CORRESPONDENCE

RESPONSE: Re: The Effects of Tamoxifen and Estrogen on Brain Metabolism in Elderly Women

Thomas Ernst, Linda Chang, Rowan Chlebowski

Affiliations of authors: T. Ernst, L. Chang, Brookhaven National Laboratory, Medical Department, Upton, NY; R. Chlebowski, Harbor–UCLA Research and Education Institute, Harbor–UCLA Medical Center, Torrance, CA.

Correspondence to: Thomas Ernst, Ph.D., Medical Department, Bldg. 490, Brookhaven National Laboratory, P.O. Box 5000, Upton, NY 11973–5000 (e-mail: ternst{at}bnl.gov).

Results from our recent report (1) demonstrate that tamoxifen may have a similar, possibly positive, effect on brain metabolism to that of estrogen. Benson (2) emphasizes that preliminary results from the Arimidex, Tamoxifen Alone, or in Combination (ATAC) trial make it mandatory to study the effects of Arimidex (anastrozole) on bone mineral density and cognitive function. According to Benson, the concerns about these preliminary results may delay the wide use of anastrozole for treatment of early breast cancer and may preclude its use as a chemopreventive treatment in healthy women.

The uncertainty regarding potential side effects of such drugs is exacerbated by the fact that little is known about the organ- or cell type-specific actions of drugs that interfere with estrogen metabolism. Benson suggests that the effects of anastrozole, an aromatase inhibitor, on cognition and bone density might differ from those of tamoxifen, a selective estrogen receptor modulator (SERM), because these two drugs differ in their core structures and basic side chains. Yet even drugs that belong to the same class, such as the two SERMs tamoxifen and raloxifene, differ in their estrogenic side effect profiles. For example, tamoxifen is associated with an increased risk of endometrial cancer, whereas raloxifene may not be. One possible mechanism underlying this differential action of tamoxifen versus raloxifene was recently reported by Shang and Brown (3), who demonstrated that the difference in endometrial cancer risk was associated with a high level of steroid receptor coactivator-1 (SRC-1) expression in the uterus, which caused estrogen-like activity by tamoxifen but not by raloxifene. However, it can be expected that other molecular mechanisms may cause additional differential drug side effects in the uterus and other organs. Currently, we can only speculate about the potential molecular effects of these drugs in the brain.

Therefore, we agree with Benson's assessment that a careful evaluation of the side effect profile of anastrozole is necessary, and we propose that all agents that have the potential to influence estrogen function should be studied for their potential side effects on the brain and other organs. Some negative side effects of drugs used for successful treatment of breast cancer may well be acceptable. However, when these drugs are administered to a large number of healthy women for the purpose of preventing breast cancer, even seemingly rare side effects may easily outweigh the potential benefits provided by a reduction in breast cancer incidence.

REFERENCES

1 Ernst T, Chang L, Cooray D, Salvador C, Jovicich J, Walot I, et al. The effects of tamoxifen and estrogen on brain metabolism in elderly women. J Natl Cancer Inst 2002;94:592–7.[Abstract/Free Full Text]

2 The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359:2131–9.[Medline]

3 Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs. Science 2002;295:2465–8.[Abstract/Free Full Text]



             
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