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Metadata supporting data files in the published article: Pitfalls in Assessing Stromal Tumor Infiltrating Lymphocytes (sTILs) in Breast Cancer

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posted on 18.03.2020, 16:45 by Zuzana Kos, Elvire Roblin, Rim Kim, Stefan Michiels, Brandon D. Gallas, Weijie Chen, Koen K. van de Vijver, Shom Goel, Sylvia Adams, Sandra Demaria, Giuseppe Viale, Torsten O. Nielsen, Sunil Badve, Fraser Symmans, Christos Sotiriou, David L. Rimm, Stephen Hewitt, Carsten Denkert, Sibylle Loibl, Stephen J. Luen, John Bartlett, Peter Savas, Giancarlo Pruneri, Deborah A. Dillon, Maggie Cheang, Andrew Tutt, Jacqueline A. Hall, Marleen Kok, Hugo M. Horlings, Anant Madabhushi, Jeroen van der Laak, Francesco Ciompi, Anne-Vibeke Laenkholm, Enrique Bellolio, Tina Gruosso, Stephen B. Fox, Juan Carlos Araya, Giuseppe Floris, Jan Hudeček, Leonie Voorwerk, Andrew H. Beck, Jen Kerner, Denis Larsimont, Sabine Declercq, Gert van den Eynden, Lajos Pusztai, Anna Ehinger, Wentao Yang, Khalid AbdulJabbar, Yinyin Yuan, Rajendra Singh, Crispin Hiley, Maise al Bakir, Alexander J. Lazar, Stephen Naber, Stephan Wienert, Miluska Castillo, Giuseppe Curigliano, Maria-Vittoria Dieci, Fabrice André, Charles Swanton, Jorge Reis-Filho, Joseph Sparano, Eva Balslev, IChun Chen, Elisabeth Ida Specht Stovgaard, Katherine Pogue-Geile, Kim R.M. Blenman, Frédérique Penault-Llorca, Stuart Schnitt, Sunil R. Lakhani, Anne Vincent-Salomon, Federico Rojo, Jeremy P. Braybrooke, Matthew G. Hanna, Teresa Soler, Daniel Bethmann, Carlos Castaneda, Karen Willard-Gallo, Ashish Sharma, Huang-Chun Lien, Susan Fineberg, Jeppe Thagaard, Laura Comerma, Paula Gonzalez-Ericsson, Edi Brogi, Sherene Loi, Joel Saltz, Frederick Klaushen, Lee Cooper, Mohamed Amgad, David A. Moore, Roberto Salgado on behalf of the International ImmunoOncology Biomarker Working Group
In an effort to identify the sources of variation in assessment of stromal tumor infiltrating lymphocytes (sTILs), the authors analysed data and images from three ring studies performed by TIL-Working Group (WG) pathologists specifically evaluating concordance in sTIL evaluation in breast cancer.

Data access: Data supporting figure 3, tables 1-5 and supplementary tables 1-3 are not publicly available in order to protect patient privacy. These datasets can be accessed on request from Roberto Salgado, Department of Pathology GZA-ZNA, Antwerp, Belgium; Division of Research, Peter MacCallum Cancer Center, Melbourne, Australia, email: roberto@salgado.be, upon the completion of a Data Usage Agreement, according to policies from the German Breast Group and NSABP. The histology images supporting figure 2 and figures 4-8, are publicly available in the figshare repository, as part of this record. Figure 9 and supplementary figures 1-8, were generated using the publicly available prognosis tool at www.tilsinbreastcancer.org/, which utilises datasets from a pooled analysis of 9 phase 3 breast cancer trials, including BIG 02-98, ECOG 1199, ECOG 2197, FinHER, GR, IBCSG 22-00, IEO, PACS01 and PACS04 (https://doi.org/10.1200/JCO.18.01010).

Study approval and patient consent: The ring studies were performed on clinical trials material. All participating patients gave written informed consent to sample collection and the use of these samples for translational biomarker research, as approved by the Ethics Commission of the Charité Universitätsmedizin Berlin and NSABP. All relevant ethical regulations have been complied with for this study.

Study aims and methodology: Stromal tumor infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. This study aimed to evaluate sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies, and identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool.

The authors identified 3 ring studies evaluating concordance of sTIL assessment in breast cancer performed by TIL-WG pathologists, for which they could obtain individual pathologist data and images. In ring study 1, 32 pathologists evaluated 60 scanned breast cancer core biopsy slides. Scores were missing for 5 slides; the missing values were replaced by the mean of the 31 remaining scores. Ring study 2 was an extension of the first study. A subset of 28 of the original 32 pathologists participated and scored 60 different scanned breast cancer core biopsy slides. Ring study 3 was performed by six TIL-WG pathologists who independently scored 100 scanned whole slide breast cancer cases. In total, 220 slides were included. For each individual slide, the variability (standard deviation) among pathologists was measured from individual sTILs scores. For more details on the methodology, please read the related published article.

Datasets supporting the figures, tables, and supplementary figures and tables in the published article: Data file Kos et al.xlsx includes the names, file formats and links to the datasets used to generate the figures, tables and the supplementary figures and tables in the published article.

Software needed to access data: The scanned slides in .vsf file format, are specific for a virtual microscope (CognitionMaster Professional Suite, VMScope, vmscope.com).

Funding

Individual authors have received funding form BCRF, grant No. 17-194, Susan G Komen Foundation (CCR18547966), Young investigator Grant from Breast Cancer Alliance, Canadian Cancer Society,the National Cancer Institute of the National Institutes of Health under award numbers 1U24CA199374-01, R01CA202752-01A1, R01CA208236-01A1, R01 CA216579-01A1, R01 CA220581-01A1, 1U01 CA239055-01, National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund and the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University, NCI grants UG3CA225021 and U24CA215109, the Francis Crick Institute that receives its core funding from Cancer Research UK (FC001169, FC001202), the UK Medical Research Council (FC001169, FC001202), and the Wellcome Trust (FC001169, FC001202), Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C).

Additionally, authors received funding from the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), the Prostate Cancer Foundation, the Breast Cancer Research Foundation (BCRF); the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013), Consolidator Grant (FP7-THESEUS-626 617844), European Commission ITN (FP7-PloidyNet 607722), ERC Advanced Grant (PROTEUS), the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 835297), Chromavision, the European’s Union Horizon 2020 research and innovation programme (grant agreement No. 665233), National Institute for Health Research, the University College London Hospitals Biomedical Research Centre, and the Cancer Research UK University College London Experimental Cancer Medicine Centre. RK and KP-G acknowledge research leading to or reported in this publication was supported by NCI U10CA180868, -180822, UG1-189867, and U24-196067 the Breast Cancer Research Foundation and Genentech.

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