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Pharmacogenetics: Making cancer treatment safer and more effective pp 45–59Cite as

Pharmacogenetics in the Management of Breast Cancer

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Abstract

The estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) represent key pharmacogenomic targets for effective therapies in breast oncology. Furthermore, recent advances in genomic approaches to clarify prognosis have refined the use of cytotoxic chemotherapy, although a great many women still receive unnecessary and often ineffective treatment. Pharmacogenetic factors involved in the metabolism of some of these drugs, and in particular the influence of CYP2D6 polymorphisms in the metabolism of tamoxifen, have begun to change clinical practice. The routine genotyping of drug metabolic pathways may well become another standard measure in breast oncology in the near future.

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References

  • Albain K, Barlow W, O’Malley F et al (2004) Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: mature outcomes and new biologic correlates on phase III Intergroup trial 0100 (SWOG-8814). Breast Cancer Res Treat 88(Suppl 1):37

    Google Scholar 

  • Allen E, Doisy E (1923) An ovarian hormone. Preliminary report on its localization, extraction and partial purification, and action in test animals. JAMA 81:819–821

    CAS  Google Scholar 

  • Ambrosone CB, Ahn J, Singh KK et al (2005) Polymorphisms in genes related to oxidative stress (MPO, MnSOD, CAT) and survival after treatment for breast cancer. Cancer Res 65:1105–1111

    CAS  Google Scholar 

  • Ambrosone CB, Sweeney C, Coles BF et al (2001) Polymorphisms in glutathione S-transferases (GSTM1 and GSTT1) and survival after treatment for breast cancer. Cancer Res 61:7130–7135

    CAS  PubMed  Google Scholar 

  • Baselga J, Tripathy D, Mendelsohn J et al (1996) Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14:737–744

    CAS  PubMed  Google Scholar 

  • Baum M, Budzar AU, Cuzick J et al (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359:2131–2139

    Article  CAS  PubMed  Google Scholar 

  • Beatson G (1896) On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet 2:162–165

    Article  Google Scholar 

  • Berry DA, Cronin KA, Plevritis SK et al (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353:1784–1792

    Article  CAS  PubMed  Google Scholar 

  • Bewick MA, Conlon MS, Lafrenie RM (2006) Polymorphisms in XRCC1, XRCC3, and CCND1 and survival after treatment for metastatic breast cancer. J Clin Oncol 24:5645–651

    Google Scholar 

  • Blackhall FH, Howell S, Newman B (2006) Pharmacogenetics in the management of breast cancer – prospects for individualised treatment. Fam Cancer 5:151–157

    Article  PubMed  Google Scholar 

  • Boccardo F, Rubagotti A, Guglielmini P et al (2006) Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian tamoxifen anastrozole (ITA) trial. Ann Oncol 17(Suppl 7):vii10–14

    Google Scholar 

  • Bogaerts J, Cardoso F, Buyse M et al (2006) Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial. Nat Clin Pract Oncol 3:540–551

    Article  CAS  PubMed  Google Scholar 

  • Borges S, Desta Z, Li L, Skaar TC et al (2006) Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment. Clin Pharmacol Ther 80:61–74

    Article  CAS  PubMed  Google Scholar 

  • Bradford LD (2002) CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 3:229–243

    Article  CAS  PubMed  Google Scholar 

  • Carter P, Presta L, Gorman CM et al (1992) Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89:4285–4289

    Article  CAS  PubMed  Google Scholar 

  • Coates AS, Keshaviah A, Thurlimann B et al (2007) 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 Oncol 25:486–492

    Article  CAS  PubMed  Google Scholar 

  • Cobleigh MA, Vogel CL, Tripathy D et al (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639–2648

    CAS  PubMed  Google Scholar 

  • Coombes RC, Kilburn LS, Snowdon CF et al (2007) Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369:559–570

    Article  CAS  PubMed  Google Scholar 

  • Coussens L, Yang-Feng TL, Liao YC et al (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230:1132–1139

    Article  CAS  PubMed  Google Scholar 

  • Cuzick J, Sestak I, Cella D, Fallowfield L (2008) Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: a retrospective analysis of the ATAC trial. Lancet Oncol 9:1143–1148

    Article  CAS  PubMed  Google Scholar 

  • Dai H, van’t Veer L, Lamb J et al (2005) A cell proliferation signature is a marker of extremely poor outcome in a subpopulation of breast cancer patients. Cancer Res 65:4059–4066

    Article  CAS  PubMed  Google Scholar 

  • 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 310:1062–1075

    Article  CAS  PubMed  Google Scholar 

  • Dezentje VO, Guchelaar HJ, Nortier JW, van de Velde CJ, Gelderblom H (2009) Clinical implications of CYP2D6 genotyping in tamoxifen treatment for breast cancer. Clin Cancer Res 15:15–21

    Article  CAS  PubMed  Google Scholar 

  • Drebin JA, Link VC, Stern DF, Weinberg RA, Greene MI (1985) Down-modulation of an oncogene protein product and reversion of the transformed phenotype by monoclonal antibodies. Cell 41:697–706

    Article  CAS  PubMed  Google Scholar 

  • Drebin JA, Link VC, Weinberg RA, Greene MI (1986) Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen. Proc Natl Acad Sci USA 83:9129–9133

    Article  CAS  PubMed  Google Scholar 

  • Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717

    Article  Google Scholar 

  • Ein-Dor L, Kela I, Getz G, Givol D, Domany E (2005) Outcome signature genes in breast cancer: is there a unique set? Bioinformatics 21:171–178

    Article  CAS  PubMed  Google Scholar 

  • Fan L, Goh BC, Wong CI et al (2008) Genotype of human carbonyl reductase CBR3 correlates with doxorubicin disposition and toxicity. Pharmacogenet Genomics 18:621–631

    Article  CAS  PubMed  Google Scholar 

  • Foekens JA, Atkins D, Zhang Y et al (2006) Multicenter validation of a gene expression-based prognostic signature in lymph node-negative primary breast cancer. J Clin Oncol 24:1665–1671

    Article  CAS  PubMed  Google Scholar 

  • Galea MH, Blamey RW, Elston CE, Ellis IO (1992) The Nottingham Prognostic Index in primary breast cancer. Breast Cancer Res Treat 22:207–219

    Article  CAS  PubMed  Google Scholar 

  • Goetz M, Ames M, Gnant M et al (2008) Pharmacogenetic (CYP2D6) and gene expression profiles (HOXB13/IL17BR and molecular grade index) for prediction of adjuvant endocrine therapy benefit in the ABCSG 8 trial. SABCS: San Antonio, Texas, 10–14 December 2008

    Google Scholar 

  • Goetz MP, Knox SK, Suman VJ et al (2007) The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 101:113–121

    Article  CAS  PubMed  Google Scholar 

  • Goetz MP, Rae JM, Suman VJ et al (2005) Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312–9318

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Santiago S, Zárate R, Haba-Rodríguez J et al (2007) CYP2D6*4 polymorphism as blood predictive biomarker of breast cancer relapse in patients receiving adjuvant tamoxifen. ASCO annual meeting Chicago, Il 2–5 June 2007

    Google Scholar 

  • Green S, Walter P, Greene G, et al (1986) Cloning of the human oestrogen receptor cDNA. J Steroid Biochem 24:77–83

    Article  CAS  PubMed  Google Scholar 

  • Hu Z, Fan C, Oh DS et al (2006) The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 7:96

    Article  PubMed  Google Scholar 

  • Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A (1989) p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 9:1165–1172

    CAS  PubMed  Google Scholar 

  • Iglehart JD, Kraus MH, Langton BC, Huper G, Kerns BJ, Marks JR (1990) Increased erbB-2 gene copies and expression in multiple stages of breast cancer. Cancer Res 50:6701–6707

    CAS  PubMed  Google Scholar 

  • Jakesz R, Gnant M, Griel R et al (2008) Tamoxifen and anastrozole as a sequencing strategy in postmenopausal women with hormone-responsive early breast cancer: updated data from the Austrian breast and colorectal cancer study group trial 8. SABCS: San Antonio, Texas, 10–14 December 2008

    Google Scholar 

  • Jin Y, Desta Z, Stearns V et al (2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30–39

    Article  CAS  PubMed  Google Scholar 

  • Joensuu H, Kellokumpu-Lehtinen PL, Bono P et al (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809–820

    Article  CAS  PubMed  Google Scholar 

  • Kafka A, Sauer G, Jaeger C et al (2003) Polymorphism C3435T of the MDR-1 gene predicts response to preoperative chemotherapy in locally advanced breast cancer. Int J Oncol 22:1117–1121

    CAS  PubMed  Google Scholar 

  • King CR, Kraus MH, Aaronson SA (1985) Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 229:974–976

    Article  CAS  PubMed  Google Scholar 

  • Kiyotani K, Mushiroda T, Sasa M, et al (2008) Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci 99:995–999

    Article  CAS  PubMed  Google Scholar 

  • Largillier R, Etienne-Grimaldi MC, Formento JL et al (2006) Pharmacogenetics of capecitabine in advanced breast cancer patients. Clin Cancer Res 12:5496–5502

    Article  CAS  PubMed  Google Scholar 

  • Lee KH, Ward BA, Desta Z, Flockhart DA, Jones DR (2003) Quantification of tamoxifen and three metabolites in plasma by high-performance liquid chromatography with fluorescence detection: application to a clinical trial. J Chromatogr B Analyt Technol Biomed Life Sci 791:245–253

    Article  CAS  PubMed  Google Scholar 

  • Loi S, Haibe-Kains B, Desmedt C et al (2007) Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol 25:1239–1246

    Article  CAS  PubMed  Google Scholar 

  • Lupu R, Colomer R, Zugmaier G et al (1990) Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2. Science 249:1552–1555

    Article  CAS  PubMed  Google Scholar 

  • Lynn Henry N, Rae JM, Li L et al (2009) Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. Breast Cancer Res Treat Jan 20 [Epub ahead of print]

    Google Scholar 

  • Marsh S, Paul J, King CR, Gifford G, McLeod HL, Brown R (2007) Pharmacogenetic assessment of toxicity and outcome after platinum plus taxane chemotherapy in ovarian cancer: the Scottish Randomised Trial in Ovarian Cancer. J Clin Oncol 25:4528–4235

    Google Scholar 

  • Newman WG, Hadfield KD, Latif A et al (2008) Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res 14:5913–5938

    Article  CAS  PubMed  Google Scholar 

  • Nowell SA, Ahn J, Rae JM et al (2005) Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat 91:249–258

    Article  CAS  PubMed  Google Scholar 

  • Okishiro M, Taguchi T, Jin Kim S et al (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 115:952–961

    Article  CAS  PubMed  Google Scholar 

  • Olivotto IA, Bajdik CD, Ravdin PM et al (2005) Population-based validation of the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol 23:2716–2725

    Article  PubMed  Google Scholar 

  • Paik S, Shak S, Tang G et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826

    Article  CAS  PubMed  Google Scholar 

  • Paik S, Tang G, Shak S et al (2006) Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24:3726–3734

    Article  CAS  PubMed  Google Scholar 

  • Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752

    Article  CAS  PubMed  Google Scholar 

  • Piccart-Gebhart M (2005) Treatment guidelines for systemic adjuvant therapy of breast cancer: strength and weaknesses. Breast Cancer Res Treat 94(Suppl 1):1

    Google Scholar 

  • 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 100:642–648

    Article  CAS  PubMed  Google Scholar 

  • Ravdin PM (1996) A computer program to assist in making breast cancer adjuvant therapy decisions. Semin Oncol 23:43–50

    CAS  PubMed  Google Scholar 

  • Rha SY, Jeung HC, Choi YH, et al (2007) An association between RRM1 haplotype and gemcitabine-induced neutropenia in breast cancer patients. Oncologist 12:622–630

    Article  CAS  PubMed  Google Scholar 

  • Romond EH, Perez EA, Bryant J et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673–1684

    Article  CAS  PubMed  Google Scholar 

  • Roses AD (2000) Pharmacogenetics and the practice of medicine. Nature 405: 857–865

    Article  CAS  PubMed  Google Scholar 

  • Sandanaraj E, Lal S, Selvarajan V et al (2008) PXR pharmacogenetics: association of haplotypes with hepatic CYP3A4 and ABCB1 messenger RNA expression and doxorubicin clearance in Asian breast cancer patients. Clin Cancer Res 14:7116–7126

    Article  CAS  PubMed  Google Scholar 

  • Schroth W, Antoniadou L, Fritz P et al (2007) Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25:5187–5193

    Article  CAS  PubMed  Google Scholar 

  • Schwab M, Zanger UM, Marx C et al (2008) Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 26:2131–2138

    Article  CAS  PubMed  Google Scholar 

  • Shih C, Padhy LC, Murray M, Weinberg RA (1981) Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 290:261–264

    Article  CAS  PubMed  Google Scholar 

  • Sissung TM, Mross K, Steinberg SM et al (2006) Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia. Eur J Cancer 42:2893–2896

    Article  CAS  PubMed  Google Scholar 

  • Slamon D, Eiermann W, Robert N et al (2006) 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. Breast Cancer Res Treat 100(Suppl 1):52

    Google Scholar 

  • Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182

    Article  CAS  PubMed  Google Scholar 

  • Smith I, Procter M, Gelber RD et al (2007) 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369:29–36

    Article  CAS  PubMed  Google Scholar 

  • Sorlie T, Tibshirani R, Parker J et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA, 100:8418–8423

    Article  CAS  PubMed  Google Scholar 

  • Sparano JA, Paik S (2008) Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol 26:721–728

    Article  PubMed  Google Scholar 

  • Stearns V, Johnson MD, Rae JM et al (2003) Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758–1764

    Article  CAS  PubMed  Google Scholar 

  • Sugiyama E, Kaniwa N, Kim SR et al (2007) Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. J Clin Oncol 25:32–42

    Article  CAS  PubMed  Google Scholar 

  • van’t Veer LJ, Paik S, Hayes DF (2005) Gene expression profiling of breast cancer: a new tumor marker. J Clin Oncol 23:1631–1635

    Article  PubMed  Google Scholar 

  • van’t Veer LJ, Dai H, van de Vijver MJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536

    Article  Google Scholar 

  • van de Vijver MJ, He YD, van’t Veer LJ et al (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009

    Article  PubMed  Google Scholar 

  • Vogel CL, Cobleigh MA, Tripathy D et al (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726

    Article  CAS  PubMed  Google Scholar 

  • Walker RA, Bartlett JM, Dowsett M et al (2008) HER2 testing in the UK: further update to recommendations. J Clin Pathol 61:818–824

    Article  CAS  PubMed  Google Scholar 

  • 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:R7

    Google Scholar 

  • Wegman P, Vainikka L, Stal O et al (2005) Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res 7:R284–290

    Google Scholar 

  • Westlake S, Cooper N (2008) Cancer incidence and mortality: trends in the United Kingdom and constituent countries, 1993 to 2004. Health Stat Q 38:33–46

    PubMed  Google Scholar 

  • Wu X, 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 69:1722–1727

    Article  CAS  PubMed  Google Scholar 

  • Xu Y, Sun Y, Yao L et al (2008) Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol 19: 1423–1429

    Article  CAS  PubMed  Google Scholar 

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  1. Breast Biology Group, Division of Cancer Studies, Paterson Institute for Cancer Research, University of Manchester, Manchester, M20 4BX, UK

    Sacha J. Howell

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  1. Science Centre (MAHSC), University of Manchester, St. Mary’s Hospital, Manchester, M13 9PL, United Kingdom

    William G. Newman

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Howell, S.J. (2010). Pharmacogenetics in the Management of Breast Cancer. In: Newman, W. (eds) Pharmacogenetics: Making cancer treatment safer and more effective. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-8618-1_4

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