Journal of the National Cancer Institute Advance Access originally published online on September 9, 2008
JNCI Journal of the National Cancer Institute 2008 100(18):1331-1332; doi:10.1093/jnci/djn272
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© The Author 2008. Published by Oxford University Press.
CORRESPONDENCE |
Re: Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A Modeling Analysis
Affiliations of authors: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA (RTC); Center for Outcomes Research and Evaluation Maine Medical Center, Portland, ME (NC)
Correspondence to: Rowan T. Chlebowski, MD, PhD, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA, 90502 (e-mail: rchlebowski{at}gmail.com).
Although we concur in general with the interpretation of the CYP2D6 analyses reported by Punglia et al. (1), we believe that their findings need to be placed in a broader context that includes consideration of the toxicity as well as the efficacy of treatments. The Markov model that generated their findings did not include any adverse events associated with either treatment. This would be a plausible approach only if both treatments had equivalent side-effect profiles. However, there is ample evidence showing that tamoxifen carries greater risks of drug-related serious adverse events than anastrozole, especially among older postmenopausal women (2,3). Current perceptions regarding tamoxifen toxicity already limit its clinical use in the low-risk prevention setting (4). Even in the absence of CYP2D6 genotype selection, severe adverse events, including gynecologic problems, endometrial cancer, and venous and arterial vascular events, were substantially lower on anastrozole than on tamoxifen in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (202 vs 341, odds ratio = 0.57 [95% confidence interval = 0.47 to 0.68], P <. 001 (3). If the Markov model developed by Punglia et al. (1) had also included serious side effects of treatment, including endometrial cancer, pulmonary emboli, and stroke, a substantially less favorable toxicity profile for tamoxifen would have likely emerged in the context of their model, especially among postmenopausal women, whose baseline risks for these events are substantial. Although aromatase inhibitors did increase fracture risk, in the ATAC trial with 100 months follow-up, anastrozole was not associated with increased risk of hip fracture (3), and aromatase inhibitor–associated bone loss is now recognized as a preventable and treatable condition (5). In addition, the incidence of myocardial infarction in the anastrozole arm was almost identical to that seen in the tamoxifen arm (3).
Perhaps the major benefit of CYP2D6 genotype evaluation will be to identify premenopausal women, in whom endometrial and arterial vascular risks are minor, who are most appropriate for tamoxifen chemoprevention. In this setting, a large population of women who would potentially benefit from tamoxifen use has already been identified (6). Finally, consideration of the influence of CYP2D6 genotype on clinical findings suggests a hypothesis regarding the interpretation of hormone therapy switching trials. Because women who are homozygous for CYP2D6 mutations that are associated with a reduced ability to metabolize tamoxifen into more active endoxifen (ie, women who are poor metabolizers) are more likely to adhere to tamoxifen regimens than women without such mutations (7), the switching trials, which require adherence to 2–3 years of tamoxifen as an entry criterion, are likely to have relatively high proportions of such poor metabolizers. Poor metabolizers with lower endoxifen levels are less likely to benefit from tamoxifen use than women without such CYP2D6 mutations. Therefore, selection for poor metabolizers in the switching trials could provide an explanation for the observed trend for relatively greater aromatase inhibitor benefit vs tamoxifen seen in such trials compared with those evaluating upfront use of these agents at initial randomization, when such selection would not occur.
REFERENCES
1. Punglia RC, Burstein H, Winer EP, Weeks JC. Pharmacogenomic variation of CYP2D6 and the choice of optimal adjuvant endocrine therapy for postmenopausal breast cancer: a modeling analysis. J Natl Cancer Inst (2008) 100(9):642–648.
2. Coates A, Keshaviah A, Thurlimann B. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol (2007) 25(5A):486–492.
3. Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists Group. Effects of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol (2007) 9(1):45–53.[CrossRef][Web of Science]
4. Chlebowski RT. Current options for breast cancer risk reduction. Menopause Manage (2008) 17(S1):20–24.
5. Hillner B, Ingle J, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update of the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol (2003) 21:4042–4057.
6. Freedman AN, Graubard BI, Rao SR, et al. Estimates of the number of US women who could benefit from tamoxifen for breast cancer chemoprevention. J Natl Cancer Inst (2003) 95:526–532.
7. Rae JM, Sikora MJ, Henry MJ, et al. Cytochrome P450 2D6 activity predicts adherence to tamoxifen therapy. Breast Cancer Res Treat (2007) 106(suppl_1):521.
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