Breast Cancer Research and Treatment

, Volume 122, Issue 3, pp 609–617 | Cite as

Cytochrome P450 2D6 and outcomes of adjuvant tamoxifen therapy: results of a meta-analysis



Pharmacological evidence shows that cytochrome P450 2D6 (CYP2D6) function is important in the conversion of tamoxifen to its active metabolites. Many retrospective analyses have assessed the role of both CYP2D6 genotype and concurrent administration of drug inhibitors of CYP2D6 on outcome of tamoxifen therapy. These studies have frequently been of small size and their data highly variable. A published data meta-analysis of trials evaluating outcomes of tamoxifen therapy in early breast cancer was undertaken. Hazard ratios (HRs) were extracted for disease-free survival (DFS) and overall survival (OS). Pooled estimates were computed using inverse-variance and random-effect modeling. Data from 10 studies assessing CYP2D6 genotype were included in a meta-analysis. There was significant heterogeneity in the definition of comparison groups between studies. When compared to reduced CYP2D6 function, normal function was associated with a trend toward improved DFS (HR 2.07, 95% CI 0.96–4.49, P = 0.06) but not OS (HR 1.36, 95% CI 0.73–2.52, P = 0.34). Pooling of data from two studies evaluating CYP2D6 drug inhibitors showed that concomitant administration of these with tamoxifen was associated with a non-significant association with DFS (HR 1.37, 95% CI 0.69–2.73, P = 0.37). Analysis of the effect of CYP2D6 drug inhibitors on OS was not possible. The effect of CYP2D6 genotype on breast cancer seems to be relatively small and may not warrant testing of CYP2D6 genotype in all women with hormone receptor positive breast cancer. The effect of CYP2D6 genotype on outcome in low-risk patients may not be clinically relevant, while the upfront use of aromatase inhibitors is a reasonable alternative to tamoxifen in high-risk post-menopausal women, irrespective of CYP2D6 genotype. There are limited data supporting the association of potent inhibitors of CYP2D6 and detrimental outcome, but avoidance of such drugs seems reasonable.


Adjuvant Cytochrome P450 2D6 Drug inhibitors Genotype Survival Tamoxifen 


  1. 1.
    Dehal SS, Kupfer D (1997) CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Cancer Res 57:3402–3406PubMedGoogle Scholar
  2. 2.
    Desta Z, Ward BA, Soukhova NV, Flockhart DA (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 310:1062–1075CrossRefPubMedGoogle Scholar
  3. 3.
    Johnson MD, Zuo H, Lee KH, Trebley JP, Rae JM, Weatherman RV, Desta Z, Flockhart DA, Skaar TC (2004) Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat 85:151–159CrossRefPubMedGoogle Scholar
  4. 4.
    Lim YC, Li L, Desta Z, Zhao Q, Rae JM, Flockhart DA, Skaar TC (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 318:503–512CrossRefPubMedGoogle Scholar
  5. 5.
    Wu XL, Hawse JR, Subramaniam M, Goetz MP, Ingle JN, Spelsberg TC (2009) The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res 69:1722–1727CrossRefPubMedGoogle Scholar
  6. 6.
    Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, Flockhart DA (2003) Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758–1764PubMedGoogle Scholar
  7. 7.
    Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C (2007) Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 116:496–526CrossRefPubMedGoogle Scholar
  8. 8.
    Bradford LD (2002) CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 3:229–243CrossRefPubMedGoogle Scholar
  9. 9.
    Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA (2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30–39CrossRefPubMedGoogle Scholar
  10. 10.
    Lim HS, Ju LH, Seok LK, Sook LE, Jang IJ, Ro J (2007) Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25:3837–3845CrossRefPubMedGoogle Scholar
  11. 11.
    Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN (2005) Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312–9318CrossRefPubMedGoogle Scholar
  12. 12.
    Kiyotani K, Mushiroda T, Imamura CK, Hosono N, Tsunoda T, Kubo M, Tanigawara Y, Flockhart DA, Desta Z, Skaar TC, Aki F, Hirata K, Takatsuka Y, Okazaki M, Ohsumi S, Yamakawa T, Sasa M, Nakamura Y, Zembutsu H (2010) Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients. J Clin Oncol 28:1287–1293CrossRefPubMedGoogle Scholar
  13. 13.
    Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P, Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Bolander J, Strick R, Beckmann MW, Koelbl H, Weinshilboum RM, Ingle JN, Eichelbaum M, Schwab M, Brauch H (2009) Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA 302:1429–1436CrossRefPubMedGoogle Scholar
  14. 14.
    Xu Y, Sun Y, Yao L, Shi L, Wu Y, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, He L, Li P, Xie Y (2008) Association between CYP2D6*10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol 19:1423–1429CrossRefPubMedGoogle Scholar
  15. 15.
    Nowell SA, Ahn JY, Rae JM, Scheys JO, Trovato A, Sweeney C, MacLeod SL, Kadlubar FF, Ambrosone CB (2005) Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat 91:249–258CrossRefPubMedGoogle Scholar
  16. 16.
    Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, Simon W, Eichelbaum M, Brauch H (2007) Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25:5187–5193CrossRefPubMedGoogle Scholar
  17. 17.
    Wegman P, Elingarami S, Carstensen J, Stal O, Nordenskjold B, Wingren S (2007) Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 9:R7CrossRefPubMedGoogle Scholar
  18. 18.
    Aubert RE, Stanek EJ, Yao J, Teagarden JR, Subar M, Epstein RS, Skaar TC, Desta Z, Flockhart DA (2009) Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors. J Clin Oncol (Meeting Abstracts) 27:CRA508Google Scholar
  19. 19.
    Dezentje V, Van Blijderveen NJ, Gelderblom H, Putter H, Van Herk-Sukel MP, Casparie MK, Egberts AC, Nortier JW, Guchelaar HJ (2009) Concomitant CYP2D6 inhibitor use and tamoxifen adherence in early-stage breast cancer: a pharmacoepidemiologic study. J Clin Oncol (Meeting Abstracts) 27:CRA509Google Scholar
  20. 20.
    Kelly CM, Juurlink DN, Gomes T, Duong-Hua M, Pritchard KI, Austin PC, Paszat LF (2010) Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 340:c693CrossRefPubMedGoogle Scholar
  21. 21.
    Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, Atkins D (2001) Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med 20:21–35CrossRefPubMedGoogle Scholar
  22. 22.
    Deeks JJ, Higgins, JPT, Altman DG (eds) (2006) Analysing and presenting results. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5. In: The Cochrane Library, Chichester, UK, John Wiley & Sons, LtdGoogle Scholar
  23. 23.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188CrossRefPubMedGoogle Scholar
  24. 24.
    Gonzalez-Santiago S, Zarate R, Haba-Rodriguez J, Gomez A, Bandres E, Borrega P, Garcia-Foncillas J, Aranda E (2006) Genetic polymorphism CYP2D6(*4) interaction in clinical outcomes of tamoxifen-treated breast cancer patients. Ann Oncol 17:62–63CrossRefGoogle Scholar
  25. 25.
    Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM, Desta Z, Nguyen A, Flockhart DA, Perez EA, Ingle JN (2007) The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 101:113–121CrossRefPubMedGoogle Scholar
  26. 26.
    Newman WG, Hadfield KD, Latif A, Roberts SA, Shenton A, McHague C, Lalloo F, Howell S, Evans DG (2008) Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res 14:5913–5918CrossRefPubMedGoogle Scholar
  27. 27.
    Goetz MP, Berry DA, Klein TE (2009) Adjuvant tamoxifen treatment outcome according to cytochrome P450 2D6 (CYP2D6) phenotype in early stage breast cancer: findings from the International Tamoxifen Pharmacogenomics Consortium. Cancer Res 69:492S–493SCrossRefGoogle Scholar
  28. 28.
    Thompson A, Quinlan P, Bray S, Johnson A, Nikoloff M, Fontecha M, Ferraldeschi R, Howell A, Lawrence J, Newman W (2009) CYP2D6 genotype affects outcome in postmenopausal breast cancer patients treated with tamoxifen monotherapy. In: Proc Am Soc Clin Oncol Breast Cancer Symposium, Abstract 35.Google Scholar
  29. 29.
    Okishiro M, Taguchi T, Kim SJ, Shimazu K, Tamaki Y, Noguchi S (2009) 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 115:952–961CrossRefPubMedGoogle Scholar
  30. 30.
    Kiyotani K, Mushiroda T, Sasa M, Bando Y, Sumitomo I, Hosono N, Kubo M, Nakamura Y, Zembutsu H (2008) Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci 99:995–999CrossRefPubMedGoogle Scholar
  31. 31.
    Abraham JE, Maranian M, Driver K, Greenberg D, Shah MN, Earl HM, Dunning AM, Pharoah PPDP, Caldas C (2009) Cytochrome P450 2D6 variants and their association with breast cancer survival. Cancer Res 69:229SGoogle Scholar
  32. 32.
    Wegman P, Vainikka L, Stal O, Nordenskjold B, Skoog L, Rutqvist LE, Wingren S (2005) Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res 7:R284–R290CrossRefPubMedGoogle Scholar
  33. 33.
    Toyama T, Yamashita H, Sugiura H, Kondo N, Iwase H, Fujii Y (2009) No association between CYP2D6*10 genotype and survival of node-negative Japanese breast cancer patients receiving adjuvant tamoxifen treatment. Jpn J Clin Oncol 39:651–656CrossRefPubMedGoogle Scholar
  34. 34.
    Ramon y Cajal T, Altes A, Pare L, del Rio E, Alonso C, Barnadas A, Baiget M (2010) Impact of CYP2D6 polymorphisms in tamoxifen adjuvant breast cancer treatment. Breast Cancer Res Treat 119:33–38CrossRefPubMedGoogle Scholar
  35. 35.
    Bijl MJ, van Schaik RHN, Lammers LA, Hofman A, Vulto AG, van Gelder T, Stricker BHC, Visser LE (2009) The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users. Breast Cancer Res Treat 118:125–130CrossRefPubMedGoogle Scholar
  36. 36.
    Rae JM, Thibert J, Sikora MJ, Johnson MD, Skene A, A’Hern R, Smith IE, Dowsett M (2009) Lack of correlation between genetic polymorphisms in tamoxifen metabolizing enzymes with primary endpoints in the IMPACT trial. Cancer Res 69:595S–596SGoogle Scholar
  37. 37.
    Lash TL, Cronin-Fenton D, Ahern TP, Rosenberg CL, Lunetta KL, Silliman RA, Hamilton-Dutoit S, Garne JP, Ewertz M, Sorensen HT, Pedersen L (2010) Breast cancer recurrence risk related to concurrent use of SSRI antidepressants and tamoxifen. Acta Oncol 49:305–312CrossRefPubMedGoogle Scholar
  38. 38.
    (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 351:1451–1467Google Scholar
  39. 39.
    Decensi A, Robertson C, Viale G, Pigatto F, Johansson H, Kisanga ER, Veronesi P, Torrisi R, Cazzaniga M, Mora S, Sandri MT, Pelosi G, Luini A, Goldhirsch A, Lien EA, Veronesi U (2003) A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers. J Natl Cancer Inst 95:779–790CrossRefPubMedGoogle Scholar
  40. 40.
    Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M (2008) Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 9:45–53CrossRefPubMedGoogle Scholar
  41. 41.
    Mouridsen H, Giobbie-Hurder A, Goldhirsch A, Thurlimann B, Paridaens R, Smith I, Mauriac L, Forbes JF, Price KN, Regan MM, Gelber RD, Coates AS (2009) Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med 361:766–776CrossRefPubMedGoogle Scholar
  42. 42.
    Punglia RS, Burstein HJ, Winer EP, Weeks JC (2008) Pharmacogenomic variation of CYP2D6 and the choice of optimal adjuvant endocrine therapy for postmenopausal breast cancer: a modeling analysis. J Natl Cancer Inst 100:642–648CrossRefPubMedGoogle Scholar
  43. 43.
    Lynn HN, Rae JM, Li L, Azzouz F, Skaar TC, Desta Z, Sikora MJ, Philips S, Nguyen AT, Storniolo AM, Hayes DF, Flockhart DA, Stearns V (2009) Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. Breast Cancer Res Treat 117:571–575CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  1. 1.Division of Medical Oncology and HematologyPrincess Margaret Hospital and University of TorontoTorontoCanada

Personalised recommendations