NCI NGS MeetingMay ?, 2012

So Now What Do We Do?:NGS in Clinical Laboratories

Stan Hamilton, MD

Professor and Head

Pathology and Laboratory Medicine

SPECIMENS

IACS

IPCT

THORACIC LAB

OTHERS

MOLECULARPATHOLOGY

MTMTF

MTEC

RESEARCHPre-CLIAdevelopment

CLIA Labs(CAP-accredited)

Cell blocks

Biopsyspecimens

Biopsyspecimens

Surgicalspecimens

OR Suites

Tissue Qualification

Lab

OutpatientClinics

Outside Facilities

CytologyLab

ExpeditorOffice

CLINICAL

MolecularDiagnostics

Lab

OtherP&LM

ClinicalLabs

ASSAYS

PATIENTS

The ClinicalGenomics

Biorepository(TCGB)

RoutineHistology

Lab

Alkek G5 & Mays Clinic

FrozenSection Labs

IR, US & Endoscopy

Suites

FNAspecimens

Blocks &slides

Assay results

TISSUE MOLECULAR BIOMARKER CONTINUUM

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

Ordering physician/ designee submits

request using Order Set / ClinicStation

Expeditor office prints request and

patient history reports (most recent case)

Pathologist performs Initial

Review of available slides

and reports

Pathologist selects the block(s) that he/she wants to use for the case

Expeditor takes the case

paperwork and on-hand materials to the Pathologist

Expeditor takes the

material to the Histology Lab

Histology Lab cuts the material and returns materials to the Expeditor

The Expeditor progresses “R” case to “Slide Marking”, sorts cases by subspecialty and takes the cut material to

the Pathologist

Is the selected material

on-site ?

No

Expeditor requests the material from storage facility or

another facility

Materials are received by

Outside Slides area

Expeditors received

material from Outside Slides

The Expeditor progresses “R” case to “Materials to Lab” and places materials

in Courier Outbox

Sufficient tumor cells/slides for testing

No

Yes

Courier takes material to Labs

BioMarkers - Pathology Pre-Analytic Process FlowCurrent State as of Jan 2012

Expeditor collects any on-hand materials from slide room

Expeditor completes online Histology

Request and progresses “R” case to ”Materials sent to

Histology”

Pathologist reviews materials,

marks slides, circles tumor cells, H&E and identifies

% tumor cell

Does History Indicate that MDL may have source

materials on hand?

DNA Available

Slides Available

Slides Prepared

Storage facility or another facility sends materials

Leave case with

Pathologist

Wait while Pathologist

marks slide(s)No

Yes

Pathologist requests additional materials

Yes

Ordering Physician

Histology Lab

Outside SlidesStorage/ facility

Surgical PathologistExpeditor

Courier

YesCharges needed

Issue PO

No

Yes

Submit Communication Form to CPAS & Home Center for

Financial Clearance

Expeditor progresses “R” case to “Additional Materials Requested” or “Warehouse Requested

Ready for MDL Lab to Process & Analyze

Accession “R” case in PowerPath;

progress case to “Material to Expeditors”

The Expeditor progresses “R”

case to “Materials to

MDL”

Ask MDL if enough DNA is

on hand

No (95+%)

Enough Source

Material On-Hand?

Yes (<5%)Yes

No

Powerpath/ ClinicStation Tracking Updates

NoCancel

Support Svcs. Mgr.

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

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

I B > 0, consistent

II B 0 or inconsistent

II C > 1, consistent

III C 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– 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

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)

SPECIMENS

TISSUE MOLECULAR BIOMARKER CONTINUUM

IACS

IPCT

THORACIC LAB

OTHERS

MOLECULARPATHOLOGY

MTMTF

MTEC

RESEARCHPre-CLIAdevelopment

CLIA Labs(CAP-accredited)

Cell blocks

Biopsyspecimens

Biopsyspecimens

Surgicalspecimens

OR Suites

Tissue Qualification

Lab

OutpatientClinics

Outside Facilities

CytologyLab

ExpeditorOffice

CLINICAL

MolecularDiagnostics

Lab

OtherP&LM

ClinicalLabs

ASSAYS

PATIENTS

The ClinicalGenomics

Biorepository(TCGB)

RoutineHistology

Lab

Alkek G5 & Mays Clinic

FrozenSection Labs

IR, US & Endoscopy

Suites

FNAspecimens

Blocks &slides

Assay results

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.