Pathology and Imaging In Biomarker Development

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					Pathology and Imaging In
Biomarker Development


C. Carl Jaffe, MD, FACC
 Cancer Imaging Program
 National Cancer Institute
Biomarker
NIH Workshop definition (2001):



a characteristic that is objectively measured
  … as an indicator of normal biologic or
  pathogenic processes or pharmacological
  responses to a therapeutic intervention




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Linguistic distinctions


        • biomarker
           • prognostic
           • predictive
        • „qualified‟ biomarker
        • „surrogate‟ marker




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Types of Biomarkers


• Prognostic -- portend disease outcome
  at time of diagnosis without reference to
  any specific therapy
• Predictive -- predict outcome of a
  particular therapy
• Monitoring-- measure response to
  treatment and early detect disease
  progression or relapse


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Predictive vs Prognostic


• Predictive markers can be used to make
  decisions about specific treatments
  • are essential for adaptive trial design
  • a predictive marker may not be prognostic if it
    does not predict outcome in untreated patients
• Prognostic markers may not be predictive
  • i.e. doesn’t interact with particular treatment




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FDG-PET prediction of overall survival
after chemo in patients with NSCLC




                     Weber WA et al. J Clin Oncol 2003.
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     FDG-PET Monitoring Response to Gleevec in GIST




Baseline         24 hours      7 days       2 months       5.5 months

  Baseline       24 hrs       7 days       2 mos          5.5 mos

                                              Dana-Farber Cancer Institute

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“Surrogate” biomarker


• Biomarker used in place of definitive
  endpoint
• May be observed earlier than definitive
  endpoint




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Context: Current Oncology Drugs

 Failure rate and development costs are high:

 >80% of drugs entering clinical development fail to get
    marketing approval
 50% of new drugs reaching Phase III trials fail
 Development costs per drug from discovery through Phase III
    has been estimated at $0.8–1.7 billion requiring 8–10 years
    of time
 For new molecularly targeted oncology drugs, there are
    specific development issues
 Very promising oncology drugs may be effective only in
    selected cancer patients or risk groups
 Inhibition of critical signal transduction pathways may lead to
    collateral toxicity




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Biomarker Consortium

OBQI - public-private partnerships
• coordinated by Foundation for the NIH through the
Biomarker Consortium, - a larger public-private
partnership to promote discovery, development,
qualification, and regulatory acceptance of biomarkers;
• make research results and data arising under
consortium projects publicly available
• develop safe, innovative, and effective medicines and
diagnostics to improve medical care, and improve public
health.




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In this context –
How might Imaging Informatics and Digital Imaging help?



• Image storage and transmission
• Distributed network communication
• Database biospecimens
• Integrate the broader healthcare record
  and enterprise
• Enable performance auditing




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caBIG objectives

                                 software suite that provides a means of
                                 capturing, storing and sharing medical
                                 images.
                                 confederated archive for images and
                                 related data connected interoperably


 Clinical Research   Imaging




 Molecular Biology   Pathology

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              caTISSUE
     050107



                    Suite




An enhanced application for
 biospecimen management




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                       caTissue Suite
• Enhanced Collection Protocol Definition
   Pre-define specimen processing schemes
   Define multiple study arms and time points

• Facilitated Specimen Accession
   Pre-defined specimen and specimen-related data creation

• Collection Protocol Consent Tracking
• Pathology Annotation (CAE)
   CAP protocol pathology annotation for major organ systems

• caTIES-like Pathology Report Annotation
• Custom Annotation (Dynamic Extensions)
• Advanced Query “Wizard”
   Create and save complex, pre-defined or parameterized searches

• Specimen Requisition and Request Tracking
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Enhanced Protocol Definition
          Summary View


                         1. Specimens expected at
                         selected collection point




                          3. Expected aliquots of
                            derivative specimen




                         2. Expected derivative of
                             selected specimen

                                Storage Definition
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      Pathology Annotation
Pathology annotation forms for major organ systems




                                           Pre-defined
                                           pathology annotation
                                           forms


Pathology annotation
for case (SCG)




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                      caTissue Suite v1.0
• Demonstration Site: http://catissuecore.wustl.edu
• Application release: 4/15/2008
• What‟s next –
   Usability enhancements
   Security and control for multi-bank user environment
   Improved custom form generation
   Temporal queries
   Other enhancements based on user feedback




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                                                                                                            Figure 2



                                  lactate
                                   mI

                                  creatine

                                           Glu, Gln

                                          mI
                                          mI

                               taurine
                                     sI
                                                     taurine, mI, Etn
                                                           GPC, PC
                             PA, PEtn                              choline

                                        creatine, lysine, PCr




                                             Glu, Gln




                                           PA, Glu, Gln
                                                                                                                       MR Spectroscopy: Prostate

                                                                                       In vivo 1.5T 300mg




                                    PA


Ex-vivo 11.4T 7mg CIP NCIA                       alanine
                                                                             lactate




                                               lipids, leu, Ile, Val
           UCSF
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National Cancer Institute Imaging Archive


     • repository for oncology image data including ongoing and former
       clinical trials, reference image collections and phantom data
     • Image visualization, interpretation and mark-up tool
     • A project to develop free and open source software for acquisition,
       archival and flexible distribution of images and related data via:
         •   Internet portal
         •   caGRID
         •   DICOM Query Retrieve
         •   API




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How Does It Fit The “Big” Picture?

 • caBIG modules:
    • caTissue: manage users,
      authentication/authorization, specimen
      registration, search, and specimen
      distribution.
    • caMicroscope: image viewer, data services,
      and image streaming.
 • caMicrosocpe
    • Will host the data service as a caGrid service
    • Uses GridFTP to stream large images
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What are the unresolved challenges ?




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Annotation is a challenge




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Vocabularies and Common Data
Elements/Standards and Interoperability


    AIM: Image Annotation and Structured Data Capture

                         CAVITARY MASS

                                             Finding: mass
                                                Mass ID: 1
                                           Margins: spiculated
                                             Length: 2.3cm
                                              Width: 1.2cm
                                               Cavitary: Y
                                               Calcified: N
                                          Spatial relationships:
                                          Abuts pleural surface;
                                              invades aorta




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Common problem: Lack of a radiology
Lexicon/Ontology

• Limited radiology terminology in Snomed CT
  (Systematized Nomenclature of Medicine
  Clinical Terms) or UMLS (Unified Medical
  Language System)
• Current general medical lexicons only include
  about 20% of terms used in radiology reports
• Don‟t have consensus on acquisition
  parameters such as MRI sequences including
  GRASS, ROAST, etc. to describe acquisition
  standards

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Lesson 5: Making a Tool caBIG™ Compatible
What is Data Compatibility?


• caBIG™ compatibility is about using standards to
  ensure interoperability among tools – so that data can
  be exchanged and understood between systems.




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     TRANSFORMING PATHOLOGY:
Emerging technology driving practice innovation