Pharmacogenetics of Tamoxifen: Who Should Undergo CYP2D6 Genetic Testing?

Many women with hormone receptor–positive breast cancer will receive tamoxifen at some point in their treatment course. Tamoxifen is biotransformed to the potent antiestrogen endoxifen almost exclusively through the cytochrome P450 (CYP) 2D6 isoform. Although prospective data are lacking, the balance of evidence available currently suggests that a single nucleotide polymorphism in the CYP2D6 gene, particularly the presence of 2 null alleles, predicts for reduced tamoxifen metabolism and possibly poorer outcome than expected in patients with a wild-type genotype. Studies evaluating the impact of genetic polymorphisms that result in CYP2D6 with reduced or no activity on long-term outcome have been mostly retrospective and conducted on archival tissues or those obtained previously in prospective studies of tamoxifen. Until data are available from retrospective examinations of the large prospective trials already conducted, or adequately powered prospective analyses, transforming this information into guidelines for individual patients remains challenging. The authors do not currently recommend routine testing for CYP2D6 genotype for making clinical decisions regarding tamoxifen. Use of concomitant strong or intermediate inhibitors of CYP2D6 should be avoided when alternate medications are available. Ongoing research is directed toward identifying other polymorphisms that may influence the efficacy and safety of tamoxifen, other hormonal agents, and chemotherapies used to treat breast cancer. The hope is that in the future, not only tumor-associated factors but also germ-line host genetics can be used to determine whether a woman should receive treatment, and with which specific agents, to prevent breast cancer recurrence or death or avoid drug-related toxicities.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Correspondence: Vered Stearns, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans Street, CRB I, Room 145, Baltimore, MD 21231-1000. E-mail: vstearn1@jhmi.edu

References

  • 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. Lancet2005;365:16871717.

    • Search Google Scholar
    • Export Citation
  • 2

    GuttmacherAECollinsFS. Welcome to the genomic era. N Engl J Med2003;349:996998.

  • 3

    WeinshilboumR. Inheritance and drug response. N Engl J Med2003;348:529537.

  • 4

    EvansWEMcLeodHL. Pharmacogenomics—drug disposition, drug targets, and side effects. N Engl J Med2003;348:538549.

  • 5

    DestaZWardBASoukhovaNV. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther2004;310:10621075.

    • Search Google Scholar
    • Export Citation
  • 6

    FabianCTilzerLSternsonL. Comparative binding affinities of tamoxifen, 4-hydroxytamoxifen, and desmethyltamoxifen for estrogen receptors isolated from human breast carcinoma: correlation with blood levels in patients with metastatic breast cancer. Biopharm Drug Dispos1981;2:381390.

    • Search Google Scholar
    • Export Citation
  • 7

    JohnsonMDZouHLeeKH. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res Treat2004;85:151159.

    • Search Google Scholar
    • Export Citation
  • 8

    LimYCLiLDestaZ. 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 Ther2006;318:503512.

    • Search Google Scholar
    • Export Citation
  • 9

    BorgesSDestaZLiL. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther2006;80:6174.

    • Search Google Scholar
    • Export Citation
  • 10

    SunDSharmaAKDellingerRW. Glucuronidation of active tamoxifen metabolites by the human UDP glucuronosyltransferases. Drug Metab Dispos2007;35:20062014.

    • Search Google Scholar
    • Export Citation
  • 11

    Rodriguez-AntonaCIngelman-SundbergM. Cytochrome P450 pharmacogenetics and cancer. Oncogene2006;25:16791691.

  • 12

    BradfordLD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics2002;3:229243.

  • 13

    GarteSGaspariLAlexandrieAK. Metabolic gene polymorphism frequencies in control populations. Cancer Epidemiol Biomarkers Prev2001;10:12391248.

    • Search Google Scholar
    • Export Citation
  • 14

    Ingelman-SundbergM. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J2005;5:613.

    • Search Google Scholar
    • Export Citation
  • 15

    DahlMLJohanssonIPalmertzMP. Analysis of the CYP2D6 gene in relation to debrisoquin and desipramine hydroxylation in a Swedish population. Clin Pharmacol Ther1992;51:1217.

    • Search Google Scholar
    • Export Citation
  • 16

    SachseCBrockmollerJBauerS. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet1997;60:284295.

    • Search Google Scholar
    • Export Citation
  • 17

    ShenHHeMMLiuH. Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. Drug Metab Dispos2007;35:12921300.

    • Search Google Scholar
    • Export Citation
  • 18

    GrieseEUZangerUMBrudermannsU. Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics1998;8:1526.

    • Search Google Scholar
    • Export Citation
  • 19

    DahlMLJohanssonIBertilssonL. Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. J Pharmacol Exp Ther1995;274:516520.

    • Search Google Scholar
    • Export Citation
  • 20

    AlfaroCLLamYWSimpsonJ. CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations. J Clin Pharmacol2000;40:5866.

    • Search Google Scholar
    • Export Citation
  • 21

    StearnsV. Clinical update: new treatments for hot flushes. Lancet2007;369:20622064.

  • 22

    StearnsVJohnsonMDRaeJM. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst2003;95:17581764.

    • Search Google Scholar
    • Export Citation
  • 23

    JinYDestaZStearnsV. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst2005;97:3039.

    • Search Google Scholar
    • Export Citation
  • 24

    IngleJNSumanVJMailliardJA. 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 Treat2006;98:217222.

    • Search Google Scholar
    • Export Citation
  • 25

    GoetzMPRaeJMSumanVJ. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol2005;23:93129318.

    • Search Google Scholar
    • Export Citation
  • 26

    GoetzMPKnoxSKSumanVJ. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat2007;101:113121.

    • Search Google Scholar
    • Export Citation
  • 27

    HawseJRWuXSubramaniamM. Endoxifen but not 4-hydroxytamoxifen degrades the estrogen receptor in breast cancer cells: a differential mechanism of action potentially explaining CYP2D6 effect. Available at: http://www.sabcs.org/EnduringMaterials/index.asp#slidereview. Accessed December 15 2008.

    • Search Google Scholar
    • Export Citation
  • 28

    WegmanPVainikkaLStalO. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res2005;7:R284290.

    • Search Google Scholar
    • Export Citation
  • 29

    WegmanPElingaramiSCarstensenJ. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res2007;9:R7.

    • Search Google Scholar
    • Export Citation
  • 30

    NowellSAAhnJRaeJM. Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat2005;91:249258.

    • Search Google Scholar
    • Export Citation
  • 31

    SchrothWAntoniadouLFritzP. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol2007;25:51875193.

    • Search Google Scholar
    • Export Citation
  • 32

    LimHSJu LeeHSeok LeeK. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol2007;25:38373845.

    • Search Google Scholar
    • Export Citation
  • 33

    XuYSunYYaoL. Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol2008;19:14231429.

    • Search Google Scholar
    • Export Citation
  • 34

    KiyotaniKMushirodaTSasaM. Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci2008;99:995999.

    • Search Google Scholar
    • Export Citation
  • 35

    NewmanWGHadfieldKDLatifA. Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res2008;14:59135918.

    • Search Google Scholar
    • Export Citation
  • 36

    BonanniBMacisDMaisonneuveP. Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial. J Clin Oncol2006;24:37083709; author reply 3709.

    • Search Google Scholar
    • Export Citation
  • 37

    GoetzMPAmesMGnantM. Pharmacogenetic (CYP2D6) and gene expression profiles (molecular grade index and HOXB13/IL17BR) for prediction of adjuvant endocrine therapy benefit in the ABCSG 8 trial. Available from: http://www.sabcs.org/EnduringMaterials/index.asp#slidereview. Accessed December 15 2008.

    • Search Google Scholar
    • Export Citation
  • 38

    McGuireWCarbonePPSearsME. Estrogen receptors in human breast cancer. In: McGuireWLCarbonePPVollmerEP eds. Estrogen Receptors in Human Breast Cancer. New York, New York: Raven Press; 1975:17.

    • Search Google Scholar
    • Export Citation
  • 39

    GallacchiPSchoumacherFEppenberger-CastoriS. Increased expression of estrogen-receptor exon-5-deletion variant in relapse tissues of human breast cancer. Int J Cancer1998;79:448.

    • Search Google Scholar
    • Export Citation
  • 40

    ZhangQXBorgAWolfDM. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res1997;57:12441249.

    • Search Google Scholar
    • Export Citation
  • 41

    NowellSSweeneyCWintersM. Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapy. J Natl Cancer Inst2002;94:16351640.

    • Search Google Scholar
    • Export Citation
  • 42

    RaeJMSikoraMJHenryNL. Cytochrome P450 2D6 activity predicts adherence to tamoxifen therapy. Presented at the 30th Annual San Antonio Breast Cancer Symposium; San Antonio, Texas; December 13–26, 2007.

    • Search Google Scholar
    • Export Citation
  • 43

    HenryNLRaeJMLiL. Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. Breast Cancer Res Treat2009; in press.

    • Search Google Scholar
    • Export Citation
  • 44

    JinYHayesDFLiL. Estrogen receptor genotypes influence hot flash prevalence and composite score before and after tamoxifen therapy. J Clin Oncol2008;26:58495854.

    • Search Google Scholar
    • Export Citation
  • 45

    HenryNLNguyenARobargeJ. Association of chemotherapy and estrogen receptor genotype with change in bone mineral density after one year of tamoxifen therapy. Presented at the 30th Annual San Antonio Breast Cancer Symposium; San Antonio, Texas; December 13–26, 2007.

    • Search Google Scholar
    • Export Citation
  • 46

    NtukidemNINguyenATStearnsV. Estrogen receptor genotypes, menopausal status, and the lipid effects of tamoxifen. Clin Pharmacol Ther2008;83:702710.

    • Search Google Scholar
    • Export Citation
  • 47

    ForbesJFCuzickJBuzdarA. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol2008;9:4553.

    • Search Google Scholar
    • Export Citation
  • 48

    CoatesASKeshaviahAThurlimannB. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol2007;25:486492.

    • Search Google Scholar
    • Export Citation
  • 49

    CoombesRCKilburnLSSnowdonCF. Survival and safety of exemestane versus tamoxifen after 2-3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet2007;369:559570.

    • Search Google Scholar
    • Export Citation
  • 50

    JakeszRGreilRGnantM. Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group Trial 6a. J Natl Cancer Inst2007;99:18451853.

    • Search Google Scholar
    • Export Citation
  • 51

    GossPEIngleJNMartinoS. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst2005;97:12621271.

    • Search Google Scholar
    • Export Citation
  • 52

    MamounasEPJeongJHWickerhamDL. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast and Bowel Project B-33 trial. J Clin Oncol2008;26:19651971.

    • Search Google Scholar
    • Export Citation
  • 53

    WinerEPHudisCBursteinHJ. 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 Oncol2005;23:619629.

    • Search Google Scholar
    • Export Citation
  • 54

    CarlsonRWBrownEBursteinHJ. NCCN Task Force Report: Adjuvant Therapy for Breast Cancer. J Natl Compr Canc Netw2006;4(Suppl 1):S126.

  • 55

    GoldhirschAWoodWCGelberRD. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol2007;18:11331144.

    • Search Google Scholar
    • Export Citation
  • 56

    PungliaRSBursteinHJWinerEP. Pharmacogenomic variation of CYP2D6 and the choice of optimal adjuvant endocrine therapy for postmenopausal breast cancer: a modeling analysis. J Natl Cancer Inst2008;100:642648.

    • Search Google Scholar
    • Export Citation
  • 57

    HayesDFStearnsVRaeJ. A model citizen? Is tamoxifen more effective than aromatase inhibitors if we pick the right patients?J Natl Cancer Inst2008;100:610613.

    • Search Google Scholar
    • Export Citation
  • 58

    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. Lancet2005;365:16871717.

    • Search Google Scholar
    • Export Citation
  • 59

    GnantMMlineritschBSchippingerWL. Adjuvant ovarian suppression combined with tamoxifen or anastrazole, alone or in combination with zoledronic acid, in premenopausal women with hormone-responsive, stage I and II breast cancer: first efficacy results from ABCSG-12 [abstract]. J Clin Oncol2008;26(20 Suppl): Abstract LBA4.

    • Search Google Scholar
    • Export Citation
  • 60

    GanzPA. Monitoring the physical health of cancer survivors: a survivorship-focused medical history. J Clin Oncol2006;24:51055111.

  • 61

    GanzPADesmondKABelinTR. Predictors of sexual health in women after a breast cancer diagnosis. J Clin Oncol1999;17:23712380.

Article Information

Cited By

PubMed

Google Scholar

Related Articles

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 93 93 13
PDF Downloads 30 29 4
EPUB Downloads 0 0 0