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Pharmacogenomics Eric Jorgenson.

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Presentation on theme: "Pharmacogenomics Eric Jorgenson."— Presentation transcript:

1 Pharmacogenomics Eric Jorgenson

2 Outline Introduction Pharmacogenetics Pharmacogenomics TPMT CYP2D6
GWAS Gene Expression

3 What is Pharmacogenetics?
The study of the role of inheritance in the individual variation in drug response. Efficacy Toxicity

4 Adverse Drug Reactions are common
Phillips et al. JAMA 2001

5 Events in Pharmacogenetics
Meyer Nature Reviews Genetics 2004

6 PTC and Pharmacogenetics
Meyer Nature Reviews Genetics 2004

7 Bimodal Distribution of PTC
No Toxicity Non-Responders Toxicity Responders

8 Diplotype and PTC Score
Kim et al. Science 2003

9 Adapted from Bufe et al. Current Biology 2005

10 Pharmacogenetic Study Design
Family Studies Linkage Analysis Candidate Gene Studies Family and Linkage are difficult to do for some phenotypes: Severe toxicity Rare diseases (need multiple affected family members)

11 Drug transport, targeting, and metabolism

12 Pharmacodynamics How a drug acts Drug target

13 Pharmacokinetics How a drug is processed ADME Drug Levels (dosage)
Absorption Distribution Metabolism Excretion Drug Levels (dosage) Efficacy Toxicity

14 Drug levels in the body Plasma concentration Metabolic Ratio
Compare blood vs. urine Probe drug Can be measured over time

15 Outline Introduction Pharmacogenetics Pharmacogenomics TPMT CYP2D6
GWAS Gene Expression

16 TPMT and 6-mercaptopurine

17 Thiopurine S-methyltransferase (TPMT)
Drugs: 6-mercaptopurine azathiopurine Diseases: Acute lymphoblastic leukemia Inflammatory bowel disease Toxicity: Fatal myelosuppression Hematopoietic toxicity

18 Pharmacogenetics of TPMT

19 TPMT Haplotypes and Activity

20 Standard TPMT Dosing

21 Drug Exposure and Toxicity

22 Genotype Specific TPMT Dosing

23 Drug Exposure and Toxicity

24 More on TPMT Pharmacogenetics Knowledge Base (PharmGKB)

25 Pharmacogenetics of CYP2D6
Weinshilboum NEJM 2003

26 CYP2D6 Copy Number Variation
Meyer Nature Reviews Genetics 2004

27 Pharmacogenetics of Nortriptyline
Weinshilboum NEJM 2003

28 CYP2D6 and Race/Ethnicity

29 Pharmacogenetics and Race/Ethnicity
Weinshilboum NEJM 2003

30 Drug Metabolism and ADRs

31 GenotypePhenotype Studies
Survey genetic variation in genes of interest Test genetic variants in laboratory studies Recruit subjects with known variant genotypes Pharmacogenomics of Membrane Transporters (PMT)

32 Outline Introduction Pharmacogenetics Pharmacogenomics TPMT CYP2D6
GWAS Gene Expression

33 Pharmacogenetics and Pharmacogenomics

34 What is Pharmacogenomics and how is it different from Pharmacogenetics?
Genomic scale Array based platforms

35 Pharmacogenomics Evans and Relling Nature 2004

36 GWAS of Statin-Induced Myopathy

37 Quantile-Quantile (QQ) Plot

38 Manhattan Plot

39 Odds ratios for rs

40 Cumulative risk of myopathy

41 GWAS of Platelet Aggregation in Response to Clopidogrel

42 Platelet Aggregation in Response to Clopidogrel
Shuldiner et al. JAMA 2009

43 Dubai Plot

44 CYP2C19*2 modifies platelet aggregation in response to clopidogrel

45 Event-free survival

46 3 GWAS of sustained virological response to PEGylated interferon- and ribavirin

47 Manhattan Plot Tanaka et al. Nature Genetics 2009

48 Variation in Il28B predicts Sustained Virological Response in Hepatitis C
Ge Nature Genetics 2009

49 Haplotype effects Supiah et al. Nature Genetics 2009

50 GWAS of acenocoumarol mainenance dosage

51 Acenocoumarol maintenance dosage
Teichert et al. Human Molecular Genetics 2009

52 Acenocoumarol maintenance dosage adjusted for top SNPs

53 Acenocumarol dosage variance explained

54 ROC Curves Attia et al. JAMA 2009

55 Challenges for Pharmacogenomics
How predictive is a test? Does the test apply to all groups? Is a test superior to current clinical practice? Will testing improve outcomes? Is testing cost effective?

56 Oncotype uses 21 genes to calculate a recurrence score
16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 BAG1 GSTM1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC CD68 The final gene set used for the Oncotype DX assay includes the 16 cancer genes identified in the clinical trials: 5 genes are in the proliferation group, 2 in the HER2 group, 4 in the estrogen receptor group, 2 in the invasion group, and 3 are unaligned. Some of the genes are well known in the breast cancer literature; others are relatively new. The 5 reference genes are used for normalizing the expression of the cancer-related genes. The 16 genes presented in this slide were selected for the Oncotype DX™ assay based on the three clinical trials, which demonstrated a consistent statistical link between these genes and distant breast cancer recurrence and the most robust predictive power across the three studies. Paik et al. N Engl J Med. 2004;351:

57 Oncotype Recurrence Score
RS is 30. What is the chance of recurrence within 10 years? The likelihood of distant recurrence at 10 years increases continuously with increase in Recurrence Score. Patients with a Recurrence Score of 3 have a much lower risk of distant recurrence than patients with a Recurrence Score of 17, even though both have scores in the “low risk” group. The use of the Recurrence Score as a continuous predictor provides an estimate of the likelihood of distant recurrence at 10 years (mean and 95% CI) that is accurate and precise. In the example presented in this slide, the patient has a Recurrence Score of 30; therefore, the risk of a distant recurrence at 10 years for this patient is 20% [95% confidence interval (CI): 15%, 24%] 95% CI

58 Recurrence Score and 10-Year Distant Recurrence-Free Survival
Of the 675 available blocks in the NSABP library, 668 underwent successful evaluation with RT-PCR, representing a 99% success rate. This graph demonstrates the difference in DRFS over time for the different risk categories. The distant recurrence-free survival for the high- and low-risk groups were statistically significantly different; the 10-year distant recurrence-free survival for the low-risk category was 93% compared to 69% for the high-risk category. Paik et al. N Engl J Med. 2004;351:

59 Summary of Treatment Benefit Related to RS and Breast Cancer Death in NSABP B-14 and B-20
Shown here are the Kaplan-Meier estimates of the risk of breast cancer death at 10 years for the NSABP B-14 and B-20 studies The results on top are for patients in the B-14 arm with no systemic therapy. The results in the middle are the patients treated with hormonal therapy, both in B-14 tam and in B-20 tam. The results at the bottom are for patients treated with hormonal therapy plus chemotherapy in NSABP B-20. The Recurrence Score is optimized for hormonal therapy-treated patients and you can see in the middle the greatest discrimination, and that low-risk patients are low risk; intermediate-risk patients are intermediate; and high-risk patients are high risk.

60 Largest Tamoxifen Benefit Observed in Low- and Intermediate-Risk Recurrence Score Groups
This slide indicates important trends. The largest benefits of tamoxifen are observed in the low-risk and the intermediate-risk patients. One should not expect a large benefit of tamoxifen for patients in the high-risk group.

61 Largest Chemotherapy Benefit Observed in High-Risk Recurrence Score Group
This slide indicates important trends. The largest benefits of chemotherapy are observed in the high-risk patients. In ER-positive breast cancer (also known as luminal breast cancer), molecular expression can discriminate a continuous distribution of tumor types. Tumors with low Recurrence Scores are less likely to recur, tend to benefit from hormonal therapy, and benefit little, if any, from chemotherapy. Breast cancers with high Recurrence Scores are likely to recur, have less benefit from hormonal therapy, but actually benefit the most from chemotherapy.

62 Chemotherapy benefit in high RS patients
28% Absolute Benefit Little, if any, benefit All patients Low RS High RS Intermediate RS These results indicate that not all women benefit equally from chemotherapy. (A)- shows all 651 patients within this trial showing the overall benefit of chemotherapy in these evaluable patients of 4.4% absolute benefit from tamoxifen + chemotherapy. Is this small overall benefit due to a little benefit in many or most of the patients, or is this small benefit due to a large benefit in a subset of the patients? (These results recapitulate the seminal findings from the original B-20 study (Fisher B, Dignam J, Wolmark N, et al. J Natl Cancer Inst. 1997;89: ) which helped open the door to widespread use of adjuvant cytotoxic therapy for this population. (D)The results in patients in the high-risk group (Recurrence Score >31) are shown here. It appears that much of the benefit associated with CMF therapy in the B-20 study was a function of the risk reduction experienced by this high-risk cohort, which represents approximately 25% of the population. The high-risk patients have a large benefit (28% absolute) from the addition of chemotherapy. (B) The results in patients in the low-risk group (Recurrence Score <18) are shown here. These patients have a very low likelihood of distant recurrence. The difference between the tamoxifen alone and tamoxifen plus chemotherapy groups is not statistically significant, so the benefit of chemotherapy appears to be minimal, if any. (C)The results in patients in the intermediate-risk group (Recurrence Score 18-30) are shown here. The patients in the intermediate-risk group, as expected, had a higher risk of distant recurrence than those in the low-risk group. The benefit of chemotherapy in the intermediate-risk patients does not appear to be large and remains unclear. We will be addressing this intermediate risk group later in our discussion (TAILORx) This type of assay helps to inform decisions about patient management. For example, patients at high risk of recurrence and/or with large chemotherapy benefit may decide, together with their physicians, to receive appropriate chemotherapy. While those at low risk and/or with little chemotherapy benefit may decide, together with their physicians, to avoid to unwanted toxicities associated with chemotherapy. Paik et al. J Clin Oncol. 2006;24:


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