Chemoprevention of breast cancer by tamoxifen: Risks and opportunities

The antiestrogen tamoxifen is widely used in the adjuvant therapy of breast cancers in women and helps to prevent the occurrence of breast tumors in h ealthy women. However, epidemiological studies have shown tamoxifen treatme nt to be associated with a 2- to 5-fold increased risk of endometrial cance r. In rats but not in mice, long-term administration of tamoxifen results i n an increase in hepatocellular carcinomas. Mechanistically, this occurs th rough metabolic activation of the drug, mainly by the CYP3A family, to an e lectrophilic species, that causes DNA damage in target tissues, and subsequ ently leads to gene mutations. It is controversial whether low levels of DN A damage occur in human uterine tissues, and there is no evidence that this can be causally related to the mechanisms of carcinogenesis. In healthy wo men, the risk:benefits for the use of tamoxifen is in part related to the r isk of developing breast cancer. The results from the carcinogenicity studi es in rats do not predict the likelihood that women will develop liver canc er or indeed cancers in other organs. The mechanism of endometrial cancer i n women remains unresolved, but the experience with tamoxifen has highlight ed the potential problems that need to be addressed in the assessment of fu ture generations of selective estrogen receptor modulators.