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O’Regan et al.(1) report stimulation of growth of a human estrogen receptorpositive endometrial tumor in athymic mice by two “antiestrogens” and to a greater degree by estrogen. On the basis of these observations, they (1) suggest, “toremifene, like tamoxifen, may be associated with an increased incidence of endometrial cancer,” presumably less so than estrogen, based on their model. This suggestion, however, ignores a published report of a side-by-side trial of the two drugs in which endometrial cancer occurred in two of 565 women receiving tamoxifen and in none of 592 women receiving toremifene(2). Various reasons for the apparent nonconcordance can be adduced, but one consideration is that the carcinogenicity of tamoxifen in humans may be a consequence of DNA alkylation in the endometrium(3) together with enhanced cell proliferation (4), a combination known to greatly increase the carcinogenic effects of other DNA-reactive carcinogens. O’Regan et al.(1) take the position that the appearance of endometrial cancer in women after fewer than 2 years of treatment is not consistent with a DNA adduct mechanism and that tamoxifen is involved only in “activation and detection of pre-existing disease.” This theory, of course, would not apply to later occurring tumors and ignores possible associations with other cancers (5). Moreover, it is noteworthy that, in the induction of rat liver tumors by tamoxifen (6), for which the authors have also implicated a promoting effect, liver preneoplastic lesions occur within 2 weeks (7), undoubtedly as a consequence of DNA reactivity (6). In principle, neoplastic transformation by a mutagenic carcinogen such as tamoxifen can occur in the first division of an affected cell, and thus the carcinogenicity of DNAreactive agents can be quite rapid. Finally, O’Regan et al.(1) cite our paper (6) showing that toremifene has not been demonstrated to form DNA adducts in rat liver stating that “it was thought, therefore, that it would be less likely than tamoxifen to result in an increased risk for endometrial cancer.” No such statement was made in our paper. Nevertheless, I do believe that, on the basis of nonclinical toxicology(6,7)and available clinical observations(2,5), toremifene poses less of a potential cancer risk to patients than tamoxifen at most sites, including, so far, endometrium.

Re: Effects of the Antiestrogens Tamoxifen, Toremifene, and ICI 182,780 on Endometrial Cancer Growth