Tamoxifen is widely used for the treatment of all stages of hormone receptor–positive breast cancer and has now also been approved for use in the prevention of breast cancer in women at high risk of the disease. However, the efficacy of tamoxifen treatment for breast cancer varies widely among women. The drug is metabolized by several cytochrome P450 (CYP) enzymes, including CYP2D6. Some SSRIs, which are commonly prescribed to treat hot flashes in women who take tamoxifen, are known to inhibit CYP2D6.
To examine the effects of SSRI use and variations of the CYP2D6 allele on plasma concentrations of tamoxifen and its metabolites, David A. Flockhart, M.D., Ph.D., of the Indiana University School of Medicine in Indianapolis, and colleagues studied 80 women with newly diagnosed breast cancer who were beginning tamoxifen therapy. Twenty-four of these women were taking an SSRI during their treatment. The researchers genotyped the women for common alleles of CYP2D6 and several other genes that encode tamoxifen-metabolizing enzymes and measured plasma concentrations of tamoxifen and its metabolites.
After 4 months of tamoxifen therapy, women carrying one or two copies of a CYP2D6 variant allele had lower plasma concentrations of endoxifen (an active tamoxifen metabolite) than women with the homozygous wild-type genotype. Among women carrying two copies of the wild-type CYP2D6 allele, the plasma endoxifen concentration was 58% lower in women taking an SSRI than in women who were not taking the drug. The authors conclude that interactions between CYP2D6 polymorphisms and some SSRIs may be associated with altered tamoxifen activity.
"SSRIs are likely to gain increasing importance as therapeutic alternatives to estrogen for the treatment of hot flashes in patients with breast cancer as well as in unaffected women, in addition to their already established role in treatment of depression and other psychiatric illnesses. It is possible that testing of CYP2D6 genetic variants and careful attention to use of CYP2D6 inhibitors may help identify a group of women who may experience greater benefit from tamoxifen and/or who might benefit more from treatment with one SSRI over another. Firm clinical recommendations about which SSRI to use and whether genotype predicts clinical response of tamoxifen must await results from definitive clinical trials," the authors write.
Contact: David Flockhart, Indiana University School of Medicine, 317-630-8795, dflockha@iupui.edu
Citation: Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee K-H, et al. Association Between CYP2D6 Genotype and Antidepressants, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment. J Natl Cancer Inst 2004;97:30–39.
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JNCI Journal of the National Cancer Institute