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

(2016) MODERN PATHOLOGY. 29(10). p.1155-1164
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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 o60 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.
Keywords
NEOADJUVANT CHEMOTHERAPY, CARBOPLATIN, TRIALS

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Please use this url to cite or link to this publication:

Chicago
Denkert, Carsten, Stephan Wienert, Audrey Poterie, Sibylle Loibl, Jan Budczies, Sunil Badve, Zsuzsanna Bago-Horvath, et al. 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): 1155–1164.
APA
Denkert, C., Wienert, S., Poterie, A., Loibl, S., Budczies, J., Badve, S., Bago-Horvath, Z., et al. (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), 1155–1164.
Vancouver
1.
Denkert C, Wienert S, Poterie A, Loibl S, Budczies J, Badve S, 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. 2016;29(10):1155–64.
MLA
Denkert, Carsten, Stephan Wienert, Audrey Poterie, 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): 1155–1164. Print.
@article{8578522,
  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 o60 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.},
  author       = {Denkert, Carsten and Wienert, Stephan and Poterie, Audrey and Loibl, Sibylle and Budczies, Jan and Badve, Sunil and Bago-Horvath, Zsuzsanna and Bane, Anita and Bedri, Shahinaz and Brock, Jane and Chmielik, Ewa and Christgen, Matthias and Colpaert, Cecile and Demaria, Sandra and Van den Eynden, Gert and Floris, Giuseppe and Fox, Stephen B and Gao, Dongxia and Heppner, Barbara Ingold and Kim, S Rim and Kos, Zuzana and Kreipe, Hans H and Lakhani, Sunil R and Penault-Llorca, Frederique and Pruneri, Giancarlo and Radosevic-Robin, Nina and Rimm, David L and Schnitt, Stuart J and Sinn, Bruno V and Sinn, Peter and Sirtaine, Nicolas and O'Toole, Sandra A and Viale, Giuseppe and Van de Vijver, Koen and de Wind, Roland and von Minckwitz, Gunter and Klauschen, Frederick and Untch, Michael and Fasching, Peter A and Reimer, Toralf and Willard-Gallo, Karen and Michiels, Stefan and Loi, Sherene and Salgado, Roberto},
  issn         = {0893-3952},
  journal      = {MODERN PATHOLOGY},
  keywords     = {NEOADJUVANT CHEMOTHERAPY,CARBOPLATIN,TRIALS},
  language     = {eng},
  number       = {10},
  pages        = {1155--1164},
  title        = {Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer : results of the ring studies of the international immuno-oncology biomarker working group},
  url          = {http://dx.doi.org/10.1038/modpathol.2016.109},
  volume       = {29},
  year         = {2016},
}

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