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Pharmacogenetics and Pharmacogenomics Kevin Zbuk, MD Medical Oncologist Juravinski Cancer Centre McMaster University.

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Presentation on theme: "Pharmacogenetics and Pharmacogenomics Kevin Zbuk, MD Medical Oncologist Juravinski Cancer Centre McMaster University."— Presentation transcript:

1 Pharmacogenetics and Pharmacogenomics Kevin Zbuk, MD Medical Oncologist Juravinski Cancer Centre McMaster University

2 Outline Introduction and definitions Basic concepts Case studies Conclusions

3 Pharmacogenetic versus Pharmacogenomic No universally accepted definitions of either Often used interchangeably Pharmacogenetics used for more than 40 years to denote the science about how heritability affects the response to drugs. Pharmacogenomics is new science about how the systematic identification of all the human genes, their products, interindividual variation, intraindividual variation in expression and function over time affects drug response/metabolism etc. The term pharmacogenomics was coined in connection with the human genome project Most use pharmacogenetics to depict the study of single genes and their effects on interindividual differences in (mainly) drug metabolising enzymes, and pharmacogenomics to depict the study of not just single genes but the functions and interactions of all genes in the genome in the overall variability of drugs response

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6 Pharmacogenetics “Pharmacogenetics is the study of how genetic variations affect the disposition of drugs, including their metabolism and transport and their safety and efficacy” J. Hoskins et. al NRC 2009

7 Pharmacogenetics involves both PK and PD Pharmacokinetic “The process by which a drug is absorbed, distributed, metabolized, and eliminated by the body” Pharmacodynamic “the biochemical and physiological effects of drugs and the mechanisms of their actions”

8 Goals of Pharmacogen(etics)omics Maximize drug efficacy Minimize drug toxicity Predict patients who will respond to intervention Aid in new drug development

9 The Hope of Pharmacogenomics Individuals genetic makeup with allow selective use of medications such that – Efficacy maximized – Side effect minimized

10 This is the hope/hype

11 In the Beginning Mendelian genetics “single gene – single disease” – single wild type allele and single disease allele – Patterns of inheritance included autosomal dominant (need only one disease allele) and autosomal recessive (need two disease alleles) Followed soon thereafter by additive (co- dominant) model – Both alleles contribute to phenotype

12 Dominant/Recessive

13 Co-dominance

14 Empiric observations suggesting Pharmacogenetics important Clinical response to many drugs varies widely amongst individuals Same drug-> same dose -> same indication in different individuals – Some respond – Some don’t – Some don’t respond and have serious toxicity

15 EARLY PK EXAMPLES

16 The beginning of pharmacogenetics 1950s – “Inheritance might explain variation in individuals response and adverse effects from drugs” Motulsty – “Pharmacogenetics defined as “study of role of Genetics in drug response” Vogel – Most of studies for next several decades of “high penetrance monogenic” gene-drug interactions – Def: Monogenetic disease. Mutation at single locus sufficient to result in disorder

17 Penetrance Penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. – Eg. if a mutation in the gene responsible for a particular autosomal dominantdisorder has 95% penetrance, then 95% of those with the mutation will develop the disease, while 5% will not.

18 Victor McKusick Established Online Mendelian Inheritance in Man in early 80s Categorized majority of Mendelian Disorders Became very clear that there are many different disease alleles for many disorders (allelic heterogeneity) Recently many disorders have associated modifier genes that modify disease phenotype – Eg. Age-of-onset and severity

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20 Example 1- Success of Pharmacogenetics in Oncology TPMT

21 Main metabolizer of chemotherapeutic agents 6MP and azothiopurine (used mainly in blood based malignancies) TPMT deficiency leads to severe toxicity associated with treatment (potential mortality)

22 TPMT enzyme activity distribution

23 Hematologic toxicity according to TPMT genotype

24 Evans Nature Reviews Cancer 2006

25 FDA approved pharmacogenetic tests GeneDrugConsequence TPMT6MPToxicity CYP2D6TamoxifenDecreased efficacy UGT1A1IrinotecanToxicity CYP2D6CodeineIneffective analgesia These genes all modulate Pharmokinetics

26 Contribution of High Penetrance Monogenic Model to PG Contribution likely not as large as initially anticipated For most pharmacologic traits might be 15-20% at most – Could consider this penetrance Redundancy likely a major contributing factor MANY ENZYMES INVOLVED IN DRUG METABOLISM WITH MANY ALTERNATE PATHWAYS Dichotomous disease versus quantitative trait Much more likely polygenic model with gene- environment interactions

27 Some of it ain’t genetic Age Co-morbidities Renal and hepatic function (dysfunction) Concomitant medications Diet and smoking

28 Common Disease Common Variant Hypothesis Most complex diseases are strongly influenced by combination of frequent alleles that each only exert modest effect

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30 Approach to polygenic pharmacogenomic traits

31 Polygenic Model and PG Elucidation unlikely possible before advances in genomics Technologic advances – High throughput sequencing of DNA – Affordable genotyping of 100ks to 1-2M SNPs Genomic knowledge advances: – Especially Human Genome Project and HapMap Projects

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39 Cost of Genotyping In 2005 (5 years ago!) – $1600 to genotype 250K SNPs in one individual 2009 – $250 to genotype >1Million SNPs 2014 -$200-250 to genotype >5 millions SNPs

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43 Hapmap project There are an estimated 10 million SNPs with MAF >1% Hapmap project genotyped Chinese, Japanese, African and European individuals (families)

44 HapMap Project Phase 1Phase 2Phase 3 Samples & POP panels 269 samples (4 panels) 270 samples (4 panels) 1,115 samples (11 panels) Genotyping centers HapMap International Consortium PerlegenBroad & Sanger Unique QC+ SNPs 1.1 M3.8 M (phase I+II) 1.6 M (Affy 6.0 & Illumina 1M) ReferenceNature (2005) 437:p1299 Nature (2007) 449:p851 Draft Rel. 3 (2010)

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46 A more in depth look at PK in clinical practice Tamoxifen use and CYP2D6

47 Tamoxifen metabolism Needs to be converted to endoxifen to be active – catalysed by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6) – 6-10% European population deficient in this enzyme Efficacy of tamoxifen likely low in this population Suggests consider alterative treatments

48 J. Hoskins et. al NRC 2009

49 About the CYPs Membrane bound enzymatic proteins – Involved in oxidation, peroxidation and reductive metabolism – Responsible for >90% of drug transformation Greater than 50 different CYP genes encoding 50 different proteins CYP2D6 present mainly in liver and a major player in drug metabolism from antidepressants to antihypertensive to chemotherapy

50 Evolution of CYP nomenclature Initially astute clinical observation of unusual drug response Such responses then found to be heritable Early example of phenotype to genotype approach CYP2D6 polymorphism the first described Increasing recognition of poor metabolizer phenotype occurred at time that genotyping technology in evolution

51 About CYP2D6 Location 22q 13.1 P arm Q arm

52 CYP2D6 alleles There are >70 described in this gene – Bottom line: variants either cause no change, decrease somewhat, or significantly decrease metabolism Extensive metabolizers ( EM), intermediate (IM) metabolizers, and poor metabolizers (PM) EM is the standard metabolism allele against which others are compared (consider it the wild type)

53 Hoskins et al. Nature Reviews Cancer 2009

54 CYP2D6 alleles Copy Number Variation Throughout the genome there are areas of DNA that are represented in variable copies in individuals (CNV) CYP2D6 is one such area Up to 16 copies seen in some individuals – “NORMAL VARIANT” ULTRARAPID METABOLIZERS

55 Consequence of CYP2D6 alleles? EM/EM or EM/IM(PM) normal metabolizers IM/IM or IM/PM intermediate metabolizers PM/PM poor metabolizers Poor/(Intermediate) metabolizers have much lower levels of endoxifen than intermediate/ rapid metabolizers

56 CYP2D6 Genotype and clinical outcomes Several (small trials) have suggested decreased efficacy of Tamoxifen in poor (intermediate) metabolizers both in adjuvant therapy and in treatment of metastatic disease (see Hoskins NRC 2009 for details) – All retrospective – Largest was only statistically significant association in univariate analysis – In additions several trials have not confirmed these results

57 Reasons for discordant results in CYP2D6 trials Did not genotype many of the rarer poor metabolizer alleles Did not account for concurrent use of other drugs metabolized by CYP2D6 in many cases Different dose of Tamoxifen in several trials Did not assay endoxifen levels Power (poor metabolizers rare) Unknown variants in other genes whose products involved in tamoxifen metabolism

58 So what is needed to clarify the issue of relevance of CYP2D6 genotype and clinical relevance? Large randomized trial that compares standard dosing of tamoxifen to genotype adjusted dosing Until that point clinical utility of testing (commerically available) unclear – Should recommend avoiding SSRIs that inhibit CYP2D6 significantly (see later)

59 Provocative thoughts In post-menopausal breast cancer tamoxifen is falling out of favor due to the efficacy of Aromatase Inhibitors (inhibit extragonadal production of estrogen) – AI shows increased efficacy c/w tamoxifen BUT MUCH MORE EXPENSIVE AND DIFFERENT S/E PROFILE Some suggestion that increased efficacy of AI completely explained by decreased efficacy of Tamoxifen in CYP2D6 IM and PM – Punglia (2008) JNCI

60 More relevant to pre-menopausal woman Can’t use AI alone In poor metabolizer could consider – Increased dose??? – Alternative estrogen receptor modulator not metabolized by CYP2D6 (eg. raloxifen) – Consider AI with ovarian ablation (chemical or otherwise)

61 Ethnic Differences in IM and PM of CYP2D6 PM alleles more common in European population IM alleles much more common in East Asian and African population – In East Asians Intermediate Metabolizers show similar in vitro CYP2D6 activity c/w Poor Metabolizers in European populations Gene-gene or gene-environment interactions

62 Drug Co-administration Antidepressant use common in breast cancer patients – Depression more common in breast cancer patients and antidepressant often used to treat how flashes associated with tamoxifen use SSRIs (eg. Fluoxetine and paroxetine) inhibit CYP2D6 Level of inhibition varies between different drugs with paroxetine having most inhibition and venlafaxine causing none Kelly et al. BMJ 2010 – Population based cohort study of women receiving tamoxifen adjuvantly for treatment breast cancer – Mortality from breast cancer increased in group using paroxtetine concurrent with tamoxifen

63 Irinotecan – PK example in Colon Cancer Excreted after conjugation (glucuronidation) by UGT1A1 TATA element (consists of TA repeats) in UGT1A1 promoter shows correlation with transcription levels – More repeats lower transcription levels – An example of a non-SNP variant with clinical relevance Homozygosity for 7-repeat allele, also known as UGT1A1*28 associated with severe toxicity (diarrhea and low WBC counts mainly) – Results have been somewhat inconsistent but meta-analysis confirms same especially with higher doses of Irinotecan – Homozygosity only in 5-15% of individuals

64 PD example in Colon Cancer Treatment EGFR inhibitors used in treatment of advanced colon cancer (eg. Cetuximab) Tumors with k-RAS (and probably BRAF) mutations will NOT respond to EGFR inhibition Nature Rev. Cancer July 2009

65 Review Paper by Pare et al.

66 Effect of Clopidogrel as Compared with Placebo on Clinical Outcomes among Patients with Acute Coronary Syndromes in the CURE trial, Stratified According to Metabolizer Phenotype. Paré G et al. N Engl J Med 2010;363:1704-1714

67 Kaplan–Meier Curves for Event-free Survival According to CYP2C19 Loss-of-Function and Gain-of-Function Allele Carrier Status among European and Latin American Patients with Acute Coronary Syndromes in the CURE Trial. Paré G et al. N Engl J Med 2010;363:1704-1714

68 Effect of Clopidogrel as Compared with Placebo on Clinical Outcomes among Patients with Atrial Fibrillation in ACTIVE A, Stratified According to Metabolizer Phenotype. Paré G et al. N Engl J Med 2010;363:1704-1714

69 Kaplan–Meier Curves for Event-free Survival According to CYP2C19 Loss-of-Function and Gain-of-Function Allele Carrier Status among European Patients with Atrial Fibrillation in ACTIVE A. Paré G et al. N Engl J Med 2010;363:1704-1714

70 Baseline Characteristics of Genotyped Patients in the CURE and ACTIVE A Trials. Paré G et al. N Engl J Med 2010;363:1704-1714

71 Why is pharmacogenomics not widely utilized in the clinic It required a shift in clinician attitude and beliefs “not one dose fits all” Paucity of studies demonstrating improved clinical benefit from use of pharmacogenomic data – Still much to be learned Even some of the black block warnings currently on drug labels may be overcalls of importance Genome wide interrogation will likely be important to get the entire picture

72 Conclusion Genetic variation contributes to inter-individual differences in drug response phenotype at every pharmacologic step Through individualized treatments, pharmacogenetics and pharmacogenomics are expected to lead to: Better, safer drugs the first time More accurate methods of determining appropriate drug dosages Pharmacogenomics offers unprecedented opportunities to understand the genetic architecture of drug response HOWEVER IN MANY CASES NOT YET READY FOR PRIME TIME!!!


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