Breast cancer and sex steroids: Critical review of epidemiological, experimental and clinical investigations on etiopathogenesis, chemoprevention and endocrine treatment of breast cancer

There is strong epidemiological, experimental and clinical evidence that the etiology of breast cancer is closely related to long-term exposure of breast epithelium to sex steroid hormones. Estrogens can enhance the development of breast cancer by stimulating cell proliferation rate and thereby increasing the number of errors occurring during DNA replication, as well as by causing DNAdamage via their genotoxic metabolites produced during oxidation reactions. Anti-estrogenic drugs, including tamoxifen, raloxifene and anastrozole, have been tested with promising results in the chemoprevention of breast cancer in high-risk women. As for the use of exogenous sex-steroids in the gynecological practice, data about breast cancer risk associated with oral contraception are reassuring, and available data on oral hormone replacement therapy (HRT) use for not more than 5 years have failed to detect a significant increase in the risk of developing a breast cancer. Long-term HRT administration increases the incidence of this tumor slightly, with a relative risk ranging from 1 to 2 depending on hormone preparation. Estrogens alone, even if taken for long periods of time, seem to be safer than estrogen/progestin combinations. New administration routes and novel hormone regimens are currently under evaluation,.and these new HRT modalities could have different impact on breast cancer risk because of their metabolic and pharmacodynamic effects. As for the management of hormone sensitive breast cancer, anti-estrogen drugs have been used both for adjuvant therapy of early disease and for treatment of advanced and metastatic disease. The standard drug for adjuvant endocrine therapy is tamoxifen. However, recent studies appear to suggest a possible role for anastrozole and letrozole in adjuvant setting. First-line hormonal treatment of advanced or metastatic breast cancer consists of tamoxifen plus a gonadotropin-releasing hormone (GnRH) agonist in premenopausal patients, and anastrozole, letrozole or exemestane in postmenopausal ones. The establishment of an optimal sequence of endocrine therapies should give significant clinical benefits to breast cancer patients.