ANTIESTROGEN THERAPY - UNCERTAINTIES AND RISK ASSESSMENT

Tamoxifen is by far the most clinically tested antiestrogenic drug cur rently used as adjuvant therapy for breast cancer and it continues to provide considerable benefit in this setting. The balance from clinica l trials indicates a strong association between the use of tamoxifen a nd an increase in uterine tumors (three to sixfold). In rats, tamoxife n is a mutagenic, genotoxic hepatocarcinogen. These actions are not re lated to estrogen antagonist activity but have been shown to be as a r esult of metabolic activation of this drug by cytochrome P450 enzymes, resulting in irreversible binding to cellular DNA. The mechanism of e ndometrial cancer associated with tamoxifen treatment is unclear, alth ough there are two plausible hypotheses: (1), tamoxifen causes damage and mutation to DNA in uterine cells or (2), it promotes the developme nt of endometrial tumors through its estrogen agonist activity. The ev idence for a genotoxic effect of tamoxifen in the uterus is highly con tentious and, on balance, we have concluded that it is more likely tha t the estrogenic effects of tamoxifen promote tumor development.