The tamoxifen dilemma.

The anti-oestrogen tamoxifen is widely used for adjuvant therapy in the treatment 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 tamoxifen 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 for caution come from studies in rats that show that tamoxifen is a genotoxic mutagenic liver carcinogen. Initiation of tumours in the rat is the result of metabolic activation of tamoxifen by CYP enzymes to an electrophile(s) that binds irreversibly to DNA. This is not related to the oestrogen receptor status of the tissue. The extent of DNA damage, detected by 32P-post-labelling or accelerator mass spectrometry, is dependent both on the dose and the length of exposure. Studies have been carried out to see if such binding occurs in the uterine endometrium from tamoxifen-treated women. Results are presently inconclusive, but if such irreversible DNA binding occurs, it is at very low levels. Based on a mechanistic understanding of tamoxifen-induced liver carcinogenesis in the rat, it seems that in humans hepatic DNA damage will be close to the limit of detection by 32P-post-labelling and liver cancer will not be a significant carcinogenic risk. We cannot be certain of the mode of action of tamoxifen that results in the increase in endometrial cancers in treated women but it seems unlikely that this will be associated with a classical genotoxic mechanism.