Prevention of breast cancer: focus on chemoprevention.

Present prospects of breast cancer prevention are being developed in three main areas: (a) genetics, to understand the real importance of familial breast cancer and genetic testing; (b) lifestyle, to study various risk factors, including delayed first pregnancies and smaller number of pregnancies, and months of breast feeding; (c) chemoprevention, to identify chemical agents potentially able to inhibit the development of invasive cancer either by blocking the DNA damage that initiates carcinogenesis or by arresting or reversing the progression of premalignant cells. Different target populations for breast cancer chemoprevention may be recognized. Primary chemoprevention may involve a wide population of healthy women with a moderate risk due to nonpenetrant genetic factors (e.g., one first-degree relative with breast cancer) or exposure to known promoting agents (e.g., hormone replacement therapy). A second level of primary chemoprevention may involve a limited population at very high risk because of highly penetrating genetic predisposition to cancer (e.g., BRCA1 mutation carriers). Secondary chemoprevention may involve subjects with premalignant or early malignant lesions, e.g., breast atypical hyperplasia and carcinoma in situ or microinvasive disease. Prevention trials using clinical endpoints are always subject to high costs. Also, the risk of unexpected detrimental effects has recently been high-lighted, and much emphasis has been put on the search for intermediate, surrogate endpoints. Surrogate endpoints are biological markers that may be assessed or observed prior to the clinical appearance of the disease, bearing some relationship to the development of that disease. They are referred to as intermediate since they occur some time between a given intervention that affected the disease process and the time of the clinical diagnosis of the disease. The use of surrogate endpoint biomarkers in pivotal cancer chemoprevention trials may lead to a rational choice of agents which are likely to affect cancer incidence in subsequent phase III trials.