Genomic Medicine: Genomic Medicine: A Revolution in Medical A Revolution in Medical Practice in the 21Practice in the 21stst CenturyCentury

Francis S. Collins, M.D., Ph.D.Francis S. Collins, M.D., Ph.D.National Human Genome Research National Human Genome Research

InstituteInstituteWorld Health Care CongressWorld Health Care Congress

April 17, 2006April 17, 2006

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All of the original goals All of the original goals of the Human Genome of the Human Genome Project have been Project have been accomplishedaccomplished

What’s What’s next?next?

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

But until now, terribly But until now, terribly difficult.difficult.

Variant Variant AA

Variant Variant BB

www.hapmap.org

The First HapMap Success Story:The First HapMap Success Story:Age-Related Macular Age-Related Macular DegenerationDegeneration

Two other risk variants havebeen identified in the last two months.

Together these account for 74%of risk, and point to powerfulnew approaches to preventionand treatment.

Diagnostics

Preventive Medicine

Disease with Genetic Component

Time

Identify Genetic Defect(s)

Accelerated byHuman GenomeProject andHapMap

PKU ScreeningPKU Screening All published studies show that All published studies show that

PKU screening and treatment PKU screening and treatment represent a net direct cost represent a net direct cost savings to societysavings to society

Phenylketonuria: Screening and Management NIH Consensus Statement Online 2000

Hereditary NonPolyposis Colon Cancer (HNPCC)

Hereditary NonPolyposis Colon Cancer (HNPCC)

UterineCancer

48

UterineCancer

48

ColonCancer

56

ColonCancer

56

ColonCancer

51

ColonCancer

51

Identifying Those At RiskIdentifying Those At Risk

UterineCancer

48

UterineCancer

48

ColonCancer

51

ColonCancer

51

ColonCancer

56

ColonCancer

56

HNPCCHNPCC Screening – is Screening – is it cost-effective?it cost-effective? Need Need to know…to know… Sensitivity, specificity, and timing of Sensitivity, specificity, and timing of

genetic testgenetic test Genotype-phenotype associationGenotype-phenotype association Prevalence of genetic mutationsPrevalence of genetic mutations Clinical outcome and severityClinical outcome and severity Interventions available for mutation Interventions available for mutation

carrierscarriers Effectiveness of interventionsEffectiveness of interventions

Cost Results Depend on Cost Results Depend on Family RelationshipsFamily Relationships Patients only = $42,210 per life-Patients only = $42,210 per life-

year gainedyear gained Patients + siblings + children = Patients + siblings + children =

$7,556 per life-year gained$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 byHuman GenomeProject andHapMap

Source: N Engl J Med, Vol 344 (8), 2001.

Overview of Procedures for Microarray Analysis of Tumor Samples

---- 95% confidence interval curves

Recurrence 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 Gene Expression Profiling for Breast Cancer for Breast Cancer Recurrence:Recurrence:Economic Benefits?Economic Benefits?

Hypothetical Analyses: Hypothetical Analyses:

– Oncotype DX (Genomic Health)Oncotype DX (Genomic Health)– Hornberger et al., Am J Manag Care. 2005; Hornberger et al., Am J Manag Care. 2005;

11: 313-32411: 313-324

– MammaPrint – Netherlands/Agendia U.S. MammaPrint – Netherlands/Agendia U.S. – Oestreicher et al., Genet Med 2005; 7:380-Oestreicher et al., Genet Med 2005; 7:380-

389389

Diagnostics

Preventive Medicine

Disease with Genetic Component

Time

Identify Genetic Defect(s)

Pharmacogenomics

Accelerated byHuman GenomeProject andHapMap

Using Genetic Information to Predict Using Genetic Information to Predict Drug Metabolism:Drug Metabolism: The AmpliChip The AmpliChip CYP450CYP450

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 benefitPredicted economic benefit of of CYP2C9 testingCYP2C9 testing for warfarin for warfarin dosingdosing

Predict 1 major bleed prevented for Predict 1 major bleed prevented for every 44 patients screened every 44 patients screened ($135/assay)($135/assay)

$6,000 testing costs ~ cost of 1 $6,000 testing costs ~ cost of 1 major bleedmajor bleed

Neutral economic result, but Neutral economic result, but significant improvement in patient significant improvement in patient outcome outcome

Prospective trial neededProspective trial neededHigashi and Veenstra, Am J Manag Care 2003; 9: 493-500

Diagnostics

TherapeuticDevelopments• Gene Therapy • Drug Therapy

Preventive Medicine

Disease with Genetic Component

Time

Identify Genetic Defect(s)

Pharmacogenomics

Accelerated byHuman GenomeProject andHapMap

Gleevec™ – Specifically TargetsAn Abnormal Protein, Blocking Its Ability To Cause Chronic Myeloid LeukemiaChromosome 9;22

translocation

CML

Bcr-Abl fusion protein

Gleevec™

Bcr-Abl fusion protein

Normal

Cost-Effective?Cost-Effective?

Gleevec as 1Gleevec as 1stst line therapy for line therapy for CMLCML

6 years increased survival over 6 years increased survival over interferon-alpha therapy interferon-alpha therapy

$43,100/per life-year saved$43,100/per life-year savedReed et al, Cancer 101:2574-83, 2004

S.306109th

HR.1227

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Genomic Medicine:Genomic Medicine:

Predictive, Predictive, personalized, and pre-personalized, and pre-emptiveemptive