2. Genomics-Based Personalized Healthcare Presented by: Charis Eng, MD, PhD -Chair & Director -Genomic Medicine Institute -Director -Center for Personalized Genetic Healthcare

3. Insert Text Both Have Asthmatic Attacks B-Adrenergic Inhalers Asthma Attack Stopped Dead Why the Different Responses to Same Treatment? Bottom Child Has a Genetic Variant In B-Adrenergic Receptor Gene Example Problem at Hand

4. Early Stage Breast Cancer Breast Conserving Surgery Adjuvant Chemotherapy Breast Conserving Surgery Adjuvant Chemotherapy Cured Dies of Ovarian Cancer 10 Years Later “Normal” Gene “Altered” Gene Why the difference? Example Problem at Hand

5. Who is at risk for which disease(s)?

6. Based on Objective Genomic or Genetic Data: WHO is at risk of developing disease(s) ? Potentially Entire Population Personalized risk assessment WHAT can we do about genomic risk? Personalized risk management Personalized preventive and curative measures? WHEN is age (range) of highest risk? WHERE: Can surveillance be organ-specific? WHY and HOW? Patient-Oriented Genomics/Genetics Research

7. Current Dogma Genetic Load for Any Disease “Sporadic” “Environmental Exposure” “Bad Luck” “Sporadic” “Environmental Exposure” “Bad Luck” “ Some Genetic Component” “Familial Clustering” “ Some Genetic Component” “Familial Clustering” High Penetrance Disease Susceptibility Gene(s) Emerging Dogma Normal Gene: THE BIG RED DOG. Mutated Genes: THE BIG R. THE BIR EDD OG. Variants: A BIG RED DOG. THE BIG RED GOD.

8. High Penetrance Disease Susceptibility Gene(s) High Penetrance Breast Cancer Susceptibility Genes BRCA1 BRCA2 PTEN TP53 LKB1 High Penetrance Breast Cancer Susceptibility Genes BRCA1 BRCA2 PTEN TP53 LKB1 Mutation in Gene > High Likelihood of Developing Breast and Other Component Cancers

9. Variants: A BIG RED DOG. THE BIG RED GOD. Genome-Wide Association Studies Common Low Penetrance Variants Associated with Breast Cancer A BIG RED DOG. THE BIG RED GOD. THE BIG RED DOG. THE BIG RED RIG. WOW BIG RED DOG. CasesControls 1004,000 70 70 55 70 1,500 10 2,500 25 FGFR2 TNRC9 MAP3K1 LSP1 CASP8 FGFR2 TNRC9 MAP3K1 LSP1 CASP8 Easton DF et al Nature 2007 Cox A et al Nature Genet 2007 Pharoah et al PloS Genet 2007 Easton DF et al Nature 2007 Cox A et al Nature Genet 2007 Pharoah et al PloS Genet 2007

10. Low Penetrance Variants in Various Genes Associated with Various Diseases *That Have Replicated ( 1.15 (low level risk) Subsets of: Breast Cancer Prostate Cancer Diabetes Mellitus Type 2 Obesity Coronary Heart Disease Crohn Disease Others

11. LOH N Ep. Somatic Genetic Alterations in Sporadic Carcinomas Epithelial component of carcinomas believed to be the neoplastic component Pathologists measure invasion by whether the neoplastic epithelial cells invade membrane Genetic alterations believed in epithelium

12. Normal Tissue Ep TP53 Exon 2 Mutation Normal St TP53 Exon 6 Mutation Somatic TP53 and Other Gene Mutations in Stroma of Breast Carcinomas Kurose et al Nature Genet 2002, Fukino et al JAMA 2007

13. Stromal (Not Epithelial) Genomic Alterations Associated with Tumor Aggressiveness and Metastases in Breast and Head and Neck Cancers St TP53 Mutation Weber et al JAMA 2007, Fukino et al JAMA 2007, Patocs et al N Engl J Med (almost in press)

14. Personalized Genetic Health Assessment and Management 2007 Is it hereditary or sporadic? Epidemiology says 10-15% caused by high penetrance mutant genes, BUT which 10-15%? Personal & Family History Age at Onset Other Types of Cancer One or More Organs Pedigree Drawing High Risk Pre-Test Genetic Counseling Genetic Testing Test Positive Risk Management Screening Prophylactic Surgery Low Risk Receive Gene Test Results Post-Test Counseling Test Negative ACS Guidelines General Population Breast Cancer Or Any Disease Center for Personalized Genetic Healthcare

15. Genomics-Based Personalized Healthcare for Cancer 2008-09 Multidisciplinary Cancer Consult Including Genomic Medicine And Genetic Counseling Multidisciplinary Cancer Consult Including Genomic Medicine And Genetic Counseling Multiple Generation Pedigree For Cancer Genetic Risk Assessment Multiple Generation Pedigree For Cancer Genetic Risk Assessment Somatic Genomic Profiling of Cancer Epithelium & Stroma Somatic Genomic Profiling of Cancer Epithelium & Stroma Biopsy of Cancer Histopathology Select Multi-Agent Targeted Therapy With >99% Likelihood of Durable Response & <1% Likelihood Of Adverse Effects Select Multi-Agent Targeted Therapy With >99% Likelihood of Durable Response & <1% Likelihood Of Adverse Effects Clinical Screening, Preventative Measures, Behavior Modification Clinical Screening, Preventative Measures, Behavior Modification Prioritization & Testing of Known High Penetrance Cancer Genes in Setting of Genetic Counseling Prioritization & Testing of Known High Penetrance Cancer Genes in Setting of Genetic Counseling Germline Variant Profling