Affiliation of authors: Department of Oncology, Division of Medical Oncology, Mayo Clinic, Mayo Foundation, Rochester, MN.
Correspondence to: Charles L. Loprinzi, MD, Department of Oncology, Division of Medical Oncology, Mayo Clinic, Mayo Foundation, 200 First St. SW, Rochester, MN 55905 (e-mail: cloprinzi{at}mayo.edu)
Tamoxifen will continue to be an important drug for the treatment of hormone-dependent breast cancer despite results suggesting that aromatase inhibitors will play an increasing role in the treatment of breast cancer for postmenopausal women (14). With more drugs available to treat patients with breast cancer, it is clear that patients would benefit from information that would allow their health care providers to individualize therapy. However, designing individualized therapies is complicated because for many drugs, including tamoxifen, the efficacies and toxicities differ among patients. The reasons for many of the interindividual differences are unknown.
Despite its proven benefit, tamoxifen is known to have adverse side effects, including increased risks of endometrial cancer and vascular-related thrombotic events (i.e., stroke, venous thrombosis, and pulmonary emboli), as well as nonlife-threatening side effects that can reduce quality of life and can affect patient compliance. Hot flashes, the most common side effect of tamoxifen, occur in up to 80% of women receiving tamoxifen (5), and the occurrence of hot flashes can result in patient noncompliance (6,7). Although hormone replacement therapy is the most effective treatment for reducing hot flashes, its use in women with a history of breast cancer is generally not recommended because of a concern that pharmacologic doses of hormones could promote growth of subclinical breast cancer metastases. Consequently, a search for other therapies for the treatment of hot flash symptoms has been undertaken.
The newer antidepressant drugs, such as the selective serotonin reuptake inhibitors (SSRIs) and the serotonin and norepinephrine reuptake inhibitors (SNRIs), are some of the most promising nonhormonal therapies for the treatment of hot flashes. In separate, placebo-controlled, randomized trials, administration of venlafaxine, paroxetine, or fluoxetine to women with vasomotor symptoms resulted in an approximately 60% reduction in the number and severity of hot flashes, compared with a 20%30% reduction after administration of a placebo (810). Pilot studies (11,12) have suggested that the therapeutic effects seen with these three antidepressants are also observed with other similar drugs, such as citalopram and mirtazapine.
In this issue of the Journal, Stearns et al. (13) have provided substantial insight into the metabolism and pharmacogenetics of tamoxifen and have identified a potentially important interaction between paroxetine and tamoxifen. Their initial hypothesis was based on the fact that newer antidepressants (e.g., venlafaxine, fluoxetine, and paroxetine) studied for the treatment of hot flashes are all metabolized by cytochrome P450 2D6 (CYP2D6) and are potent inhibitors of this enzyme (14,15). Because several studies (1618) suggest that the CYP2D6 enzyme plays a crucial role in the catalysis of tamoxifen to 4-hydroxy-tamoxifen, Stearns et al. (13) hypothesized that coadministration of paroxetine with tamoxifen could inhibit the metabolic activation of tamoxifen to 4-hydroxy-tamoxifen, a metabolite approximately 100-fold more potent as an antiestrogen than tamoxifen (19,20).
Stearns et al. (13) found that paroxetine does indeed perturb the activation of tamoxifen, although surprisingly, not by inhibiting the formation of 4-hydroxy-tamoxifen. They demonstrated that, instead, paroxetine statistically significantly reduced the concentrations of 4-hydroxy-N-desmethyl-tamoxifen (which they referred to as endoxifen), a metabolite resulting from CYP2D6-mediated hydroxylation of N-desmethyl-tamoxifen. It is important to note that they also showed that endoxifen suppressed estradiol-stimulated MCF7 proliferation, with potency comparable to that of 4-hydroxy-tamoxifen. Because baseline steady-state levels of endoxifen were present at concentrations much higher than that of 4-hydroxy-tamoxifen, endoxifen may be even more important than 4-hydroxy-tamoxifen in mediating the anticancer effects of tamoxifen.
Previously, it has been surmised that individuals carrying genetic variants associated with low or absent CYP2D6 activity and who are treated with tamoxifen would form little or no 4-hydroxy-tamoxifen (18). Consequently, in these individuals, administration of tamoxifen might result in diminished therapeutic efficacy and/or potential differences in toxicity relative to individuals with wild-type CYP2D6 activity. Unexpectedly, Stearns et al. (13) found that the presence, or absence, of CYP2D6 genetic variants did not affect 4-hydroxy-tamoxifen levels but, rather, were associated with differences in plasma levels of endoxifen. By demonstrating that quinidine, a potent inhibitor of CYP2D6, inhibited the hydroxylation of N-desmethyl-tamoxifen, with a consequent decrease in endoxifen, CYP2D6 was identified as the enzyme isoform responsible for this metabolic step.
Although these findings appear to have increased our understanding of tamoxifen metabolism, the clinical implications of reduced levels of endoxifen (either secondary to pharmacogenetic variations in CYP2D6 activity or drug-induced inhibition of CYP2D6) are unclear. Because the newer antidepressants studied for the treatment of hot flashes (venlafaxine, fluoxetine, and paroxetine) have differing levels of CYP2D6 inhibition, the pharmacokinetic interaction between tamoxifen and these antidepressants needs to be studied. For example, in vitro data suggest that venlafaxine is a much weaker inhibitor of CYP2D6 than fluoxetine (21), whereas mirtazapine reportedly does not inhibit CYP2D6 (22). In the interim, we fully concur with the recommendations made by Stearns et al. (13) that further information is necessary "before definitive recommendations for or against concomitant tamoxifen and SSRI use should be made."
Finally, the results of this pharmacogenetic study (13) and another recent report (23) demonstrating the effect of genetic variation in the SULT1A1 gene involved in the sulfation of 4-hydroxy-tamoxifen clearly demonstrate that the metabolism of tamoxifen is complex, and that its effect is determined by the interplay of multiple gene products that govern its pharmacokinetics and pharmacodynamics. Studies currently being conducted by our group and by others will help to clarify whether the CYP2D6 genotype, as well as variation in multiple different genes involved in the uptake, distribution, and metabolism of tamoxifen, will affect the important clinical outcomes associated with tamoxifen. It is clear that the results of these studies continue to move us toward a time when ready access to gene sequence information, when used properly, will improve the ability of health care professionals to individualize therapy.
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