Genomic Medicine: A Revolution in Medical Practice in the 21 st Century Francis S. Collins, M.D., Ph.D. National Human Genome Research Institute World Health Care Congress April 17, 2006

All of the original goals of the Human Genome Project have been accomplished What’s next?

Finding the genes that contribute to common conditions like cancer, diabetes, congestive heart failure, Parkinson’s disease, schizophrenia, autism, stroke, and osteoporosis is critically important. But until now, terribly difficult.

Variant A Variant B

The First HapMap Success Story: Age-Related Macular Degeneration Two other risk variants have been identified in the last two months. Together these account for 74% of risk, and point to powerful new approaches to prevention and treatment.

Diagnostics Preventive Medicine Disease with Genetic Component Time Identify Genetic Defect(s) Accelerated by Human Genome Project and HapMap

PKU Screening All published studies show that PKU screening and treatment represent a net direct cost savings to society All published studies show that PKU screening and treatment represent a net direct cost savings to society Phenylketonuria: Screening and Management NIH Consensus Statement Online 2000

Hereditary NonPolyposis Colon Cancer (HNPCC) Uterine Cancer 48 Uterine Cancer 48 Colon Cancer 56 Colon Cancer 56 Colon Cancer 51 Colon Cancer 51

Identifying Those At Risk Uterine Cancer 48 Uterine Cancer 48 Colon Cancer 51 Colon Cancer 51 Colon Cancer 56 Colon Cancer 56

HNPCC Screening – is it cost-effective? Need to know… Sensitivity, specificity, and timing of genetic test Sensitivity, specificity, and timing of genetic test Genotype-phenotype association Genotype-phenotype association Prevalence of genetic mutations Prevalence of genetic mutations Clinical outcome and severity Clinical outcome and severity Interventions available for mutation carriers Interventions available for mutation carriers Effectiveness of interventions Effectiveness of interventions

Cost Results Depend on Family Relationships Patients only = $42,210 per life-year gained Patients only = $42,210 per life-year gained Patients + siblings + children = $7,556 per life-year gained Patients + siblings + children = $7,556 per life-year gained Ramsey et al., Ann Intern Med 135:577-88, 2001

Diagnostics Preventive Medicine Disease with Genetic Component Time Identify Genetic Defect(s) Accelerated by Human Genome Project and HapMap

Source: N Engl J Med, Vol 344 (8), Overview of Procedures for Microarray Analysis of Tumor Samples

% confidence interval curves R ecurrence score for individual patients Source: Paik, et al., N Engl J Med, December 2004 Multigene Assay Predicts Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer Gene expression analysis was combined with an algorithm for calculating risk for distant recurrence of breast cancer.

Gene Expression Profiling for Breast Cancer Recurrence: Economic Benefits? Hypothetical Analyses: Hypothetical Analyses: –Oncotype DX (Genomic Health) –Hornberger et al., Am J Manag Care. 2005; 11: –MammaPrint – Netherlands/Agendia U.S. –Oestreicher et al., Genet Med 2005; 7:

Diagnostics Preventive Medicine Disease with Genetic Component Time Identify Genetic Defect(s) Pharmacogenomics Accelerated by Human Genome Project and HapMap

Using Genetic Information to Predict Drug Metabolism: The AmpliChip CYP450 Source: Caraco, Y., N Engl J Med, 2004 A range of drug metabolism phenotypes is observed for individuals based upon the particular cytochrome P-450 genes they possess.

Predicted economic benefit of CYP2C9 testing for warfarin dosing Predict 1 major bleed prevented for every 44 patients screened ($135/assay) Predict 1 major bleed prevented for every 44 patients screened ($135/assay) $6,000 testing costs ~ cost of 1 major bleed $6,000 testing costs ~ cost of 1 major bleed Neutral economic result, but significant improvement in patient outcome Neutral economic result, but significant improvement in patient outcome Prospective trial needed Prospective trial needed Higashi and Veenstra, Am J Manag Care 2003; 9:

Diagnostics Therapeutic Developments Gene Therapy Drug Therapy Preventive Medicine Disease with Genetic Component Time Identify Genetic Defect(s) Pharmacogenomics Accelerated by Human Genome Project and HapMap

Gleevec™ – Specifically Targets An Abnormal Protein, Blocking Its Ability To Cause Chronic Myeloid Leukemia Chromosome 9;22 translocation CML Bcr-Abl fusion protein Gleevec™ Bcr-Abl fusion protein Normal

Cost-Effective? Gleevec as 1 st line therapy for CML Gleevec as 1 st line therapy for CML 6 years increased survival over interferon-alpha therapy 6 years increased survival over interferon-alpha therapy $43,100/per life-year saved $43,100/per life-year saved Reed et al, Cancer 101: , 2004

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Genomic Medicine: Predictive, personalized, and pre-emptive