TISSUE PROCUREMENT AT CANCER CENTERS

1. TISSUE PROCUREMENT AT CANCER CENTERS Carl Morrison M.D., D.V.M. Roswell Park Cancer Institute

2. 1) FUNCTIONAL REQUIREMENTS: What are the operational standards that should be acceptable for TP at any Cancer Center???? • 2) INFRASTRUCTURE ISSUES: Costs, administration, Department priorities???? • 3) NATIONAL POLICY: What changes are needed at the NCI to promote TP????

3. FUNCTIONAL REQUIREMENTS for TISSUE PROCUREMENT: • Collect gram quantities of tumor from greater than 95% of remnant eligible specimens. • Provide detailed monthly accounting process of procured and distributed specimens to outside parties. • Bank tissue for every procured remnant specimen. • Detailed quality control of procured specimens. • Universal method of tumor classification. • Prioritize distribution of specimens. • Extend the use of specimens by distribution of macromolecules (DNA/RNA). • Universal Direct Consent

4. TP Requirement #1: Collect gram quantities of tumor from greater than 95% of remnant eligible specimens. • Probably the most common TP problem – procuring small samples for only a subset of eligible specimens. • Define: • Small samples • Eligible specimens

5. TP Requirement #1: Collect gram quantities of tumor from greater than 95% of remnant eligible specimens. • Small samples – relevant to the size of the tumor. • Guideline: Procure 25 to 50% of the tumor. • Example: 2 x 2 x 2 cm tumor weighs 8 grams x 0.80 = 6.4 grams x 25% or 50% = 1.6 to 3.2 grams • Eligible specimens • Guideline: Invasive tumor > 1cm

6. TP Requirement #1: Collect gram quantities of tumor from greater than 95% of remnant eligible specimens. SOLUTION: • Director of TP must be a practicing Surgical Pathologist. • Standardized grossing of surgical pathology specimens. • Specific requirements for procurement staff. • Confidence of Pathology Faculty that process does no harm.

8. Standardized grossing and procurement for prostatectomy specimens.

9. TP Requirement #2: Provide monthly accounting process. • Must document every surgical procedure and if tissue was collected; if not, then why. • Must document what happened to the procured tissue. • Report must be available to specific groups outside the Department of Pathology. RPCI: Monthly Specimen Distribution and Procurement Report

10. TP Requirement #3: Bank tissue for every procured remnant specimen. • How much – not less than 200 mg. • Future – will have to decide on banking frozen tissue for clinical purposes. RPCI: Intent is to utilize specimens for macromolecule processing (DNA/RNA).

11. TP Requirement #4: Detailed quality control of procured specimens. • Best dollars spent by the Cancer Center. • Detailed QC means more than just tumor present. • Per cent neoplastic cells versus per cent non-neoplastic cells. • Per cent necrosis. • Written report with every specimen distributed.

13. TP Requirement #5: Universal method of tumor classification. • Excellent means of standardizing data sharing between various Cancer Centers. • Should be caBIG compatible. • Should apply to daily Surgical Pathology practice and be part of synoptic reporting. SNOMED-CT: T-code = anatomic site M- code = diagnosis by WHO classification

15. TP Requirement #6: Prioritize distribution of specimens. • Should be independent of Pathology. • Should emphasize translational research. • Should have both clinicians and researchers involved. • Overall process should have defining principles. Tissue Utilization Committee – overall governance. RPCI: Disease Site Related Groups (DSRG) – breast, GI, GU, lung, etc…

16. TP Requirement #7: Extend the use of specimens by distribution of macromolecules (DNA/RNA). • Frozen tissue solid tumors: - 1 to 2 ug DNA/RNA per mg tissue. • RNA quality dependent on tissue type. • 10 to 100x more efficient that distributing tissue. • Cost effective – a dime to quarter per ug DNA/RNA – distribution $1/ug – investigators think quite cheap compared to buying tissue and extraction

17. TP Requirement #8: Universal Direct Consent. • Definition of Universal Direct Consent: Consent of all patients done outside of the surgical setting. • Major advantage – not restricted to current surgical procedure • Difficult process • Requires expertise in many areas • Number of patient portal entries into system is directly related to difficulty of process • To be most effective requires information to be conveyed to TP in real time via electronic format

18. TP Requirement #8: Universal Direct Consent. If not possible what are alternatives: • Consent in the surgical setting • No specific TP consent, only surgical consent

20. Challenges and Solutions for Tissue Procurement CONSENT PATHOLOGIST RESEARCHER CLINICIAN Sure I want to be involved, just let me know what I have to do be in charge. You want me to do more? Trade my cell lines for your tissue, no way!

21. Challenges and Solutions for Tissue Procurement • Universal Direct Consent • Requires administrative support • Requires IT support CONSENT

22. Challenges and Solutions for Tissue Procurement • Involvement in the Decision Process and provide opportunities for Collaboration with basic investigators: • Prioritization by DSRG • Monthly procurement and distribution report CLINICIAN

23. Challenges and Solutions for Tissue Procurement • Commitment by Cancer Center leadership that tissue procurement is: • Not a sideline for practicing pathologist. Requires dedicated staff and faculty. • Very expensive. Chargebacks as primary support is not realistic in the current academic research environment. PATHOLOGIST

24. Challenges and Solutions for Tissue Procurement • Key to increasing translational research: • Availability of interactions with clinicians, pathologists • out of sight, out of mind. RESEARCHER

25. 1) FUNCTIONAL REQUIREMENTS: What are the operational standards that should be acceptable for TP at any Cancer Center???? • 2) INFRASTRUCTURE ISSUES: Costs, administration, Department priorities???? • 3) NATIONAL POLICY: What changes are needed at the NCI to promote TP????

26. INFRASTRUCTURE for TISSUE PROCUREMENT: • Overall organization of TP should be within the Department of Pathology. • Administrative support should have a research as opposed to clinical reporting structure. • Strong institutional support for minimum cost recovery. • Tissue resources should be the #1 priority for Department of Pathology.

27. INFRASTRUCTURE ISSUE #1: Overall organization of TP should be within the Department of Pathology. Two general models in most cancer centers today: • Centralized Model - All components of TP from procurement to banking exist within Pathology. • Federated Model – “cooperative in which the members are individual cooperatives”. Various to all components of TP exist outside of Pathology.

28. INFRASTRUCTURE ISSUE #2: Administrative support should have a research as opposed to clinical reporting structure. At least two models in most cancer centers today: • Shared Research and Clinical Administrative Model – research administration reports to clinical administration. Typical of centralized model of TP where all components exist within Pathology. • Core Research Administrative Model – administrative hierarchy is outside the clinical arena. More typical of the federated model of TP.

29. INFRASTRUCTURE ISSUE #3: Strong institutional support for minimum cost recovery. Minimum dollars for adequate TP model: • Pathologist Assistant: 3 FTE x 0.20 = $60,000 - $100,000. • Procurement Agent: 1 FTE = $30,000 - $45,000. • Biorepository Manager: 1 FTE = $40,000 - $60,000. • Macromolecule Processing: 1 FTE = $40,000 - $60,000. • Database Manager = $30,000 - $45,000. • Administrative Support = 1 FTE x 0.30 = $30,000 - $45,000. • Pathologist: 1 FTE x 0.50 = $100,000 - $150,000. • Histology = $30,000 - $45,000. • Other supplies $30,000 - $45,000. • TOTAL = $400,000 - $600,000.

30. INFRASTRUCTURE ISSUE #3: Strong institutional support for minimum cost recovery. Cost Recovery: • Number of surgeries procured from = 1,000 – 5,000. • Number of aliquots procured = 1 to 4 per specimen. • Total number of procured specimens – 1,000 to 20,000. • Distributed specimens = 50 to 75% = 500 to 15,000. • Cost per surgery = $600 to $60. • Cost per distributed aliquot = $1,200 to $20. • Charges = $15 to $30 per distributed aliquot. • Net = +$10 to deficit of >$1,000 per aliquot

31. INFRASTRUCTURE ISSUE #3: Strong institutional support for minimum cost recovery. Personal Experience from 2 vastly different cancer centers (RPCI & OSU) and discussion with others: • True cost per aliquot procured = $75-150. • TP Cost Recovery from chargebacks = 20 to 30%. • Institutional or extramural support – 70 to 80%. • Total dollars deficit $200-500,000.

32. INFRASTRUCTURE ISSUE #4:Tissue resources should be the #1 priority for Department of Pathology. Two general organizational models of research in most cancer centers today: • Institutional Model – generally not state affiliated health centers. Clinicians are in clinical departments, researchers in Programs, etc. • State Model – cancer center only one part of a much larger state affiliated academic health setting. Clinicians and researchers in same Department, Division, etc.

33. INFRASTRUCTURE ISSUE #4: Tissue resources should be the #1 priority for Department of Pathology. Institutional Model • dollars for basic research are limited at the department level. • Department priorities tend to promote Core Facility functions. State Model • Dollars for basic research support research Faculty at the department level. • Most, but not all, research Pathology Faculty at most, but not all, academic centers are dependent on departmental funding • TP is usually not the #1 priority

34. INFRASTRUCTURE ISSUE #4: Tissue resources should be the #1 priority for Department of Pathology. In a setting with limited resources should Pathology be? • supporting individual investigators • or spending those dollars to provide the best possible tissue resources to all investigators at that particular institution?

35. 1) FUNCTIONAL REQUIREMENTS: What are the operational standards that should be acceptable for TP at any Cancer Center???? • 2) INFRASTRUCTURE ISSUES: Costs, administration, Department priorities???? • 3) NATIONAL POLICY: What changes are needed at the NCI to promote TP????

36. NATIONAL POLICY: What changes are needed at the NCI to promote TP???? What groups at the NCI are involved in issues related to TP? • Office of Biorepositories and Biospecimen Research (OBBR) • Cancer Diagnosis Program (CDP)

37. What has been the role of these groups in promoting TP on a national basis? Office of Biorepositories and Biospecimen Research (OBBR) • 2003 - National Biospecimen Network Blueprint • 2004 – RAND Report • 2007 – Best Practices White Paper

38. National standardized tissue resource “best practices” framework

39. Recommendation 1. The NBN should be organized as • a decentralized network of collection facilities with regional storage, possibly of nonprofit, tissue-repository organizations …, and • as a virtual data repository networked across the nation. • Access to both tissue and data derived from tissue should be broadly available. • Extensive external specimen sharing would be required of NBN collection centers on a national scale.

40. 3.2.2 Best Practices Collection of specimens … follow standardized protocols to the extent possible. New national standards based on best practices …. would cover every aspect of the system—collection, freezing/fixing, storing, and shipping. Such standardization would … make it easier to merge data and conduct multidisciplinary research.

41. RAND Study Government National Institutes of Health National Cancer Institute Cooperative Human Tissue Network Tissue Array Research Program Early Detection Research Network Philadelphia Familial Breast Cancer Registry National Heart Lung and Blood Institute Department of Defense Armed Forces Institute of Pathology Academia Duke University Breast SPORE Mayo Clinic Prostate SPORE UAB Breast and Ovarian SPOREs University of Pittsburgh Medical Center (CPCTR, EDRN, Lung SPORE) Industry Ardais Corporation Genomics Collaborative, Inc.

42. To assist in its examination of existing tissue resources, the NBN Design Team requested that the RAND Corporation conduct case studies of existing human tissue resources to evaluate their utility for genomics- and proteomics-based cancer research and that RAND identify “best practices” at these institutions.

43. Each of the repositories evaluated in this study was designed according to a specific vision, which was not necessarily the same as the vision of the NBN Design Team. Due to these different visions, none of the repositories in this report exhibits all of the elements identified as important by the NBN Design Team for the proposed NBN.

45. “The current NCI Best Practices do not comprise detailed laboratory procedures; rather they consist of principles by which such procedures should be developed by biospecimen resources.”

46. What has been the role of these groups in promoting TP on a national basis? Office of Biorepositories and Biospecimen Research (OBBR) 4) Funded research for evaluation of pre-analytical and post-analytical tissue variables.

47. NATIONAL POLICY: What changes are needed at the NCI to promote TP???? What groups at the NCI are involved in issues related to TP? • Office of Biorepositories and Biospecimen Research (OBBR) • Cancer Diagnosis Program (CDP)

48. Cancer Diagnosis Program (CDP) • Cooperative Human Tissue Network • Clinical Trials Cooperative Group Human Tissue Resources • Early Detection Research Network (EDRN) • Cancer Family Registries (CFRs) for Breast and Ovarian Cancer and Colorectal Cancer • Specialized Programs of Research Excellence (SPOREs).