Molecular targets for cancer chemoprevention

Key Points Clinical molecularly targeted chemoprevention has surged forward since the late 1990s, with several targeted agents that prevent cancers, intraepithelial neoplasias and/or microbial infections that lead to carcinogenesis. In addition to vaccines against hepatitis B and human papillomavirus (to prevent cancers of the liver and cervix, respectively), molecularly targeted agents are feasible and effective in preventing breast cancer (selective oestrogen receptor modulators), colorectal adenomas (celecoxib) and prostate cancer (finasteride). Completed chemoprevention trials have encountered several difficulties that pose challenges to the design and conduct of future chemoprevention trials, and hinder translation of their findings into clinical practice. These challenges may be overcome by continuing advances in molecularly targeted prevention approaches. Identification of individuals at high risk of developing cancer (based on models integrating clinical, demographic and molecular data) will assist in selecting optimal populations for chemoprevention trials. Validation of molecular markers that could serve as intermediate surrogate end points for cancer could potentially shorten the length of definitive chemoprevention trials. Development of active molecularly targeted agents (alone or in combination) for chemoprevention should be based on preclinical models, regardless of the efficacy of the drugs in advanced disease. On the other hand, positive results in advanced cancer trials should stimulate prompt evaluation of the agent in the preventive setting as well. Identification of molecular markers that will predict drug sensitivity and/or adverse events will help optimize the risk/benefit ratio of molecularly targeted drugs. Molecularly targeted strategies developed in both premalignant and advanced disease will ultimately streamline cancer prevention research. The field of cancer chemoprevention has reported its first major successes, but broad translation to the clinic is not yet a reality. Here, Lippman and colleagues review the unique challenges encountered in this field, and the promise of personalized, molecularly targeted chemoprevention strategies. Vaccines targeting infections with hepatitis B virus, a risk factor for hepatocellular cancer, and human papillomavirus, a risk factor for cervical cancer, are considered major clinical cancer chemoprevention successes. Molecularly targeted agents can prevent breast cancer (raloxifene and tamoxife