Development of Breast Cancer Chemopreventive Drugs

Abstract: Chemoprevention, or intervention with chemical agents at the precancer stage to avoid or slow the development of the carcinogenic process, is one strategy to reduce both the incidence of breast cancer and its mortality. Systematic development of cancer chemopreventive drugs calls for evaluation of pre‐clinical efficacy in well‐characterized in vitro screens and animal cancer models. Highly promising agents are also included in traditional pre‐clinical toxicity tests performed in two species. The most promising and least toxic agents enter clinical trials, including both phase I safety and pharmacokinetics evaluations and phase II and III efficacy studies. The use of populations with defined, measurable biologic alterations in tissue occurring prior to cancer development, i.e. intermediate biomarkers, is important to successful phase II chemoprevention trials. The intermediate biomarkers may be of several types, such as histological/premalignant lesions, proliferative, genetic/regulatory, differentiation‐related, or biochemical. For example, ductal and lobular carcinoma in situ are premalignant lesions in the human breast. These lesions are tissue at very high risk of malignant progression and also have the potential to be modulated by chemopreventive agents. In addition, other types of biomarkers may be identified within the lesions. These biomarkers could then serve as surrogate trial end‐points, instead of cancer incidence, for use in shorter, less costly trials.