© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 11, 973,
June 2, 1999
© 1999 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Effects of the Antiestrogens Tamoxifen, Toremifene, and ICI 182,780 on Endometrial Cancer Growth
Affiliations of authors: R. M. O'Regan (Division of Medical Oncology), V. C. Jordan (Robert H. Lurie Comprehensive Cancer Center), Northwestern University Medical School, Chicago, IL.
Correspondence to: V. Craig Jordan, Ph.D., D.Sc., Division of Medical Oncology and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, 8258 Olson, 303, E. Chicago Ave., Chicago, IL 60611.
We thank Mäenpää and colleagues for their informative letter. Although it is well known that the triphenylethylene-type antiestrogens have estrogen-like pharmacology and are converted to hydroxymetabolites in the mouse, the two events are not connected. The athymic mouse with heterotransplants of human tumors has been an important model for identifying the target-site-specific effects of antiestrogens. We found that an estrogen receptor-drug complex is interpreted as an estrogenic signal in the mouse uterus or transplanted human uterine tumor, but it is interpreted as an antiestrogenic signal in a human breast tumor transplanted into the same athymic mouse (1,2). We demonstrated that the spectrum of metabolites was the same in the target tissues, so we concluded that tamoxifen-like compounds were selectively antiestrogenic (2). The concept is now known as selective estrogen receptor modulation. In addition, a tamoxifen-stimulated tumor will grow equally well in an athymic rat (3), where the circulating metabolites are almost identical to those found in humans (4). Thus, the tissue, not the environment or metabolites, seems to be the factor that governs the biologic activity of tamoxifen-like drugs.
That being the case, we believe (as do Mäenpää et al.) that toremifene can probably stimulate the growth of pre-existing endometrial cancer. It is known that the level of occult endometrial cancer harbored in the uterus is five times that found clinically (5). So it is no surprise that tamoxifen use can increase the detection of endometrial cancer up to fourfold in postmenopausal women. Mäenpää et al. state that not a single case of endometrial cancer has been reported in patients treated with toremifene, outside a clinical trial, since its release for advanced breast cancer a few years ago. However, there were also no reports of endometrial cancer in women taking tamoxifen for more than 10 years after the drug was first available for the treatment of advanced breast cancer.
Mäenpää et al. show that an early adjuvant study with toremifene has, up to now, shown no increase in the reporting of endometrial cancer. The adjuvant result with toremifene is encouraging, but the same was said about tamoxifen 7 years ago (6). At present, there is only one adjuvant trial of toremifene ongoing, but it is important to remember that three adjuvant trials from Britain all initially reported no association between endometrial cancer incidence and tamoxifen [reviewed in (7)]. We do not believe that tamoxifen causes endometrial cancer, but we contend that if tamoxifen and toremifene have the same estrogen-like effects in the uterus, then there is the same potential risk for an increased incidence of endometrial cancer. Only large, well-documented clinical studies will prove otherwise.
EDITOR'S NOTE
V. C. Jordan is a member of the speaker's bureau for Zeneca Pharmaceuticals, the maker of tamoxifen, but he holds no stock in the company nor is he conducting research sponsored by Zeneca.
REFERENCES
1
Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan VC.
Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res 1988;48:812-5.
2 Jordan VC, Robinson SP. Species-specific pharmacology of antiestrogens: role of metabolism. Fed Proc 1987;46:1870-4.[Web of Science][Medline]cancerlit;87162551
3
Gottardis MM, Wagner RJ, Borden EC, Jordan VC. Differential
ability of antiestrogens to stimulate breast cancer cell (MCF-7) growth in vivo and in vitro. Cancer Res 1989;49:4765-9.
4 Robinson SP, Langan-Fahey SM, Johnson DA, Jordan VC. Metabolites, pharmacodynamics, and pharmacokinetics of tamoxifen in rats and mice compared to the breast cancer patient. Drug Metab Dispos 1991;19:36-43.[Abstract]cancerlit;91209192
5 Horwitz RI, Feinstein AR, Horwitz SM, Robboy SJ. Necropsy diagnosis of endometrial cancer and detection-bias in case/control studies. Lancet 1981;2:66-8.[CrossRef][Web of Science][Medline]cancerlit;81219868
6 Stewart HJ. The Scottish trial of adjuvant tamoxifen in node-negative breast cancer. Scottish Cancer Trials Breast Group. J Natl Cancer Inst Monogr 1992;11:117-20.cancerlit;92687991
7 Assikis VJ, Jordan VC. Gynecologic effects of tamoxifen and the association with endometrial carcinoma. Int J Gynecol Obstetrics 1995;49:241-57.
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