Molecularly targeted therapeutics for breast cancer.

Thomas Beatson's celebrated description in 1896 of bilateral oophorectomy as effective therapy for premenopausal breast cancer could be considered as the first demonstration of response of any cancer to a 'targeted therapy.' At that time, however, the understanding of the mechanism of the intervention was minimal. In recent years a host of new rationally designed, molecularly targeted cancer therapies have been introduced from both large pharmaceutic and small biotechnology companies, and the portfolio of new targeted treatments in the pipeline appears to be unending. The existence of this array of potential new therapies is the result of a prodigious effort in the researching and defining of the molecular components of the cancer phenotype, and the subsequent rational design of agents to target candidate pathways. Experience with endocrine therapy has shown that targeted therapies require the target to be not merely expressed in the cancer phenotype, but important in regulating growth of cancer cells. We may well look back at many of the current targeted therapy trials as unrealistically simplistic in failing to adequately and define the target phenotype. This approach risks rejecting highly active treatments for a small subgroup of a study population where minimal activity is present for the majority. The future for breast cancer therapy is promising, but it is important to be prepared for disappointment, as early success in animal models cannot guarantee a successful human therapy. Stunning results such as the adjuvant trastuzumab trials are likely to remain the exceptions rather that the rule, and most gains will be modest advances. A better understanding of the molecular biology of cancer may also aid in guiding the most appropriate use of existing therapies such as conventional chemotherapy. This knowledge will facilitate the rational selection of drug combinations and/or sequencing based on their mechanisms of action at a molecular level. The aim of this paper is to review the current state-of-the-art in novel targeted therapies for breast cancer based on an understanding of this disease at the molecular level, with particular reference to those agents entering the clinic.