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

被引：228

作者：

Denkert, Carsten ^{[1
,2
]}

Wienert, Stephan ^{[1
,3
]}

Poterie, Audrey ^{[4
]}

Loibl, Sibylle ^{[5
,6
]}

Budczies, Jan ^{[1
,2
]}

Badve, Sunil ^{[7
]}

Bago-Horvath, Zsuzsanna ^{[8
]}

Bane, Anita ^{[9
]}

Bedri, Shahinaz ^{[10
]}

Brock, Jane ^{[11
]}

Chmielik, Ewa ^{[12
,13
]}

Christgen, Matthias ^{[14
]}

Colpaert, Cecile ^{[15
]}

Demaria, Sandra ^{[16
]}

Van den Eynden, Gert ^{[17
]}

Floris, Giuseppe ^{[18
]}

Fox, Stephen B. ^{[19
]}

Gao, Dongxia ^{[20
]}

Heppner, Barbara Ingold ^{[1
]}

Kim, S. Rim ^{[21
]}

Kos, Zuzana ^{[22
]}

Kreipe, Hans H. ^{[14
]}

Lakhani, Sunil R. ^{[23
]}

Penault-Llorca, Frederique ^{[24
]}

Pruneri, Giancarlo ^{[25
]}

Radosevic-Robin, Nina ^{[24
]}

Rimm, David L. ^{[26
]}

Schnitt, Stuart J. ^{[27
]}

Sinn, Bruno V. ^{[1
,28
]}

Sinn, Peter ^{[29
]}

Sirtaine, Nicolas ^{[30
]}

O'Toole, Sandra A. ^{[31
]}

Viale, Giuseppe ^{[32
]}

Van de Vijver, Koen ^{[33
]}

de Wind, Roland ^{[34
]}

von Minckwitz, Gunter ^{[5
]}

Klauschen, Frederick ^{[1
]}

Untch, Michael ^{[35
]}

Fasching, Peter A. ^{[36
]}

Reimer, Toralf ^{[37
]}

Willard-Gallo, Karen ^{[38
]}

Michiels, Stefan ^{[39
]}

Loi, Sherene ^{[40
]}

Salgado, Roberto ^{[17
,41
]}

机构：

[1] Charite, Inst Pathol, Charitepl 1, D-10117 Berlin, Germany

[2] German Canc Consortium DKTK, Partner Site Berlin, Berlin, Germany

[3] VMscope GmbH, Berlin, Germany

[4] Inst Gustave Roussy, Serv Biostat & Epidemiol, Villejuif, France

[5] GBG, Neu Isenburg, Germany

[6] Sana Klinikum Offenbach, Clin Gynecol & Obstet, Offenbach, Germany

[7] Indiana Univ Sch Med, Indianapolis, IN 46202 USA

[8] Med Univ Wien, Clin Inst Pathol, Vienna, Austria

[9] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada

[10] Weill Cornell Med Coll, Doha, Qatar

[11] Harvard Med Sch, Boston, MA USA

[12] Maria Sklodowska Curie Mem Canc Ctr, Tumor Pathol Dept, Gliwice, Poland

[13] Inst Oncol, Gliwice Branch, Gliwice, Poland

[14] Hannover Med Sch, Inst Pathol, Hannover, Germany

[15] Sint Augustinus, GZA Ziekenhuizen, Pathol, Antwerp, Belgium

[16] Weill Cornell Med Coll, Radiat Oncol & Pathol, New York, NY USA

[17] GZA Hosp, Dept Pathol & Cytol, Antwerp, Belgium

[18] Univ Hosp Leuven, Dept Pathol, Leuven, Belgium

[19] Peter MacCallum Canc Ctr, Dept Pathol, Melbourne, Vic, Australia

[20] Vancouver Hosp, Anat Pathol, Vancouver, BC, Canada

[21] NSABP, Div Pathol, Pittsburgh, PA USA

[22] Univ Ottawa, Dept Pathol & Lab Med, Ottawa, ON, Canada

[23] Univ Queensland, Clin Res Ctr, UQ Sch Med & Pathol Queensland, Brisbane, Qld, Australia

[24] Univ Auvergne, Jean Perrin Comprehens Canc Ctr, Dept Pathol, ERTICa Res Team, EA4677, Clermont Ferrand, France

[25] Univ Milan, Div Pathol & Lab Med, Milan, Italy

[26] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA

[27] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA

[28] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[29] Heidelberg Univ, Inst Pathol, Sekt Gynakopathol, Heidelberg, Germany

[30] Inst Jules Bordet, Anat Pathol, Brussels, Belgium

[31] Royal Prince Alfred Hosp, Dept Tissue Pathol & Diagnost Oncol, Mol Diagnost Oncol, Camperdown, NSW, Australia

[32] Univ Milan, European Inst Oncol, Dept Pathol, Milan, Italy

[33] Netherlands Canc Inst, Dept Pathol, Amsterdam, Netherlands

[34] Inst Jules Bordet, Brussels, Belgium

[35] Helios Klinikum Berlin Buch, Dept Gynecol, Berlin, Germany

[36] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynecol & Obstet, Erlangen, Germany

[37] Klinikum Sudstadt Rostock, Dept Gynecol, Rostock, Germany

[38] Inst Jules Bordet, Mol Immunol Unit, Brussels, Belgium

[39] Univ Paris Saclay, Univ Paris 11, Serv Biostat & Epidemiol, Gustave Roussy,CESP,Inserm U1018, Villejuif, France

[40] Peter MacCallum Canc Ctr, Div Res & Clin Med, Melbourne, Vic, Australia

[41] Inst Jules Bordet, Breast Canc Translat Res Lab, Brussels, Belgium

来源：

MODERN PATHOLOGY | 2016年 / 29卷 / 10期

关键词：

NEOADJUVANT CHEMOTHERAPY; CARBOPLATIN; TRIALS;

D O I：

10.1038/modpathol.2016.109

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

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.

引用

页码：1155 / 1164

页数：10

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