CORRESPONDENCE

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

Michael W. DeGregorio

Correspondence to: Michael W. DeGregorio, Pharm.D., Department of Internal Medicine, Division of Hematology and Oncology, University of California, Davis, Cancer Center, 4501 X St., Rm. 3016, Sacramento, CA 95817 (e-mail: wdegregorio{at}ucdavis.edu).

O'Regan et al. (1) claim to have shed some light on the safety of toremifene on the endometrium in postmenopausal women by using a mouse model that was instructive in earlier studies concerning tamoxifen safety in the 1980s (2). However, the recently published work used a modified version of that model that does not appear very instructive. For example, in 1988, Gottardis et al. (2) reported that in obviously tamoxifen-naive tumors, tamoxifen stimulated tumor growth, whereas in the current publication, tamoxifen did not stimulate growth in so-called tamoxifen-naive tumors. The tamoxifen-naive model in the current work appears not to be as naive as the model used in the earlier work because the authors state that their "tamoxifen-naive" tumors were simply not exposed to tamoxifen for three passages. Also, the data presented in Fig. 4 of reference (1) would predict that tamoxifen and toremifene should not cause endometrial stimulation in humans, when in fact both drugs cause human endometrial proliferation. This may be explained by the fact that the doses used in the mice ranged from 60 to 180 times the dose used in women with breast cancer, consistent with an apparent toxic effect that the authors observed at high drug concentrations [Table 3 of reference (1)]. While I agree with the authors that the carcinogenic effect of tamoxifen in rat liver can be explained by the fundamental metabolic differences between rats and humans, the fact that the primary metabolic pathway of these drugs in humans is N-desmethylation and not 4-hydroxylation as observed in athymic mice may also provide an explanation for the discrepancy between this model system and clinical observations (3-5).

In addition, the authors introduce a tamoxifen-stimulated model without explaining its clinical relevance and limitations. The data in Fig. 3 of reference (1) could indicate that both tamoxifen and toremifene support the growth of tamoxifen-stimulated endometrial tumors. This appears to suggest that tamoxifen and toremifene have similar effects on the endometrium, which would support clinical observations that both drugs cause endometrial thickening, thus leading to the unmasking of previously existing, low-grade endometrial cancers in some patients. However, toremifene is not indicated in tamoxifen failures. Although unmasking of previously existing disease may account for many endometrial cancers, evidence also suggests that tamoxifen induces a potentially lethal type of endometrial cancer, indicating that there are other mechanisms of tamoxifen carcinogenesis (3-5). For toremifene, there is no conclusive evidence that the drug is associated with poor-prognostic endometrial cancer (6).

Overall, I find this article not fully informative and possibly inadequate for the drug evaluation process. It is interesting that Dr. Jordan's research team avoided testing other promising antiestrogens (7), further limiting the instructive value of this article. In summary, the authors' conclusions are not supported by their data because they missed their stated aim to replicate and generate useful data for two clinical scenarios (toremifene as first-line adjuvant therapy or after tamoxifen). This article does not include recent clinical information regarding toremifene and tamoxifen, and novel antiestrogenic drugs such as raloxifene are not even mentioned.

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 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.[Abstract]

3 Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451-67.[Medline]

4 Mignotte H, Lasset C, Bonadona V, Lesur A, Luporsi E, Rodier JF, et al. Iatrogenic risks of endometrial carcinoma after treatment for breast cancer in a large French case-control study. Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC). Int J Cancer 1998;76:325-30.[Medline]

5 Magriples U, Naftolin F, Schwartz PE, Carcangiu ML. High-grade endometrial carcinoma in tamoxifen-treated breast cancer patients. J Clin Oncol 1993;11:485-90.[Abstract]

6 Holli K, Joensuu H, Valavaara R, Blanco G, Kataja V, Pukkala E. The Finnish Breast Cancer Group, Tampere University Hospital). Interim results of the Finnish toremifene vs. tamoxifen adjuvant trial [abstract]. Proceedings of the 21st Annual San Antonio Breast Cancer Symposium; 1998 Dec 12-15; San Antonio (TX). Breast Cancer Res Treat 1998;50:283.

7 Jordan VC, Glusman JE, Eckert S, Lippman M, Powles T, Costa A, et al. Incident primary breast cancers are reduced by raloxifene, integrated data from multi-center, double-blinded, randomized trials in 12,000 postmenopausal women. Proc ASCO 1998 [abstract 446].


 

RESPONSE

Ruth O'Regan, V. Craig Jordan

Affiliation of authors: Division of Medical Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, IL.

Regrettably, DeGregorio misrepresents the situation with studies in the laboratory and their impact in medicine. Rather than going through his letter point by point (to correct his misinterpretation of laboratory results and the clinical use of antiestrogens), we will make three specific comments. The results obtained with tamoxifen using the human endometrial carcinoma model (1), first described by Satyaswaroop et al. (2) in 1984, were the trigger (3,4) that subsequently focused intense clinical attention on the link between tamoxifen and the risk of endometrial cancer. The work is recognized as a good example of translational research that provoked a clinical evaluation and a change in medical practice. A system is now in place to prevent the unnoticed development of serious endometrial cancer, i.e., a routine gynecologic examination. The risk with tamoxifen is known to be modest and the benefits of tamoxifen, as an essential drug for the treatment of breast cancer (World Health Organization list), are unimpeachable (5). It is, therefore, unreasonable for DeGregorio to state that tamoxifen was subsequently found to be associated with, "a potentially lethal type of endometrial cancer." This statement is out of date and is not the official view shared by the breast cancer clinical trial community, the American College of Obstetrics and Gynecology, the National Cancer Institute, the Food and Drug Administration, and an agency of the World Health Organization. Indeed, there was no evidence for an association between tamoxifen with "a potentially lethal type of endometrial cancer" in well women with gynecologic surveillance (6). All of the endometrial cancers observed with tamoxifen in the prevention trial were stage 1 (good grade) disease and at the modest rate predicted. It is now obvious that we have moved into an era of awareness and we better understand the concerns about selective estrogen receptor modulator (SERM). There is no need for DeGregorio to restate an old database from an era in which ignorance of the problem was the rule.

Endometrial cancer is rare and toremifene, a drug approved for the treatment of advanced breast cancer, does not have the huge clinical database required to assess the risk of endometrial cancer. However, since toremifene and tamoxifen have similar effects on the uterus and since we show that they both produce the same effect in a model of endometrial cancer growth (7), our evidence suggests that they are as good, or as bad, as each other. Women, however, need to be appraised if any risks exist. We are surprised that DeGregorio continues to persuade women to abandon tamoxifen, a proven medicine, and take a drug only he believes to be safer. Toremifene may be safer for rats but we believe it requires many years of clinical evaluation before this can be stated unequivocally for women.

DeGregorio is concerned because we evaluated toremifene rather than raloxifene. As DeGregorio knows, an evaluation requires large quantities of drug and a funding mechanism, with hundreds of thousands of dollars, to support the completion of the study. However, our academic peers on a recent review panel decided that the endometrial questions concerning tamoxifen are not a priority and the risks with raloxifene will eventually be assessed in clinical trial. The next breast cancer prevention trial, the Study of Tamoxifen And Raloxifene (STAR), will employ the standard of gynecologic care for 22 000 postmenopausal high-risk women. Results of the risks and benefits of raloxifene compared with tamoxifen will be available 7 years from now. Nevertheless, we remain curious to learn the pharmacology of any new SERM in the endometrial carcinoma growth assay. Our studies are intended to be a trigger to encourage a clinical evaluation by pharmaceutical companies for the sake of women's health.

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.[Abstract]

2 Satyaswaroop PG, Zaino RJ, Mortel R. Estrogen-like effect of tamoxifen on human endometrial carcinoma transplanted into nude mice. Cancer Res 1984;44:4006-10.[Abstract]

3 Hardell L. Tamoxifen as a risk factor for carcinoma of corpus uteri [letter]. Lancet 1988;2:563.

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 Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451-67.[Medline]

6 Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90:1371-88.[Abstract/Free Full Text]

7 O'Regan R, 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]



             
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