are numerous opportunities for pharmacologic targeting. Hormonal therapy is the prototype of a treatment targeting hormone receptors, and this class of drugs still provides the greatest overall impact on outcome. Even though chemotherapy is considered a cytotoxic and nonspecific therapy, it does modulate many key cellular pathways and therefore shares characteristics of biologic drugs. It is clear that targeted therapies are going to play a greater role in improving survival and quality of life in advanced breast cancer, with trastuzumab (Herceptin) serving as a successful model that is a relatively nontoxic agent associated with survival benefits. However, several challenges to the successful identification and application of therapeutic targets remain. These include the dissection of complicated and interacting biologic pathways and the limitations of preclinical models that will allow for a better prioritization of which drugs and combinations will succeed best in the clinic. Better methods for selecting ideal candidates for therapy need to be based on known modes of action. Mechanisms of intrinsic and acquired resistance need further exploration in order to refine drug design. Toxicities that might result from modulation of the targeted pathway must be expected and fully characterized. Some biologic strategies may need to be tested in less refractory cases, or even in early stages, even though this may be more costly and could raise safety concerns. Fortunately progress in all of these areas is expected with the availability of new technologies and a growing infrastructure for preclinical and clinical testing.