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Pharmacogenetics and breast cancer endocrine therapy: CYP2D6 as a predictive factor for tamoxifen metabolism and drug response?

Published online by Cambridge University Press:  20 November 2008

Vered Stearns  and
James M. Rae
Vered Stearns*
Affiliation:
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
James M. Rae
Affiliation:
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
*
*Corresponding author: Vered Stearns, Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Room 145, Baltimore, MD 21231-1000, USA. Tel: +1 443 287 6489; Fax: +1 410 955 0125; E-mail: [email protected]
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Abstract

The identification of genetic polymorphisms that influence the efficacy and safety of therapies for breast cancer may allow future treatments to be individualised based not only on tumour characteristics but also on host genetics. Genetic factors that affect the metabolism, efficacy and safety of tamoxifen, one of the most common drugs used for the treatment and prevention of breast cancer, have received particular attention. Cytochrome P450 2D6 (CYP2D6) is crucial in the metabolism of tamoxifen to its active metabolite endoxifen. Women with genetic variants of CYP2D6 or who take drugs that inhibit the enzyme have low endoxifen plasma concentrations and may show reduced benefits to tamoxifen treatment. CYP2D6 polymorphisms and variants in other candidate genes may also influence secondary benefits and side effects of tamoxifen. Here, we summarise data suggesting that CYP2D6 status may be an important predictor of the benefits of tamoxifen to an individual; in addition, we briefly discuss the role of variants in other candidate genes. Whether CYP2D6 status should be determined prior to initiating tamoxifen therapy is currently under debate and may be appropriate only for select women who are candidates for tamoxifen alone but for whom alternative standard options are available.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e34
Copyright
Copyright © Cambridge University Press 2008

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References

References

1Early Breast Cancer Trialists' Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365, 1687-1717CrossRefGoogle Scholar
2Berry, D.A. et al. (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353, 1784-1792Google Scholar
3Weinshilboum, R. (2003) Inheritance and drug response. N Engl J Med 348, 529-537CrossRefGoogle ScholarPubMed
4Evans, W.E. and McLeod, H.L. (2003) Pharmacogenomics–drug disposition, drug targets, and side effects. N Engl J Med 348, 538-549Google Scholar
5Winer, E.P. et al. (2005) American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 23, 619-629Google Scholar
6Brown, R.J. and Davidson, N.E. (2006) Adjuvant hormonal therapy for premenopausal women with breast cancer. Semin Oncol 33, 657-663CrossRefGoogle ScholarPubMed
7Desta, Z. et al. (2004) 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, 1062-1075CrossRefGoogle ScholarPubMed
8Sun, D. et al. (2007) Glucuronidation of active tamoxifen metabolites by the human UDP glucuronosyltransferases. Drug Metab Dispos 35, 2006-2014Google Scholar
9Nishiyama, T. et al. (2002) Reverse geometrical selectivity in glucuronidation and sulfation of cis- and trans-4-hydroxytamoxifens by human liver UDP-glucuronosyltransferases and sulfotransferases. Biochem Pharmacol 63, 1817-1830Google Scholar
10Nowell, S. and Falany, C.N. (2006) Pharmacogenetics of human cytosolic sulfotransferases. Oncogene 25, 1673-1678Google Scholar
11Dehal, SS, and Kupfer, D (1999) Cytochrome P-450 3A and 2D6 catalyze ortho hydroxylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (droloxifene) yielding tamoxifen catechol: involvement of catechols in covalent binding to hepatic proteins. Drug Metab Dispos 27, 681-688Google Scholar
12Stearns, V. et al. (2003) Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95, 1758-1764Google Scholar
13Lien, E.A. et al. (1989) Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res 49, 2175-2183Google Scholar
14Borgna, J.L. and Rochefort, H. (1981) Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J Biol Chem 256, 859-868Google Scholar
15Johnson, M.D. et al. (2004) Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 85, 151-159Google Scholar
16Lim, Y.C. et al. (2006) 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, 503-512Google Scholar
17Rodriguez-Antona, C. and Ingelman-Sundberg, M. (2006) Cytochrome P450 pharmacogenetics and cancer. Oncogene 25, 1679-1691Google Scholar
18Ingelman-Sundberg, M. (2005) Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 5, 6-13CrossRefGoogle ScholarPubMed
19Zanger, U.M., Raimundo, S. and Eichelbaum, M. (2004) Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 369, 23-37CrossRefGoogle ScholarPubMed
20Bradford, L.D. (2002) CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 3, 229-243CrossRefGoogle ScholarPubMed
21Alfaro, C.L. et al. (2000) CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations. J Clin Pharmacol 40, 58-66Google Scholar
22Jin, Y. et al. (2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97, 30-39Google Scholar
23Borges, S. et al. (2006) Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80, 61-74CrossRefGoogle ScholarPubMed
24Stearns, V. (2007) Clinical update: new treatments for hot flushes. Lancet 369, 2062-2064Google Scholar
25Rae, J.M. et al. (2003) Genotyping for polymorphic drug metabolizing enzymes from paraffin-embedded and immunohistochemically stained tumor samples. Pharmacogenetics 13, 501-507CrossRefGoogle ScholarPubMed
26Ingle, J.N. et al. (2006) Randomized trial of tamoxifen alone or combined with fluoxymesterone as adjuvant therapy in postmenopausal women with resected estrogen receptor positive breast cancer. North Central Cancer Treatment Group Trial 89-30-52. Breast Cancer Res Treat 98, 217-222CrossRefGoogle ScholarPubMed
27Goetz, M.P. et al. (2005) Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23, 9312-9318Google Scholar
28Goetz, M.P. et al. (2007) The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 101, 113-121CrossRefGoogle ScholarPubMed
29Wegman, P. et al. (2005) Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res 7, R284-290Google Scholar
30Wegman, P. et al. (2007) Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 9, R7Google Scholar
31Nowell, S.A. et al. (2005) Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat 91, 249-258Google Scholar
32Schroth, W. et al. (2007) Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25, 5187-5193CrossRefGoogle ScholarPubMed
33Lim, H.S. et al. (2007) Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25, 3837-3845Google Scholar
34Kiyotani, K. et al. (2008) Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci 99, 995-999Google Scholar
35Bonanni, B. et al. (2006) Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial. J Clin Oncol 24, 3708-3709; author reply 3709CrossRefGoogle Scholar
36Blake, M.J. et al. (2007) Ontogeny of dextromethorphan O- and N-demethylation in the first year of life. Clin Pharmacol Ther 81, 510-516Google Scholar
37Gaedigk, A. et al. (2008) The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 83, 234-242CrossRefGoogle ScholarPubMed
38Osborne, C.K. (1998) Tamoxifen in the treatment of breast cancer. N Engl J Med 339, 1609-1618Google Scholar
39Ntukidem, N.I. et al. (2008) Estrogen receptor genotypes, menopausal status, and the lipid effects of tamoxifen. Clin Pharmacol Ther 83, 702-710Google Scholar
40Henry, N.L. et al. (2007) Association of chemotherapy and estrogen receptor genotype with change in bone mineral density after one year of tamoxifen therapy. Breast Cancer Res Treat 106, S118 (abstract)Google Scholar
41Stearns, V. et al. (2007) Tamoxifen-induced hot flashes are associated with estrogen receptor polymorphisms. J Clin Oncol 25, 18S (abstract)Google Scholar
42Rae, J.M. et al. (2007) Cytochrome P450 2D6 activity predicts adherence to tamoxifen therapy. Breast Cancer Res Treat 106, S21 (abstract)Google Scholar
43Colomer, R. et al. (2008) A single-nucleotide polymorphism in the aromatase gene is associated with the efficacy of the aromatase inhibitor letrozole in advanced breast carcinoma. Clin Cancer Res 14, 811-816Google Scholar
44Stearns, V., Davidson, N.E. and Flockhart, D.A. (2004) Pharmacogenetics in the treatment of breast cancer. Pharmacogenomics J 4, 143-153Google Scholar
45Kotlyar, M. et al. (2005) Inhibition of CYP2D6 activity by bupropion. J Clin Psychopharmacol 25, 226-229Google Scholar
46Branch, R.A. et al. (2000) In vivo modulation of CYP enzymes by quinidine and rifampin. Clin Pharmacol Ther 68, 401-411CrossRefGoogle ScholarPubMed
47Skinner, M.H. et al. (2003) Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers. Clin Pharmacol Ther 73, 170-177CrossRefGoogle Scholar
48Baumann, P. et al. (1992) Dextromethorphan and mephenytoin phenotyping of patients treated with thioridazine or amitriptyline. Ther Drug Monit 14, 1-8Google Scholar
49Fukumoto, K. et al. (2006) Effect of amiodarone on the serum concentration/dose ratio of metoprolol in patients with cardiac arrhythmia. Drug Metab Pharmacokinet 21, 501-505Google Scholar
50Hamelin, B.A. et al. (2000) Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther 67, 466-477Google Scholar
51Ruderman, J. et al. (1991) Control of the cell cycle in early embryos. Cold Spring Harb Symp Quant Biol 56, 495-502Google Scholar
52Preskorn, S.H. (1997) Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 32 Suppl 1, 1-21Google Scholar
53Preskorn, S.H. et al. (2007) Comparison of duloxetine, escitalopram, and sertraline effects on cytochrome P450 2D6 function in healthy volunteers. J Clin Psychopharmacol 27, 28-34Google Scholar

Further reading, resources and contacts

Stearns, V., Davidson, N.E. and Flockhart, D.A. (2004) Pharmacogenetics in the treatment of breast cancer. Pharmacogenomics J 4, 143-153CrossRefGoogle ScholarPubMed
http://medicine.iupui.edu/flockhart/Google Scholar