Effects of Pharmacogenetics on the Pharmacokinetics and Pharmacodynamics of Tamoxifen

Clinical Pharmacokinetics

Volumn 54, Issue 8, 2015, Pages 797-810

  de Vries Schultink, Aurelia H M ^a   Zwart, Wilbert ^a   Linn, Sabine C ^a,b   Beijnen, Jos H ^a,c   Huitema, Alwin D R ^a  

^a NETHERLANDS CANCER INSTITUTE   (Netherlands)

^b UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^c UTRECHT UNIVERSITY   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; TAMOXIFEN; ANTIESTROGEN;

CONCENTRATION AT STEADY-STATE; DRUG BLOOD LEVEL; DRUG METABOLISM; DRUG RESPONSE; ENZYME POLYMORPHISM; FIRST PASS EFFECT; GENE FREQUENCY; GENOTYPE; HUMAN; PHARMACODYNAMICS; PHARMACOGENETICS; PRIORITY JOURNAL; REVIEW; SYSTEMATIC REVIEW; TREATMENT OUTCOME; BREAST NEOPLASMS; FEMALE; METABOLISM; PERSONALIZED MEDICINE; PROCEDURES;

BREAST NEOPLASMS; ESTROGEN ANTAGONISTS; FEMALE; HUMANS; PRECISION MEDICINE; TAMOXIFEN;

EID: 84937975404     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.1007/s40262-015-0273-3     Document Type: Review

References (70)

1. 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. 2005;365:1687–717.
2. Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen erceptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381:805–16.
3. Gray R, Rea D, Handley K. ATTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. J Clin Oncol. 2013;31(suppl; abstr 5).
4. Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, et al. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011;12:1101–8.
5. Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN, et al. 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. 2005;23:619–29.
6. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003;348:2431–42.
7. Early Breast Cancer Trialists’ Collaborative Group. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378:771–84.
8. Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004;310:1062–75.
9. Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol. 2005;55:471–8.
10. Johnson MD, Zuo H, Lee K, Trebley JP, Rae JM, Weatherman RV, et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat. 2004;85:151–9.
11. Thomas C, Gustafsson JÅ. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer. 2011;11:597–608.
12. Phan M, Venitz J. Summary minutes of the Advisory Committee Pharmaceutical Science Clinical Pharmacology Subcommittee. 18–19 Oct 2006. Available at: http://www.fda.gov/ohrms/dockets/ac/06/minutes/2006-4248m1.pdf. Accessed 15 Jan 2015.
13. Beelen K, Opdam M, Severson TM, Koornstra RHT, Vincent AD, Hauptmann M, et al. CYP2C19 2 predicts substantial tamoxifen benefit in postmenopausal breast cancer patients randomized between adjuvant tamoxifen and no systemic treatment. Breast Cancer Res Treat. 2013;139:649–55.
14. Borges S, Desta Z, Li L, Skaar TC, Ward BA, Nguyen A, et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther. 2006;80:61–74.
15. Chamnanphon M, Pechatanan K, Sirachainan E, Trachu N, Chantratita W, Pasomsub E, et al. Association of CYP2D6 and CYP2C19 polymorphisms and disease-free survival of Thai post-menopausal breast cancer patients who received adjuvant tamoxifen. Pharmgenomics Pers Med. 2013;6:37–48.
16. Fernández-Santander A, Gaibar M, Novillo A, Romero-Lorca A, Rubio M, Chicharro LM, et al. Relationship between genotypes Sult1a2 and Cyp2d6 and tamoxifen metabolism in breast cancer patients. PLoS One. 2013;8:e70183.
17. Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005;23:9312–8.
18. Goetz MP, Suman VJ, Hoskin TL, Gnant M, Filipits M, Safgren SL, et al. CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8. Clin Cancer Res. 2013;19:500–7.
19. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee K-H, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97:30–9.
20. Kiyotani K, Mushiroda T, Sasa M, Bando Y, Sumitomo I, Hosono N, et al. Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci. 2008;99:995–9.
21. Kiyotani K, Mushiroda T, Imamura CK, Hosono N, Tsunoda T, Kubo M, et al. Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J Clin Oncol. 2010;28:1287–93.
22. Lash TL, Cronin-Fenton D, Ahern TP, Rosenberg CL, Lunetta KL, Silliman RA, et al. CYP2D6 inhibition and breast cancer recurrence in a population-based study in Denmark. J Natl Cancer Inst. 2011;103:489–500.
23. Lim JSL, Chen XA, Singh O, Yap YS, Ng RCH, Wong NS, et al. Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients. Br J Clin Pharmacol. 2011;71:737–50.
24. Madlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW, et al. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther. 2011;89:718–25.
25. Moyer AM, Suman VJ, Weinshilboum RM, Black JL, Safgren SL, Kuffel MJ, et al. SULT1A1, CYP2C19 and disease-free survival in early breast cancer patients receiving tamoxifen. Pharmacogenomics. 2011;12:1535–43.
26. Mürdter TE, Schroth W, Bacchus-Gerybadze L, Winter S, Heinkele G, Simon W, et al. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma. Clin Pharmacol Ther. 2011;89:708–17.
27. Mwinyi J, Vokinger K, Jetter A, Breitenstein U, Hiller C, Kullak-Ublick GA, et al. Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy. Cancer Chemother Pharmacol. 2014;73:1181–8.
28. Nowell SA, Ahn J, Rae JM, Scheys JO, Trovato A, Sweeney C, 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. 2005;91:249–58.
29. Okishiro M, Taguchi T, Jin Kim S, Shimazu K, Tamaki Y, Noguchi S. 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. 2009;115:952–61.
30. Rae JM, Drury S, Hayes DF, Stearns V, Thibert JN, Haynes BP, et al. CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients. J Natl Cancer Inst. 2012;104:452–60.
31. Regan MM, Leyland-Jones B, Bouzyk M, Pagani O, Tang W, Kammler R, et al. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the Breast International Group 1-98 trial. J Natl Cancer Inst. 2012;104:441–51.
32. Saladores P, Mürdter T, Eccles D, Chowbay B, Zgheib NK, Winter S, et al. Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. Pharmacogenomics J. 2014;1:84–94.
33. Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol. 2007;25:5187–93.
34. Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009;302:1429–36.
35. Sensorn I, Sirachainan E, Chamnanphon M, Pasomsub E, Trachu N, Supavilai P, et al. Association of CYP3A4/5, ABCB1 and ABCC2 polymorphisms and clinical outcomes of Thai breast cancer patients treated with tamoxifen. Pharmgenomics Pers Med. 2013;6:93–8.
36. Teft WA, Gong IY, Dingle B, Potvin K, Younus J, Vandenberg TA, et al. CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy. Breast Cancer Res Treat. 2013;139:95–105.
37. Tucker AN, Tkaczuk KA, Lewis LM, Tomic D, Lim CK, Flaws JA. Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients. Cancer Lett. 2005;217:61–72.
38. Wegman P, Vainikka L, Stål O, Nordenskjöld B, Skoog L, Rutqvist L-E, et al. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res. 2005;7:R284–90.
39. Wegman P, Elingarami S, Carstensen J, Stål O, Nordenskjöld B, Wingren S. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res. 2007;9:R7.
40. Xu Y, Sun Y, Yao L, Shi L, Wu Y, Ouyang T, et al. Association between CYP2D6*10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol. 2008;19:1423–9.
41. Zafra-Ceres M, de Haro T, Farez-Vidal E, Blancas I, Bandres F, de Dueñas EM, et al. Influence of CYP2D6 polymorphisms on serum levels of tamoxifen metabolites in Spanish women with breast cancer. Int J Med Sci. 2013;10:932–7.
42. Gjerde J, Hauglid M, Breilid H, Lundgren S, Varhaug JE, Kisanga ER, et al. Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism. Ann Oncol. 2008;19:56–61.
43. Toyama T, Yamashita H, Sugiura H, Kondo N, Iwase H, Fujii Y. No association between CYP2D6*10 genotype and survival of node-negative Japanese breast cancer patients receiving adjuvant tamoxifen treatment. Jpn J Clin Oncol. 2009;39:651–6.
44. Stingl JC, Parmar S, Huber-Wechselberger A, Kainz A, Renner W, Seeringer A, et al. Impact of CYP2D6*4 genotype on progression free survival in tamoxifen breast cancer treatment. Curr Med Res Opin. 2010;26:2535–42.
45. Abraham JE, Maranian MJ, Driver KE, Platte R, Kalmyrzaev B, Baynes C, et al. CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen. Breast Cancer Res. 2010;12(4):R64.
46. Park IH, Ro J, Park S, Lim H-S, Lee KS, Kang HS, et al. Lack of any association between functionally significant CYP2D6 polymorphisms and clinical outcomes in early breast cancer patients receiving adjuvant tamoxifen treatment. Breast Cancer Res Treat. 2012;131:455–61.
47. Park HS, Choi J-Y, Lee M-J, Park S, Yeo C-W, Lee SS, et al. Association between genetic polymorphisms of CYP2D6 and outcomes in breast cancer patients with tamoxifen treatment. J Korean Med Sci. 2011;26:1007–13.
48. Barginear MF, Jaremko M, Peter I, Yu C, Kasai Y, Kemeny M, et al. Increasing tamoxifen dose in breast cancer patients based on CYP2D6 genotypes and endoxifen levels: effect on active metabolite isomers and the antiestrogenic activity score. Clin Pharmacol Ther. 2011;90:605–11.
49. Beelen K, Zwart W, Linn SC. Can predictive biomarkers in breast cancer guide adjuvant endocrine therapy? Nat Rev Clin Oncol. 2012;9:529–41.
50. Human cytochrome P450 (CYP) allele nomenclature T. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. Available at: http://www.cypalleles.ki.se/cyp2d6.htm. Accessed 28 Dec 2014.
51. Hudis CA, Barlow WE, Costantino JP, Gray RJ, Pritchard KI, Chapman JA, et al. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol. 2007;25:2127–32.
52. Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T, et al. The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol. 2002;54:157–67.
53. Province MA, Goetz MP, Brauch H, Flockhart DA, Hebert JM, Whaley R, et al. CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. Clin Pharmacol Ther. 2014;95:216–27.
54. Berry D. CYP2D6 genotyping and the use of tamoxifen in breast cancer. J Natl Cancer Inst. 2013;105:1267–9.
55. Berry DA. CYP2D6 genotype and adjuvant tamoxifen. Clin Pharmacol Ther. 2014;96:138–40.
56. Lash TL, Lien EA, Sørensen HT, Hamilton-Dutoit S. Genotype-guided tamoxifen therapy: time to pause for reflection? Lancet Oncol. 2009;10:825–33.
57. Blackburn HL, Ellsworth DL, Shriver CD, Ellsworth RE. Role of cytochrome P450 genes in breast cancer etiology and treatment: effects on estrogen biosynthesis, metabolism, and response to endocrine therapy. Cancer Causes Control. 2015;26(3):319–32.
58. Tsuchiya Y, Nakajima M, Yokoi T. Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett. 2005;227:115–24.
59. Gjerde J, Geisler J, Lundgren S, Ekse D, Varhaug JE, Mellgren G. Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer. BMC Cancer. 2010;10:313.
60. Jager NGL, Rosing H, Linn SC, Schellens JHM, Beijnen JH. Importance of highly selective LC–MS/MS analysis for the accurate quantification of tamoxifen and its metabolites: focus on endoxifen and 4-hydroxytamoxifen. Breast Cancer Res Treat. 2012;133:793–8.
61. Binkhorst L, Mathijssen RHJ, van Herk-Sukel MPP, Bannink M, Jager A, Wiemer EAC, et al. Unjustified prescribing of CYP2D6 inhibiting SSRIs in women treated with tamoxifen. Breast Cancer Res Treat. 2013;139:923–9.
62. Goetz MP, Sun JX, Suman VJ, Silva GO, Perou CM, Nakamura Y, et al. Loss of heterozygosity at the CYP2D6 locus in breast cancer: implications for germline pharmacogenetic studies. J Natl Cancer Inst. 2014;107(2). doi:10.1093/jnci/dju401.
63. Schroth W, Hamann U, Fasching PA, Dauser S, Winter S, Eichelbaum M, et al. CYP2D6 polymorphisms as predictors of outcome in breast cancer patients treated with tamoxifen: expanded polymorphism coverage improves risk stratification. Clin Cancer Res. 2010;16:4468–77.
64. Ratain MJ, Nakamura Y, Cox NJ. CYP2D6 genotype and tamoxifen activity: understanding interstudy variability in methodological quality. Clin Pharmacol Ther. 2014;94(2):185–7.
65. Ter Heine R, Binkhorst L, de Graan AJM, de Bruijn P, Beijnen JH, Mathijssen RHJ, et al. Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen. Br J Clin Pharmacol. 2014;78:572–86.
66. Jager NL, Rosing H, Schellens J, Linn S, Beijnen J. Tamoxifen dose and serum concentrations of tamoxifen and six of its metabolites in routine clinical outpatient care. Breast Cancer Res. 2014;143:447–83.
67. Kiyotani K, Mushiroda T, Imamura CK, Tanigawara Y, Hosono N, Kubo M, et al. Dose-adjustment study of tamoxifen based on CYP2D6 genotypes in Japanese breast cancer patients. Breast Cancer Res Treat. 2012;131:137–45.
68. Irvin WJ, Walko CM, Weck KE, Ibrahim JG, Chiu WK, Dees EC, et al. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study. J Clin Oncol. 2011;29:3232–9.
69. Bratherton D, Brown C, Buchanan R, Hall V, Kingsley Pillers E, Wheeler T, et al. A comparison of two doses of tamoxifen (Novaldex) in postmenopausal women with advanced breast cancer: 10 mg bd versus 20 mg bd. Br J Cancer. 1984;50:199–205.
70. Sismondi P, Biglia N, Volpi E, Giai M. Tamoxifen and endometrial cancer. Ann NY Acad Sci. 1994;734:310–21.