Breast Cancer Research and Treatment

, Volume 91, Issue 3, pp 249–258 | Cite as

Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients

  • Susan A. NowellEmail author
  • Jiyoung Ahn
  • James M. Rae
  • Joshua O. Scheys
  • Andrew Trovato
  • Carol Sweeney
  • Stewart L. MacLeod
  • Fred F. Kadlubar
  • Christine B. Ambrosone


Tamoxifen has been a mainstay of adjuvant therapy for breast cancer for many years. We sought to determine if genetic variability in the tamoxifen metabolic pathway influenced overall survival in breast cancer patients treated with tamoxifen. We examined functional polymorphisms in CYP2D6, the P450 catalyzing the formation of active tamoxifen metabolites, and UGT2B15, a Phase II enzyme facilitating the elimination of active metabolite in a retrospective study of breast cancer patients. We also examined whether the combination of variant alleles in SULT1A1 and UGT2B15 had more of an impact on overall survival in tamoxifen-treated patients than when the genes were examined separately.

We conducted a retrospective study using archived paraffin blocks for DNA extraction and data from pathology reports and hospital tumor registry data for information on clinical characteristics, treatment, and outcomes (162 patients receiving tamoxifen and 175 who did not). Genotypes for CYP2D6 and UGT2B15 were obtained and Cox proportional hazards modeling was performed.

After adjusting for age, race, stage of disease at diagnosis, and hormone receptor status, we found no significant association between CYP2D6 genotype and overall survival in either group of breast cancer patients. Tamoxifen-treated patients with UGT2B15 high activity genotypes had increased risk of recurrence and poorer survival. When UGT2B15 and SULT1A1 ‘at-risk’ alleles were combined, women with two variant alleles had significantly greater risk of recurrence and poorer survival than those with common alleles. These studies indicate that genetic variation in Phase II conjugating enzymes can influence the efficacy of tamoxifen therapy for breast cancer.


breast cancer CYP2D6 genetic variation SULT1A1 tamoxifen UGT2B15 


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  1. 1.
    Furr, BJ, Jordan, VC 1984The pharmacology and clinical uses of tamoxifenPharmacol Ther25127205CrossRefPubMedGoogle Scholar
  2. 2.
    Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet, 351: 1451–1467 (1998).Google Scholar
  3. 3.
    Kristensen, B, Ejlertsen, B, Dalgaard, P, Larsen, L, Holmegaard, SN, Transbol, I, Mouridsen, HT 1994Tamoxifen and bone metabolism in postmenopausal low-risk breast cancer patients: a randomized studyJ Clin Oncol12992997PubMedGoogle Scholar
  4. 4.
    Love, RR., Mazess, RB, Barden, HS, Epstein, S, Newcomb, PA, Jordan, , VC, , Carbone, PP, DeMets, DL 1992Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancerN Engl J Med326852856PubMedGoogle Scholar
  5. 5.
    Ingram, D 1990Tamoxifen use, oestrogen binding and serum lipids in postmenopausal women with breast cancerAust N Z J Surg60673675PubMedGoogle Scholar
  6. 6.
    Bruning, PF, Bonfrer, JM, Hart, AA, Jong-Bakker, M, Linders, D, Loon, J, Nooyen, WJ 1988Tamoxifen, serum lipoproteins and cardiovascular riskBr J Cancer58497499PubMedGoogle Scholar
  7. 7.
    Braithwaite, RS, Chlebowski, RT, Lau, J, George, S, Hess, R, Col, NF 2003Meta-analysis of vascular and neoplastic events associated with tamoxifenJ Gen Intern Med18937947CrossRefPubMedGoogle Scholar
  8. 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).Google Scholar
  9. 9.
    Jordan, VC, Koch, R, Langan, S, McCague, R 1988Ligand interaction at the estrogen receptor to program antiestrogen action: a study with nonsteroidal compounds in vitroEndocrinology12214491454PubMedGoogle Scholar
  10. 10.
    Johnson, MD, Zuo, H, Lee, KH, Trebley, JP, Rae, JM, Weatherman, RV, Desta, Z, Flockhart, DA, Skaar, TC 2004Pharmacological characterization of 4-hydroxy- N -desmethyl tamoxifen, a novel active metabolite of tamoxifenBreast Cancer Res Treat85151159CrossRefPubMedGoogle Scholar
  11. 11.
    Sachse, C, Brockmoller, J, Bauer, S, Roots, I 1997Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequencesAm J Hum Genet60284295PubMedGoogle Scholar
  12. 12.
    Nishiyama, T, Ogura, K, Nakano, H, Ohnuma, T, Kaku, T, Hiratsuka, A, Muro, K, Watabe, T 2002Reverse geometrical selectivity in glucuronidation and sulfation of cis- and trans-4-hydroxytamoxifens by human liver UDP-glucuronosyltransferases and sulfotransferasesBiochem Pharmacol6318171830Google Scholar
  13. 13.
    Raftogianis, RB, Wood, TC, Otterness, DM, Van Loon, JA, Weinshilboum, RM 1997Phenol sulfotransferase pharmacogenetics in humans: association of common SULT1A1 alleles with TS PST phenotypeBiochem Biophys Res Commun239298304CrossRefPubMedGoogle Scholar
  14. 14.
    Nowell, S, Ambrosone, CB, Ozawa, S, MacLeod, SL, Mrackova, G, Williams, S, Plaxco, J, Kadlubar, FF, Lang, NP 2000Relationship of phenol sulfotransferase activity (SULT1A1) genotype to sulfotransferase phenotype in platelet cytosolPharmacogenetics10789797CrossRefPubMedGoogle Scholar
  15. 15.
    Levesque, E, Beaulieu, M, Green, MD, Tephly, TR, Belanger, A, Hum, DW 1997Isolation and characterization of UGT2B15(Y85): a UDP-glucuronosyltransferase encoded by a polymorphic genePharmacogenetics7317325PubMedGoogle Scholar
  16. 16.
    Nowell, S, Sweeney, C, Winters, M, Stone, A, Lang, NP, Hutchins, LF, Kadlubar, FF, Ambrosone, CB 2002Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapyJ Natl Cancer Inst9416351640PubMedGoogle Scholar
  17. 17.
    Ambrosone, CB, Sweeney, C, Coles, BF, Thompson, PA, McClure, GY, Korourian, S, Fares, MY, Stone, A, Kadlubar, FF, Hutchins, LF 2001Polymorphisms in glutathione S-transferases (GSTM1 and GSTT1) and survival after treatment for breast cancerCancer Res6171307135PubMedGoogle Scholar
  18. 18.
    Liu, Q, Thorland, EC, Heit, JA, Sommer, SS 1997Overlapping PCR for bidirectional PCR amplification of specific alleles: a rapid one-tube method for simultaneously differentiating homozygotes and heterozygotesGenome Res7389398PubMedGoogle Scholar
  19. 19.
    Ries, LAGEisner, MPKosary, CLHankey, BFMiller, BAClegg, LMariotto, AFay, MPFeuer, EJEdwards, BK eds. 2003SEER Cancer Statistics ReviewNational Cancer InstituteBethesda, MD19752000Google Scholar
  20. 20.
    Chu, KC, Tarone, RE, Kessler, LG, Ries, LA, Hankey, BF, Miller, BA, Edwards, BK 1996Recent trends in U.S. breast cancer incidence, survival, and mortality ratesJ Natl Cancer Inst8815711579PubMedGoogle Scholar
  21. 21.
    American Cancer Society. Cancer Facts and Figures. (2003).Google Scholar
  22. 22.
    Lien, EA, Solheim, E, Kvinnsland, S, Ueland, PM 1988Identification of 4-hydroxy-N-desmethyltamoxifen as a metabolite of tamoxifen in human bileCancer Res4823042308PubMedGoogle Scholar
  23. 23.
    Lien, EA, Solheim, E, Lea, OA, Lundgren, S, Kvinnsland, S, Ueland, PM 1989Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatmentCancer Res4921752183PubMedGoogle Scholar
  24. 24.
    Stearns, V, Johnson, MD, Rae, JM, Morocho, A, Novielli, A, Bhargava, P, Hayes, DF, Desta, Z, Flockhart, DA 2003Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetineJ Natl Cancer Inst9517581764PubMedGoogle Scholar
  25. 25.
    Bradford, LD, Gaedigk, A, Leeder, JS 1998High frequency of CYP2D6 poor and “intermediate” metabolizers in black populations: a review and preliminary dataPsychopharmacol Bull34797804PubMedGoogle Scholar
  26. 26.
    Burchell, B, Nebert, DW, Nelson, DR, Bock, KW, Iyanagi, T, Jansen, PL, Lancet, D, Mulder, GJ, Chowdhury, JR, Siest, G,  et al. 1991The UDP glucuronosyltransferase gene superfamily: suggested nomenclature based on evolutionary divergenceDNA Cell Biol10487494PubMedGoogle Scholar
  27. 27.
    Green, MD, Oturu, EM, Tephly, TR 1994Stable expression of a human liver UDP-glucuronosyltransferase (UGT2B15) with activity toward steroid and xenobiotic substratesDrug Metab Dispos22799805PubMedGoogle Scholar
  28. 28.
    Katzenellenbogen, JA, Carlson, KE, Katzenellenbogen, BS 1985Facile geometric isomerization of phenolic non-steroidal estrogens and antiestrogens: limitations to the interpretation of experiments characterizing the activity of individual isomersJ Steroid Biochem22589596CrossRefGoogle Scholar
  29. 29.
    Jordan, VC, Haldemann, B, Allen, KE 1981Geometric isomers of substituted triphenylethylenes and antiestrogen actionEndocrinology10813531361PubMedGoogle Scholar
  30. 30.
    Murphy, CS, Langan-Fahey, SM, McCague, R, Jordan, VC 1990Structure-function relationships of hydroxylated metabolites of tamoxifen that control the proliferation of estrogen-responsive T47D breast cancer cells in vitroMol Pharmacol38737743PubMedGoogle Scholar
  31. 31.
    Malet, C, Spritzer, P, Cumins, C, Guillaumin, D, Mauvais-Jarvis, P, Kuttenn, F 2002Effect of 4-hydroxytamoxifen isomers on growth and ultrastructural aspects of normal human breast epithelial (HBE) cells in cultureJ Steroid Biochem Mol Biol82289296CrossRefPubMedGoogle Scholar
  32. 32.
    Crewe, HK, Notley, LM, Wunsch, RM, Lennard, MS, Gillam, EM 2002Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4’-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifenDrug Metab Dispos30869874CrossRefPubMedGoogle Scholar
  33. 33.
    Tchernof, A, Levesque, E, Beaulieu, M, Couture, P, Despres, JP, Hum, DW, Belanger, A 1999Expression of the androgen metabolizing enzyme UGT2B15 in adipose tissue and relative expression measurement using a competitive RT-PCR methodClin Endocrinol (Oxf)50637642CrossRefGoogle Scholar
  34. 34.
    Kaku, T, Ogura, K, Nishiyama, T, Ohnuma, T, Muro, K, Hiratsuka, A 2004Quaternary ammonium-linked glucuronidation of tamoxifen by human liver microsomes and UDP-glucuronosyltransferase 1A4Biochem Pharmacol6720932102PubMedGoogle Scholar
  35. 35.
    Ambrosone CB, JA, HF, CS, AT: Variants in Oxidative Stress-Related Genes (MnSOD, MPO) and Survival after Treatment for Breast Cancer. Proc Am Assoc Cancer Res (2004).Google Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Susan A. Nowell
    • 1
    Email author
  • Jiyoung Ahn
    • 1
  • James M. Rae
    • 2
  • Joshua O. Scheys
    • 2
  • Andrew Trovato
    • 3
  • Carol Sweeney
    • 4
  • Stewart L. MacLeod
    • 5
  • Fred F. Kadlubar
    • 6
  • Christine B. Ambrosone
    • 1
  1. 1.Department of EpidemiologyRoswell Park Cancer InstituteBuffaloUSA
  2. 2.Department of Internal MedicineUniversity of Michigan School of MedicineUSA
  3. 3.Merck and CompanyRahwayUSA
  4. 4.Department of Family and Preventive MedicineUniversity of UtahSalt Lake CityUSA
  5. 5.University of Arkansas for Medical SciencesUSA
  6. 6.Division of Molecular EpidemiologyNational Center for Toxicological ResearchJeffersonUSA

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