We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

The role of genetic variability in drug metabolism pathways in breast cancer prognosis

    Ji-Yeob Choi

    Roswell Park Cancer Institute, Department of Epidemiology, Elm & Carlton Sts, Buffalo, NY, 14263, USA.

    ,
    Susan A Nowell

    University of Arkansas for Medical Sciences, Department of Environmental and Occupational Health, 4301 W. Markham St, #820, Little Rock, AR 72205, USA

    ,
    Javier G Blanco

    State University of New York, Department of Pharmaceutical Sciences, 517 Hochstetter Hall, Buffalo, New York 14260–1200, USA

    &
    Christine B Ambrosone

    † Author for correspondence

    Roswell Park Cancer Institute, Department of Epidemiology, Elm & Carlton Sts, Buffalo, NY, 14263, USA.

    Published Online:https://doi.org/10.2217/14622416.7.4.613

    Among patients receiving adjuvant therapy for breast cancer, there is variability in treatment outcomes, and it is unclear which patients will receive the most benefit from treatment and which will have better disease-free survival. To date, most studies of breast cancer prognosis have focused on tumor characteristics, but it is likely that pharmacogenetics, genetic variability in the metabolism of therapeutic agents, also plays a role in the prediction of survival. In this paper, we briefly discuss the metabolic pathways of drugs commonly used for the treatment of breast cancer (cyclophosphamide, doxorubicin, taxanes, tamoxifen and aromatase inhibitors) and describe the known genetic variants that may impact those pathways. Studies that have evaluated potential effects of these genetic variants on treatment outcomes are also discussed. It is likely that the application of pharmacogenetics, particularly in the setting of randomized clinical trials, will contribute to findings that may result in individualized therapeutic dosing.

    Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

    Bibliography

    • Evans WE, Relling MV: Pharmacogenomics: translating functional genomics into rational therapeutics. Science286, 487–491 (1999).•• Excellent overview of the fundamentals of pharmacogenetics.
    • DeVita VTJr, Hellman S, Rosenberg SA (Eds): Cancer, principles and practice of oncology. Lippincott-Raven, New York, NY, USA (1997).
    • Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet352(9132), 930–942 (1998).
    • Cuzick J: Aromatase inhibitors for breast cancer prevention. J. Clin. Oncol.23(8), 1636–1643 (2005).
    • Scripture CD, Sparreboom A, Figg WD: Modulation of cytochrome P450 activity: implications for cancer therapy. Lancet Oncol.6(10), 780–789 (2005).• Comprehensive review of Phase I metabolism of chemotherapeutic agents.
    • Clarke L, Waxman DJ: Oxidative metabolism of cyclophosphamide: identification of the hepatic monooxygenase catalysts of drug activation. Cancer Res.49(9), 2344–2350 (1989).
    • Huang Z, Roy P, Waxman DJ: Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem. Pharmacol.59(8), 961–972 (2000).
    • Dirven HA, van Ommen B, van Bladeren PJ: Glutathione conjugation of alkylating cytostatic drugs with a nitrogen mustard group and the role of glutathione S-transferases. Chem. Res Toxicol.9(2), 351–360 (1996).
    • Ariyoshi N, Miyazaki M, Toide K, Sawamura Y, Kamataki T: A single nucleotide polymorphism of CYP2B6 found in Japanese enhances catalytic activity by autoactivation. Biochem. Biophys.Res Commun.281(5), 1256–1260 (2001).
    • 10  Jinno H, Tanaka-Kagawa T, Ohno A et al.: Functional characterization of cytochrome P450 2B6 allelic variants. Drug Metab. Dispos.31(4), 398–403 (2003).
    • 11  Lang T, Klein K, Fischer J et al.: Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics11(5), 399–415 (2001).
    • 12  Lang T, Klein K, Richter T et al.: Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles. J. Pharmacol. Exp. Ther.311(1), 34–43 (2004).
    • 13  Xie HJ, Yasar U, Lundgren S et al.: Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation. Pharmacogenomics J.3(1), 53–61 (2003).
    • 14  Petros WP, Hopkins PJ, Spruill S et al.: Associations between drug metabolism genotype, chemotherapy pharmacokinetics, and overall survival in patients with breast cancer. J. Clin. Oncol.23(25), 6117–6125 (2005).
    • 15  Lamba V, Lamba J, Yasuda K et al.: Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. J. Pharmacol. Exp. Ther.307(3), 906–922 (2003).
    • 16  Hesse LM, He P, Krishnaswamy S et al.: Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes. Pharmacogenetics14(4), 225–238 (2004).
    • 17  Lee SJ, Bell DA, Coulter SJ, Ghanayem B, Goldstein JA: Recombinant CYP3A4*17 is defective in metabolizing the hypertensive drug nifedipine, and the CYP3A4*17 allele may occur on the same chromosome as CYP3A5*3, representing a new putative defective CYP3A haplotype. J. Pharmacol. Exp. Ther.313(1), 302–309 (2005).
    • 18  He P, Court MH, Greenblatt DJ, Von Moltke LL: Genotype–phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin. Pharmacol. Ther.77(5), 373–387 (2005).
    • 19  Hirota T, Ieiri I, Takane H et al.: Allelic expression imbalance of the human CYP3A4 gene and individual phenotypic status. Hum. Mol. Genet.13(23), 2959–2969 (2004).
    • 20  Garcia-Martin E, Martinez C, Pizarro RM et al.: CYP3A4 variant alleles in white individuals with low CYP3A4 enzyme activity. Clin. Pharmacol. Ther.71(3), 196–204 (2002).
    • 21  Schuetz EG: Lessons from the CYP3A4 promoter. Mol. Pharmacol.65(2), 279–281 (2004).• Interesting illustration of the complexity of variability in CYP3A4.
    • 22  Raucy JL: Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab. Dispos.31, 533–539 (2003).
    • 23  Kuehl P, Zhang J, Lin Y et al.: Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nature Genet.27(4), 383–391 (2001).
    • 24  Hustert E, Haberl M, Burk O et al.: The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics11(9), 773–779 (2001).
    • 25  Goldstein JA: Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br. J. Clin. Pharmacol.52(4), 349–355 (2001).
    • 26  Giorgianni F, Bridson PK, Sorrentino BP, Pohl J, Blakley RL: Inactivation of aldophosphamide by human aldehyde dehydrogenase isozyme 3. Biochem. Pharmacol.60(3), 325–338 (2000).
    • 27  Spence JP, Liang T, Eriksson CJ et al.: Evaluation of aldehyde dehydrogenase 1 promoter polymorphisms identified in human populations. Alcohol Clin. Exp. Res.27(9), 1389–1394 (2003).
    • 28  Vasiliou V, Pappa A: Polymorphisms of human aldehyde dehydrogenases. Consequences for drug metabolism and disease. Pharmacology61(3), 192–198 (2000).
    • 29  Forrester LM, Hayes JD, Millis R et al.: Expression of glutathione S-transferases and cytochrome P450 in normal and tumor breast tissue. Carcinogenesis11(12), 2163–2170 (1990).
    • 30  Coles B, Nowell SA, MacLeod SL, Sweeney C, Lang NP, Kadlubar FF: The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk. Mutat. Res.482, 3–10 (2001).
    • 31  Morel F, Rauch C, Coles B, Le Ferrec E, Guillouzo A: The human glutathione transferase α locus: genomic organization of the gene cluster and functional characterization of the genetic polymorphism in the hGSTA1 promoter. Pharmacogenetics12(4), 277–286 (2002).
    • 32  Pandya U, Srivastava SK, Singhal SS et al.: Activity of allelic variants of π class human glutathione S-transferase toward chlorambucil. Biochem. Biophys. Res. Common.278(1), 258–262 (2000).
    • 33  Srivastava SK, Singhal SS, Hu X, Awasthi YC, Zimniak P, Singh SV: Differential catalytic efficiency of allelic variants of human glutathione S-transferase π in catalyzing the glutathione conjugation of thiotepa. Arch. Biochem. Biophys.366(1), 89–94 (1999).
    • 34  Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L: Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol. Rev.56(2), 185–229 (2004).
    • 35  Minotti G, Recalcati S, Menna P, Salvatorelli E, Corna G, Cairo G: Doxorubicin cardiotoxicity and the control of iron metabolism: quinone-dependent and independent mechanisms. Methods Ezymol.378, 340–361 (2004).
    • 36  Olson LE, Bedja D, Alvey SJ, Cardounel AJ, Gabrielson KL, Reeves RH: Protection from doxorubicin-induced cardiac toxicity in mice with a null allele of carbonyl reductase 1. Cancer Res.63(20), 6602–6606 (2003).
    • 37  Mordente A, Meucci E, Martorana GE, Giardina B, Minotti G: Human heart cytosolic reductases and anthracycline cardiotoxicity. IUBMB Life52(1–2), 83–88 (2001).
    • 38  Innocenti F, Iyer L, Ramirez J, Green MD, Ratain MJ: Epirubicin glucuronidation is catalyzed by human UDP-glucuronosyltransferase 2B7. Drug Metab. Dispos.29(5), 686–692 (2001).
    • 39  Forrest GL, Gonzalez B: Carbonyl reductase. Chem. Biol. Interact.129(1–2), 21–40 (2000).
    • 40  Lopez dC, Marin A, Idoate MA, Tunon MT, Bello J: Carbonyl reductase and NADPH cytochrome P450 reductase activities in human tumoral versus normal tissues. Eur. J. Cancer35(2), 320–324 (1999).
    • 41  Covarrubias VG, Lakhman SS, Forrest A, Relling MV, Blanco JG: Higher activity of polymorphic NAD(P)H: quinone oxidoreductase in liver cytosols from blacks compared to whites. Toxicol. Lett. (In press) (2006).
    • 42  Lakhman SS, Ghosh D, Blanco JG: Functional significance of a natural allelic variant of human carbonyl reductase 3 (CBR3). Drug Metab. Dispos.33(2), 254–257 (2005).
    • 43  Duguay Y, Baar C, Skorpen F, Guillemette C: A novel functional polymorphism in the uridine diphosphate-glucuronosyltransferase 2B7 promoter with significant impact on promoter activity. Clin. Pharmacol. Ther.75(3), 223–233 (2004).
    • 44  Mancini M, Sedghinasab M, Knowlton K, Tam A, Hockenbery D, Anderson BO: Flow cytometric measurement of mitochondrial mass and function: a novel method for assessing chemoresistance. Ann. Surg. Oncol.5(3), 287–295 (1998).
    • 45  Conklin KA: Dietary antioxidants during cancer therapy: impact on chemotherapeutic effectiveness and development of side effects. Nutr. Cancer37, 1–18 (2000).
    • 46  Kroemer G, Petit P, Zamzami N, Vayssiere JL, Mignotte B: The biochemistry of programmed cell death. FASEB J.9(13), 1277–1287 (1995).
    • 47  Costantini P, Jacotot E, Decaudin D, Kroemer G: Mitochondrion as a novel target of anticancer chemotherapy. J. Natl Cancer Inst.92(13), 1042–1053 (2000).
    • 48  Schmitt CA, Lowe SW: Apoptosis and therapy. J. Pathol.187(1), 127–137 (1999).
    • 49  Sutton A, Khoury H, Prip-Buus C, Cepanec C, Pessayre D, Degoul F: The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics13, 145–157 (2003).
    • 50  Ambrosone CB, Freudenheim JL, Thompson PA et al.: Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants and risk of breast cancer. Cancer Res.59, 602–606 (1999).
    • 51  Woodson K, Tangrea JA, Lehman TA et al.: Manganese superoxide dismutase (MnSOD) polymorphism, α-tocopherol supplementation and prosate cancer risk in the α-tocopherol, β-carotene cancer prevention study. Cancer Causes Control14(513), 518 (2003).
    • 52  Hung RJ, Boffetta P, Brennan P et al.: Genetic polymorphisms of MPO, COMT, MnSOD, NQO1, interactions with environmental expsoures and bladder cancer risk. Carcinogenesis25, 973–978 (2004).
    • 53  Wang LI, Miller DP, Sai Y et al.: Manganese superoxide dismutase alanine-to-valine polymorphism at codon 16 and lung cancer risk. J. Natl Cancer Inst.93, 1818–1821 (2001).
    • 54  Forsberg L, Lyrenas L, deFaire U, Morgenstern R: A common functional C-T substitution polymorphism in the promoter region of the human catalase gene influences transcription factor binding, reporter gene transcription and is correlated to blood catalase levels. Free Rad Biol. Med.30, 500–505 (2001).
    • 55  Ahn J, Nowell SA, Mccann SE et al.: Associations between catalase phenotype and genotype: modification by epidemiologic factors. Cancer Epidemiol. Biomarkers Prev. (In press) (2006).• Demonstration of effects on diet and other intervening variables on genotype–phenotype associations.
    • 56  Austin GE, Lam L, Zaki SR et al.: Sequence comparison of putative regulatory DNA of the 5' flanking region of the myeloperoxidase gene in normal and leukemic bone marrow cells. Leukemia7(1445), 1450 (1993).
    • 57  Piedrafita FJ, Molander RB, Vansant G, Orlova EA, Pfahl M, Reynolds WF: An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone retinoic acid response element. J. Biol. Chem.271, 14412–14420 (1996).
    • 58  Reynolds WF, Chang E, Douer D, Ball ED, Kanda V: An allelic association implicates myeloperoxidase in the etiology of acute promyelocytic leukemia. Blood90, 2730–2737 (1997).
    • 59  Herbst RS, Khuri FR: Mode of action of docetaxel – a basis for combination with novel anticancer agents. Cancer Treat. Rev.29(5), 407–415 (2003).
    • 60  Rahman A, Korzekwa KR, Grogan J, Gonzalez FJ, Harris JW: Selective biotransformation of taxol to 6 α-hydroxytaxol by human cytochrome P450 2C8. Cancer Res.54(21), 5543–5546 (1994).
    • 61  Lyseng-Williamson KA, Fenton C: Docetaxel: a review of its use in metastatic breast cancer. Drugs65(17), 2513–2531 (2005).
    • 62  Dai D, Zeldin DC, Blaisdell JA et al.: Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics7, 597–607 (2001).
    • 63  Bahadur N, Leathart JB, Mutch E et al.: CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6α-hydroxylase activity in human liver microsomes. Biochem. Pharmacol.11, 1579–1589 (2002).
    • 64  Soyama A, Saito Y, Hanioka N et al.: Nonsynonymous single nucleotide alterations found in the CYP2C8 gene result in reduced in vitro paclitaxel metabolism. Biol. Pharm. Bull.12, 1427–1430 (2001).
    • 65  Soyama A, Hanioka N, Saito Y et al.: Amiodarone N-deethylation by CYP2C8 and its variants, CYP2C8*3 and CYP2C8 P404A. Pharmacol. Toxicol.91(4), 174–178 (2002).
    • 66  Henningsson A, Marsh S, Loos WJ et al.: Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. Clin. Cancer Res.11(22), 8097–8104 (2005).
    • 67  Nakajima M, Fujiki Y, Kyo S et al.: Pharmacokinetics of paclitaxel in ovarian cancer patients and genetic polymorphisms of CYP2C8, CYP3A4, and MDR1.J. Clin. Pharmacol.45, 674–682 (2005).
    • 68  Mandlekar S, Kong AN: Mechanisms of tamoxifen-induced apoptosis. Apoptosis6(6), 469–477 (2001).
    • 69  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.310(3), 1062–1075 (2004).
    • 70  Crewe HK, Notley LM, Wunsch RM, Lennard MS, Gillam EM: Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4'-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab. Dispos.30(8), 869–874 (2002).
    • 71  Lee KH, Ward BA, Desta Z, Flockhart DA, Jones DR: 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(1–2), 245–253 (2003).
    • 72  Stearns V, Johnson MD, Rae JM et al.: Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J. Natl Cancer Inst.95(23), 1758–1764 (2003).
    • 73  Jordan VC: Metabolites of tamoxifen in animals and man: identification, pharmacology, and significance. Breast Cancer Res. Treat.2(2), 123–138 (1982).
    • 74  Dehal SS, Kupfer D: CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Cancer Res.57(16), 3402–3406 (1997).
    • 75  Nishiyama T, Ogura K, Nakano H et al.: Reverse geometrical selectivity in glucuronidation and sulfation of cis- and trans-4-hydroxytamoxifens by human liver UDP-glucuronosyltransferases and sulfotransferases. Biochem. Pharmacol.63(10), 1817–1830 (2002).
    • 76  Ingelman-Sundberg M: Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J.5(1), 6–13 (2005).• Thorough review of CYP2D6 variants.
    • 77  Daly AK: Pharmacogenetics of the major polymorphic metabolizing enzymes. Fundam. Clin. Pharmacol.17(1), 27–41 (2003).
    • 78  Green MD, Oturu EM, Tephly TR: Stable expression of a human liver UDP-glucuronosyltransferase (UGT2B15) with activity toward steroid and xenobiotic substrates. Drug Metab. Dispos.22(5), 799–805 (1994).
    • 79  Levesque E, Beaulieu M, Green MD, Tephly TR, Belanger A, Hum DW: Isolation and characterization of UGT2B15(Y85): a UDP-glucuronosyltransferase encoded by a polymorphic gene. Pharmacogenetics7(4), 317–325 (1997).
    • 80  Nowell SA, Ahn J, Rae JM et al.: Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res. Treat.91(3), 249–258 (2005).
    • 81  Nowell S, Sweeney C, Winters M et al.: Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapy. J. Natl Cancer Inst.94(21), 1635–1640 (2002).
    • 82  Wegman P, Vainikka L, Stal O et al.: Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res.7(3), R284–R290 (2005).
    • 83  Nowell SA, de Costa GG, Wu Y et al.: Sulfation of 4-hydroxytamoxifen is a novel pathway of tamoxifen-induced apoptosis in breast cancer cell lines. Proc. Amer. Assoc. Cancer Res.46, 1258 (2005).
    • 84  Brix LA, Nicoll R, Zhu X, McManus ME: Structural and functional characterisation of human sulfotransferases. Chem. Biol. Interact.109(1–3), 123–127 (1998).
    • 85  Engelke CE, Meinl W, Boeing H, Glatt H: Association between functional genetic polymorphisms of human sulfotransferases 1A1 and 1A2. Pharmacogenetics10(2), 163–169 (2000).
    • 86  Nicholson RI, Johnston SR: Endocrine therapy – current benefits and limitations. Breast Cancer Res. Treat.93, S3–S10 (2005).
    • 87  Lizard-Nacol S, Coudert B, Colosetti P, Riedinger JM, Fargeot P, Brunet-Lecomte P: Glutathione S-transferase M1 null genotype: lack of association with tumour characteristics and survival in advanced breast cancer. Breast Cancer Res.1(1), 81–87 (1999).
    • 88  Sweeney C, McClure GY, Fares MY et al.: Association between survival after treatment for breast cancer and glutathione S-transferase P1 Ile105Val polymorphism. Cancer Res.60(20), 5621–5624 (2000).
    • 89  Sweeney C, Ambrosone CB, Joseph L et al.: Association between a glutathione S-transferase A1 promoter polymorphism and survival after breast cancer treatment. Int. J. Cancer.103, 810–814 (2003).
    • 90  Ambrosone CB, Sweeney C, Coles BF et al.: Polymorphisms in glutathione S-transferases (GSTM1 and GSTT1) and survival after treatment for breast cancer. Cancer Res.61(19), 7130–7135 (2001).
    • 91  DeMichele A, Aplenc R, Botbyl J et al.: Drug-metabolizing enzyme polymorphisms predict clinical outcome in a node-positive breast cancer cohort. J. Clin. Oncol.23(24), 5552–5559 (2005).• Interesting approach to estimating total variability in drug metabolism.
    • 92  Ambrosone CB, Ahn J, Singh KK et al.: Polymorphisms in genes related to oxidative stress (MPO, MnSOD, CAT) and survival after treatment for breast cancer. Cancer Res.65(3), 1105–1111 (2005).
    • 93  Jin Y, Desta Z, Stearns V et al.: CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J. Natl Cancer Inst.97(1), 30–39 (2005).
    • 94  Goetz MP, Rae JM, Suman VJ et al.: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J. Clin. Oncol.23(36), 9312–9318 (2005).