Despite recent advances in hormonal therapy for breast cancer, tamoxifen remains a major therapeutic option, with indications ranging from primary prevention to metastatic disease. Understanding the variation in response to tamoxifen may significantly improve our ability to personalize cancer care and maximize therapeutic efficacy. One area of particular interest is the impact of cytochrome P450 CYP2D6 genetic polymorphisms on tamoxifen metabolism. Tamoxifen is considered a prodrug, whose efficacy may be dependent on active metabolites, including endoxifen. Patients with reduced CYP2D6 enzymatic activity tend to have lower endoxifen levels, but clinical relevance of reduced endoxifen levels remains to be determined. Several small to moderately sized retrospective studies have suggested an intriguing association between poor metabolizer status and increased disease recurrence. However, these data are limited by sample size and methodologic challenges, including the inability to adjust for major prognostic and confounding factors. Several subsequent studies have failed to find an association or found improved outcomes among reduced CYP2D6 metabolizers. Therefore, current findings are conflicting and should be considered preliminary. Nevertheless, the CYP2D6 test is commercially available, making clinical use possible even as evidence in this area is still evolving. More definitive clinical research is needed before routine CYP2D6 testing can be recommended and considered standard of care. Anticipated data from retrospective analysis of large adjuvant randomized trials of tamoxifen should help address the clinical utility of CYP2D6 testing.
Despite recent advances in hormonal therapy for breast cancer, tamoxifen, a selective estrogen receptor modulator first approved in the 1970s, remains one of the most effective interventions in our therapeutic armamentarium, with indications ranging from prevention of breast cancer to treatment of metastatic disease. However, for reasons that remain incompletely understood, not all patients with endocrine receptor–positive breast cancer will respond to or benefit from tamoxifen. There are now multiple alternative endocrine therapies available, with variable efficacy and toxicity profiles, making it increasingly important to understand the optimal endocrine strategy for an individual patient.
One area of particular interest is the rapidly evolving evidence in the field of pharmacogenetics, evaluating the association between genetic differences in drug metabolism and patient outcomes. Recent studies have suggested that we may soon be able to rationally select drugs for specific patients based on differing drug metabolism in addition to other clinical factors. This article will review and summarize the current data regarding the influence of the major cytochrome P450 2D6 (CYP2D6) genotypes and CYP2D6 inhibitors on tamoxifen metabolism and clinical efficacy. We will discuss the clinical relevance and limitations of this data and how to best incorporate our current understanding of CYP2D6 genotyping into our clinical practice and discussions with patients.
The majority of breast cancers are dependent on estrogen, and estrogen deprivation has been recognized as an effective treatment for breast cancer for over 100 years, following Beatson’s initial publication on the role of oophorectomy in advanced disease. Our ability to provide endocrine therapy for patients advanced markedly with the approval of tamoxifen by the US Food and Drug Administration (FDA) in 1977 for the treatment of postmenopausal women with metastatic breast cancer. In 1986, tamoxifen gained FDA approval for adjuvant therapy in postmenopausal node-positive women, and the drug has subsequently been proven effective in hormone receptor–positive premenopausal and node-negative breast cancer patients, breast cancer prevention, ductal carcinoma in situ (DCIS), and male breast cancer. Among estrogen receptor (ER)-positive breast cancers, adjuvant tamoxifen reduces the relative recurrence rate by over 40% and breast cancer mortality by approximately one-third. Tamoxifen remains the only FDA-approved hormonal agent for the treatment of premenopausal women, and DCIS.
Recent study of genetic predictors of recurrence risk and response to therapy reminds us that tamoxifen alone is a highly effective drug for early-stage breast cancer, conveying a sufficiently low risk of recurrence that chemotherapy can be avoided for many patients. While in postmenopausal women, an adjuvant strategy involving aromatase inhibitors (AIs), either alone or in sequence with tamoxifen, is now preferred for most patients, the absolute difference in disease-free survival is on the order of 3% to 4%, with no clear improvement in overall survival. The AI side-effect profile is preferable for many patients, without the risks of thrombosis and uterine malignancy observed with tamoxifen. However, some patients with severe joint symptoms or refractory osteoporosis may not be able to tolerate an AI.[9-11] Further, the higher cost for AIs compared to tamoxifen may be a treatment barrier for some patients. Tamoxifen remains a standard part of treatment for many patients with breast cancer. If the factors impacting response could be identified, we might be able to obtain even greater results for some patients on tamoxifen, and use alternative endocrine therapies for other patients. Many factors, ranging from tumor biology to adherence, likely play a role in response to tamoxifen, but recently it has become apparent that understanding differences in metabolism may provide clues that can help optimize management of endocrine-responsive breast cancer.
Tamoxifen Metabolic Pathway and Active Metabolites: Endoxifen and 4-Hydroxy-Tamoxifen
Once orally absorbed, tamoxifen is initially metabolized primarily by two hepatic enzymes in the cytochrome P450 family, CYP2D6 and CYP3A4/5. As demonstrated in Figure 1, the major metabolic pathway involves initial conversion of tamoxifen to N-desmethyl-tamoxifen via CYP3A4/5, followed by conversion of N-desmethyl-tamoxifen to endoxifen, via CYP2D6. In addition, some tamoxifen is initially metabolized by CYP2D6 to the active metabolite 4-hydroxy-tamoxifen, which in turn is either degraded or converted by CYP3A4/5 to endoxifen. Tamoxifen has weak estrogen receptor binding and is considered a prodrug. Endoxifen and 4-hydroxy-tamoxifen are much more potent blockers of the estrogen receptor than tamoxifen, with over 100 times stronger binding affinity. Furthermore, endoxifen reaches several-fold higher concentrations than 4-hydroxy-tamoxifen, suggesting that it may be the most important active tamoxifen metabolite.
Natural genetic variation in alleles for the CYP2D6 gene that lead to marked differences in CYP2D6 enzymatic activity were recognized as early as the 1970s, and variation in metabolism has been determined for a number of commonly used drugs. Over 80 different CYP2D6 alleles have now been identified and can be categorized as nonfunctional alleles (also called null alleles, mainly *3, *4, *5, *6, and *8), reduced function alleles (mainly *9, *10, *17, and *41), and wild-type (wt) alleles (mainly *1, and *2), with increased enzymatic functioning (Table 1).[14-16] Allelic frequency varies among ethnic groups (Table 1), with the nonfunctional allele CYP2D6*4 being most prevalent in Caucasians, and the reduced-functioning allele CYP2D6*10 most common among Asian populations.[14,16] Based on allele combinations, (or allele duplication) patients can be classified into four major genotypes: (1) poor metabolizers (PM)—homozygous for null alleles; (2) intermediate metabolizers (IM)—heterozygous for null or partially functional alleles; (3) extensive metabolizers (EM)—homozygous for wildtype alleles; and (4) ultrarapid metabolizers (UM)—carrying more than two CYP2D6 copies in their genome. Among Caucasian populations, the prevalence of genotypes with reduced CYP2D6 function is estimated to be roughly 5% to 10% for PM.
1. Beatson G: On the treatment of inoperable cases of carcinoma of the mammary: Suggestions for a new method of treatment, with illustrative cases. Lancet 2:104-107, 1896.
2. Osborne CK: Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609-1618, 1998.
3. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005.
4. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388, 1998.
5. Fisher B, Dignam J, Wolmark N, et al: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353:1993-2000, 1999.
6. Ribeiro G, Swindell R: Adjuvant tamoxifen for male breast cancer (MBC). Br J Cancer 65:252-254, 1992.
7. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004.
8. Ingle JN, Dowsett M, Cuzick J, et al: Aromatase inhibitors versus tamoxifen as adjuvant therapy for postmenopausal women with estrogen receptor positive breast cancer: Meta-analyses of randomized trials of monotherapy and switching strategies (abstract 12). Cancer Res 69(suppl 2):66s, 2009.
9. Howell A, Cuzick J, Baum M, et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60-62, 2005.
10. Forbes JF, Cuzick J, Buzdar A, et al: Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 9:45-53, 2008.
11. Thurlimann B, Keshaviah A, Coates AS, et al: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005.
12. Jordan VC, Collins MM, Rowsby L, et al: A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 75:305-316, 1977.
13. Mahgoub A, Idle JR, Dring LG, et al: Polymorphic hydroxylation of Debrisoquine in man. Lancet 2:584-586, 1977.
14. Beverage JN, Sissung TM, Sion AM, et al: CYP2D6 polymorphisms and the impact on tamoxifen therapy. J Pharm Sci 96:2224-2231, 2007.
15. Dalen P, Dahl ML, Bernal Ruiz ML, et al: 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther 63:444-452, 1998.
16. Bradford LD: CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 3:229-243, 2002.
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. Loprinzi CL, Sloan JA, Perez EA, et al: Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 20:1578-1583, 2002.
19. Stearns V, Beebe KL, Iyengar M, et al: Paroxetine controlled release in the treatment of menopausal hot flashes: A randomized controlled trial. JAMA 289:2827-2834, 2003.
20. Stearns V: Clinical update: New treatments for hot flushes. Lancet 369:2062-2064, 2007.
21. Love N: Patterns of Care in Medical Oncology 2(3), 2005.
22. 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.
23. 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.
24. Langan-Fahey SM, Tormey DC, Jordan VC: Tamoxifen metabolites in patients on long-term adjuvant therapy for breast cancer. Eur J Cancer 26:883-888, 1990.
25. Lash TL, Lien EA, Sorensen HT, et al: Genotype-guided tamoxifen therapy: Time to pause for reflection? Lancet Oncol 10:825-833, 2009.
26. Ingle JN, Suman VJ, Mailliard JA, et al: 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 98:217-222, 2006.
27. 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.
28. Goetz MP, Suman V, Ames M, et al: Tamoxifen pharmacogenetics of CYP2D6, CYP2C19, and SULT1A1: Long term follow-up of the North Central Cancer Treatment Group 89-30-52 adjuvant trial (abstract 6037). Cancer Res 69(suppl), 2009.
29. Schroth W, Antoniadou L, Fritz P, et al: Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25:5187-5193, 2007.
30. Kiyotani K, Mushiroda T, Sasa M, et al: Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci 99:995-999, 2008.
31. Xu Y, Sun Y, Yao L, et al: Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol 19:1423-1429, 2008.
32. Goetz MP, Ames M, Gnant M, et al: Pharmacogenetic (CYP2D6) and gene expression profiles (HOXB13/IL17BR and molecular grade index) for prediction of adjuvant endocrine therapy benefit in the ABCSG 8 trial (abstract 57). Cancer Res 69(suppl), 2009.
33. Ramon y Cahal T, Altes A, Pare L, et al: Impact of CYP2D6 polymorphisms in tamoxifen adjuvant breast cancer treatment. Breast Cancer Res Treat (epub February 3, 2009).
34. Lim HS, Ju Lee H, Seok Lee K, et al: Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25:3837-3845, 2007.
35. 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 Tamoxifen Trial. J Clin Oncol 24:3708-3709; author reply 3709, 2006.
36. Wegman P, Vainikka L, Stal O, et al: Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res 7:R284-R290, 2005.
37. 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.
38. Okishiro M, Taguchi T, Jin Kim S, et al: Genetic polymorphisms of CYP2D6 10 and CYP2C19 2, 3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer 115:952-961, 2009.
39. Aubert RE, Stanek EJ, Yao J, et al: Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors (abstract CRA508). J Clin Oncol 27(18S), 2009.
40. Dezentjé V, Van Blijderveen NJ, Gelderblom H, et al: Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early stage breast cancer: A pharmaco-epidemiological study (CRA509). J Clin Oncol 27(18S), 2009.
41. 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.
42. Lynn Henry N, Rae JM, Li L, et al: Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. Breast Cancer Res Treat 117:571-575, 2009.
43. Rae J, Sikora MJ, Henry NL. Cytochrome P450 2D6 activity predicts adherence to tamoxifen therapy (abstract). Breast Cancer Res Treat 106(suppl 1):S21, 2007.
44. Punglia RS, Burstein HJ, Winer EP, et al: Pharmacogenomic variation of CYP2D6 and the choice of optimal adjuvant endocrine therapy for postmenopausal breast cancer: A modeling analysis. J Natl Cancer Inst 100:642-648, 2008.
45. Wegman P, Elingarami S, Carstensen J, et al: Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 9(1):R7, 2007.
46. Newman WG, Hadfield KD, Latif A, et al: Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res 14:5913-5918, 2008.
47. 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.