Pharmacogenomics and Pharmacoepidemiology
Slide 1 of 32: Interventional Pharmacogenetics: Moving the Science into Practice
Howard L. McLeod
Eshelman Distinguished Professor and Director
Institute for Pharmacogenomics and Individualized Therapy (IPIT)
UNC – Chapel Hill, NC
July 21, 2009
Slide 2 of 32: The Clinical Problem
- Multiple active regimens for the treatment of most diseases
- Variation in response to therapy
- Unpredictable toxicity
- With choice comes decision
Slide 3 of 32: What Needs to be Done to Determine Hope Vs. Hype?
- Find the 'right' biomarkers
- Validate in robust datasets
- Apply them!
Slide 4 of 32: We Do Not Know Very Much About Drugs
[Image] depicting irinotecan metabolism.
Slide 5 of 32: Discovery Strategies
[Images] of model systems, HapMap, linkage, association, and expression arrays as examples of discovery strategies.
Slide 6 of 32: Centre d’Etude du Polymorphisme Human (CEPH) Cell Lines
- Large, multigeneration pedigrees widely studied
- Immortalized lymphoblastoid cell lines
[Images] of the CEPH/French Pedigree 35 and the CEPH/Utah Pedigree 1416.
Slide 7 of 32: Methodology
- Cells counted, plated at 1 x 104 / well
- Cells incubated with increasing concentrations of drug
- Alamar blue vital dye indicator added
- Viability relative to untreated control calculated by spectrophotometry
[Image] of a plate used in mass spectrometry
Slide 8 of 32: Docetaxel
Microtubule stabilizing agent used to treat lung, breast tumors
[Images] of docetaxel chemical structure.
Slide 9 of 32: Significant Variation in Cellular Sensitivity to Docetaxel
[Image] of two graphs displaying significant variation in cellular sensitivity to docetaxel based on the analysis of 427 cell lines, 38 CEPH reference pedigrees.
Slide 10 of 32: Docetaxel Cytotoxicity is a Heritable Trait!
[Image] of graph of relative cell viability for various concentrations of docetaxel.
Source: Watters et al. Proc Natl Acad Sci U S A. 2004;101(32):11809-14. Copyright 2004 National Academy of Sciences, U.S.A.
Slide 11 of 32: ‘CE-PH/F-DA’ Project
- 126 CEPH cell lines from 14 nuclear families
- All FDA approved cytotoxic drugs + new kinase inhibitors/MTOR/demethylation
- No antiestrogen or vitamin A analogues
- Evaluate degree of heritability, presence of QTL(s), and evidence for correlations between drug sensitivity patterns.
Slide 12 of 32: Examples of Genes in Chromosome 9 Interval
[Image] of single nucleotide polymorphisms (SNPs) in chromosome 9.
Slide 13 of 32: Correlative Science: Business as Usual
[Image] showing three phases:
- Phase I: In vivo Mechanism
- Phase II: Biomarker Assessment
- Phase III: Biomarker Validation
Slide 14 of 32: 2009 Estimated U.S. Cancer Cases
[Image] showing the number of new cancers, by site, anticipated in 2009 for men and women (based on American Cancer Society sources). It is estimated that 1.37 million new cases of cancer will be diagnosed in 2005. Cancers of the prostate and breast will be the most frequently diagnosed cancers in men and women, respectively, followed by lung and colorectal cancers both in men and in women.
Source: American Cancer Society, 2009. Reprinted by the permission of the American Cancer Society, Inc. from www.cancer.org. All rights reserved.
Slide 15 of 32: No Title
[Image] showing example of how to integrate biomarkers into clinical trials.
Slide 16 of 32: Tamoxifen Metabolism
[Image] showing the metabolic pathway for tamoxifen.
Slide 17 of 32: Relapse-Free Survival
[Image] showing graph of the percent of patients with relapse-free survival for EM, IM, PM 0 to 12 years after randomization.
Source: Goetz et al. Breast Cancer Res Treat. 2007; 101: 113-21. Reprinted by permission of Springer.
Slide 18 of 32: Adjuvant Tamoxifen and CYP2D6
- CYP2D6 associated with recurrence
- Goetz et al. 2005, 2007 (USA)
- Schroth et al. 2007 (Germany)
- Kiyotani et al. 2008 (Japan)
- Newman et al. 2008 (UK)
- Xu et al. 2008 (China)
- Okishiro et al. 2009 (Japan)
- Ramon et al. 2009 (Spain)
- Bijl et al. 2009 (Netherlands)
- CYP2D6 not associated with recurrence
- Wegman et al. 2005, 2007 (Sweden)
- Nowell et al. 2005 (USA)
Slide 19 of 32: Objectives
- Primary objective:
- To evaluate the change in endoxifen levels following an increase in tamoxifen dose from 20 mg to 40 mg among patients with intermediate metabolizing CYP2D6 genotypes.
Slide 20 of 32: LCCC 0801: Individualizing Tamoxifen Therapy by Genotype
- Hypothesis: We can compensate for CYP2D6 low activity by increasing tamoxifen dose to 40mg/d
[Image] showing graph of endoxifen levels for EM and IM given tamoxifen doses of 20 mg and 40 mg.
Slide 21 of 32: LCCC 0801: Active Community Participation
[Image] showing map of North Carolina and sites of community participation in study: Spartanburg, CMC, Moses Cone, UNC, Duke, ECU, REX, Hanover.
Slide 22 of 32: Laboratory and Clinical Analysis
- Amplichip® P450 test used for genotyping, including the major EM (active) alleles (*1, *2, and *35), IM (reduced activity) alleles (*9, 10, *17, *29,*36, and *41), and PM (inactive) alleles (*3, *4, *5, *6, *7, *8, *11, *15, *19, *20, and *40).
- Tamoxifen and metabolite levels at baseline and 4 months.
- Quality-of-life analysis performed using FACT-B, FACT-B (es), and BCPT Menopausal Symptom Scale at baseline and at 4 months.
Slide 23 of 32: Results
- Trial open from 7/1/08-12/30/08; accruing in 6 months
- N=119, of whom 118 are evaluable for genotyping analysis (1 withdrew study consent)
Slide 24 of 32: Genotype (% of patients)
[Image] showing table listing number and percent of patients with the following metabolism genotypes: EM/EM, EM/UM, EM/IM, EM/PM, IM/IM, IM/PM, PM/PM, and unknown.
Slide 25 of 32: Conclusions
- A high proportion of patients (72%) have at least one PM or IM allele which may result in lower levels of conversion of tamoxifen to endoxifen, the active metabolite.
- The frequency of PM alleles in Caucasians was similar to that seen in other studies.
Slide 26 of 32: No Title
- The allele frequency of reduced metabolism alleles was greater in African-Americans (62%) than in other patients (44%).
- The IM allele *17 is common in African-Americans, consistent with other reports. This raises the question of altered tamoxifen metabolism as one contributor to the disproportionately worse outcome suffered by African-American women with breast cancer.
Slide 27 of 32: No Title
- A significant portion of patients (25%) are heterozygous for an IM allele (EM/IM). The significance of EM/IM genotypes on tamoxifen metabolism requires further study.
- CYP2D6 genotyping studies that identify only the common null allele *4 would underestimate the incidence of reduced metabolism alleles, particularly in African-Americans.
Slide 28 of 32: Comprehensive Optimization of Patient Care
[Image] of four different genotypes needed to optimize patient care: disease genotypes, infection defense genotypes, supportive care genotypes, and toxicity-risk genotypes.
Slide 29 of 32: 5 Stages of Pharmacogenetics Progress
- Denial (and Isolation)
Apologies to Elizabeth Kubler-Ross, M.D., On Death and Dying (1969)
Slide 30 of 32: What Needs to Be Done to Determine Hope Vs. Hype?
- Find the 'right' biomarkers
- Support ‘anchored’ discovery
- Validate in robust datasets
- Broaden the sampling in national trials
- Build community cohorts for ‘real world’ evaluation
- Apply them!
- Develop the teams required to draw a conclusion
Slide 31 of 32: NIH Pharmacogenomics Research Network
[Image] showing map of U.S. and sites which comprise the NIH Pharmacogenetics Research Network, sponsored by NIGMS, NHLBI, NHGRI, NCI, NIEHS, and NLM. The research sites are:
- Brigham and Women’s Hosp.
- Children’s Hosp. (Oakland)
- Indiana Univ.
- Mayo Foundation
- Stanford Univ.
- UCSF X 2
- Univ. of Chicago
- Univ of Florida
- Univ of Maryland
- Univ of N. Carolina
- Vanderbilt Univ.
- Washington Univ.
Slide 32 of 32: The UNC Institute for Pharmacogenomics & Individualized Therapy
[Image] with UNC Institute for Pharmacgenomics & Individualized Therapy logo and tagline: “Because everybody’s therapy is not your body’s therapy.”