1. October 9 th, 2015 University of Pennsylvania TIES Cancer Research Network Y3 Face to Face Meeting U24 CA 180921 Session 6 User Stories and Pilot Studies

2. Philosophy behind the Pilot Projects Eat your own dogfood Educate ourselves about the steps required Test every center and every type of study (aggregate, data, biospecimen) Identify gaps and problems and deal with them before we have rushed users (e.g. email sent to wrong person) Develop materials to help guide users through the process In addition, we have targeted a small number of users to work with us, but always with a TCRN partner on the other side Based on the number of issues we saw in the first five projects – we may need another 5 this year to get to saturation Identify target date for open use for network users

3. TCRN Pilot Projects RPCI – Small ulcerated breast cancers – should they be T4? Dr. Thaer Khoury and Dr. Rebecca Jacobson (UPCI) TIES Data and Ancillary Data (Cancer Registry) University of Pennsylvania – Is there an infectious agent behind Rosai Dorfman Disease? Dr. Mike Feldman and Dr. Liron Pantanowitz (UPCI) TIES Data and FFPE – Breast Papillomas – Value of subsequent resection Dr. Mike Feldman TIES Data University of Pittsburgh – Barret’s esophagus with and without subsequent HG dysplasia/cancer Dr. Yang Liu and Dr. Michael Feldman (Penn) TIES Data and FFPE Georgia Regents University – Pigmented Villonodular Synovitis (PVNS) case series Dr. Roni Bollag TIES Data and Ancillary Data 3

4. TCRN F2F Meeting 2015 RPCI Pilot Project

5. Pilot Project Summary Title: Does tumor size matter in tumor pathology stage 4 (pT4) ? Background: The AJCC guidelines stage breast cancer (BC) with skin ulceration (SU) as pT4b (locally advanced disease) regardless of the tumor size. Purpose: To evaluate if SU is an independent risk of survival. Motivation for Using TCRN: insufficient number of cases at any single institution PIs: Dr. Thaer Khoury (RPCI) and Rebecca Jacobson (UPMC), Cases Source and Number: TCRN RPCI: 22 UPMC: 55 (out 99 identified by TIES) Non-TCRN: 33 (Vanderbilt, Ohio State, Wash U, SW Dallas, Montefiore) Data: Pathology reports, therapy modality, outcomes

6. Pilot Project Benefits and Challenges Access to a valuable unique new resource Broader collaboration Access to a large number of cases Quick turnaround time Publications Three Abstracts submitted to USCAP Conference One manuscript in preparation Challenges CR and pathology data format difference Needed data management support to clean data for analysis Navigating from individual reports to case set (system familiarity) Lessons learned: A network with the appropriate infrastructures can make a big difference. “I am going to do another project.”

7. Pilot Project Abstracts Inconsistency in Following the AJCC Reporting Guidelines for T-Staging of Breast Cancer with Skin Ulceration Skin Ulceration in Breast Cancer Carries No Increased Risk of Disease Free or Overall Survival Breast Cancer with Skin Ulceration: Should All Cases Be Staged as pT4b?

8. Q&A Thanks! Questions or comments?

9. Research study Rosai Dorfman Disease Rosai Dorfman disease is an idiopathic reactive condition characterized by exuberant macrophage reaction in lymph nodes or soft tissue Etiology is unknown but some studies have implicated a virus, Herpes virus 6 in some cases Pathochip is a microarray technology – All known pathogenic virus and bacteria and fungi arrayed – Allows FFPE to be probed for infectious signature in lesional tissue compared to normal controls

10. Rosai Dorfman Query Penn ~ 10 cases identified – Tissue blocks have been cut and ready for extraction Pitt ~ 40 cases identified – Case are currently being pulled together for cutting – Collaborator at Pitt is Dr Liron Pantanowitz – Control tissue will be reactive lymph nodes

11. “Breast Papilloma study” Find all breast needle cores with diagnosis of a papilloma or papillomatosis – but nothing worse (atypia, DCIS, IDC, LCIS, ILC) at the time of the core biopsy who then went on to a subsequent resection – In the resection after the papilloma core biopsy, what is the frequency of finding either in situ or invasive carcinoma – Compare the carcinoma rate to carcinoma in a random core biopsy population with BIRADS4

12. Query Breast Core Papilloma Carcinoma Atypia Atypical hyperplasia

13. Results Penn – 24 patients, 73 reports Pitt – 410 patients, 1225 reports Reviewing quality of results, numbers seem low

14. Pitt Pilot Study Yang Liu, PhD University of Pittsburgh 14

15. Recent Yang Liu Publication citing TIES 15

16. Identifying cohort with specific progression sequence 16

17. Progress Approximately 40 patients at Pitt – Rather surprising to us, so we investigated in other sources to see if we had sizable cohort with repeat endoscopy and surveillance Number of cases identified is small at Penn (~15 including both HG dysplasia and cancer) Workaround using case sets developed from other sources from Penn (useful trick) Potential to try this across all four centers 17

18. Pilot Project: Demographic Characterization of Tenosynovial Giant Cell Tumor Roni J. Bollag, MD, PhD Suash Sharma, MD

19. PVNS/GCT Pigmented Villonodular Synovitis (PVNS) Tenosynovial Giant Cell Tumor (TGCT) = Giant Cell Tumor of Tendon Sheath Incidence ~ 600 new cases per year in US, often young adults Clonal neoplastic process resulting in over-expression of CSF1 in synovium  Frequently due to genetic translocation: t(1;2) CSF1:COL6A3  Propagation of neoplastic clone (autocrine)  Reactive inflammatory process with proliferation & recruitment of CSF1R-expressing cells: macrophages, giant cells, osteoclasts Surgery is standard of care (e.g., joint replacement, amputation) Pharmaceutical target: blockade of CSF-1 Receptor (orphan drug designation?)

20. Proposal for TCRN Submission Tenosynovial giant cell tumor, also known as Giant cell tumor of the tendon sheath and pigmented villonodular synovitis are benign tumors of connective tissue. The subclassification is based primarily on the site of occurrence, broadly subdivided into localized-type distal (hands or feet) and diffuse-type proximal (knee, hip, shoulder joint space) respectively. Surgical excision is definitive, but at present no adjuvant therapeutic options are available. Moreover, demographic data on incidence, age at diagnosis, race and sexual predilection is also scant. With novel directed therapies targeting CSF-1 receptor blockade, more precise tumor demographic data are desirable. With the advent of multidisciplinary pathological archival data made possible by the TCRN network, improved demographic characterization may be possible.

21. Mining TCRN By mining aggregate diagnostic information in the TCRN database, we hope to derive a more extensive understanding of: Overall incidence Age at diagnosis Sexual predilection Racial predilection Recurrence status The demographic features are to be stratified for proximal and distal incidences, and where possible, longitudinal follow-up data including median lifespan and other outcome data shall be sought. Separate characterization of the extraordinarily rare malignant sarcomatoid variant may also derive from the aggregate data review.

22. CSF1R Blockade Phase I Trials (July 2015)

23. Demographic Analysis of PVNS Citation of WHO Compilation of older clinicopathologic case series (next slides)

28. TCRN Access!

29. Tenosynovial Giant Cell Tumor - comprehensive Tenosynovial Giant Cell tumor (C1318543): total 1590 reports (1437 patients) UPENN: 370 reports (347 patients) UPMC: 1160 reports (1035 patients) Roswell Park: 8 reports (7 patients) GRU: 52 reports (48 patients)

30. Tenosynovial Giant Cell Tumor by age

31. TGCT - Demographics

33. PVNS Demographics

34. Summary Project approved! Preliminary Data compelling Age/gender/racial predilection … benchmark? Concept library evaluation TGCT – 1590 PVNS – 508 TGCT, PVNS – 508 Aggregate data useful to power up demographic analysis

35. New Pilot Projects How many more Pilot Projects do we need to run? What parts of the machinery have not yet been exercised enough? How much longer until we provide broader access to investigators?