Personalized Medicine in the Era of GenomicsPersonalized Medicine in the Era of Genomics

Wylie Burke MD PhDWylie Burke MD PhD

Department of Medical History and Ethics

Center for Genomics and Healthcare Equality

University of Washington

Department of Medical History and Ethics

Center for Genomics and Healthcare Equality

University of Washington

Personalized medicineOne view

Personalized medicineOne view

The right treatment, for the right patient, at the right time

The right treatment, for the right patient, at the right time

Personalized medicineAnother view

Personalized medicineAnother view

– Attending to the whole person, in context of personal & medical history and life circumstances

Safran 2003 Ann Intern Med 138:248

– “Working alliance” of doctor & patient – Agreement on goals of treatment– Collaboration– Liking and trust

Fuertes et al 2006 Pat Ed Counsel 66:29

– Attending to the whole person, in context of personal & medical history and life circumstances

Safran 2003 Ann Intern Med 138:248

– “Working alliance” of doctor & patient – Agreement on goals of treatment– Collaboration– Liking and trust

Fuertes et al 2006 Pat Ed Counsel 66:29

Newborn screening for PKU Newborn screening for PKU

Screen for newborn for elevated phenylanaine

Identify affected newborns

Diet to prevent mental retardation

Screen for newborn for elevated phenylanaine

Identify affected newborns

Diet to prevent mental retardation

Personalized care for children with PKU

Personalized care for children with PKU

– Cost of diet

– Social barriers to maintaining diet

– Child’s commitment to lifetime diet

– Cost of diet

– Social barriers to maintaining diet

– Child’s commitment to lifetime diet

Pathways from genetic research to clinical benefit

Pathways from genetic research to clinical benefit

Research

on genetics

& disease

Research

on genetics

& disease

Testing to diagnose or identify riskTesting to diagnose or identify risk

Innovative therapyInnovative therapy

Improved disease classificationImproved disease classification

Medullary thyroid cancer & RET mutation testing:

Multiple Endocrine Neoplasia 2 (MEN2)

Medullary thyroid cancer & RET mutation testing:

Multiple Endocrine Neoplasia 2 (MEN2)

Medullary thyroid cancerMedullary thyroid cancer

Medullary thyroid cancer, RET mutation +Medullary thyroid cancer, RET mutation +

If RET +, offer prophylactic thyroidectomyIf RET +, offer prophylactic thyroidectomy

Predicting toxicity from chemotherapy

Retrospective analysis of clinical trial data

Predicting toxicity from chemotherapy

Retrospective analysis of clinical trial data

020406080

100

Low High

JNCI 1999;91: 2001JNCI 1999;91: 2001

% with toxicity in children with leukemia% with toxicity in children with leukemia

Thiopurine methyltransferase (TPMT) activityThiopurine methyltransferase (TPMT) activity

Pathway from test to benefitPathway from test to benefit

Test Test Health benefitHealth benefit+ Result+ Result

ACTIONACTION

Spectrum of genetic contribution to diseaseSpectrum of genetic

contribution to disease

Mostly GeneticMostly Genetic

Genes and Environment Genes and

Environment Mostly

EnvironmentMostly

Environment

Cystic fibrosisCystic fibrosis

DiabetesAsthma

DiabetesAsthma

Chicken poxChicken pox

Gene variants associated with common complex diseases

Gene variants associated with common complex diseases

– Low relative risk (most <2.0)

– Polygenic

– Often account for only a small percentage of disease cases

– Low relative risk (most <2.0)

– Polygenic

– Often account for only a small percentage of disease cases

Multiple contributors to asthmaMultiple contributors to asthma

Genetics Environment -beta-adrenergic -mites

receptor -cockroaches, -GSTM1, GSTT1 -pollens -IL-4, IL-4RA, IL-13 -animal danders, -TNF-alpha -cigarette smoke, -30-50 others -diesel fuel

Asthma

Genetics Environment -beta-adrenergic -mites

receptor -cockroaches, -GSTM1, GSTT1 -pollens -IL-4, IL-4RA, IL-13 -animal danders, -TNF-alpha -cigarette smoke, -30-50 others -diesel fuel

Asthma

Can genetic test results provide a threshold for clinical intervention?Can genetic test results provide a threshold for clinical intervention?

Genetic test

USUAL CARE

ACTIONImproved outcome

No reduction in outcome

+

-or

NO ACTION

Estimate of lifetime diabetes risk Based on presence/absence

of disease-associated mutation

Estimate of lifetime diabetes risk Based on presence/absence

of disease-associated mutation

020406080

100

PPARG CAPN10 TCF7L2

No copy

1 copy

2 copies

Janssens & Khoury, It J Pub Health 2005; 3:35-41Janssens & Khoury, It J Pub Health 2005; 3:35-41

%

Risk of age-related macular degenerationEffect of population variation in 3 genes

Risk of age-related macular degenerationEffect of population variation in 3 genes

1% have > 50% risk of AMD

MOST have risk close to average

1% have > 50% risk of AMD

MOST have risk close to averageNat Genet 2006; 38:1055-9Nat Genet 2006; 38:1055-9

Data gapsData gaps

Often not known: –Whether testing leads to improved health

outcome

–Whether testing influences management decisions

–Whether testing is associated with direct or indirect harms

Policy questions if benefit is present

Policy questions if benefit is present

– Does the benefit outweigh potential harms?

– Who participates in decisions about appropriate use?

– How is equitable access assured?

– Does the benefit outweigh potential harms?

– Who participates in decisions about appropriate use?

– How is equitable access assured?

Guiding principleGuiding principle

(After Osler)

“More important to know the patient

who has the genotype than the

genotype that has the patient”

(After Osler)

“More important to know the patient

who has the genotype than the

genotype that has the patient”