Pharmacogenetics and pharmacogenomics of anticancer agents

Large interindividual variation is observed in both the response and toxicity associated with anticancer therapy. The etiology of this variation is multifactorial, but is due in part to host genetic variations. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy. This review provides an overview of the progress made in the field of pharmacogenetics and pharmacogenomics using a five‐stage architecture, which includes 1) determining the role of genetics in drug response; 2) screening and identifying genetic markers; 3) validating genetic markers; 4) clinical utility assessment; and 5) pharmacoeconomic impact. Examples are provided to illustrate the identification, validation, utility, and challenges of these pharmacogenetic and pharmacogenomic markers, with the focus on the current application of this knowledge in cancer therapy. With the advance of technology, it becomes feasible to evaluate the human genome in a relatively inexpensive and efficient manner; however, extensive pharmacogenetic research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside. CA Cancer J Clin 2009;59:42–55. © 2009 American Cancer Society.

[1]  Julian Peto,et al.  A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3 , 2008, Nature Genetics.

[2]  H. McLeod,et al.  The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics. , 2002, Pharmacogenomics.

[3]  Urs A. Meyer,et al.  Pharmacogenetics – five decades of therapeutic lessons from genetic diversity , 2004, Nature Reviews Genetics.

[4]  D. Gurwitz,et al.  clinical practice: a case study of thiopurine methyltransferase genotyping in acute lymphoblastic leukemia in Europe , 2006 .

[5]  David Goldman,et al.  Alcoholism: genes and mechanisms. , 2004, Pharmacogenomics.

[6]  S. Cha,et al.  Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  F. Couch,et al.  A Two-Gene Expression Ratio of Homeobox 13 and Interleukin-17B Receptor for Prediction of Recurrence and Survival in Women Receiving Adjuvant Tamoxifen , 2006, Clinical Cancer Research.

[8]  E. Winer,et al.  Pharmacogenomic variation of CYP2D6 and the choice of optimal adjuvant endocrine therapy for postmenopausal breast cancer: a modeling analysis. , 2008, Journal of the National Cancer Institute.

[9]  A. Gaedigk,et al.  The CYP2D6 Activity Score: Translating Genotype Information into a Qualitative Measure of Phenotype , 2008, Clinical pharmacology and therapeutics.

[10]  M. Ratain.  From Bedside to Bench to Bedside to Clinical Practice: An Odyssey with Irinotecan , 2006, Clinical Cancer Research.

[11]  M. Stratton,et al.  COSMIC 2005 , 2006, British Journal of Cancer.

[12]  R. Weinshilboum,et al.  Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. , 1980, American journal of human genetics.

[13]  M. Schrappe,et al.  Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. , 2005, JAMA.

[14]  W. Petros,et al.  Pharmacogenomics in cancer therapy: is host genome variability important? , 2004, Trends in pharmacological sciences.

[15]  S. Groshen,et al.  Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy , 2001, The Pharmacogenomics Journal.

[16]  Michel Eichelbaum,et al.  Pharmacogenomics and individualized drug therapy. , 2006, Annual review of medicine.

[17]  D. Neuberg,et al.  Polymorphisms in ERCC1 and Grade 3 or 4 Toxicity in Non–Small Cell Lung Cancer Patients , 2005, Clinical Cancer Research.

[18]  F. Demard,et al.  Influence of sex and age on fluorouracil clearance. , 1992, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  S. Gabriel,et al.  Whole-genome association study of bipolar disorder , 2008, Molecular Psychiatry.

[20]  R. Bast,et al.  American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  United States General Accounting Office GAO Report to Congressional Requesters January 2000 ADVERSE DRUG EVENTS The Magnitude of Health Risk Is Uncertain Because of Limited Incidence Data , 2022 .

[22]  F. Demard,et al.  Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. , 1992, Cancer research.

[23]  P. Watkins,et al.  Pharmacogenetics and clinical gastroenterology. , 2003, Gastroenterology.

[24]  C. Kitagawa,et al.  Rapid detection of UGT1A1 gene polymorphisms by newly developed Invader assay. , 2004, Clinical chemistry.

[25]  M Ingelman-Sundberg,et al.  Cytochrome P450 pharmacogenetics and cancer , 2006, Oncogene.

[26]  M. Olivier.  A haplotype map of the human genome , 2003, Nature.

[27]  Y. Cheung,et al.  Pharmacogenetic profiling across the irinotecan pathway in Asian patients with cancer. , 2005, British journal of clinical pharmacology.

[28]  H. Dressman,et al.  Genomic signatures to guide the use of chemotherapeutics , 2006, Nature Medicine.

[29]  H. McLeod,et al.  Should DPD analysis be required prior to prescribing fluoropyrimidines? , 2007, European journal of cancer.

[30]  D Lindhout,et al.  The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. , 1995, The New England journal of medicine.

[31]  J. Meyerhardt,et al.  Relationship of baseline serum bilirubin to efficacy and toxicity of single-agent irinotecan in patients with metastatic colorectal cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  V. Jordan,et al.  A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. , 1977, The Journal of endocrinology.

[33]  D. Tregouet,et al.  Thymidylate Synthase Gene Polymorphism Predicts Toxicity in Colorectal Cancer Patients Receiving 5-Fluorouracil-based Chemotherapy , 2004, Clinical Cancer Research.

[34]  Shiwei Duan,et al.  Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach. , 2007, American journal of human genetics.

[35]  A. V. van Kuilenburg,et al.  Increased risk of grade IV neutropenia after administration of 5‐fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: High prevalence of the IVS14+1g>a mutation , 2002, International journal of cancer.

[36]  M. Ratain,et al.  Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. , 1998, The Journal of clinical investigation.

[37]  S. Kuo,et al.  Expression of rTSbeta as a 5-fluorouracil resistance marker in patients with primary breast cancer. , 2008, Oncology reports.

[38]  S D Hall,et al.  Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily. , 1994, Biochemical pharmacology.

[39]  J. Lupski,et al.  The complete genome of an individual by massively parallel DNA sequencing , 2008, Nature.

[40]  R. Weinshilboum,et al.  Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia , 1990, The Lancet.

[41]  F. Innocenti,et al.  Translation of pharmacogenetic knowledge into cancer therapeutics. , 2007, Clinical advances in hematology & oncology : H&O.

[42]  O. Dassonville,et al.  [Population study of dihydropyrimidine dehydrogenase in cancer patients]. , 1994, Bulletin du cancer.

[43]  N. Martin,et al.  "No thanks, it keeps me awake": the genetics of coffee-attributed sleep disturbance. , 2007, Sleep.

[44]  D. Macaya,et al.  The incidence of duplicate genetic testing , 2008, Genetics in Medicine.

[45]  D. Bates,et al.  Error in Medicine: What Have We Learned? , 2000, Annals of Internal Medicine.

[46]  R. Collins,et al.  SLCO1B1 variants and statin-induced myopathy--a genomewide study. , 2008, The New England journal of medicine.

[47]  S. Wingren,et al.  Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer , 2007, Breast Cancer Research.

[48]  Aiming Yu,et al.  Cytochrome P450 Pharmacogenetics , 2003 .

[49]  R. Herrmann,et al.  Relative importance of dose, body surface area, sex, and age for 5-fluorouracil clearance. , 1991, Oncology.

[50]  B. Obama,et al.  The genomics and Personalized Medicine Act of 2006. , 2007, Clinical advances in hematology & oncology : H&O.

[51]  Yusuke Nakamura,et al.  Impact of CYP2D6*10 on recurrence‐free survival in breast cancer patients receiving adjuvant tamoxifen therapy , 2008, Cancer science.

[52]  W. Ichikawa,et al.  Orotate Phosphoribosyltransferase Gene Polymorphism Predicts Toxicity in Patients Treated with Bolus 5-Fluorouracil Regimen , 2006, Clinical Cancer Research.

[53]  Magnus Ingelman-Sundberg,et al.  Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. , 2007, Pharmacology & therapeutics.

[54]  M. Maitland,et al.  TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy? , 2006, Trends in pharmacological sciences.

[55]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[56]  C. Lerman,et al.  Genetics and smoking behavior , 2007, Current psychiatry reports.

[57]  R. Diasio,et al.  Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. , 1993, Cancer research.

[58]  Catherine Legrand.  1687Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials : Early Breast Cancer Trialists' Collaborative Group (EBCTCG) , 2005 .

[59]  G. Scagliotti,et al.  Thymidylate Synthase Expression in Gastroenteropancreatic and Pulmonary Neuroendocrine Tumors , 2008, Clinical Cancer Research.

[60]  E. Winer,et al.  Re: Pharmacogenomic Variation of CYP2D6 and the Choice of Optimal Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A Modeling Analysis , 2008 .

[61]  M. Ratain,et al.  Haplotypes of variants in the UDP-glucuronosyltransferase1A9 and 1A1 genes , 2005, Pharmacogenetics and genomics.

[62]  Wolfgang Simon,et al.  Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  H. Okuda,et al.  Lethal drug interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[64]  Linnea M Baudhuin,et al.  Comparison of three methods for genotyping the UGT1A1 (TA)n repeat polymorphism. , 2007, Clinical biochemistry.

[65]  R. Diasio,et al.  Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity. , 1988, The Journal of clinical investigation.

[66]  M. Buyse,et al.  Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[67]  J. Verweij,et al.  Irinotecan‐induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein , 2007, Clinical pharmacology and therapeutics.

[68]  J. Schellens,et al.  Genetic Polymorphisms of Drug-Metabolising Enzymes and Drug Transporters in the Chemotherapeutic Treatment of Cancer , 2006, Clinical pharmacokinetics.

[69]  M. Rothenberg.  Efficacy and toxicity of irinotecan in patients with colorectal cancer. , 1998, Seminars in oncology.

[70]  Timothy B. Stockwell,et al.  The Diploid Genome Sequence of an Individual Human , 2007, PLoS biology.

[71]  David A. Flockhart,et al.  The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen , 2006, Breast Cancer Research and Treatment.

[72]  J. Woodcock,et al.  Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective , 2004, Nature Reviews Drug Discovery.

[73]  M. Eileen Dolan,et al.  A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity , 2007, Proceedings of the National Academy of Sciences.

[74]  E. Cook,et al.  Heritability and Linkage Analysis of Sensitivity to Cisplatin-Induced Cytotoxicity , 2004, Cancer Research.

[75]  S. Duan,et al.  Mapping genes that contribute to daunorubicin-induced cytotoxicity. , 2007, Cancer research.

[76]  Sharon Marsh,et al.  Thymidylate synthase pharmacogenetics , 2005, Investigational New Drugs.

[77]  James D. Brooks,et al.  Multiple loci identified in a genome-wide association study of prostate cancer , 2008 .

[78]  G. Milano,et al.  Methylenetetrahydrofolate reductase (MTHFR) variants and fluorouracil-based treatments in colorectal cancer. , 2007, Pharmacogenomics.

[79]  A. Griffiths.  Introduction to Genetic Analysis , 1976 .

[80]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[81]  Jukka Corander,et al.  CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure , 2007, Pharmacogenetics and genomics.

[82]  David A. Flockhart,et al.  CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. , 2005, Journal of the National Cancer Institute.

[83]  Y Wang,et al.  Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials , 2005, The Lancet.

[84]  K. Chansky,et al.  Differences in toxicity between men and women treated with 5‐fluorouracil therapy for colorectal carcinoma , 2005, Cancer.

[85]  Michelle Meadows,et al.  Genomics and personalized medicine. , 2005, FDA consumer.

[86]  Michel Eichelbaum,et al.  Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. , 2004, Pharmacogenetics.

[87]  Shufeng Zhou.  Clinical pharmacogenomics of thiopurine S-methyltransferase. , 2006, Current clinical pharmacology.

[88]  S. Lundgren,et al.  Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[89]  D. Boomsma,et al.  Inherited susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes. , 1999, Journal of the National Cancer Institute.

[90]  Fergus J Couch,et al.  Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[91]  P. Soulié,et al.  Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance , 2006, Molecular Cancer Therapeutics.

[92]  Zeruesenay Desta,et al.  Endoxifen, a Secondary Metabolite of Tamoxifen, and 4-OH-Tamoxifen Induce Similar Changes in Global Gene Expression Patterns in MCF-7 Breast Cancer Cells , 2006, Journal of Pharmacology and Experimental Therapeutics.

[93]  Aldi Kraja,et al.  Genome-wide discovery of loci influencing chemotherapy cytotoxicity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[94]  M. Olivier.  A haplotype map of the human genome. , 2003, Nature.

[95]  Joseph G Ibrahim,et al.  UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. , 2007, Journal of the National Cancer Institute.

[96]  Minetta C. Liu,et al.  Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling , 2003, Oncogene.

[97]  K. Christensen,et al.  What genome-wide association studies can do for medicine. , 2007, The New England journal of medicine.

[98]  Alexander F. Wilson,et al.  Heritability of Platelet Responsiveness to Aspirin in Activation Pathways Directly and Indirectly Related to Cyclooxygenase-1 , 2007, Circulation.

[99]  Cheng Cheng,et al.  Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. , 2004, The New England journal of medicine.

[100]  E. Shin,et al.  Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[101]  U. Hofmann,et al.  Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[102]  M. Dolan,et al.  Identifying genetic variants that contribute to chemotherapy-induced cytotoxicity. , 2007, Pharmacogenomics.

[103]  M. Volm,et al.  Pharmacogenetics for individualized cancer chemotherapy. , 2005, Pharmacology & therapeutics.

[104]  R. Schiff,et al.  Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. , 2008, Cancer research.

[105]  H. McLeod,et al.  Characterization of the human dihydropyrimidine dehydrogenase gene. , 1998, Genomics.

[106]  D. Flockhart,et al.  Germline pharmacogenetics of tamoxifen response: have we learned enough? , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[107]  Hyunyoung Jeong,et al.  Use of the erythromycin breath test for in vivo assessments of cytochrome P4503A activity and dosage individualization , 2001, Clinical pharmacology and therapeutics.

[108]  N. Meropol,et al.  UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.