© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 8, 722-723,
April 21, 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: Division of Medical Oncology and The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical Center, Chicago, IL.
Correspondence to: V. Craig Jordan, Ph.D., D.Sc., Robert H. Lurie Comprehensive Cancer Center, Olson Pavillion 8258, 303 East Chicago Ave., Chicago, IL 60611-3008.
Dr. Williams is to be congratulated for his persistence in pointing out the carcinogenicity of tamoxifen. This has stimulated critical laboratory research worldwide to show that the rat is a poor model to predict the risk of human liver cancer with tamoxifen. Originally, the animal data caused great concern, but the result in the laboratory was a paradox. After 20 years of clinical use around the world, there is no epidemic of hepatocellular carcinoma in women who took tamoxifen (1). We now know that rat liver cells activate tamoxifen to a DNA adduct as the first step in liver carcinogenesis but that human liver cells do not (2,3). This is why DNA adducts are not detected in liver samples from women taking tamoxifen (4). Nevertheless, members of the toxicology community suggested that it was not relevant that the human liver was unaffected by tamoxifen; the fact that endometrial cancer was increased was proof of principle. This position was predictable. Dr. Williams cites the work of Hemminki et al. (see above) as support for tamoxifen being an initiator of cancer in the human endometrium. However, Dr. Williams shares only one side of the story. Others have been unable to find adducts in human endometrium (5) but, most importantly, parallel studies using the same methods as those of Hemminki et al. have been unable to detect an adduct (6). Indeed, although there has been enormous progress in identifying adducts from tamoxifen in rat liver, no one has yet identified the "phantom" adduct in human uterus. Be that as it may, we are reassured there are no differences in genetic markers in uterine samples from control or tamoxifen-treated women (7). Therefore, if tamoxifen is not genotoxic in the human uterus, other mechanisms need to be considered to explain the increase in endometrial cancer associated with tamoxifen use in postmenopausal women.
We have chosen to take a practical, rather than a theoretical, approach to the safety of antiestrogens in the uterus. Both tamoxifen and toremifene have sufficient estrogenicity in the uterus to encourage the growth of a laboratory model of human endometrial cancer. The pure antiestrogen ICI 182,780, with no estrogenic properties, does not cause endometrial tumor growth. Since the model originally predicted the increase in the detection of endometrial cancer in postmenopausal women treated with tamoxifen, why should women and physicians not be apprised of the potential risk associated with toremifene use? This is not a large risk, even if the effects of toremifene and tamoxifen in the uterus are found to be equivalent. However, until clinical data are available, we believe that physicians should assume that the risks from tamoxifen and toremifene are comparable.
Endometrial cancer is rare, so huge populations are necessary to establish an accurate association between toremifene and an elevated risk of the disease. At present, it is not possible to state that no association exists because the available clinical population for study, mentioned by Dr. Williams, is too small. Although toremifene has been studied for 15 years, its clinical drug development is at the point tamoxifen was in 1980—i.e., the use in advanced disease is approved in the United States, adjuvant clinical trials are ongoing, and no endometrial cancer has been reported. Only extensive clinical evidence of safety will provide a rationale for the expanded use of toremifene outside the treatment of advanced breast cancer.
NOTES
V. C. Jordan is a member of the Speaker's Bureau of Zeneca Pharmaceuticals, the manufacturer of tamoxifen, but he neither holds stock in the firm nor is conducting research sponsored by the firm.
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