NCI NGS Meeting May ?, 2012 So Now What Do We Do?: NGS in Clinical Laboratories

1. NCI NGS MeetingMay ?, 2012So Now What Do We Do?:NGS in Clinical Laboratories Stan Hamilton, MD Professor and Head Pathology and Laboratory Medicine

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

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. 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

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 • 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

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 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 Tissue Qualification Lab Outpatient Clinics Routine Histology Lab Biopsy specimens PATIENTS ASSAYS MTMTF MOLECULAR PATHOLOGY Biopsy specimens Cell blocks IR, US & Endoscopy Suites Cytology Lab FNA specimens THORACIC LAB Molecular Diagnostics 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.