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Journal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5147-5149 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.4957
Germline Pharmacogenetics of Tamoxifen Response: Have We Learned Enough?Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN The selective estrogen receptor modulator tamoxifen is effective for the treatment of estrogen receptor–positive breast cancer and for the prevention of breast cancer in women at high risk.1,2 However, women taking tamoxifen are at increased risk for rare, yet potentially life-threatening adverse effects such as endometrial cancer and deep venous thrombosis.1 Tamoxifen may also reduce quality of life and compliance through non–life-threatening common adverse effects such as hot flashes.1,3 Since both the beneficial and adverse effects of tamoxifen are largely unpredictable for individual patients, it is important to attempt to develop predictors that will allow clinicians to anticipate risks and benefits. In this issue of the Journal, Schroth et al4 tested the ability of germline genetic variants in five tamoxifen-metabolizing genes to predict breast cancer events during tamoxifen treatment. Sixteen genetic variants were analyzed in DNA samples obtained from 206 patients on adjuvant tamoxifen monotherapy and 280 patients without tamoxifen therapy in a nonrandomized cohort study. With a median follow-up of 71 months, the authors found that women with the CYP2D6 variant alleles experienced significantly more recurrence of their disease, shorter relapse-free time, and shorter event-free survival (hazard ratio, 2.24; P = .02). No data are presented on whether CYP2D6 variants were associated with any of the adverse effects of tamoxifen. Patients who carried the CYP2C19*17 allele had significantly fewer breast cancer events during tamoxifen therapy. No impact of the reduced-function CYP2C19*2 and *3 genotypes was observed with tamoxifen response, so the mechanism by which CYP2C19*17 influences tamoxifen response deserves further study. The authors conclude that genotyping for CYP2D6 variants and the CYP2C19*17 allele may identify patients who are most likely to derive benefit from tamoxifen therapy. The role of metabolic activation in tamoxifen activity was recognized during the 1970s by Jordan et al, who also characterized the first potent antiestrogen metabolite, 4-hydroxytamoxifen, which has 100-fold greater affinity than tamoxifen toward estrogen receptors.5 This metabolite was later shown to be 30- to 100-fold more potent than tamoxifen in suppressing estrogen-dependent cell proliferation.6-8 As a result, 4-hydroxytamoxifen has been a focus of research for the past three decades, and is now a standard laboratory tool used as a substitute for the parent drug in vitro. Despite its high potency as an antiestrogen, the contribution of this metabolite to the overall clinical effect of tamoxifen has remained unclear because its plasma concentrations are relatively small compared with tamoxifen or some of its metabolites.6 Our knowledge of the link between tamoxifen metabolism and response expanded rapidly subsequent to the characterization of another active metabolite, N-desmethyl 4-hydroxy-tamoxifen (endoxifen), by our group some 5 years ago.9,10 Endoxifen was identified in the late 1980s,11 but until recently, its biologic activity remained obscure. A series of laboratory studies carried out to characterize its pharmacology have now established that endoxifen has equivalent potency to 4-hydroxytamoxifen in terms of binding affinity to estrogen receptors,10 suppression of estrogen-dependent proliferation of breast cancer cells,10,12 and modulation of estrogen-mediated global gene expression.13 In vitro, we have shown that endoxifen is formed primarily via 4-hydroxylation of the primary tamoxifen metabolite, N-desmethyltamoxifen, by the CYP2D6 enzyme.14 Consistent with these in vitro findings, the steady-state endoxifen plasma concentrations during tamoxifen treatment were substantially reduced in women that carry CYP2D6 genetic variants or are coprescribed CYP2D6 inhibitors,9,15,16 while the concentrations of tamoxifen or other metabolites remained unaffected by CYP2D6 metabolic status. More importantly, the plasma concentrations of endoxifen were on average 10-fold higher than those of 4-hydroxytamoxifen, with a large degree of interpatient variability (up to 100-fold greater endoxifen exposure relative to 4-hydroxytamoxifen in some patients).9,16 The first clinical evidence linking endoxifen to tamoxifen response was provided by Goetz et al,17 who analyzed a prospective, randomized phase III trial, and reported that the CYP2D6*4 variant allele was an independent predictor of a higher risk of relapse and a lower incidence of hot flashes in postmenopausal women. A subsequent study18 reported that coprescription of CYP2D6 inhibitors, in addition to CYP2D6 genetic variation, was an independent predictor of breast cancer outcome in postmenopausal women receiving tamoxifen. These new clinical data and the mechanistic information described above prompted the US Food and Drug Administration Pharmaceutical Science Advisory Committee (Clinical Pharmacology Subcommittee) to consider relabeling of tamoxifen. During its October 18, 2006, meeting, the committee endorsed the need to incorporate in the label the fact that CYP2D6 is an important pathway in the formation of endoxifen and that this metabolite contributes importantly to the in vitro activity of tamoxifen. However, two studies have reported contradictory results. In a retrospective study of banked samples by Nowell et al, the CYP2D6*4 allele did not predict tamoxifen response or breast cancer prognosis.19 Wegman et al, reported that patients who were treated with tamoxifen and who carried the CYP2D6*4 variant allele had a decreased recurrence rate compared with those not treated.20 Differences in chemotherapeutic regimens, length of tamoxifen treatment, and tamoxifen doses in the studies by Wegman et al, as well as the lack of consistent, central testing for estrogen receptor status, and the different inclusion criteria of these trials,19,20 make comparison with the data presented by Goetz et al17,18 difficult. Given the apparent disparity in study results, the findings of Schroth et al,4 showing a robust association between CYP2D6 genetic variation and tamoxifen response in a large cohort, are important. By genotyping an extended number of variants of the CYP2D6 gene for the first time, including those associated with reduced function (eg, *41 and *10), the authors reported an improved predictive value of CYP2D6 genotype toward tamoxifen response. The conclusions derived from their results are essentially similar to those of Goetz et al17,18 and of a recent study in the metastatic setting in Korean patients.21 In all these studies,4,17,18 a gene-dose effect of CYP2D6 genotypes on tamoxifen response has been suggested, consistent with a similar relationship observed between CYP2D6 metabolic status and endoxifen exposure in patients. The predictive value of CYP2D6 genotype does not seem to be limited to treatment of breast cancer with tamoxifen. Recently, Bonanni et al, provided evidence that suggests that tamoxifen chemoprevention may be compromised in carriers of the CYP2D6*4/*4 genotype.22 Together, the results from the studies by all of these authors advance our understanding of the pharmacogenetics of tamoxifen metabolism, and the data are lent credence by the mechanistic data linking endoxifen to tamoxifen activity and to CYP2D6 metabolic status. Despite this progress, a large number of important questions remain: What is the relationship between endoxifen and 4-hydroxytamoxifen serum concentrations and outcome? Could these be used as biomarkers of effective tamoxifen therapy? Since the current data are nearly all from white populations, what might be the result of CYP2D6 testing in African or Asian populations in the adjuvant settings? Since the absolute differences in outcomes between tamoxifen and aromatase inhibitor therapy in the majority of trials is in the 2% to 4% range, are there subpopulations of patients who would achieve better responses with tamoxifen? Could biomarker-driven therapeutic approaches using the pharmacogenetics of CYP2D6, polymorphic transporters, or estrogen receptors identify these patients, or patients who are more or less likely to experience the adverse effects that limit tamoxifen treatment? The data available at present to address these questions represent retrospective analyses of banked samples and of a single prospective trial. No prospective trial has been conducted to test the hypothesis that CYP2D6 pharmacogenetic testing can predict outcomes. In the absence of primary evidence from prospective trials, it seems reasonable at present to use clinical judgment to address this question and to confine CYP2D6 testing to situations where tamoxifen is being seriously considered in postmenopausal women, and where an alternative such as an aromatase inhibitor is available. For example, if the risks of an aromatase inhibitor seem significant because of a high risk of osteoporosis, it would be reasonable to perform CYP2D6 testing, and to prescribe tamoxifen if the genotype predicts an extensive metabolizer, but otherwise, to use an aromatase inhibitor with a bisphosphonate. Formal recommendations that address the use of germline pharmacogenetic testing for CYP2D6 and other genetically polymorphic genes must await further data. Clearly, the journey of deciphering germline polymorphisms that predict tamoxifen response has begun, but much work remains before we are able to effectively translate this progress to clinical outcomes of safety and efficacy. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: David A. Flockhart, Labcorp, Roche Molecular Diagnostics (C) Stock Ownership: None Honoraria: David A. Flockhart, Roche Molecular Diagnostics Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Zeruesenay Desta, David A. Flockhart Manuscript writing: Zeruesenay Desta, David A. Flockhart Final approval of manuscript: Zeruesenay Desta, David A. Flockhart ACKNOWLEDGMENTS This study was in part funded by National Institute of General Medical Sciences (Bethesda, MD) Grants No. 1R01GM078501-01A and U01 GM061373-05. We would like to acknowledge James Ingle, MD, and Vered Stearns, MD, for valuable discussions during the preparation of this Editorial. REFERENCES
1. Osborne CK: Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609-1618, 1998 2. Tamoxifen for early breast cancer: An overview of the randomised trials—Early Breast Cancer Trialists' Collaborative Group. Lancet 351:1451-1467, 1998[CrossRef][Medline] 3. Stearns V, Ullmer L, Lopez JF, et al: Hot flushes. Lancet 360:1851-1861, 2002[CrossRef][Medline] 4. Schroth W, Antoniadou L, Fritz P, et al: Breast cancer treatment outcome with adjuvant tamoxifen in relation to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25:5187-5193, 2007 5. Jordan VC, Collins MM, Rowsby L, et al: A monohydroxylated metabolite of tamoxifen with potent antiestrogenic activity. J Endocrinol 75:305-316, 1977[Medline] 6. Jordan VC: Metabolites of tamoxifen in animals and man: Identification, pharmacology, and significance. Breast Cancer Res Treat 2:123-138, 1982[CrossRef][Medline] 7. Robertson DW, Katzenellenbogen JA, Long DJ, et al: Tamoxifen antiestrogens: A comparison of the activity, pharmacokinetics, and metabolic activation of the cis and trans isomers of tamoxifen. J Steroid Biochem 16:1-13, 1982[Medline] 8. Coezy E, Borgna JL, Rochefort H: Tamoxifen and metabolites in MCF7 cells: Correlation between binding to estrogen receptor and inhibition of cell growth. Cancer Res 42:317-323, 1982 9. Stearns V, Johnson MD, Rae JM, et al: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758-1764, 2003 10. Johnson MD, Zuo H, Lee KH, et al: Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 85:151-159, 2004[CrossRef][Medline] 11. Lien EA, Solheim E, Kvinnsland S, et al: Identification of 4-hydroxy-N-desmethyltamoxifen as a metabolite of tamoxifen in human bile. Cancer Res 48:2304-2308, 1988 12. Lim YC, Desta Z, Flockhart DA, et al: Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol 55:471-478, 2005[CrossRef][Medline] 13. Lim YC, Li L, Desta Z, et al: Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells. J Pharmacol Exp Ther 318:503-512, 2006 14. Desta Z, Ward BA, Soukhova NV, et al: Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: Prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 310:1062-1075, 2004 15. Jin Y, Desta Z, Stearns V, et al: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30-39, 2005 16. Borges S, Desta Z, Li L, et al: Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: Implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80:61-74, 2006[CrossRef][Medline] 17. Goetz MP, Rae JM, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312-9318, 2005 18. Goetz MP, Knox SK, Suman VJ, et al: The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 101:113-121, 2007[CrossRef][Medline] 19. Nowell SA, Ahn J, Rae JM, et al: Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat 91:249-258, 2005[CrossRef][Medline] 20. Wegman P, Vainikka L, Stål O, et al: Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res 7:R284-R290, 2005[CrossRef][Medline] 21. Lim H-S, Lee HJ, Lee ES, et al: Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25:3837-3845, 2007 22. Bonanni B, Macis D, Maisonneuve P, et al: Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: Data from the Italian Tamoxen Trial. J Clin Oncol 24:3708-3709, 2006 Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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