The tamoxifen dilemma

The anti-oestrogen tamoxifen is widely used for adjuvant therapy in the tre atment of women with breast cancer and has a low incidence of serious side- effects. It could also play a role as a breast cancer chemopreventive agent , However, epidemiological studies in both tamoxifen-treated breast cancer patients and in healthy women have shown that treatment results in a small increase in the incidence of endometrial cancers. While the use of tamoxife n in breast cancer patients is clearly justified, the situation for its use as a chemopreventive agent in healthy women is not so clear cut. Reasons f or caution come from studies in rats that show that tamoxifen is a genotoxi c mutagenic liver carcinogen. Initiation of rumours in the rat is the resul t of metabolic activation of tamoxifen by CYP enzymes to an electrophile(s) that binds irreversibly to DNA. This is not related to the oestrogen recep tor status of the tissue. The extent of DNA damage, detected by P-32-post-l abelling or accelerator mass spectrometry, is dependent both on the dose an d the length of exposure. Studies have been carried out to see if such bind ing occurs in the uterine endometrium from tamoxifen-treated women, Results are presently inconclusive, but if such irreversible DNA binding occurs, i t is at very low levels. Based on a mechanistic understanding of tamoxifen- induced liver carcinogenesis in the rat, it seems that in humans hepatic DN A damage will be close to the limit of detection by P-32-post-labelling and liver cancer will not be a significant carcinogenic risk. We cannot be cer tain of the mode of action of tamoxifen that results in the increase in end ometrial cancers in treated women but it seems unlikely that this will be a ssociated with a classical genotoxic mechanism.