CORRESPONDENCE

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

Juhani Mäenpää, Juha Ellmén, Taru Pasanen, Maija Kaukonen

Affiliations of authors: J. Mäenpää, Department of Obstetrics and Gynecology, Tampere University Hospital, Finland; J. Ellmén, T. Pasanen, M. Kaukonen, Clinical Research and Development. Orion Pharma, Turku, Finland.

Correspondence to: Juhani Mäenpää, M.D., Department of Obstetrics and Gynecology, Tampere University Hospital, P. O. Box 2000, FI-33521 Tampere, Finland (e-mail: lljuma{at}uta.fi).

On the basis of their study conducted in nude mice, O'Regan et al. (1) concluded that toremifene, like tamoxifen, is likely to be associated with an increased incidence of endometrial cancer. It is, however, controversial to draw conclusions about human carcinogenicity on the basis of studies in rodents. The mouse is a problematic species to use in this respect, because both drugs are more estrogenic in mice than in humans (2), even if one takes into account that O'Regan et al. studied human tumor xenografts in nude mice. Moreover, as shown in the article, the main metabolite of toremifene in mice is the 4-OH derivative, which comprised 67% of the total serum concentration of toremifene and its metabolites at 8 hours after toremifene administration (1). The concentration of this estrogenic metabolite was up to 30 times higher than the concentration of the corresponding metabolite of tamoxifen. In humans given therapeutic doses of toremifene, this metabolite is not seen (3).

However, because the above article raised a concern about the possible carcinogenic effect of toremifene on human endometrium, we checked the endometrial carcinomas reported in patients who received toremifene. As of September 30, 1998, the total cumulative clinical exposure to toremifene was more than 100 000 patient-years, and the drug had been administered to 3402 breast cancer patients in clinical trials (Table 1)Go. Adjuvant treatment trials in breast cancer were initiated in 1992, and more than 1100 patients have now been given toremifene, with a median treatment duration of 30 months.


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Table 1. Annual hazard rate (per 1000 patient-years) of developing endometrial cancer in postmenopausal patients with breast cancer treated with toremifene

 
It is interesting that no cases of endometrial carcinoma have thus far been reported in the marketed use of toremifene. In the clinical trials since 1982, a total of seven nonfatal endometrial carcinomas have been reported worldwide in patients receiving toremifene. Six of these patients participated in trials for breast cancer (three patients had advanced cancer, the other three received adjuvant therapy), and one was given toremifene for a desmoid tumor. The doses of toremifene ranged from 40 mg/day (two patients) to 60 mg/day (three patients) and 200 mg/day (one patient) to 240 mg/day (one patient). Of the seven patients, five had received toremifene for less than 1 year before the diagnosis of endometrial cancer (1, 4, 5, 6, and 9 months, respectively). Two patients had been treated with toremifene for approximately 2 years, and one of these was the patient with the desmoid tumor. The patient with the desmoid tumor, and another patient who had received toremifene for only 4 months had previously been on long-term tamoxifen (for 3 years).

Even if one assumes that the six reported cases of concomitant breast and endometrial cancers are linked to toremifene (which is in fact unlikely), the annual hazard rate (per 1000 patient-years) of developing endometrial carcinoma in postmenopausal breast cancer patients exposed to toremifene is only 0.96. It is noteworthy that the hazard rate is almost the same, or 1.08, for patients participating in adjuvant treatment trials, although these patients had received toremifene for a median of 30 months. In comparison, the hazard rates, as calculated from the literature, are 2.0 and 0.4 for patients exposed in adjuvant trials to tamoxifen and placebo, respectively (4-6).

In conclusion, the findings of O'Regan et al. (1) should be interpreted with caution because toremifene (and tamoxifen) are significantly more estrogenic in mice than in humans. We do agree that toremifene may unmask pre-existing endometrial tumors through its partial estrogen agonist activity (7). However, no clinical data exist to support the view that toremifene would increase the risk of endometrial cancer in postmenopausal women with breast cancer.

REFERENCES

1 O'Regan RM, Cisneros A, England GM, MacGregor JI, Muenzner HD, Assikis VJ, et al. Effects of the antiestrogens tamoxifen, toremifene, and ICI 182,780 on endometrial cancer growth. J Natl Cancer Inst 1998;90:1552-8.[Abstract/Free Full Text]

2 Kallio S, Kangas L, Blanco G, Johansson R, Karjalainen A, Perila M, et al. A new triphenylethylene compound, Fc-1157a. I. Hormonal effects. Cancer Chemother Pharmacol 1986;17:103-8.[Medline]

3 Anttila M, Valavaara R, Kivinen S, Maenpaa J. Pharmacokinetics of toremifene. J Steroid Biochem 1990;36:249-52.[Medline]

4 Fornander T, Rutqvist LE, Cedermark B, Glas U, Mattsson A, Silfversward C, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989;1:117-20.[Medline]

5 Andersson M, Storm HH, Mouridsen HT. Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer. J Natl Cancer Inst 1991;83:1013-7.[Abstract]

6 Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM, et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994;86:527-37.[Abstract]

7 Tomas E, Kauppila A, Blanco G, Apaja-Sarkkinen M, Laatikainen T. Comparison between the effects of tamoxifen and toremifene on the uterus in postmenopausal breast cancer patients. Gynecol Oncol 1995;59:261-6.[Medline]


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