Familial Cancer

, Volume 5, Issue 2, pp 151–157 | Cite as

Pharmacogenetics in the Management of Breast Cancer – Prospects for Individualised Treatment

  • Fiona H. Blackhall
  • Sacha Howell
  • Bill NewmanEmail author


Increased understanding of how variants in genes encoding metabolising enzymes, transporters and receptors affect drug efficacy and toxicity, in parallel with advances in genotyping technology means that clinical pharmacogenetics is drawing tantalisingly close to reality. This review considers some of the pharmacogenetic variants that have been described that are relevant to the management of women with breast cancer and how these may soon translate into clinical practice.

Key words

breast cancer pharmacogenetics 


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  1. 1.
    Roses, AD 2000Pharmacogenetics and the practice of medicineNature40585765PubMedCrossRefGoogle Scholar
  2. 2.
    EBCTCG. Tamoxifen for early breast cancer. Cochrane Database Syst Rev 2001;1:CD000486Google Scholar
  3. 3.
    Stearns, V, Johnson, MD, Rae, JM,  et al. 2003Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetineJ Natl Cancer Inst95175864PubMedGoogle Scholar
  4. 4.
    Desta, Z, Ward, BA, Soukhova, NV, Flockhart, DA 2004Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6J Pharmacol Exp Ther310106275PubMedCrossRefGoogle Scholar
  5. 5.
    Nowell, S, Sweeney, C, Winters, M,  et al. 2002Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapyJ Natl Cancer Inst941635 40PubMedGoogle Scholar
  6. 6.
    Coombes, RC, Hall, E, Gibson, LJ,  et al. 2004A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancerN Engl J Med350108192PubMedCrossRefGoogle Scholar
  7. 7.
    Novelli, G, Margiotti, K, Chiocca, AM, Spera, E, Micali, F, Reichardt, JK 2004Pharmacogenetics of human androgens and prostate cancer – an updatePharmacogenomics528394PubMedCrossRefGoogle Scholar
  8. 8.
    Miller, WR, Dixon, JM 2001Local endocrine effects of aromatase inhibitors within the breastJ Steroid Biochem Mol Biol7993102PubMedCrossRefGoogle Scholar
  9. 9.
    Cuzick, J, Powles, T, Veronesi, U, Forbes, J, Edwards, R, Ashley, S, Boyle, P 2003Overview of the main outcomes in breast-cancer prevention trialsLancet361296300PubMedCrossRefGoogle Scholar
  10. 10.
    Duggan, C, Marriott, K, Edwards, R, Cuzick, J 2003Inherited and acquired risk factors for venous thromboembolic disease among women taking tamoxifen to prevent breast cancerJ Clin Oncol21358893PubMedCrossRefGoogle Scholar
  11. 11.
    Martino, S, Costantino, J, McNabb, M,  et al. 2004The role of selective estrogen receptor modulators in the prevention of breast cancer: comparison of the clinical trialsOncologist911625PubMedCrossRefGoogle Scholar
  12. 12.
    Pappas, SG, Jordan, VC 2002Chemoprevention of breast cancer: current and future prospectsCancer Metastasis Rev2131121PubMedCrossRefGoogle Scholar
  13. 13.
    Goss, PE 2003Breast cancer prevention–clinical trials strategies involving aromatase inhibitorsJ Steroid Biochem Mol Biol8648793PubMedCrossRefGoogle Scholar
  14. 14.
    Bardou, VJ, Arpino, G, Elledge, RM, Osborne, CK, Clark, GM 2003Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databasesJ Clin Oncol21197379PubMedCrossRefGoogle Scholar
  15. 15.
    Nicholson, RI, Gee, JM, Knowlden, J,  et al. 2003The biology of antihormone failure in breast cancerBreast Cancer Res Treat80S29S34PubMedCrossRefGoogle Scholar
  16. 16.
    Gallacchi, P, Schoumacher, F, Eppenberger-Castori, S,  et al. 1998Increased expression of estrogen-receptor exon-5-deletion variant in relapse tissues of human breast cancerInt J Cancer794448PubMedCrossRefGoogle Scholar
  17. 17.
    Roodi, N, Bailey, LR, Kao, WY,  et al. 1995Estrogen receptor gene analysis in estrogen receptor-positive and receptor-negative primary breast cancerJ Natl Cancer Inst8744651PubMedGoogle Scholar
  18. 18.
    Zhang, QX, Borg, A, Wolf, DM, Oesterreich, S, Fuqua, SA 1997An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancerCancer Res57124449PubMedGoogle Scholar
  19. 19.
    Levenson, AS, Catherino, WH, Jordan, VC 1997Estrogenic activity is increased for an antiestrogen by a natural mutation of the estrogen receptorJ Steroid Biochem Mol Biol6026168PubMedCrossRefGoogle Scholar
  20. 20.
    Widschwendter, M, Siegmund, KD, Muller, HM,  et al. 2004Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifenCancer Res6438071PubMedCrossRefGoogle Scholar
  21. 21.
    Hutcheson, IR, Knowlden, JM, Madden, TA,  et al. 2003Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cellsBreast Cancer Res Treat818193PubMedCrossRefGoogle Scholar
  22. 22.
    Ma, XJ, Wang, Z, Ryan, PD,  et al. 2004A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifenCancer Cell560716PubMedCrossRefGoogle Scholar
  23. 23.
    Diasio, RB, Beavers, TL, Carpenter, JT 1988Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicityJ Clin Invest814751PubMedCrossRefGoogle Scholar
  24. 24.
    Diasio, RB, Johnson, MR 1999Dihydropyrimidine dehydrogenase: its role in 5-fluorouracil clinical toxicity and tumor resistanceClin Cancer Res5267273PubMedGoogle Scholar
  25. 25.
    Kuilenburg, AB, Meinsma, R, Zonnenberg, BA,  et al. 2003Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicityClin Cancer Res9436367PubMedGoogle Scholar
  26. 26.
    Watters, JW, Kraja, A, Meucci, MA, Province, MA, McLeod, HL 2004Genome-wide discovery of loci influencing chemotherapy cytotoxicityProc Natl Acad Sci USA1011180914PubMedCrossRefGoogle Scholar
  27. 27.
    Marsh, S, McLeod, HL 2001Thymidylate synthase pharmacogenetics in colorectal cancerClin Colorectal Cancer117578PubMedCrossRefGoogle Scholar
  28. 28.
    Kafka, A, Sauer, G, Jaeger, C,  et al. 2003Polymorphism C3435T of the MDR-1 gene predicts response to preoperative chemotherapy in locally advanced breast cancerInt J Oncol22111721PubMedGoogle Scholar
  29. 29.
    Aries, A, Paradis, P, Lefebvre, C, Schwartz, RJ, Nemer, M 2004Essential role of GATA-4 in cell survival and drug-induced cardiotoxicityProc Natl Acad Sci U S A101697580PubMedCrossRefGoogle Scholar
  30. 30.
    Petricoin, EF, Rajapaske, V, Herman, EH,  et al. 2004Toxicoproteomics: serum proteomic pattern diagnostics for early detection of drug induced cardiac toxicities and cardioprotectionToxicol Pathol112230CrossRefGoogle Scholar
  31. 31.
    Maeno, K, Ito, K, Hama, Y,  et al. 2003Mutation of the class I beta-tubulin gene does not predict response to paclitaxel for breast cancerCancer Lett1988997PubMedCrossRefGoogle Scholar
  32. 32.
    Edelman, MJ, Quam, H, Mullins, B 2001Interactions of gemcitabine, carboplatin and paclitaxel in molecularly defined non-small-cell lung cancer cell linesCancer Chemother Pharmacol.4814144PubMedCrossRefGoogle Scholar
  33. 33.
    Perez-Soler, R, Kemp, B, Wu, QP,  et al. 2000Response and determinants of sensitivity to paclitaxel in human non-small cell lung cancer tumors heterotransplanted in nude miceClin Cancer Res6493238PubMedGoogle Scholar
  34. 34.
    Konecny, GE, Thomssen, C, Luck, HJ,  et al. 2004Her-2/neu gene amplification and response to paclitaxel in patients with metastatic breast cancerJ Natl Cancer Inst96114151PubMedCrossRefGoogle Scholar
  35. 35.
    Bergman, AM, Pinedo, HM, Peters, GJ 2002Determinants of resistance to 2′,2′-difluorodeoxycytidine (gemcitabine)Drug Resist Updat51933PubMedCrossRefGoogle Scholar
  36. 36.
    Oshika, Y, Nakamura, M, Tokunaga, T,  et al. 1998Multidrug resistance-associated protein and mutant p53 protein expression in non-small cell lung cancerMod Pathol.11105963PubMedGoogle Scholar
  37. 37.
    Paez, JG, Janne, PA, Lee, JC,  et al. 2004EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapyScience3041497500PubMedCrossRefGoogle Scholar
  38. 38.
    Lynch, TJ, Bell, DW, Sordella, R,  et al. 2004Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinibN Engl J Med350212939PubMedCrossRefGoogle Scholar
  39. 39.
    Szabo, CI, Schutte, M, Broeks, A,  et al. 2004Are ATM mutations 7271T–>G and IVS10-6T–>G really high-risk breast cancer-susceptibility alleles?Cancer Res6484043PubMedCrossRefGoogle Scholar
  40. 40.
    Broeks, A, Urbanus, JH, Floore, AN,  et al. 2000ATM-heterozygous germline mutations contribute to breast cancer-susceptibilityAm J Hum Genet66494500PubMedCrossRefGoogle Scholar
  41. 41.
    Angele, S,  et al. 2003ATM haplotypes and cellular response to DNA damage: association with breast cancer risk and clinical radiosensitivityCancer Res.63871725PubMedGoogle Scholar
  42. 42.
    Appleby, JM, Barber, JB, Levine, E,  et al. 1997Absence of mutations in the ATM gene in breast cancer patients with severe responses to radiotherapyBr J Cancer76154649PubMedGoogle Scholar
  43. 43.
    Iannuzzi, CM, Atencio, DP, Green, S, Stock, RG, Rosenstein, BS 2002ATM mutations in female breast cancer patients predict for an increase in radiation-induced late effectsInt J Radiat Oncol Biol Phys5260613PubMedCrossRefGoogle Scholar
  44. 44.
    Daly, MB 2004Tailoring breast cancer treatment to genetic status: the challenges aheadJ Clin Oncol22177677PubMedCrossRefGoogle Scholar
  45. 45.
    Mitrunen, K, Kataja, V, Eskelinen, M,  et al. 2002Combined COMT and GST genotypes and hormone replacement therapy associated breast cancer riskPharmacogenetics126772PubMedCrossRefGoogle Scholar
  46. 46.
    Our inheritance, our future-realising the potential of genetics in the NHS. Department of Health, 2003. Cm5791Google Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  • Fiona H. Blackhall
    • 1
  • Sacha Howell
    • 1
  • Bill Newman
    • 2
    Email author
  1. 1.Department of Medical OncologyChristie Hospital NHS TrustUK
  2. 2.Academic Department of Medical GeneticsSt Mary’s Hospital, University of ManchesterUK

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