Transcript What Are Biomarkers? - National Coalition for Cancer Research

EDRN Bringing Biomarkers to Clinical
Fruition — It Takes a Village
Sudhir Srivastava, Ph.D., MPH
Chief, Cancer Biomarkers Research Group
EDRN: Early Detection Research Network, Division of Cancer Prevention, NCI
October 27, 2015
NCI’s Mission
To help people live longer,
healthier lives by
supporting research to
reduce the incidence of
cancer and to improve the
outlook for patients who
develop cancer
How Can We Save More Lives from Cancer?
 Most cancers are diagnosed when they are 1–4 cm in size
 By this time many have already metastasized
 To reduce cancer-specific mortality, we need effective
Biomarkers and Methods for:
 Risk Assessment
 Early Detection
 Therapy
“It costs $1 billion to funnel a single cancer medication through the regulatory pipeline.
For a fraction of that, new diagnostics to spot cancers in their earliest stages ultimately could
save more lives.” Dr. Lee Hartwell, President, Fred Hutchinson Cancer Research Center
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What Are Biomarkers?
Biological Marker
(Biomarker)—A characteristic
that is objectively measured
and evaluated as an indicator
of normal biological processes,
pathogenic processes, or
pharmacologic responses to a
therapeutic intervention.
Types of Biomarkers
• Biomarkers of Risk
• Biomarkers of Early
Detection and Diagnosis
• Prognostic Biomarkers
• Predictive Biomarkers
Source: NIH Biomarker Definitions Working Group - 1998
A Modified Definition of Precision Medicine
Interventions to prevent, diagnose, or treat a disease (e.g. cancer),
based on a molecular and/or mechanistic understanding of the
causes, pathogenesis, and/or pathology of the disease. Where the
individual characteristics of the patient are sufficiently distinct,
interventions can be concentrated on those who will benefit, sparing
expense and side effects for those who will not.
Modified by Doug Lowy, M.D. from: IOM’s Toward Precision Medicine, 2011
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Steps Towards Precision Medicine
The Case for Early Detection
SEER = The NCI Surveillance, Epidemiology, and End Results Program is a coordinated
system of cancer registries that provides information on cancer statistics on cancer
incidence and survival in the U.S. population.
Etzioni et al., Nature Reviews Cancer 3, 243-252 (2003)
State of the Science in Biomarker Research
 More than 40,000 papers on cancer biomarkers each year
 Around 4000–5000 on biomarkers for early detection, diagnosis and
prognosis
 99% claims >90% sensitivity and specificity
 But, very few are supported by evidence sufficient for regulatory
approval
• Rigorous standards for validation of clinical relevance in appropriate populations
(i.e., in detecting preclinical disease, predicting progression/extent of disease)
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Cancer Biomarkers: Missing the Mark
 Biology of early disease not fully
explored
 Differences in analytical techniques
 Differences in statistical methods
(study designs)
 Unintentional selective reporting
 Incomplete protocol reporting
 Lack of appropriate specimens and
reagents
 Variations in interpretation
 Bias, chance and overfitting
 Lack of appropriate controls
 Need for additional knowledge in
translation of laboratory tests into
clinical tests
 Need for more collaboration
Need for More Collaboration
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Why is Discovery of Clinically Useful
Biomarkers Difficult?
Iceberg of Cancer
 Biology
 Need for Infrastructural Support
Known Genetic Changes from
Frankly Malignant Tumors
 Need for Collaborations Among
Stakeholders
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Basic scientists
Clinicians
Public Health Professionals
Informaticians and Bioinformaticians
Advocates
Funding organizations
Regulatory authorities
Unknown Genetic Changes in
Preneoplastic (in situ lesion) and
Neoplastic (benign or malignant
conditions)
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The Need
 Non-invasive, highly sensitive and specific biomarkers for
cancer detection
 Clinically-driven, evidence-based discovery and validation of
biomarkers for risk assessment, early detection, diagnosis and
prognosis
 Rigor and demonstration of reproducibility in discovery
approaches
 Team science driven biomarker research
 Empowerment of stakeholders
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EDRN Answering the Need with a Team Science
Approach
 Scientists in the business of discovery
EDRN Organization
 Scientific laboratory experts to validate and
standardize assays
 Clinician-scientists who identify biomarker
applications and criteria for clinical success, and
develop methods for validation
 Biostatisticians who oversee process at every
juncture
 Infrastructure, including data management and
biorepositories – linked by informatics
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EDRN Program Objectives
 Establish an investigator-initiated infrastructure to support
development and validation of early detection biomarkers and markers
of progression
 Foster interaction between academic, clinical and industrial leaders
 Standardize biomarker validation criteria
 Develop a quality assurance program
 Bring biomarkers to clinical use
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Strategic Partnerships: It Takes a Village
 Federal Partnerships
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National Institute of Standards and Technology
Center for Prostate Disease Research, DOD
Pacific Northwest National Laboratory, DOE
Jet Propulsion Laboratory (JPL), NASA
 Non-Profit Foundations — Leveraging Resources
 Canary Foundation uses EDRN Data Management System for lung and prostate markers
 Lustgarten Foundation funded 20-hybridoma cell lines for pancreatic candidate markers
 Precompetitive data sharing with industry (e.g., prostate cancer marker proPSA with Beckman
Coulter, PCA3 with GenProbe)
 International Partnerships
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Turkey, Chile (mesothelioma)
China (hepatocellular carcinoma, lung)
Cancer Research UK (in progress; pancreatic, lung)
The European Advanced Translational Research Infrastructure (in progress; www.eatris.eu)
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Meeting the Goals
 Provide Integrated Infrastructure
 Build Resources for Biomarker Research
 Establish Standardized Criteria for Biomarker Discovery and
Validation
 Quality Assurance Programs
 Ensure Research Reproducibility
 Improve Screening and Diagnostic Tests for Common Clinical
Dilemmas
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Rigor and Reproducibility:
Study Designs for Biomarker Development
Phases of Biomarker Discovery and Validation
PRoBE
Study
Design:
ProspectiveSpecimenCollection,
RetrospectiveBlindedEvaluation
Preclinical
Exploratory
PHASE 1
Promising directions identified
Clinical Assay
and
Validation
PHASE 2
Clinical assay detects established
disease
Retrospective
Longitudinal
PHASE 3
Biomarker detects preclinical disease
and a “screen positive” rule defined
Prospective
Screening
PHASE 4
Extent and characteristics of disease
detected by the test and the false
referral rate are identified
Cancer
Control
PHASE 5
Impact of screening on reducing
burden of disease on population is
quantified
Phases of Biomarker Development
for Early Detection of Cancer
Margaret Sullivan Pepe et al.
J Natl Cancer Inst, Vol. 93, No. 14, July 18, 2001
Pivotal Evaluation of the Accuracy of a Biomarker Used for
Classification or Prediction: Standards for Study Design
Margaret Sullivan Pepe et al.
J Natl Cancer Inst 2008; 100:1432-1438
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Integrated Infrastructure
 Vertically integrated infrastructure for discovery, development and validation
of biomarkers:
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>200 active protocols; >100 Material Transfer Agreements (MTAs) and
Institutional Review Board (IRB) approvals
>900 candidate biomarkers prioritized for evaluation
~300 moved forward to Phase II and Phase III validation
>10,000 subjects enrolled
>12 clinical validation studies
 Policy and Procedures in place for transparency and effective management
 Effective hand-off mechanism
EDRN cited as a model organization (best practices for project management driven by
milestones and operational guidelines, manual of operations, and team approach) by AACR,
NCI Translational Research Working Group, IOM, Nature, Science, J. Proteome Research.
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Building Resources for Clinical Studies
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Platform for multi-center biomarker validation studies
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Appropriate clinical laboratories to develop and test assays
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Mechanism for biomarker triaging prior to large, expensive
validation studies (use of biospecimen Reference Sets)
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>100,000 clinically-annotated biospecimens using common
data elements (CDEs)
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Centralized statistical center for data analysis and informatics
infrastructure to share data
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NASA/JPL Informatics Center
NASA-NCI partnership, leveraging
informatics and data science technologies
from Earth and Planetary Science
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Reproducible, Big Data systems for exploring
the universe
Received 2011 NASA Group Award for
“innovative use of NASA software
technologies to support cancer research”
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Key Objectives of EDRN Informatics
 Build enabling informatics infrastructure for collaboration, sharing
and dissemination
 Develop structured data collection, storage and curation for
biomarker validation studies, biomarker database
 Organize data that are searchable and informative
 Development of an advanced Knowledge System for EDRN to
capture, share and support reproducible analysis data from the
biomarker studies
 Integrate data from a variety of experimental platforms and
laboratories into a Knowledge Environment that is easily accessible
to support analysis and reproducibility
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Leveraged Informatics and Data Science
Capabilities
 National data sharing architectures
 Common data elements and models
 Big data infrastructure
 Analytical data pipelines
 Intelligent data algorithms
 Visualization techniques
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Capturing and Sharing Biomarker Data
Laboratory
Data Warehouse
EDRN Data Curation
Investigator Upload
Laboratory Data
Generation
EDRN Data
Warehouse
EDRN Public Portal
(http://edrn.nci.nih.gov)
Biomarker
Database
Towards a distributed, national biomarkers knowledge system
Specimens,
Protocols,
Publications,
etc.
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Accessing EDRN Data Across the EDRN:
Data May Come from Any of These Sources
 Biomarker annotations
 Biomarker data
 Protocols
 Specimens
 Linked through Public Portal
 Access to analytical data
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What has Emerged…
The EDRN Knowledge System
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EDRN’s Accomplishments
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Eleven CLIA Certified Diagnostic Tests
Biomarker Assay
Purpose
EDRN Principal
Investigator/CLIA
Laboratory
MiPS (Mi Prostate Score Urine test), Multiplex analysis of T2-ERG
Detection of prostate cancer
A. Chinnaiyan/Gen-Probe
IHC and FISH for T2-ERG fusion
Detection of prostate cancer
A. Chinnaiyan/Roche
GSTP1 methylation
Repeat biopsies in prostate
cancer
D. Sidransky/OncoMethylome
Mitochondrial deletion
Detection of prostate cancer
NIST/Mitomics
Proteomic panel
Detection of lung cancer
W. Rom/Celera
Aptamer-based markers
Detection of lung cancer
W. Rom/Somalogic
80-gene panel
Detection of lung cancer
A. Spira/Allegro
Vimentin methylation in stool
Detection of colon cancer
S. Markowitz/LabCorp
Galectin-3 ligand
Detection of advanced
adenomas and colon cancer
R. Bresalier/BG Medicine
GP73
Risk of hepatocellular
carcinoma
T. Block/Beckman Coulter
8-gene Panel for Barrett’s Esophagus
Progression Prediction of BE
gene fusion, PCA3 and serum PSA
Stephen Meltzer//Diagnovus
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Five FDA Approved Diagnostic Tests
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PCA3 Molecular Urine Test:
Non-coding mRNA (PROGENSA)
 To determine the need for repeat prostate biopsies in men who have
had a previous negative biopsy: Gen-Probe, Inc.
 FDA approved 2/15/2012
 High risk cut-off
score >35
High Risk
80
Very
High Risk
70
% Cancer
60
Equivocal Risk
50
40
30
Low
Risk
20
10
0
<5
5 to 19
20 to 34
35 to 49
50 to 100
> 100
PCA3 Scores
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The 1st Proteomics IVDMIA (In vitro Diagnostic
Multivariate Index Assays)
FDA approved 3/9/2010
Proteomic Approaches to Tumor Marker Discovery: Identification of Biomarkers for Ovarian Cancer. Alex J. Rai ……Daniel W. Chan. Archives
of Pathology and Laboratory Medicine, 2002.
Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Z Zhang …..DW Chan. Cancer
Research, 2004.
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Health Economics
Use of Biomarkers – less expensive and less invasive
 For example, 7.5 million screening colonoscopies are performed each year in the
United States
 Average cost: $1,600 per colonoscopy
 A 10% reduction in screening colonoscopies using biomarkers could save
more than $1 billion
 Approximately 600,000 indeterminate lung nodules, 8-30 mm size, undergo
diagnostic work-up each year in the United States
 On average, one-third are cancer and two-thirds are benign
 The costs of the related diagnostic work-up total approximately $9 billion/year
 Estimates indicate that up to a third of these costs could be saved utilizing a
blood test to identify lung cancer biomarkers
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A Modified Definition of Precision Medicine
Interventions to prevent, diagnose, or treat a disease (e.g. cancer),
based on a molecular and/or mechanistic understanding of the
causes, pathogenesis, and/or pathology of the disease. Where the
individual characteristics of the patient are sufficiently distinct,
interventions can be concentrated on those who will benefit, sparing
expense and side effects for those who will not.
Modified by Doug Lowy, M.D. from: IOM’s Toward Precision Medicine, 2011
31
Thank You!!!
www.cancer.gov
www.cancer.gov/espanol