1. Stan Hamilton, MD Professor and Head Pathology and Laboratory Medicine
NCI NGS Meeting May ?, So Now What Do We Do?: NGS in Clinical Laboratories
Stan Hamilton, MD
Professor and Head
Pathology and Laboratory Medicine

2. TISSUE MOLECULAR BIOMARKER CONTINUUM
SPECIMENS
IACS
IPCT
THORACIC LAB
OTHERS
MOLECULAR
PATHOLOGY
MTMTF
MTEC
RESEARCH
Pre-CLIA
development
CLIA Labs
(CAP-accredited)
Cell blocks
Biopsy
specimens
Surgical
OR Suites
Tissue Qualification
Lab
Outpatient
Clinics
Outside Facilities
Cytology
Expeditor
Office
CLINICAL
Molecular
Diagnostics
Other
P&LM
Clinical
Labs
ASSAYS
PATIENTS
The Clinical
Genomics
Biorepository
(TCGB)
Routine
Histology
Alkek G5 &
Mays Clinic
Frozen
Section Labs
IR, US & Endoscopy Suites
FNA
Blocks &
slides
Assay results

3. Roles for clinical labs
Address all phases of testing
Pre-analytical, analytical, post-analytical
Fulfill clinical needs (and wants)
Criteria
Provide quality for patient safety
Maintain regulatory compliance
Achieve fiscal goals

5. New roles for the pathologist
Assay selection and development
Clinical therapeutics consultation
Specimen acquisition and qualification
Assay quality control/quality assurance
Assay results interpretation
Regulatory and fiscal environment
Competitive environment

6. Deciding on what’s ready for clinical use

7. Whole genome sequencing (WGS)
NGS strategies
Whole genome sequencing (WGS)
Somatic mutations in tumor
Germline mutations and polymorphisms
Whole exome sequencing (WXS)
Sequencing of targets for actionable alterations (ACGS)
Informatics support

8. NGS strategies for clinical labs
The driver: Clinical utilization of sequence data
The problem of reporting complex results in clinically understandable format
“Umbrella” trials of new targeted agents
Novel usage of existing agents to target pathways
Novel combinations of agents
Validated and actionable data

9. NGS beyond nucleotide substitutions
Small insertions and deletions (indels)
Copy number variations
Amplifications
Losses
Chromosomal re-arrangements
Methylation
Gene expression
Functional genomics

10. Evaluation of evidence
Levels
Green and Byar, 1984
TMUGS, 1996
Lassere et al., 2007
NCCN Task Force, 2011
Depth
Breadth

11. Levels of evidence: NCCN Task Force
TMUGS level
Archived tissue level
Validation studies I A
Not required B
> 0, consistent II
0 or inconsistent C
> 1, consistent
III
0 or 1, consistent or inconsistent
IV-V D
N/A

12. New roles for the pathologist
Assay selection and development
Clinical therapeutics consultation
Specimen acquisition and qualification
Assay quality control/quality assurance
Assay results interpretation
Regulatory and fiscal environment
Competitive environment

13. Clinical therapeutics consultation
Drugs for a patient,
or patients for drugs.
Manuel Hidalgo, MD
Clinical care or clinical trial

14. New roles for the pathologist
Assay selection and development
Clinical therapeutics consultation
Specimen acquisition and qualification
Assay quality control/quality assurance
Assay results interpretation
Regulatory and fiscal environment
Competitive environment

15. Updated November 2011

16. Quality of specimens Labile analytes Smaller samples
mRNA
Proteins
Phosphoproteins
Smaller samples
Real-time non-destructive qualification (e.g. optical confluence tomography)

17. Quality of specimens Fit-for-purpose selection of sources
Primary tumor
Metastatic tumor
Non-neoplastic control tissue for specific assays: peripheral blood leukocytes or tissue
Elapsed time between specimen and test
Potential effects of prior therapy
Circulating tumor cells

19. New roles for the pathologist
Intratumoral heterogeneity

20. Hamilton S #02.jpg

21. N Engl J Med 2012

22. Tumor heterogeneity
Importance for analytes of interest: Comparison of primary CRC to metastasis and comparison among metastases
KRAS: Relatively concordant (90%)
NRAS: Highly discordant
Loss from primary
Acquisition in metastasis
Size of abnormal subpopulations

23. New roles for the pathologist
Assay selection and development
Clinical therapeutics consultation
Specimen acquisition and qualification
Assay quality control/quality assurance
Assay results interpretation
Regulatory and fiscal environment
Competitive environment

24. Circ Cardiovasc Genet, 2010

25. New roles for the pathologist
Assay selection and development
Clinical therapeutics consultation
Specimen acquisition and qualification
Assay quality control/quality assurance
Assay results interpretation
Regulatory and fiscal environment
Competitive environment

27. The regulatory environment
CLIA vs. FDA
Laboratory-developed tests (LDTs)
Complex assays
FDA
Companion diagnostics
NCI Cancer Diagnostics Program (CDP)
Professional organizations: ASCO, NCCN, CAP, ASCP, AMP, IOM, etc., etc.
Gene patents

28. The fiscal environment
The $1,000 genome,
the $100,000 analysis.
Elaine Mardis, PhD
Washington University,
St. Louis

29. The fiscal environment
Who wants to pay?
Who pays?
Who gets to decide?

30. The fiscal environment
Who wants to pay?
Nobody
Who pays?
Who gets to decide?

31. Molecular Testing Evaluation Committee (MTEC)

32. TISSUE MOLECULAR BIOMARKER CONTINUUM IR, US & Endoscopy Suites
SPECIMENS
CLINICAL
CLIA Labs
(CAP-accredited)
Pre-CLIA
development
RESEARCH
IACS
Other
P&LM
Clinical
Labs
The Clinical
Genomics
Biorepository
(TCGB)
OR Suites
Surgical
specimens
IPCT
Alkek G5 &
Mays Clinic
Frozen
Section Labs
Outpatient
Clinics
Tissue Qualification
Lab
Routine
Histology
Lab
PATIENTS
Biopsy
specimens
ASSAYS
MTMTF
MOLECULAR
PATHOLOGY
Biopsy
specimens
Cell blocks
IR, US & Endoscopy Suites
Cytology
Lab
FNA
specimens
Molecular
Diagnostics
Lab
THORACIC LAB
Outside Facilities
Expeditor
Office
Blocks &
slides
Assay results
MTEC
OTHERS

33. MTEC roster and governance
Multidisciplinary clinical Division Heads, Department Chairs, and faculty
Administrative personnel: Clinical activities, patient services, compliance, billing, and clinical research
Patient data acquisition and analysis
Patient advocacy
Subcommittee of the Executive Committee of the Medical Staff and reports to the Medical Practice Committee

34. Charge to the MTEC Standard of care Routine clinical ordering
EMR order entry sets
Investment of institutional funds
Documentation for negotiations with third-party and second-party payers
Advanced Beneficiary Notification (ABN)
Documentation of medical necessity, billing compliance, and utilization

35. New roles for the pathologist
Assay selection and development
Clinical therapeutics consultation
Specimen acquisition and qualification
Assay quality control/quality assurance
Assay results interpretation
Regulatory and fiscal environment
Competitive environment

36. Competition for reimbursement
Hospital labs
Reference labs: Megalabs, niche labs
Diagnostic assay companies
Benefits management companies
Direct-to-consumer or -physician companies
Advisory and educational service companies
Non-pathologist professionals
Accountable Care Organizations

37. Summary Current great emphasis on NGS biomarkers
Need for information- and intelligence-driven decisions
Complex processes
Need for regulatory compliance
Stringency of approach for quality

38. Thanks for your attention.