Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group

Denkert C, Wienert S, Poterie A, Loibl S, Budczies J, Badve S, Bago-Horvath Z, Bane A, Bedri S, Brock J, Chmielik E, Christgen M, Colpaert C, Demaria S, Van Den Eynden G, Floris G, Fox SB, Gao D, Heppner BI, Kim SR, Kos Z, Kreipe HH, Lakhani SR, Penault-Llorca F, Pruneri G, Radosevic-Robin N, Rimm DL, Schnitt SJ, Sinn BV, Sinn P, Sirtaine N, O'Toole SA, Viale G, Van De Vijver K, De Wind R, Von Minckwitz G, Klauschen F, Untch M, Fasching P, Reimer T, Willard-Gallo K, Michiels S, Loi S, Salgado R (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 29

Pages Range: 1155-64

Journal Issue: 10

DOI: 10.1038/modpathol.2016.109

Abstract

Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62-0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85-0.92). The Fleiss' kappa value for <60 vs ≥60% TIL improved from 0.45 (ring study 1) to 0.63 in RS2 and the mean concordance improved from 88 to 92%. This large international standardization project shows that reproducible evaluation of TIL is feasible in breast cancer. This opens the way for standardized reporting of tumor immunological parameters in clinical studies and diagnostic practice. The software-guided image evaluation approach used in ring study 2 may be of value as a tool for evaluation of TIL in clinical trials and diagnostic practice. The experience gained from this approach might be applicable to the standardization of other diagnostic parameters in histopathology.

Authors with CRIS profile

Involved external institutions

Charité - Universitätsmedizin Berlin Germany (DE) Institut Gustave-Roussy France (FR) GBG Forschungs GmbH (German Breast Group) Germany (DE) Indiana University – Purdue University Indianapolis United States (USA) (US) Medizinische Universität Wien Austria (AT) McMaster University Canada (CA) Cornell University United States (USA) (US) Harvard University United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) GZA Ziekenhuizen Belgium (BE) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Peter MacCallum Cancer Centre Australia (AU) Vancouver General Hospital Canada (CA) National Surgical Adjuvant Breast and Bowel Project Foundation (NSABP) United States (USA) (US) University of Ottawa Canada (CA) Università degli studi di Milano Italy (IT) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) University of Queensland Australia (AU) University of Clermont Auvergne France (FR) Yale University United States (USA) (US) Beth Israel Deaconess Medical Center (BIDMC) United States (USA) (US) Ruprecht-Karls-Universität Heidelberg Germany (DE) Institut Jules Bordet Belgium (BE) Royal Prince Alfred Hospital Australia (AU) HELIOS Kliniken Germany (DE) Klinikum Südstadt Rostock Germany (DE) École Polytechnique - Université Paris-Saclay France (FR)

How to cite

APA:

Denkert, C., Wienert, S., Poterie, A., Loibl, S., Budczies, J., Badve, S.,... Salgado, R. (2016). Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group. Modern Pathology, 29(10), 1155-64. https://doi.org/10.1038/modpathol.2016.109

MLA:

Denkert, Carsten, et al. "Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group." Modern Pathology 29.10 (2016): 1155-64.

BibTeX: Download