Abstract

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.

Details

Title
Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group
Author
Mohamed, Amgad 1   VIAFID ORCID Logo  ; Specht, Stovgaard Elisabeth 2 ; Balslev, Eva 2 ; Thagaard Jeppe 3 ; Chen, Weijie 4 ; Dudgeon, Sarah 4 ; Sharma, Ashish 1   VIAFID ORCID Logo  ; Kerner, Jennifer K 5 ; Denkert Carsten 6 ; Yuan Yinyin 7 ; AbdulJabbar Khalid 7 ; Wienert Stephan 8 ; Savas, Peter 9   VIAFID ORCID Logo  ; Voorwerk Leonie 10 ; Beck, Andrew H 5 ; Madabhushi Anant 11 ; Hartman, Johan 12 ; Sebastian, Manu M 13 ; Horlings Hugo M 14 ; Hudeček, Jan 15   VIAFID ORCID Logo  ; Ciompi Francesco 16 ; Moore, David A 17 ; Singh, Rajendra 18 ; Roblin Elvire 19 ; Balancin, Marcelo Luiz 20 ; Mathieu Marie-Christine 21 ; Lennerz, Jochen K 22 ; Kirtani Pawan 23 ; I-Chun, Chen 24 ; Braybrooke, Jeremy P 25   VIAFID ORCID Logo  ; Pruneri Giancarlo 26 ; Demaria, Sandra 27   VIAFID ORCID Logo  ; Adams, Sylvia 28 ; Schnitt, Stuart J 29 ; Lakhani, Sunil R 30 ; Rojo Federico 31 ; Comerma, Laura 31   VIAFID ORCID Logo  ; Badve, Sunil S 32   VIAFID ORCID Logo  ; Khojasteh Mehrnoush 33 ; Fraser, Symmans W 34   VIAFID ORCID Logo  ; Sotiriou Christos 35 ; Gonzalez-Ericsson, Paula 36   VIAFID ORCID Logo  ; Pogue-Geile, Katherine L 37 ; Kim, Rim S 37 ; Rimm, David L 38   VIAFID ORCID Logo  ; Viale Giuseppe 39 ; Hewitt, Stephen M 40 ; Bartlett, John M, S 41 ; Penault-Llorca Frédérique 42 ; Goel Shom 43 ; Huang-Chun, Lien 44 ; Loibl Sibylle 45 ; Kos Zuzana 46 ; Loi Sherene 47   VIAFID ORCID Logo  ; Hanna, Matthew G 48   VIAFID ORCID Logo  ; Michiels, Stefan 49 ; Kok Marleen 50 ; Nielsen, Torsten O 51 ; Lazar, Alexander J 52   VIAFID ORCID Logo  ; Bago-Horvath Zsuzsanna 53   VIAFID ORCID Logo  ; Kooreman, Loes F, S 54 ; van der Laak Jeroen A W M 55   VIAFID ORCID Logo  ; Saltz, Joel 56 ; Gallas, Brandon D 57   VIAFID ORCID Logo  ; Kurkure Uday 58   VIAFID ORCID Logo  ; Barnes, Michael 59 ; Salgado, Roberto 60 ; Cooper Lee A D 61   VIAFID ORCID Logo  ; Hyytiäinen Aini 62 ; Hida, Akira I 63 ; Thompson, Alastair 64 ; Lefevre, Alex 65 ; Gown Allen 66 ; Lo, Amy 67 ; Sapino, Anna 68 ; Moreira, Andre 69 ; Richardson, Andrea 70 ; Vingiani Andrea 71 ; Bellizzi, Andrew M 72 ; Tutt, Andrew 73 ; Guerrero-Zotano, Angel 74 ; Grigoriadis, Anita 75 ; Ehinger, Anna 76 ; Garrido-Castro, Anna C 77 ; Vincent-Salomon, Anne 78 ; Anne-Vibeke, Laenkholm 79 ; Cimino-Mathews, Ashley 80 ; Srinivasan, Ashok 81 ; Acs Balazs 82 ; Singh, Baljit 83 ; Calhoun, Benjamin 84 ; Benjamin, Haibe-Kans 85 ; Solomon, Benjamin 86 ; Thapa Bibhusal 87 ; Nelson, Brad H 88 ; Castaneda, Carlos 89 ; Ballesteroes-Merino Carmen 90 ; Criscitiello, Carmen 91 ; Boeckx Carolien 92 ; Colpaert Cecile 93 ; Quinn, Cecily 94 ; Chennubhotla, Chakra S 95 ; Swanton, Charles 96 ; Solinas Cinzia 97 ; Hiley Crispin 96 ; Drubay Damien 49 ; Bethmann, Daniel 98 ; Dillon, Deborah A 99 ; Larsimont Denis 100 ; Dhanusha, Sabanathan 101 ; Peeters Dieter 102 ; Zardavas Dimitrios 103 ; Höflmayer Doris 104 ; Johnson, Douglas B 105 ; Aubrey, Thompson E 106 ; Brogi Edi 48 ; Perez, Edith 107 ; ElGabry, Ehab A 108 ; Blackley, Elizabeth F 86 ; Reisenbichler Emily 38 ; Bellolio Enrique 109 ; Chmielik Ewa 110 ; Gaire Fabien 111 ; Andre, Fabrice 112 ; Fang-I, Lu 113 ; Azmoudeh-Ardalan Farid 114 ; Gruosso, Forbius Tina 115 ; Peale Franklin 116 ; Hirsch, Fred R 117 ; Klaushen Frederick 118 ; Acosta-Haab, Gabriela 119 ; Gelareh, Farshid 120 ; van den Eynden Gert 121 ; Curigliano Giuseppe 122 ; Floris Giuseppe 123 ; Broeckx Glenn 124 ; Koeppen Harmut 67 ; Haynes, Harry R 125 ; McArthur, Heather 126 ; Joensuu Heikki 127 ; Olofsson, Helena 128 ; Cree, Ian 129 ; Nederlof Iris 130 ; Frahm, Isabel 131 ; Brcic Iva 132 ; Chan, Jack 133 ; Hall, Jacqueline A 134 ; Ziai, James 67 ; Brock, Jane 29 ; Wesseling Jelle 135 ; Giltnane, Jennifer 67 ; Lemonnier Jerome 136 ; Zha Jiping 137 ; M Ribeiro Joana 138 ; Carter, Jodi M 139 ; Hainfellner Johannes 140 ; Quesne John Le 141 ; Juco, Jonathan W 142 ; Reis-Filho, Jorge 143 ; van den Berg Jose 144 ; Sanchez Joselyn 145 ; Sparano, Joseph 146 ; Cucherousset Joël 147 ; Araya, Juan Carlos 148 ; Julien, Adam 149 ; Balko, Justin M 150 ; Saeger Kai 151 ; Siziopikou Kalliopi 152 ; Willard-Gallo, Karen 153 ; Sikorska Karolina 154 ; Weber, Karsten 155 ; Steele, Keith E 137 ; Emancipator, Kenneth 142 ; El Bairi Khalid 156 ; Blenman Kim R M 157 ; Allison, Kimberly H 158 ; van de Vijver Koen K 159 ; Korski Konstanty 160 ; Pusztai Lajos 157 ; Buisseret Laurence 153 ; Shi Leming 161 ; Shi-wei, Liu 162 ; Molinero Luciana 163 ; Valeria, Estrada M 164 ; Maartje, van Seijen 14 ; Lacroix-Triki Magali 165 ; Cheang Maggie C U 166 ; Bakir Maise al 96 ; van de Vijver Marc 167 ; Dieci, Maria Vittoria 168 ; Rebelatto Marlon C 137 ; Piccart Martine 169 ; Goetz, Matthew P 107 ; Preusser Matthias 140 ; Sanders, Melinda E 170 ; Regan, Meredith M 171 ; Christie, Michael 172 ; Misialek, Michael 173 ; Ignatiadis Michail 174 ; de Maaker Michiel 14 ; Mieke, van Bockstal 175 ; Castillo Miluska 145 ; Harbeck Nadia 176 ; Tung, Nadine 177 ; Laudus Nele 178 ; Sirtaine Nicolas 179 ; Burchardi, Nicole 180 ; Ternes Nils 181 ; Radosevic-Robin Nina 182 ; Gluz Oleg 183 ; Grimm, Oliver 111 ; Nuciforo Paolo 184 ; Jank, Paul 185 ; Jelinic Petar 142 ; Watson, Peter H 186 ; Francis, Prudence A 47 ; Russell, Prudence A 187 ; Pierce, Robert H 188 ; Hills, Robert 189 ; Leon-Ferre, Roberto 107 ; de Wind Roland 179 ; Shui Ruohong 190 ; Declercq Sabine 191 ; Leung, Sam 51 ; Tabbarah Sami 192 ; Souza, Sandra C 193 ; O’Toole Sandra 194 ; Swain, Sandra 195 ; Willis Scooter 196 ; Ely, Scott 197 ; Kim Seong- Rim 81 ; Bedri Shahinaz 198 ; Irshad Sheeba 199 ; Shi-Wei, Liu 200 ; Hendry Shona 201 ; Bianchi Simonetta 202 ; Bragança Sofia 203 ; Paik Soonmyung 81 ; Fox, Stephen B 201 ; Luen, Stephen J 204 ; Naber, Stephen 205 ; Sua, Luz 206 ; Fineberg, Susan 207 ; Soler, Teresa 208 ; Gevaert, Thomas 209 ; d’Alfons Timothy 48 ; Tom, John 210 ; Tomohagu, Sugie 211 ; Bossuyt Veerle 22 ; Manem Venkata 85 ; Cámaea Vincente Peg 212 ; Weida, Tong 213 ; Yang, Wentao 190 ; Tran, William T 192 ; Wang, Yihong 214 ; Allory Yves 215 ; Husain Zaheed 216 

 Emory University School of Medicine, Department of Biomedical Informatics, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
 University of Copenhagen, Department of Pathology, Herlev and Gentofte Hospital, Herlev, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
 Technical University of Denmark, DTU Compute, Department of Applied Mathematics, Lyngby, Denmark (GRID:grid.5170.3) (ISNI:0000 0001 2181 8870); Visiopharm A/S, Hørsholm, Denmark (GRID:grid.5170.3) 
 FDA/CDRH/OSEL/Division of Imaging, Diagnostics, and Software Reliability, Silver Spring, USA (GRID:grid.5170.3) 
 PathAI, Cambridge, USA (GRID:grid.479429.5) 
 Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg, Philipps-Universität Marburg, Institut für Pathologie, Marburg, Germany (GRID:grid.10253.35) (ISNI:0000 0004 1936 9756); Institute of Pathology, Philipps-University Marburg, Marburg, Germany (GRID:grid.10253.35) (ISNI:0000 0004 1936 9756); German Cancer Consortium (DKTK), Partner Site Charité, Berlin, Germany (GRID:grid.10253.35) 
 The Institute of Cancer Research, Centre for Evolution and Cancer, London, UK (GRID:grid.18886.3f) (ISNI:0000 0001 1271 4623); The Institute of Cancer Research, Division of Molecular Pathology, London, UK (GRID:grid.18886.3f) (ISNI:0000 0001 1271 4623) 
 Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg, Philipps-Universität Marburg, Institut für Pathologie, Marburg, Germany (GRID:grid.10253.35) (ISNI:0000 0004 1936 9756) 
 University of Melbourne, Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, Victoria, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); University of Melbourne, Sir Peter MacCallum Department of Oncology, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
10  The Netherlands Cancer Institute, Department of Tumor Biology & Immunology, Amsterdam, The Netherlands (GRID:grid.430814.a) 
11  Case Western Reserve University, Department of Biomedical Engineering, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847); Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, USA (GRID:grid.410349.b) (ISNI:0000 0004 0420 190X) 
12  Karolinska Institutet and University Hospital, Department of Oncology and Pathology, Solna, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705) 
13  The University of Texas MD Anderson Cancer Center, Departments of Epigenetics and Molecular Carcinogenesis, Houston, USA (GRID:grid.240145.6) (ISNI:0000 0001 2291 4776) 
14  The Netherlands Cancer Institute, Division of Molecular Pathology, Amsterdam, The Netherlands (GRID:grid.430814.a) 
15  The Netherlands Cancer Institute, Department of Research IT, Amsterdam, The Netherlands (GRID:grid.430814.a) 
16  Radboud University Medical Center, Department of Pathology, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
17  UCL Cancer Institute, Department of Pathology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
18  Icahn School of Medicine at Mount Sinai, Department of Pathology and Laboratory Medicine, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
19  Université Paris-Saclay, Univ. Paris-Sud, Villejuif, France (GRID:grid.5842.b) (ISNI:0000 0001 2171 2558) 
20  University of São Paulo, Department of Pathology, Faculty of Medicine, São Paulo, Brazil (GRID:grid.11899.38) (ISNI:0000 0004 1937 0722) 
21  Gustave Roussy Cancer Campus, Department of Medical Biology and Pathology, Villejuif, France (GRID:grid.14925.3b) (ISNI:0000 0001 2284 9388) 
22  Massachusetts General Hospital, Department of Pathology, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
23  Manipal Hospitals Dwarka, Department of Histopathology, New Delhi, India (GRID:grid.32224.35) 
24  National Taiwan University Cancer Center, Department of Oncology, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241) 
25  University of Oxford, Nuffield Department of Population Health, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); University Hospitals Bristol NHS Foundation Trust, Department of Medical Oncology, Bristol, UK (GRID:grid.410421.2) (ISNI:0000 0004 0380 7336) 
26  Fondazione IRCCS Istituto Nazionale Tumori and University of Milan, School of Medicine, Pathology Department, Milan, Italy (GRID:grid.4708.b) (ISNI:0000 0004 1757 2822) 
27  Weill Cornell Medical College, New York, USA (GRID:grid.5386.8) (ISNI:000000041936877X) 
28  Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, USA (GRID:grid.240324.3) (ISNI:0000 0001 2109 4251) 
29  Brigham and Women’s Hospital, Department of Pathology, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
30  The University of Queensland Centre for Clinical Research and Pathology Queensland, Brisbane, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537) 
31  CIBERONC-Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Pathology Department, Madrid, Spain (GRID:grid.5515.4) (ISNI:0000000119578126); GEICAM-Spanish Breast Cancer Research Group, Madrid, Spain (GRID:grid.430580.a) 
32  Indiana University School of Medicine, Department of Pathology and Laboratory Medicine, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919) 
33  Roche Tissue Diagnostics, Digital Pathology, Santa Clara, USA (GRID:grid.257413.6) 
34  The University of Texas MD Anderson Cancer Center, Department of Pathology, Houston, USA (GRID:grid.240145.6) (ISNI:0000 0001 2291 4776) 
35  Université Libre de Bruxelles (ULB), Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Brussels, Belgium (GRID:grid.4989.c) (ISNI:0000 0001 2348 0746); ULB-Cancer Research Center (U-CRC) Université Libre de Bruxelles, Brussels, Belgium (GRID:grid.4989.c) (ISNI:0000 0001 2348 0746) 
36  Vanderbilt University Medical Center, Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916) 
37  NRG Oncology/NSABP, Pittsburgh, USA (GRID:grid.412807.8) 
38  Yale University School of Medicine, Department of Pathology, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
39  IEO, European Institute of Oncology IRCCS & State University of Milan, Department of Pathology, Milan, Italy (GRID:grid.15667.33) (ISNI:0000 0004 1757 0843) 
40  National Cancer Institute, National Institutes of Health, Laboratory of Pathology, Bethesda, USA (GRID:grid.48336.3a) (ISNI:0000 0004 1936 8075) 
41  Ontario Institute for Cancer Research, Toronto, Canada (GRID:grid.419890.d) (ISNI:0000 0004 0626 690X); Western General Hospital, Edinburgh Cancer Research Centre, Edinburgh, UK (GRID:grid.417068.c) (ISNI:0000 0004 0624 9907) 
42  Centre Jean Perrin, Department of Pathology and Molecular Pathology, Clermont-Ferrand, France (GRID:grid.418113.e) (ISNI:0000 0004 1795 1689); Universite Clermont Auvergne, UMR INSERM 1240, Clermont-Ferrand, France (GRID:grid.494717.8) (ISNI:0000000115480420) 
43  Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre building, Melbourne, Australia (GRID:grid.1055.1) (ISNI:0000000403978434) 
44  National Taiwan University Hospital, Department of Pathology, Taipei, Taiwan (GRID:grid.412094.a) (ISNI:0000 0004 0572 7815) 
45  German Breast Group, c/o GBG-Forschungs GmbH, Neu-Isenburg, Germany (GRID:grid.434440.3) (ISNI:0000 0004 0457 2954) 
46  BC Cancer, Department of Pathology, Vancouver, Canada (GRID:grid.434440.3) 
47  University of Melbourne, Sir Peter MacCallum Department of Oncology, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); Peter MacCallum Cancer Centre, Melbourne, Australia (GRID:grid.1055.1) (ISNI:0000000403978434) 
48  Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, USA (GRID:grid.51462.34) (ISNI:0000 0001 2171 9952) 
49  Universite Paris-Saclay, Gustave Roussy, Villejuif, France (GRID:grid.460789.4) (ISNI:0000 0004 4910 6535); Université Paris-Sud, Institut National de la Santé et de la Recherche Médicale, Villejuif, France (GRID:grid.5842.b) (ISNI:0000 0001 2171 2558) 
50  The Netherlands Cancer Institute, Division of Molecular Oncology & Immunology, Amsterdam, The Netherlands (GRID:grid.430814.a); The Netherlands Cancer Institute, Department of Medical Oncology, Amsterdam, The Netherlands (GRID:grid.430814.a) 
51  University of British Columbia, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830) 
52  The University of Texas MD Anderson Cancer Center, Department of Pathology, Houston, USA (GRID:grid.240145.6) (ISNI:0000 0001 2291 4776); The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine, Houston, USA (GRID:grid.240145.6) (ISNI:0000 0001 2291 4776); The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology, Houston, USA (GRID:grid.240145.6) (ISNI:0000 0001 2291 4776); The University of Texas MD Anderson Cancer Center, Department of Dermatology, Houston, USA (GRID:grid.240145.6) (ISNI:0000 0001 2291 4776) 
53  Medical University of Vienna, Department of Pathology, Vienna, Austria (GRID:grid.22937.3d) (ISNI:0000 0000 9259 8492) 
54  Maastricht University Medical Centre, GROW - School for Oncology and Developmental Biology, Maastricht, The Netherlands (GRID:grid.412966.e) (ISNI:0000 0004 0480 1382); Maastricht University Medical Centre, Department of Pathology, Maastricht, The Netherlands (GRID:grid.412966.e) (ISNI:0000 0004 0480 1382) 
55  Radboud University Medical Center, Department of Pathology, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); Linköping University, Center for Medical Image Science and Visualization, Linköping, Sweden (GRID:grid.5640.7) (ISNI:0000 0001 2162 9922) 
56  Stony Brook University, Department of Biomedical Informatics, Stony Brook, USA (GRID:grid.36425.36) (ISNI:0000 0001 2216 9681) 
57  FDA/CDRH/OSEL/Division of Imaging, Diagnostics, and Software Reliability, Silver Spring, USA (GRID:grid.36425.36) 
58  Roche Tissue Diagnostics, Digital Pathology, Santa Clara, USA (GRID:grid.36425.36) 
59  Roche Diagnostics Information Solutions, Belmont, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718) 
60  University of Melbourne, Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, Victoria, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); GZA-ZNA Ziekenhuizen, Department of Pathology, Antwerp, Belgium (GRID:grid.428965.4) (ISNI:0000 0004 7536 2436) 
61  Northwestern University Feinberg School of Medicine, Department of Pathology, Chicago, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507) 
62  Department of Oral and Maxillofacial Diseases, Helsinki, Finland (GRID:grid.16753.36) 
63  Matsuyama Shimin Hospital, Department of Pathology, Matsuyama, Japan (GRID:grid.459780.7) (ISNI:0000 0004 1772 4320) 
64  Baylor College of Medicine, Surgical Oncology, Texas, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
65  Roche Diagnostics, Machelen, Belgium (GRID:grid.39382.33) 
66  PhenoPath Laboratories, Seattle, USA (GRID:grid.39382.33) 
67  Genentech Inc., Research Pathology, South San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718) 
68  University of Turin, Italy and Candiolo Cancer Institute - FPO, IRCCS, Department of Medical Sciences, Candiolo, Italy (GRID:grid.7605.4) (ISNI:0000 0001 2336 6580) 
69  New York University, Pulmonary Pathology, New York University Center for Biospecimen Research and Development, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753) 
70  Johns Hopkins Hospital, Department of Pathology, Baltimore, USA (GRID:grid.411935.b) (ISNI:0000 0001 2192 2723) 
71  University of Milan, Department of Pathology, Istituto Europeo di Oncologia, Milan, Italy (GRID:grid.4708.b) (ISNI:0000 0004 1757 2822) 
72  University of Iowa Hospitals and Clinics, Department of Pathology, Iowa City, USA (GRID:grid.412584.e) (ISNI:0000 0004 0434 9816) 
73  The Institute of Cancer Research, Breast Cancer Now Toby Robins Research Centre, London, UK (GRID:grid.18886.3f) (ISNI:0000 0001 1271 4623) 
74  Instituto Valenciano de Oncología, Department of Oncology, Valencia, Spain (GRID:grid.418082.7) (ISNI:0000 0004 1771 144X) 
75  Cancer Centre at Guy’s Hospital, Cancer Bioinformatics Lab, London, UK (GRID:grid.239826.4) (ISNI:0000 0004 0391 895X); King’s College London, School of Life Sciences and Medicine, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
76  Skåne University Hospital, Lund University, Department of Clinical Genetics and Pathology, Lund, Sweden (GRID:grid.13097.3c) 
77  Dana-Farber Cancer Institute, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910) 
78  Paris Sciences Lettres Université, Inserm U934, Department of Pathology, Institut Curie, Paris, France (GRID:grid.7429.8) (ISNI:0000000121866389) 
79  Department of Surgical Pathology Zealand University Hospital, Køge, Denmark (GRID:grid.476266.7) 
80  The Johns Hopkins Hospital, Departments of Pathology and Oncology, Baltimore, USA (GRID:grid.411935.b) (ISNI:0000 0001 2192 2723) 
81  National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
82  Karolinska Institute, Department of Pathology, Solna, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
83  New York University Langone Medical Centre, Department of Pathology, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753) 
84  UNC School of Medicine, Department of Pathology and Laboratory Medicine, Columbia, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
85  Laval University, Québec Heart and Lung Institute Research Center, Quebec city, Canada (GRID:grid.23856.3a) (ISNI:0000 0004 1936 8390) 
86  Peter MacCallum Cancer Centre, Department of Medical Oncology, Melbourne, Australia (GRID:grid.1055.1) (ISNI:0000000403978434) 
87  University of Melbourne, Department of Medicine, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
88  British Columbia Cancer Agency, Trev & Joyce Deeley Research Centre, Victoria, Canada (GRID:grid.248762.d) (ISNI:0000 0001 0702 3000) 
89  Instituto Nacional de Enfermedades Neoplásicas, Department of Medical Oncology, Lima, Perú (GRID:grid.419177.d) (ISNI:0000 0004 0644 4024); Instituto Nacional de Enfermedades Neoplasicas, Department of Research, Lima, Peru (GRID:grid.419177.d) (ISNI:0000 0004 0644 4024) 
90  Providence Cancer Research Center, Portland, Oregon, USA (GRID:grid.419177.d) 
91  Department of Medical Oncology, Istituto Europeo di Oncologia, Milan, Italy (GRID:grid.15667.33) (ISNI:0000 0004 1757 0843) 
92  Roche Diagnostics, Machelen, Belgium (GRID:grid.15667.33) 
93  Department of Pathology, AZ Turnhout, Turnhout, Belgium (GRID:grid.476094.8) 
94  St Vincent’s University Hospital and University College Dublin, Department of Pathology, Dublin, Ireland (GRID:grid.412751.4) (ISNI:0000 0001 0315 8143) 
95  University of Pittsburgh, Department of Computational and Systems Biology, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
96  University College London Cancer Institute, University College London, Cancer Research UK Lung Cancer Centre of Excellence, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
97  Regional Hospital of Aosta, Azienda AUSL, Aosta, Italy (GRID:grid.83440.3b) 
98  University Hospital Halle (Saale), Institute of Pathology, Halle, Germany (GRID:grid.461820.9) (ISNI:0000 0004 0390 1701) 
99  Brigham and Women’s Hospital, Boston, MA Department of Pathology, Dana Farber Cancer Institute, Department of Pathology, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
100  Jules Bordet Institute, Department of Pathology, Brussels, Belgium (GRID:grid.418119.4) (ISNI:0000 0001 0684 291X) 
101  Macquarie University, Department of Clinical Medicine, Sydney, Australia (GRID:grid.1004.5) (ISNI:0000 0001 2158 5405) 
102  HistoGeneX NV, Antwerp, Belgium and AZ Sint-Maarten Hospital, Mechelen, Belgium (GRID:grid.1004.5) 
103  Bristol-Myers Squibb, Oncology Clinical Development, Princeton, USA (GRID:grid.419971.3) 
104  Institut für Pathologie, UK Hamburg, Hamburg, Germany (GRID:grid.419971.3) 
105  Vanderbilt University Medical Centre, Department of Medicine, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916) 
106  Department of Cancer Biology, Mayo Clinic, Jacksonville, USA (GRID:grid.417467.7) (ISNI:0000 0004 0443 9942) 
107  Department of Oncology, Mayo Clinic, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X) 
108  Roche, Tucson, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718) 
109  Universidad de La Frontera, Department of Pathology, Temuco, Chile (GRID:grid.412163.3) (ISNI:0000 0001 2287 9552); Universidad de La Frontera, Departamento de Anatomía Patológica, Temuco, Chile (GRID:grid.412163.3) (ISNI:0000 0001 2287 9552) 
110  Maria Sklodowska-Curie Memorial Cancer Center, Tumor Pathology Department, Gliwice, Poland (GRID:grid.418165.f) (ISNI:0000 0004 0540 2543) 
111  Pathology and Tissue Analytics, Roche, Machelen, Belgium (GRID:grid.476562.4) 
112  Department of Medical Oncology, Gustave Roussy, Villejuif, France (GRID:grid.14925.3b) (ISNI:0000 0001 2284 9388) 
113  Sunnybrook Health Sciences Centre, Toronto, Canada (GRID:grid.413104.3) (ISNI:0000 0000 9743 1587) 
114  Tehran University of Medical Sciences, Tehran, Iran (GRID:grid.411705.6) (ISNI:0000 0001 0166 0922) 
115  Translational Research, Montreal, Canada (GRID:grid.411705.6) 
116  Oncology Biomarker Development, Genentech-Roche, Machelen, Belgium (GRID:grid.411705.6) 
117  Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X) 
118  Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) 
119  Hospital de Oncología Maria Curie, Department of Pathology, Buenos Aires, Argentina (GRID:grid.6363.0) 
120  Directorate of Surgical Pathology, SA Pathology, Adelaide, Australia (GRID:grid.414733.6) (ISNI:0000 0001 2294 430X) 
121  GZA-ZNA Hospitals, Department of Pathology, Wilrijk, Belgium (GRID:grid.414733.6) 
122  University of Milano, Istituto Europeo di Oncologia, IRCCS, Milano, Italy (GRID:grid.4708.b) (ISNI:0000 0004 1757 2822); Division of Early Drug Development for Innovative Therapy, IEO, European Institute of Oncology IRCCS, Milan, Italy (GRID:grid.15667.33) (ISNI:0000 0004 1757 0843) 
123  Laboratory of Translational Cell & Tissue Research, Department of Imaging and Pathology, Leuven, Belgium (GRID:grid.15667.33); KU Leuven- University Hospitals Leuven, Department of Pathology, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884) 
124  University Hospital Antwerp, Department of Pathology, Antwerp, Belgium (GRID:grid.411414.5) (ISNI:0000 0004 0626 3418) 
125  Translational Health Sciences, Department of Cellular Pathology, North Bristol NHS Trust, University of Bristol, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603) 
126  Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, USA (GRID:grid.50956.3f) (ISNI:0000 0001 2152 9905) 
127  Helsinki University Central Hospital, Helsinki, Finland (GRID:grid.15485.3d) (ISNI:0000 0000 9950 5666) 
128  Akademiska University Hospital, Department of Clinical Pathology, Uppsala, Sweden (GRID:grid.412354.5) (ISNI:0000 0001 2351 3333) 
129  International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France (GRID:grid.17703.32) (ISNI:0000000405980095) 
130  Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands (GRID:grid.430814.a) 
131  Department of Pathology, Sanatorio Mater Dei, Buenos Aires, Argentina (GRID:grid.430814.a) 
132  Institute of Pathology, Medical University of Graz, Graz, Austria (GRID:grid.11598.34) (ISNI:0000 0000 8988 2476) 
133  National Cancer Centre, Department of Oncology, Singapore, Singapore (GRID:grid.410724.4) (ISNI:0000 0004 0620 9745) 
134  Vivactiv Ltd, Bellingdon, Bucks, UK (GRID:grid.410724.4) 
135  Netherlands Cancer Institute, Department of Pathology, Amsterdam, The Netherlands (GRID:grid.430814.a) 
136  R&D UNICANCER, Paris, France (GRID:grid.418158.1) 
137  Translational Sciences, MedImmune, Gaithersberg, USA (GRID:grid.418152.b) 
138  Breast Unit, Champalimaud Clinical Centre, Lisboa, Portugal (GRID:grid.418152.b) 
139  Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X) 
140  Clinical Division of Oncology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Department of Medicine, Vienna, Austria (GRID:grid.22937.3d) (ISNI:0000 0000 9259 8492) 
141  University of Leicester, Leicester, and MRC Toxicology Unit, University of Cambridge, Leicester Cancer Research Centre, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
142  Merck & Co., Inc, Kenilworth, USA (GRID:grid.417993.1) (ISNI:0000 0001 2260 0793) 
143  Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, USA (GRID:grid.51462.34) (ISNI:0000 0001 2171 9952); Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA (GRID:grid.51462.34) (ISNI:0000 0001 2171 9952) 
144  The Netherlands Cancer Institute, Department of Pathology, Amsterdam, The Netherlands (GRID:grid.430814.a) 
145  Instituto Nacional de Enfermedades Neoplasicas, Department of Research, Lima, Peru (GRID:grid.419177.d) (ISNI:0000 0004 0644 4024) 
146  Department of Medicine, Department of Obstetrics & Gynecology and Women’s Health, Albert Einstein Medical Center, Bronx, USA (GRID:grid.419177.d) 
147  GHI Le Raincy-Montfermeil, Chelles, Île-de-France, France (GRID:grid.420138.c) (ISNI:0000 0000 8620 9964) 
148  Universidad de La Frontera, Department of Pathology, Temuco, Chile (GRID:grid.412163.3) (ISNI:0000 0001 2287 9552) 
149  Department of Pathology, Gustave Roussy, Grand Paris, France (GRID:grid.14925.3b) (ISNI:0000 0001 2284 9388) 
150  Vanderbilt University Medical Centre, Departments of Medicine and Cancer Biology, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916) 
151  Vm Scope, Berlin, Germany (GRID:grid.412807.8) 
152  Breast Pathology Section, Northwestern University, Department of Pathology, Chicago, USA (GRID:grid.16753.36) (ISNI:0000 0001 2299 3507) 
153  Institut Jules Bordet, Université Libre de Bruxelles, Molecular Immunology Unit, Brussels, Belgium (GRID:grid.418119.4) (ISNI:0000 0001 0684 291X) 
154  The Netherlands Cancer Institute, Department of Biometrics, Amsterdam, The Netherlands (GRID:grid.430814.a) 
155  German Breast Group, Neu-Isenburg, Germany (GRID:grid.434440.3) (ISNI:0000 0004 0457 2954) 
156  Université Mohamed Premier, Cancer Biomarkers Working Group, Faculty of Medicine and Pharmacy, Oujda, Morocco (GRID:grid.410890.4) (ISNI:0000 0004 1772 8348) 
157  Yale Cancer Center Genetics, Genomics and Epigenetics Program, Yale School of Medicine, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710) 
158  Stanford University Medical Centre, Pathology Department, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
159  University Hospital Ghent, Department of Pathology, Ghent, Belgium (GRID:grid.410566.0) (ISNI:0000 0004 0626 3303) 
160  Pathology and Tissue Analytics, Roche Innovation Centre Munich, Penzberg, Germany (GRID:grid.410566.0) 
161  Center for Pharmacogenomics and Fudan-Zhangjiang, Center for Clinical Genomics School of Life Sciences and Shanghai Cancer Center, Fudan University, Fudan, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443) 
162  Sichuan Cancer Hospital, Chengdu, China (GRID:grid.415880.0) (ISNI:0000 0004 1755 2258) 
163  Oncology Biomarker Development, Genentech-Roche, Machelen, Belgium (GRID:grid.415880.0) 
164  University of California San Diego, Biorepository and Tissue Technology Shared Resources, San Diego, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
165  Department of Pathology, Gustave Roussy, Villejuif, France (GRID:grid.14925.3b) (ISNI:0000 0001 2284 9388) 
166  The Institute of Cancer Research, Institute of Cancer Research Clinical Trials and Statistics Unit, Surrey, UK (GRID:grid.18886.3f) (ISNI:0000 0001 1271 4623) 
167  Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands (GRID:grid.5650.6) (ISNI:0000000404654431) 
168  University of Padova, Department of Surgery, Oncology and Gastroenterology, Padua, Italy (GRID:grid.5608.b) (ISNI:0000 0004 1757 3470) 
169  Universite Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium (GRID:grid.4989.c) (ISNI:0000 0001 2348 0746) 
170  Vanderbilt University Medical Centre, Department of Pathology, Microbiology and Immunology, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916) 
171  Harvard Medical School, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Division of Biostatistics, Dana-Farber Cancer Institute, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910) 
172  Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville, Australia (GRID:grid.416153.4) (ISNI:0000 0004 0624 1200) 
173  Vernon Cancer Center, Newton-Wellesley Hospital, Newton, USA (GRID:grid.416176.3) (ISNI:0000 0000 9957 1751) 
174  Université Libre de Bruxelles, Department of Medical Oncology, Institut Jules Bordet, Brussels, Belgium (GRID:grid.4989.c) (ISNI:0000 0001 2348 0746) 
175  Cliniques universitaires Saint-Luc, Department of Pathology, Brussels, Belgium (GRID:grid.48769.34) (ISNI:0000 0004 0461 6320) 
176  Breast Center, Dept. OB&GYN and CCC (LMU), University of Munich, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
177  Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, USA (GRID:grid.239395.7) (ISNI:0000 0000 9011 8547) 
178  University of Leuven, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884) 
179  Université Libre de Bruxelles, Department of Pathology, Institut Jules Bordet, Brussels, Belgium (GRID:grid.4989.c) (ISNI:0000 0001 2348 0746) 
180  German Breast Group GmbH, Neu-Isenburg, Germany (GRID:grid.434440.3) (ISNI:0000 0004 0457 2954) 
181  Service de Biostatistique et d’Epidémiologie, Gustave Roussy, CESP, Université-Paris Sud, Université Paris-Saclay, Villejuif, France (GRID:grid.14925.3b) (ISNI:0000 0001 2284 9388) 
182  Department of Surgical Pathology and Biopathology, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand, France (GRID:grid.14925.3b) 
183  Johanniter GmbH - Evangelisches Krankenhaus Bethesda Mönchengladbach, West German Study Group, Mönchengladbach, Germany (GRID:grid.476830.e) 
184  Molecular Oncology Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain (GRID:grid.411083.f) (ISNI:0000 0001 0675 8654) 
185  University of Marburg, Department of Pathology, Marburg, Germany (GRID:grid.10253.35) (ISNI:0000 0004 1936 9756) 
186  University of British Columbia, Department of Pathology and Laboratory Medicine, Columbia, USA (GRID:grid.417993.1) 
187  St Vincent’s Hospital Melbourne, Department of Anatomical Pathology, Fitzroy, Australia (GRID:grid.413105.2) (ISNI:0000 0000 8606 2560) 
188  Cancer Immunotherapy Trials Network, Central Laboratory and Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, USA (GRID:grid.270240.3) (ISNI:0000 0001 2180 1622) 
189  University of Oxford, Clinical Trial Service Unit & Epidemiological Studies Unit, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
190  Fudan University Shanghai Cancer Center, Department of Pathology, Shanghai, China (GRID:grid.452404.3) (ISNI:0000 0004 1808 0942) 
191  GZA-ZNA Hospitals, Department of Pathology, Antwerp, Belgium (GRID:grid.428965.4) (ISNI:0000 0004 7536 2436) 
192  Odette Cancer Centre, Sunnybrook Research Institute, Department of Radiation Oncology, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
193  Oncology Merck & Co, New Jersey, USA (GRID:grid.17063.33) 
194  The Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Australian Clinical Labs, Darlinghurst, Australia (GRID:grid.415306.5) (ISNI:0000 0000 9983 6924) 
195  Georgetown University Medical Center, Washington DC, USA (GRID:grid.411667.3) (ISNI:0000 0001 2186 0438) 
196  Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, USA (GRID:grid.414118.9) (ISNI:0000 0004 0464 4831) 
197  Translational Medicine, Bristol-Myers Squibb, Princeton, USA (GRID:grid.419971.3) 
198  Anatomic Pathology, Boston, USA (GRID:grid.21925.3d) 
199  King’s College London, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); Guy’s Hospital, London, UK (GRID:grid.239826.4) (ISNI:0000 0004 0391 895X) 
200  Peking University First Hospital Breast Disease Center, Beijing, China (GRID:grid.411472.5) (ISNI:0000 0004 1764 1621) 
201  Peter MacCallum Cancer Centre, Department of Pathology, Melbourne, Australia (GRID:grid.1055.1) (ISNI:0000000403978434) 
202  Dipartimento di Scienze della Salute (DSS), Firenze, Italy (GRID:grid.1055.1) 
203  Department of Oncology, Champalimaud Clinical Centre, Lisbon, Portugal (GRID:grid.1055.1) 
204  University of Melbourne, Division of Research and Cancer Medicine, Peter MacCallum Cancer Centre, Victoria, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
205  Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, USA (GRID:grid.67033.31) (ISNI:0000 0000 8934 4045) 
206  Department of Pathology, Fundación Valle del Lili, Cali, Colombia (GRID:grid.477264.4) 
207  Department of Pathology, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, USA (GRID:grid.240283.f) (ISNI:0000 0001 2152 0791) 
208  University Hospital of Bellvitge, Oncobell, IDIBELL, L’Hospitalet del Llobregat, Department of Pathology, Barcelona, Spain (GRID:grid.240283.f) 
209  Department of Development and Regeneration, Laboratory of Experimental Urology, KU Leuven, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884) 
210  Department of Medical Oncology, Austin Health, Heidelberg, Australia (GRID:grid.410678.c) 
211  Kansai Medical University to Tomoharu Sugie, Breast Surgery, Kansai Medical University Hospital, Department of Surgery, Hirakata, Japan (GRID:grid.410783.9) (ISNI:0000 0001 2172 5041) 
212  Pathology Department, H.U. Vall d’Hebron, Barcelona, Spain (GRID:grid.23856.3a) 
213  Division of Bioinformatics and Biostatistics, U.S. Food and Drug Administration, Wuhan, USA (GRID:grid.417587.8) (ISNI:0000 0001 2243 3366) 
214  Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Providence, USA (GRID:grid.17063.33) 
215  Université Paris-Est, Créteil, France (GRID:grid.410511.0) (ISNI:0000 0001 2149 7878) 
216  Praava Health, Dhaka, Bangladesh (GRID:grid.410511.0) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
23744677
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2488351921
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.