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

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

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

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

Deciding on what’s ready for clinical use

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

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

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

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

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

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

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

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

Updated November 2011

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

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

New roles for the pathologist Intratumoral heterogeneity

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N Engl J Med 2012

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

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

Circ Cardiovasc Genet, 2010

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

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

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

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

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

Molecular Testing Evaluation Committee (MTEC)

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

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

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

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

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

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

Thanks for your attention.