preanalytics: the imprecision in precision medicine...and biologically reactive molecular...
TRANSCRIPT
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© College of American Pathologists
Carolyn Compton, MD, PhD, FCAP August 13, 2020
Preanalytics:The Imprecision in Precision MedicineThe Challenge Before Us;The Solutions Ahead
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© College of American Pathologists
Webinar Host
• This series is sponsored by the Personalized Healthcare Committee (PHC)
• Today’s webinar host is Frederick Eyerer, MD
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© College of American Pathologists
Housekeeping
• This presentation will be recorded. The recording and PDF will go out to all registrants in one week
• All lines are muted during the presentation
• Please send in your questions as you think of them via the “Question Box” in your control panel
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© College of American Pathologists
Carolyn Compton, MD, PhD, FCAP• Academic pathologist specializing in
gastrointestinal disease.
• Professor of Life Sciences at Arizona State University and Professor of Laboratory Medicine and Pathology at the Mayo Clinic School of Medicine.
• Adjunct Professor of Pathology at the Johns Hopkins Medical Institutions.
• Research interests include biospecimen science and the development of prognostication tools for cancer patients.
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© College of American Pathologists
Disclaimer
• The CAP does not permit reproduction of any substantial portion of the material in this Webinar without its written authorization. The CAP hereby authorizes attendees of the CAP Webinar to use the PDF presentation solely for educational purposes within their own institutions. The CAP prohibits use of the material in the Webinar – and any unauthorized use of the CAP’s name or logo – in connection with promotional efforts by marketers of laboratory equipment, reagents, materials, or services.
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© College of American Pathologists
Disclaimer, continued
• Opinions expressed by the speaker are the speaker’s own and do not necessarily reflect an endorsement by the CAP of any organizations, equipment, reagents, materials, or services used by participating laboratories.
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© College of American Pathologists 7
The Challenge Before Us;The Solutions Ahead
• Molecular analysis of patient specimens: the foundation of precision medicine
• The critical role of preanalytics in molecular testing
• The state of the science and the experience of experts
• Defining a solution
• Next steps and a vision for the future
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© College of American Pathologists
Unianalyte Tests
Multianalyte Tests
Networks and Systems
Evolution Of Biomarker Testing In The “Omics Era”
Omics Analyses
Technology Development Has Driven the Evolution of Molecular Analysis
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© College of American Pathologists 13 August 2020 9
The Complexity of Laboratory Analysis Is Destined to Increase Further
• Complex molecular biomarkers raise the bar for biospecimen quality and consistency.
• Going forward, the requirement to generate data necessary to understand higher levels of biological function will increase.
• Their specimens are the patients’ investment in the future, as molecular analysis may be needed on archived specimens.
• Currently, exceedingly few biospecimens meet these challenges!
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© College of American Pathologists
• It is impossible to build precision medicine on a foundation of widespread imprecision related to patient specimens.
• High-quality test results depend on high-quality test analytes from biospecimens as starting materials.
• The control of specimen quality involves every step in the supply chain and every person in the chain of custody.
The Vision of Precision Medicine
1013 August 2020
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© College of American Pathologists 11
The Challenge Before Us;The Solutions Ahead
• Molecular analysis of patient specimens: the foundation of precision medicine
• The critical role of preanalytics in molecular testing
• The state of the science and the experience of experts
• Defining a solution
• Next steps and a vision for the future
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© College of American Pathologists
• Definition: all factors and steps that precede a specimen analysis
• May artefactually alter analytes; altered analytes alter test results
• May cause two different types of molecular alterationo Molecular content (via stress responses in viable specimens)
o Molecular integrity
• Requires rigorous real-time, up-front management o You can’t go back and restore lost quality
What Is/Are “Preanalytics”
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© College of American Pathologists
Patient Acquisition Handling/Processing Storage Distribution Scientific
AnalysisMedical/SurgicalProcedures
RestockingUnusedSample
Pre-analytical Factors Affect BothMolecular Composition and Molecular Quality
Time 0
Post-acquisitionPre-acquisition
Factors (examples):� Time at room temperature� Temperature of room� Type of fixative� Time in fixative� Rate of freezing� Size of aliquots
Factors (examples):� Antibiotics� Other drugs� Type of anesthesia� Duration of anesthesia� Arterial clamp time
Specimen is viableand biologically reactive
Molecular composition subject to further alteration/degradation
ANALYS I S
STORAGE
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© College of American Pathologists
HER2/CEP17 = 0.98
HER2/CEP17 = 0.29
Do Preanalytics Matter? Everyone Agrees It Does.
Common laboratory artifacts caused by inappropriate sample collection and transport: how to get the most out of a sample. Gilor and Gilor. Top Companion Anim Med. 2011 May;26(2):109-18. doi: 10.1053/j.tcam.2011.02.003.
Preanalytical challenges – time for solutions. https://doi.org/10.1515/cclm-2018-1334 Received December 17, 2018; accepted January 8, 2019
Pre-analytical issues in the haemostasis laboratory: guidance for the clinical laboratories. Magnette et al. Thrombosis Journal 2016
The cost of poor blood specimen quality and errors in preanalytical processes. Sol F. Green. Clinical Biochem 2013. Stony Brook School of Medicine
Where Are the Preanalytical Stability Standards?Corinne R. Fantz, Dina N. Greene DOI: 10.1373/jalm.2018.026062 Published April 2018
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© College of American Pathologists
HER2/CEP17 = 0.98
HER2/CEP17 = 0.29
Indirect Evidence
ORIGINAL ARTICLES Variable Specimen Handling Affects Hormone Receptor Test Results in Women With Breast Cancer: A Large Multihospital Retrospective StudyFlory L. Nkoy, MD, et al. Arch Pathol Lab Med 2010; 134: 606-612.
Frequency of ER/PR negativity was calculated for each surgery day and compared among hospitals and between 2 groups: • Regular (specimens obtained Sunday through Thursday, more likely to be
tested within 24 hours of surgery) • Prolonged (specimens obtained on Friday and Saturday, more likely to be
tested more than 24 hours after surgery) specimen handling conditions.
Estrogen receptor and PR negativity remained highly variable among hospitals despite use of a single laboratory and tended to be significantly associated with prolonged specimen handling.
Intermountain Healthcare, Utah
Conclusion for patients: Don’t have your breast surgery on Friday!
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© College of American Pathologists
Current State of Patient Specimen Quality in the USA: ~ 30% Are High Quality
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© College of American Pathologists
Powerful Technologies Bring Powerful Risks
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• No technology can spin straw into gold – you must begin with gold!
• The technological capacity exists to produce low-quality data from low-quality analytes with unprecedented efficiency.
• We now have the ability to get the wrong answers with unprecedented speed.
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© College of American PathologistsKhoury T, et al., Mod Pathol. 2009 Nov;22(11):1457-67
a
c
HER2/CEP17 = 0.98
HER2/CEP17 = 0.29
30 min
2 hr
4 hr delay
HER2 IHC and FISH in Breast Cancer:Loss of Signal with Time to Fixation
pMAPK IHC of Colon Cancer : Gain of Signal with Time to Fixation
10 min
20 min
60 min
Hartmut Juhl, Indivumed GmbH, BRN
Cold Ischemia Time Affects Molecular Assay Results
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© College of American Pathologists
Gene ExpressionPre vs. Post Surgery
(Number of Gene Changing Expression)
Protein ExpressionPre vs. Post Surgery
(% Change)
David DA, et al. Oncotarget 2014 Nov 30;5(22):11017-28. doi: 10.18632/oncotarget.26
The variability of gene expression was significantly higher in cancer tissue than normal tissue.
>2-fold Change in Expression of 15% of Genes and 60% of Proteins with Warm Ischemia Time
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© College of American Pathologists
ProcessingProcedure,Temperatureand Time
Blood Draw Procedure
CollectionTubes and Order ofdraw
Distribution& Storage
MolecularAnalysis
Patient Consent and Preparation
Blood Collection and Plasma Processing: Biomarkers and Circulating Tumor Cells
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© College of American Pathologists
Preanalytical Variables and Blood/Plasma
� Tourniquet vs. none
� Tourniquet time
� Central line vs. peripheral vein
� Draw order
� Tube type
� Tube volume
� Tube inversions
� Total time of draw
� Vacuum, butterfly vs. syringe
� Needle bore
� Type of port (if used for access)
� Tube agitation during transport*
� Time to centrifugation
� Centrifuge speed
� Centrifuge temperature
� Number of centrifugations
� Use or not of discard tube
� Temperature, duration storage 13 August 2020 21
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© College of American Pathologists
Biospecimen Quality Drives Molecular Diagnosis
Biospecimen Analysis Biospecimen Collection
Biospecimen processing and ba
Molecular Data Diagnosis / TherapyDiagnostics / Therapeutics Development
PRECISION MEDICINE
Biospecimen Handling and Processing
QUALITY HERE
Starts with the Patient
Ends with the Patient
DETERMINES QUALITY HERE
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© College of American Pathologists
2000 2010 2020
Sample collection and collection design
Sequencing
Data reductionData management
Downstream analysis
Are pathologists prepared for what’s coming with the changing focus on samples?
From Ken Bloom, MD, GE Healthcare, June 2014
Estimating the Changing Aspects of NGS
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© College of American Pathologists
• Place where test is doneo CLIA/CAP laboratory accreditation
• People doing the testo Educationo Proficiency testingo Licensure
• Platforms used for testingo CDRH approved devices
• Processes followed for testingo SOPs o Quality management
• Patient samples to be testedo One enforced standard: ASCO/CAP guideline breast cancer
Rigor and Reproducibility in the Pathology Lab: How Is It Assured?
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© College of American Pathologists
Rigor and Reproducibility for Biomarker Measurement in the Clinical Lab: How Is It Assured?
More is known about the quality of beef in
supermarkets than about the quality of human biospecimens used in molecular testing
because the USDA regulates the quality of beef.
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© College of American Pathologists 26
The Challenge Before Us;The Solutions Ahead
• Molecular analysis of patient specimens: the foundation of precision medicine
• The critical role of preanalytics in molecular testing
• The state of the science and the experience of experts
• Defining a solution
• Next steps and a vision for the future
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© College of American Pathologists
Biomarker Tests for Molecularly Targeted Therapies: Key to Unlocking Precision Medicine
National Academies Press, Jun 30, 2016
• One of the 10 stated goals is to specifically address biospecimen quality.
• Goal 9) Enhance specimen handling and documentation to ensure patient safety and the accuracy of biomarker test results.
“The reliability of biomarker test results depends on the quality of the patient specimens.”
“Professional organizations and health care institutions should develop and implement standards for obtaining adequate specimens.”
The National Academy of Sciences, Engineering and Medicine (IOM) Speaks
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© College of American Pathologists
Biospecimen
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© College of American Pathologists
• Academic genomics experts (scientists: basic and translational)• Academic proteomics experts (scientists: basic and translational)• Expert molecular pathologists• CAP leadership:
o Presidento President Electo Immediate Past President
• Surgeons• Patient advocacy groups• Funders: NCI, advocacy organizations• Regulators: FDA• Leadership of professional societies: ASCO, AACR• Payers: CMS, Palmetto, Aetna, BC/BS• Industry (Pharma, Platform manufacturers, Tissue providers):
Illumina, Genetech, Caprion, Indivumed, Becton-Dickenson, Novartis, Abbott
55 Experts Representing All Stakeholder Groups and Points of View
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© College of American Pathologists
Goal:
• Agree on the pre-analytical steps in the biospecimen lifecycle that MOST compromise the quality of tissue and blood
– “Top 10 List”
• Identify where the greatest value can be delivered in the control of pre-analytical variation (biggest quality bang for the buck)
• “Top 5 List” + Metadata
NBDA Convergence Conference 2014
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© College of American Pathologists
1. Time to stabilization
2. Method of stabilization
3. Method of processing
4. Tissue processor variables
5. Storage conditions
6. Documentation of all above
1. Time to processing
2. Method of acquisition
3. Method of stabilization
4. Method of processing
5. Storage conditions
6. Documentation of all above
Tissue Blood/Plasma
The CAP PPMPT Verifies the Consensus Lists
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© College of American Pathologists 32
The Challenge Before Us;The Solutions Ahead
• Molecular analysis of patient specimens: the foundation of precision medicine
• The critical role of preanalytics in molecular testing
• The state of the science and the experience of experts
• Defining a solution
• Next steps and a vision for the future
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© College of American Pathologists
• CAP Preanalytics for Precision Medicine Project Team (PPMPT)• Verification of the Top 5 lists - review human literature and
benchmark comparisons with CLSI, ISBER, NCI, ISO• Establish professional performance metrics for Top 5
o Data-driveno Practical
• Educate pathology workforce and professionals upstream of pathology in the quality chaino Preanalytics Summit Conference, December 2019
• Implement and enforce performance metrics through the CAP LAP• COC enforcement outside of pathology • Seek reinforcement through FDA guidance, research funder
requirements, pharma companies with companion diagnosticso Personalized Medicine Coalition working group formed
Actions
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© College of American Pathologists
Compton CC, Robb JA, Anderson MW, Berry AB, Birdsong GG, Bloom KJ, Branton PA, Crothers JW, Cushman-Vokoun AM, Hicks DG, Khoury JD, Laser J, Marshall CB, Misialek MJ, Natale KE, Nowak JA, Olson D, Pfeifer JD, Schade A, Vance GH, Walk EE, Yohe SL. Preanalytics and Precision Pathology: Pathology Practices to Ensure Molecular Integrity of Cancer Patient Biospecimens for Precision Medicine. Arch Pathol Lab Med. 2019; 143:1346-1363.
“Fast” Forward Five Years
PPMPT now revising all CAP LAP
checklist
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© College of American Pathologists
1. Time to stabilization: 60 minutes or less
2. Method of processing
o Section thickness: ≤5 mm
o Volume formalin/size tissue ratio: ≥4:1 (optimal ≥10:1)
3. Method of stabilization
o Type of fixative: 10% neutral phosphate-buffered formalin
o Time in fixative: 6-36 hours (optimal 24) - greater for fatty tissues
4. Tissue processor variables
o Maintenance schedule: Manufacturer’s recommendation
o Paraffin type: low melt <60°C
o Forbid non-standard practices (“topping off with non-standard solutions)
5. Storage conditions: Room temperature (e.g., 20-25°C); dry; pest-free
6. [Metadata to be collected]: Any deviation from the above recommendations
PPMPT Verified Recommendations: Tissue
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© College of American Pathologists
1.Time to first processing step: ≥ 60 min or less (4-6 hr EDTA tube / ≥48 hr cell stabilization tube)
2.Method of acquisitiono Tube type appropriate for test
o Volume / tube fill / mixing: complete fill; 10 inversions additive mixing
o Draw order: order specified per WHO 2010 (contamination precluded)
3.Method of processingo Centrifuge time/speed: validated protocol per molecule being measured
o Temperature: room temperature (e.g., 20-25°C)
4.Storage conditions: 1 freeze-thaw only (nucleic acids/proteins use aliquots)
5.Documentation data: for above and any deviation from the above Compton et al. Preanalytics and Precision Pathology; Pathology Practices to Ensure Molecular Integrity of Cancer Patient Biospecimens for Precision Medicine. Archives Pathol Lab Med July 2019; doi: 10.5858/arpa.2019-0009-SA.
PPMPT Verified Recommendation: Blood
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© College of American Pathologists 37
The Challenge Before Us;The Solutions Ahead
• Molecular analysis of patient specimens: the foundation of precision medicine
• The critical role of preanalytics in molecular testing
• The state of the science and the experience of experts
• Defining a solution
• Next steps and going forward
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© College of American Pathologists
Garbage in…
…Garbage out
The Challenge
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© College of American Pathologists
It’s Not Just the Pathologists
Links in the quality chain:
• Surgeons
• Nurses
• Transport personnel
• Phlebotomists
• Interventional radiologists
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© College of American Pathologists
Call to Action and Desired Future State
• Call to action for all professionals in the specimen quality
chain• Seamless chain of custody from patient to analysis
• Enforcement through Joint Commission and/or COC
• Billing codes from payers• Grants requirements from NIH and advocacy
• FDA guidance
• Transformative impact on the quality of molecular analyses for patient care and translation research
• Reduction of irreproducibility in medicine and science
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© College of American Pathologists
It Won’t Be the First Time Pathologists Lead the Way
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© College of American Pathologists
Medicine, Science and The Right Thing to Do
It’s for our patients.
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© College of American Pathologists
Thank You
• Fellow CAP members and pathology colleagueso Members of the CAP Personalized Healthcare Committee
from 2015 – presento Members of the Preanalytics for Precision Medicine Project
Team from 2015 – presento CAP Presidents 2010 – present
• CAP Staff:o PHC 2015 – presento Librarianso CAP LAP
• Everyone listening today
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© College of American Pathologists
CAP’s Precision Medicine Webpage
• The webpage includes brief, relevant articles by CAP members that enable the reader to gain a better understanding of a particular area of precision medicine.o Examples include pharmacogenetics, immune response genes, and the latest
in the molecular drivers of cancer.
o Access them www.cap.org > Member Resources > Precision Medicine
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© College of American Pathologists
• The CAP has created the Pathology Resource Guides to assist pathologists in understanding key emerging technologies. o Printed guides are now available for members ($39) and non-members ($69)o The digital copy of the Resource Guides are a complimentary member benefito Access them www.cap.org > Resources and Publications
CAP’s Pathology Resource Guide: Precision Medicine
© 2018 College of American Pathologists. All rights reserved.
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© College of American Pathologists
THANK YOU!
Thank you for attending our webinar,“Preanalytics: The Imprecision in Precision Medicine”
by Carolyn Compton, MD, PhD, FCAP
For comments about this webinar or suggestions for upcoming webinars, please contact
NOTE: There is no CME/CE credit available for today’s free webinar. The PDF of the presentation will be sent out in a week.
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© College of American Pathologists