The Cancer Genome Atlas and The Future of Personalized Medicine

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The Cancer Genome Atlas and The Future of
Personalized Medicine

• BIO IT Coalition ConferenceMay 4, 2006
• Anna D. Barker, Ph.D.Deputy Director, National
  Cancer Institute

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A National and International Imperative to
Eliminate the Cancer Burden
Iceland 1,000 / 500
Sweden 43,000 / 22,000
Norway 21,000 / 11,000
Japan 521,000 / 311,000
Estonia 5,000 / 3,000
Canada 138,000 / 66,000
Ireland 13,000 / 8,000
Germany 408,000 / 218,000
United States of America 1.4M / 566,000
China 2.2M / 1.6M
United Kingdom 277,000 / 156,000
Austria 37,000 / 19,000
Korea 109,000 / 62,000
Switzerland 35,000 / 17,000
France 269,000 / 149,000
7.6 millionpeople died of cancer in 2005
Republic of Singapore 10,000 / 6,000
Australia 86,000 / 37,000
Cancer Incidence / Mortality per year
Source Derived from International Agency for
Research on Cancer, GLOBOCAN 2002 database
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The Human and Economic Burden of Cancer

• 570,280 Americans will die of cancer this year
• 1,372,910 Americans will hear the words you have
  cancer this year
• 189 billion per year on healthcare costs for
  cancer alone

Source for 2005 deaths and diagnoses American
Cancer Society (ACS) 2005 Cancer Facts  Figures
Atlanta, Georgia Source for 2003 age-adjusted
death rate National Center for Health
Statistics, U.S. Department of Health and Human
Services, NCHS Public-use file for 2003 deaths.
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Cancers Reach
In the United States

• Men have an almost 1 in 2 lifetime risk of
  developing cancer.

Women have a more than 1 in 3 lifetime risk of
developing cancer.
Source Cancer Facts Figures 2004, American
Cancer Society
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Current Healthcare System Reactive

• Focus on treatment, at the expense of prevention,
  results in
• Significant unnecessary cost for expensive,
  acute care
• Significant burden on healthcare system
  especially in low-income communities
• Significant pain, suffering, and death for
  patients and their families
• Individual and national wealth and healthcare
  spending do not reduce these problems
• Rates of diabetes, hypertension, heart disease,
  myocardial infarction, stroke, lung disease, and
  cancer are higher in United States than other
  nation, even among wealthiest populations
• JAMA
• Journal of the American Medical Association
  20062952037-2045
• May 3, 2006

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The Shift to 21st Century Personalized Medicine
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Convergence Molecular Biology, Advanced
Technologies, Bioinformatics/Broadband
A Defining Moment in the Nations war on cancer
Unprecedented Potential for Exponential
Progress Toward Personalized Medicine (Molecular
Oncology)
Image courtesy of Nature, Feb. 15, 2001
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What is a Genomic Alteration?
Segments of the genome
DNA is inherited. It is passed from one
generation to the next.
The entire content of a persons DNA is known as
their genome.
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Data Generation Unprecedented Scale
ClinicalData
Molecular Data
Databases (Current and Developing) partial
genomes SNPs gene expression profiles gene
sequence chromosome changes copy number
changes chemical genomic libraries epigenomics
signatures disease biomarkers pathologic
imaging various types chemical libraries
proteins (mass spec) proteins (chips)
biospecimens/biorepositories patient records
antibodies pathology molecular pathology
clinical trials adverse events
pharmacogenomics molecular epidemology
...........
.
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Bioinformatics The Cancer Bioinformatics Grid
(CaBIG)

• Piloted in cancer centers
• System, common software and systems
• Standards based
• Open source plug and play
• common language (e.g, clinical trials
  biospecimens genomic and clinical data )
• Capability to integrate genomics, proteomics,
  animal models, etc. with clinical data
• Broad capability to connect all sectors
• Can provide support for electronic medical record
• Integrated with FDAs clinical trials reporting
  systems

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Standards
E
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Proof of Concept Setting the Stage for The
Cancer Genome Atlas
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The Human Genome Project Changed Everything

• HGP Resulted In
• Understanding of genomic alteration and disease
• Sequencing of many genes
• Development of advanced genomics analysis
  technologies

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Gleevec 50 Years From Discovery to Delivery
1960-1989
1990-1999
2000-Present
1960 Philadelphia chromosome discovered
1993 Preclinical testing on STI571 begins
2001 Gleevec receives FDA approval for
patients who have failed IFN therapy Phase III
Trials begin
2000 Expanded Access Program enrolls 7,000
patients
2002 Gleevec receives FDA approval for newly
diagnosed CML
1973 Bcr-Abl oncogene linked to Philadelphia
chromosome
1998 Phase I Trials begin
1999 Phase II Trials begin
1996 Ciba-Geigy/ Sandoz merger to form
Novartis Toxicity concerns stall STI571
development
Clinical Trials/Approval Process (1998 2002)
Patient Acceptance and Use (1997 Present)
1986-1987 Bcr-Abl tyrosine kinase discovered
as the direct cause of CML
Health Care System Use (2001 Present)
1997 CML Internet Support Group formed
1999 Patient petition lobbying Novartis to
expand access and speed production
Coverage and Payment (2001 Present)
Empirical
Target-Driven
Sources Brian Druker, Janet Rowley, and New
England Healthcare Institute
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1st Generation Personalized Medicine Is Underway

• Clinical applications now include
• Selection of breast cancer patients for optimal
  therapy
• Prevention of drug toxicity in the treatment of
  colorectal cancer and acute lymphoblastic
  leukemia
• Identification of individuals with high risk of
  breast cancer or melanoma for increased
  surveillance and preventive treatment
• FDA is committed to advancing molecular medicine
  The Critical Path
• Over 100 IND submissions to FDA contain
  pharmacogenomic data
• Pharmacogenomic data is being used to rescue
  drugs in clinical trials
• Major insurers (e.g., Blue Cross/Blue Shield and
  United Healthcare) are conducting cost-benefit
  studies for specific pharmacogenomic tests

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TCGA Pilot Project
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Critical Importance of the TCGA?

• TCGA is among the first efforts to systematically
  use data generated by the Human Genome Project to
  better understand a specific disease cancer.
• An atlas of genomic alterations associated with
  major types of cancer could enable new scientific
  discoveries.
• Scientific discoveries arising from TCGA data may
  translate into
• New targets for cancer therapeutics
• Ability to more specifically assign patients
  within clinical trials
• Assessment of risk for specific cancers

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What is TCGA?

• The Cancer Genome Atlas (TCGA) is a 3-year, 100
  million pilot project of the National Cancer
  Institute (NCI) and the National Human Genome
  Research Institute (NHGRI).
• TCGA Mission Increase scientific understanding
  of the molecular basis of cancer and apply this
  information to improve our ability to diagnose,
  treat, and prevent cancer.
• TCGA Purpose Determine the feasibility of a
  full-scale project to develop a complete atlas
  of all genomic alterations involved in cancer.

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Project Development History
2003
2005
2004
September 2003 NCAB Ad hoc Committee formed
July 2005 Community Input meeting
April 2004 NCI-NHGRI Public Workshop
December 2005 TCGA Pilot Project launched
February 2005 NCI-NHGRI Working Group formed
November 2004 Presentation to NCI BSA
November 2005 Presentation to NCI BSA Approval
January 2005 Project RFI issued
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Broad Interest and Support

• Positive response from scientific community,
  business community, and the public.

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How TCGA Will Function
Data Management, Bioinformatics, and
Computational Analysis
An integrated database providing access to all of
the information generated by the TCGA pilot
project
Cancer Genome Characterization Centers
Genome Sequencing Centers
High-throughput sequencing of genes identified
through cancer genome characterization centers
Technologies to investigate and characterize
genes that may be associated with cancer
Human Cancer BiospecimenCore Resource
Centralized facility to catalog and store tumor
samples, and distribute genetic material to TCGA
research centers
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Biospecimen Core Resource

• Verify authenticity and perform the pathologic QC
  of qualified tumors from existing collections
• Perform central processing of specimens
• Develop and monitor the standard operating
  procedures for prospective specimen collection
• Track all specimen-related operations (consent,
  acquisition, transport, processing, QC,
  distribution) through caBIG
• Provide samples for technology platform
  comparisons
• Distribute materials

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Cancer Genome Characterization Centers (CGCCs)

• Genome characterization
• Expression profiling
• Copy number changes
• Epigenomics
• Improve existing technologies
• Epigenomics to meet required throughput rate
• Copy number detection and expression profiling
  for characterizing small amounts of biological
  samples
• Real-time data release into public database
• CGCCs RFA
• Mechanism U24 (cooperative agreement)

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Genome Sequencing Centers

• High-throughput Genome Sequencing Centers (NHGRI)
• Sequence large number of targets from at least 2
  tumor types
• Develop and integrate sequencing technologies
• Genome Sequencing Centers RFA
• Mechanism U54 (cooperative agreement)

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caBIG-Based Bioinformatics Core

• caBIG principles open source, open access, open
  development
• Common, widely distributed infrastructure allows
  research community to focus on discovery
• Infrastructure
• Data management
• Database development
• Specific analytic tools
• Inter-program communication

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Technology Development

• Opportunities For Technology Development
• Genomic rearrangement, epigenetic assays
• Highly parallel single molecule assays
• Method for selecting/enriching defined regions of
  genome
• Magnitude improvement in cost, throughput,
  accuracy, and precision
• Technology Development RFA
• Mechanisms SBIR/STTR R21 (exploratory/developmen
  t)

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TCGA Next Steps
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TCGA Milestones for 2006
Fiscal Year 2006
Fiscal Year 2006
3rd Quarter NHGRI Funding of High-throughput
Sequencing Centers
1st Quarter NHGRI Issuance of RFAs

• 2nd Quarter
• NCI Issuance of RFAs and RFP
• Data Release Workshop
• Selection of Tumor Sets

4th Quarter Issuance of NCI Awards
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TCGA Pilot Project Milestones
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5
1
2
3
Identify genomic changes associated with cancer
in individual patients.
Identify genomic patterns associated with the
disease, and use that information to inform
cancer diagnosis, treatment, and prevention.
Make information available to scientists as it is
produced, to speed treatment and prevention
research and help doctors and patients make
treatment decisions.
Collect/Utilize tumor tissue samples and medical
information from cancer patients during
treatment.
Catalog and store samples at a centralized
facility and send genetic material to research
centers involved in the project.
Graphics credit The Washington Post, December
14, 2005
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How Will TCGA Decide Which Tumors to Study First?

• Criteria
• The tumor samples are derived from patients
  entered in a clinical trial with
• Uniform entry criteria
• Consistent treatment
• Clinical data that has undergone regular audits
• Samples represent a single type of tumor and/or
  (if a solid tumor) derived from a single cancer
  site (e.g. brain, breast, lung, etc.)
• Tumors are from a primary tumor site
• Samples are properly consented for use in this
  project

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How Will TCGA Decide Which Tumors to Study First?

• Criteria continued
• There must be a sufficient amount of each tumor
  sample to conduct the necessary analysis
• Tumor samples have been obtained and stored in a
  manner that meets the technical requirements of
  TCGA
• At least 500 individual samples from unique
  cancer cases are available
• All tumors samples have matched normal samples
• Individual tumor samples should contain at least
  80 tumor cells

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Success Factors for TCGA

• By end of the 3-year pilot project, we hope to
  have
• Completion of genomic analysis of two tumors,
  leading to identification of new genes involved
  in cancer
• Ability to find specific genomic alterations in
  the genes associated with cancer
• Ability to differentiate tumor subtypes based on
  genomic alterations
• Establishment of a genomics database that
  scientists can access
• Ability to translate genomic information into
  positive clinical outcomes

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Cancer Biomedical Informatics Grid -
caBIGhttp//cabig.nci.nih.gov
Currently 800 Individuals - 80 Organizations
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Vision 21st Century Personalized Medicine
Look for genetic links to disease
predict
detect
Monitoring and prevention
pinpoint
Better targeted diagnostics (In-vitro
diagnostics, imaging)
treat
personalize
Treatment selection
Treatment
track
Treatment monitoring (In-vitro diagnostics,
imaging)
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TCGA is an Important Step Toward Personalized
Medicine But Barriers remain

• Lack of technology standards (genomics,
  informatics, emerging technologies)
• Lack of common technology platforms to enable the
  sharing of information and transfer to clinical
  application
• Lack of common reagents and highly qualified
  public data sets
• Inability to manage and interpret large
  quantities of pre-processed data
• Disconnect in developing tools needed for
  assessing the science in the development process
  Led to the FDAs Critical Path
• Lack of a coordinated, integrated system
• Lack of common vocabularies
• Need for new funding mechanisms to facilitate
  data sharing and collaboration
• Need for new clinical trials design models
• Existence of cultural barriers
• No sector can meet all of these challenges

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Personalized Medicine Is Transforming
Discovery/Development/Delivery
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How To Stay Involved in TCGA

• Updates on TCGA website http//cancergenome.nih.
  gov
• Updates in the NCI Cancer Bulletin
  www.cancer.gov
• Coming SoonSign up at the TCGA website to
  receive automatic email updates

http//cancergenome.nih.gov