Genetics and Genomics Research to Enable the Practice of Personalized Cancer Care Charis Eng, MD, PhD, FACP Chair, Genomic Medicine Institute Director, Center for Personalized Genetic Healthcare Medical Director, Clinical Cancer Genetics Service Member, Taussig Cancer Institute Cleveland Clinic AFMR Transl Med Symposium, April 11, 2011
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Genetics and Genomics Research to Enable the Practice of Personalized Cancer Care
Genetics and Genomics Research to Enable the Practice of Personalized Cancer Care. Charis Eng, MD, PhD, FACP Chair, Genomic Medicine Institute Director, Center for Personalized Genetic Healthcare Medical Director, Clinical Cancer Genetics Service Member, Taussig Cancer Institute - PowerPoint PPT Presentation
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Genetics and Genomics Research to Enable the Practice of Personalized
Cancer Care
Charis Eng, MD, PhD, FACP
Chair, Genomic Medicine Institute
Director, Center for Personalized Genetic Healthcare
Medical Director, Clinical Cancer Genetics Service
Member, Taussig Cancer Institute
Cleveland Clinic
AFMR Transl Med Symposium, April 11, 2011
Genomic Medicine Institute
Contributors to Premature Mortality
Behavior Genetics Social Medical Access Environmental
D.M. Cosgrove, MD, State of the Clinic 2008April, 2009
Genomic Medicine Institute
Elias A. Zerhouni, M.D September 13, 2006Need to Transform Health and Medicine in the 21stCentury
20th Century Medicine 21st Century Medicine
Treat disease when symptoms appear and normal function is lost
Intervene before symptoms appear and preserve normal function for as long as
possible
Did not understand the molecular and cellular events that lead to disease
Understanding preclinical molecular events and ability to detect patients at risk
Expensive in financial and disability costs Order of magnitude more effective
Health & Medicine Transformation Need to Transform Health & Medicine
in the 21st Century
Genomic Medicine Institute
Historical Imperative for Prevention
•Superior doctors prevent the disease.
•Mediocre doctors treat the disease before evident.
Inferior doctors treat the full blown disease.
Nai-Ching (2600 B.C. 1st Chinese Medical Text)
Genomic Medicine Institute
• Medicare and the Drug Plan
• Care and Coverage of the Uninsured
• Rise of the Healthcare Consumer
• Focus on Prevention
• Calls for Patient Safety to Drive HealthCare IT Investments
• Diminishing Drug Pipeline
• Pay for Performance
• Technology Backbone
• Labor Shortages
Top Nine Health Industry Issues in 2010 PricewaterhouseCooper’s Health Research Institute
Genomic Medicine Institute
• Phenomics– Meticulous Documentation of Clinical Features
– Objective Means (Not Self Reports)
• Disease Risk Assessment
• Interpretation– (Must Have Clinical Context[Outcome] and Scientific Content [Research Data])
– To Fellow Professionals
– To Patients / Consumers
• Personalized Risk Management
– Broadest Sense– Prevention
– Treatment
– Behavior Modification
– And so on
• Ethical, Legal, Social Issues and Education
Breath of Personalized Healthcare(ie, Everyone Can Contribute)
Genomic Medicine Institute
Breath of Translational Research
• Myth: Translational Research = Drug Development and Therapeutic Trials – Caution: This is how NIH defines it!
• Truth: Translational Research = All Patient-Oriented Research that Spans the Breath to Refine Diagnostics and Risk Assessment to Genetic Counseling to Preventative Maneuvers and Therapeutics
• “Right Diagnosis – Right Treatment”
Genomic Medicine Institute
Genomics
GeneticsUncommon,
Mendelian, Single-Gene Disorders
(Strong Effect)Eg. Cystic fibrosisLynch syndrome
Hemophilia ASickle-cell anemia
Common Diseases
(multi-gene, smalleffect each)Eg. Obesity
Heart diseaseDiabetesAutism
Alzhemier’s
Genetics and Genomics Important Bases for Personalizing Clinical Care
3,993 number of genes currently known to be associated with disease out of an estimated 35,000 (~12%)
THE BIG RED DOG.THE IGR EDD OG.
THE BIG RED DOG.A BIG RED DOG.
Genomic Medicine Institute
Multidisciplinary CancerConsult Including Genomic Medicine
And Genetic Counseling
Multidisciplinary CancerConsult Including Genomic Medicine
And Genetic Counseling
Multiple Generation PedigreeFor Cancer Genetic Risk Assessment
Genomic Predisposition to Common Diseases:Diabetes/Obesity (Serre)Reverse Cholesterol Transport (Sehayek)Malaria and Populations (Serre)Solid Tumors (Eng)
Somatic Genetics/Epigenetics:Metabiomics (Eng, Sehayek, Serre)Colon CA and Prostate CA Epigenomics (Ting)Microenvironment and Outcome (Eng)Wilms Tumor/HNSCC (Aldred)
Genomics ELSI (Center for Genomic Bioethics)DTC Genomic Testing (Eng, Sharp)Returning Results to Participants who Donated to Biorepository-Based ResearchGenetic Testing in Pediatric Populations (Moran, Sharp)Informed Consent in MFM (Moran, Farrell)
Genomic Medicine Institute
Eng Lab – Translational Cancer Genetics/Genomics
Multidisciplinary CancerConsult Including Genomic Medicine
And Genetic Counseling
Multidisciplinary CancerConsult Including Genomic Medicine
And Genetic Counseling
Multiple Generation PedigreeFor Cancer Genetic Risk Assessment
Germline Predisposition and Cancer Risk PredictionPTEN mutations/variations in Cowden syndrome (breast/thyroid)SDH variants in Cowden syndromeKLLLN germline hypermethylation
Nontraditional Mechanisms of PTEN Loss-of-FunctionNuclear-Cytoplasmic trafficking of PTENEpigenetic modification
FBE Gene Hunt
Complex DisordersGermline homozygosity & predisposition to common solid tumors
Variably Increased P-AKT and P-MAPK Resulting from Germline PTEN Mutation Positive CS/CSL
Genomic Medicine Institute
Variably Increased P-AKT and P-MAPK Resulting from Germline SDHB/SDHD Mutation/Variant Positive CS/CSL Individuals without PTEN Mutations
Ni et al. Am J Hum Genet 2008
Genomic Medicine Institute
Proposed Cross-Talk Between PTEN and SDH Pathways
Genomic Medicine Institute
Cancer Risks in SDH Mutation/Variant Positive versus Cancer Risks in PTEN Mutation Positive CS/CSL
Cancer SDH Mut%
95% CIPTEN Mut
%
95% CIP-Value*
Renal 2/1020%
5-52%4/230
1.2%
0.5-4.5%0.03
Thyroid 5/1050%
25-76%15/206
7.2%
4-12%<0.001
Breast 6/966.7%
36-88%30/107
28%
22-34%<0.001
Uterine 1/911%
0-45%15/107
14%
8-22%0.64
Colon 0/100
0-32%4/210
6.7%
0.6-5%>0.99
*Fisher 2-Tailed Exact TestNi et al. Am J Hum Genet 2008, Eng et al, unpublished
Genomic Medicine Institute
Proposed Clinical Algorithm for Gene Testing in CS and CSL Probands
Ni et al. Am J Hum Genet 2008
Genomic Medicine Institute
Example of Work Flow for a Translational Genetics Research (PTEN) Protocol & the Team Ensuring the Flow
Mut + ResultsChecked in CLIALab -> to Patients
Mut+/Var+ Patients Choice ofEnrollment in Annual Questionnaire
Study
PI Conceives of Hypotheses & Study Design & is Responsible for the Study Protocol.PI can & does Delegate Various Responsibilities to Protocol Members
PI: C Eng; GC Coordinator: Jessi Mester; General Research Coordinator: Dawn Caraballo
CPGH Physicians and GC’sCC/National/International Clinicians
CPGH Physicians and GC’sCC/National/International Clinicians
Dawn, GC Assts, GCsDawn, GC Assts, GCs
Dawn, Jessi x 2, GC Assts,Student Interns, OthersDawn, Jessi x 2, GC Assts,Student Interns, Others
LabMatrix Entry: Kim and TomLabMatrix Entry: Kim and Tom
Gloria, GC Assts, Student Interns, Others
Gloria, Others Send Out Blood KitGloria, Others Send Out Blood Kit
Genomic Medicine BiorepositoryGenomic Medicine Biorepository
Eng Lab MembersEng Lab Members
Genomics Core FacilityGenomics Core Facility
CPGH Physicians and GC’sCC/National/International Clinicians
CPGH Physicians and GC’sCC/National/International Clinicians
Jessi Me (Mut+)Dawn via email (Mut-)Jessi Me (Mut+)Dawn via email (Mut-)
Dawn Offers Questionnaire Study;A Whole New Protocol RollsDawn Offers Questionnaire Study;A Whole New Protocol Rolls
Genomic Medicine Institute
Genetics-Enabled Cancer Risk-Assessment and Management: Paradigm for Personalized Genetic Health Assessment and Management
Is it hereditaryIs it hereditaryor sporadic?or sporadic?
Epidemiology saysEpidemiology says10-15% caused by 10-15% caused by High penetrance genes, High penetrance genes, BUT which10-15%?BUT which10-15%?
Personal & Family HistoryPersonal & Family HistoryAge at OnsetAge at OnsetFamilial ClusteringFamilial ClusteringOne or More OrgansOne or More OrgansPedigree DrawingPedigree Drawing
Test PositiveTest PositiveRisk ManagementRisk ManagementScreeningScreeningProphylactic SurgeryProphylactic Surgery
High RiskHigh Risk
Low RiskLow Risk
Receive Gene Test ResultsReceive Gene Test ResultsPost-Test CounselingPost-Test Counseling Test NegativeTest Negative
Standard GuidelinesStandard GuidelinesGeneral PopulationGeneral Population
CancerCancer
Genomic Medicine Institute
Patients at Genetic Risk for Cancer Are Under-Served by Not Being Systematically Recognized
• Cleveland Clinic Health System sees ~1.8 Million New Patients/Yr– 2009: 38 Million Total Visits
• ~10% of All with Disease Due to High Penetrance Genetic Predisposition
• Should Have Referred >380,000 to Genetic Care in 2009
• In Reality, 2,900 were Referred in 2009
Eng et al., Unpublished
Genomic Medicine Institute
National Trends -- No Different
• >35,000 Healthy Patients
• ~350 Had Family Histories Consistent with Hereditary Breast-Ovarian Cancer Syndrome Due to Germline BRCA1/2 Mutations
• 35 of 350 Discussed Concerning Family History with Any Healthcare Provider
• 4 of 35 Underwent BRCA1/2 Mutation Analysis
Levy D et al. 2009
Genomic Medicine Institute
Important Reasons that Individuals at Genetic Risk of Disease are Under-Served
• Lack of systematic and comprehensive ascertainment of individuals at genetic risk of disease;
• Traditional practice model for genetics in the context of small workforce;
• Because of the exponential increase in genetics knowledge in the last 10 years, there is a lag in knowledge acquisition by both healthcare providers and the public.– Fear of Genetic Discrimination (GINA passed in 2009)
• Genetics is a 21st century subspecialty on a 19th century organizational structure
Genomic Medicine Institute
Potential Solutions that will Revolutionize Genetics-Informed Delivery of Healthcare
• To develop a process to ensure systematic and comprehensive ascertainment of individuals at genetic risk of disease– Beta Test with Cancer Genetics
• To increase access by changing the traditional practice model of genetics – Beta Testing with Cancer Genetics (Very Successful)
– Same Day Service
– Quintupled Patient Volumes
• To engrain a multi-modality cancer genetics education campaign throughout CCHS– Point of Care Education
– Genetics Champions (Non-Genetics Healthcare Provider) in Each Institute
• Working with CC leadership to bring organizational structure and practice models into the 21st century– Integration of genetics into all of healthcare
– Standardization of practice
Genomic Medicine Institute
Who is Patient Population for Future Genomic Medicine?
With Disease
Subclinical Disease(s)
Healthy
Now
But: There are Only 500 Physicians who Practise Any Genetics, and There are Perhaps 3000+/- Genetic Counselors in this Country!
Challenge to Researchers: Innovative Discoveries that FacilitateGenetics-Informed Healthcare in Setting of Caregiver Shortage