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Pitfalls in Machine Learning-Based Assessment of Tumor-Infiltrating Lymphocytes in Breast Cancer: A Report of the International Immuno-Oncology Biomarker Working Group Publisher Pubmed



Thagaard J1, 2 ; Broeckx G3, 4 ; Page DB5 ; Jahangir CA6 ; Verbandt S7 ; Kos Z8 ; Gupta R9 ; Khiroya R10 ; Abduljabbar K11 ; Acosta Haab G12 ; Acs B13, 14 ; Akturk G15 ; Almeida JS16 ; Alvaradocabrero I17 Show All Authors
Authors
  1. Thagaard J1, 2
  2. Broeckx G3, 4
  3. Page DB5
  4. Jahangir CA6
  5. Verbandt S7
  6. Kos Z8
  7. Gupta R9
  8. Khiroya R10
  9. Abduljabbar K11
  10. Acosta Haab G12
  11. Acs B13, 14
  12. Akturk G15
  13. Almeida JS16
  14. Alvaradocabrero I17
  15. Amgad M18
  16. Azmoudehardalan F19
  17. Badve S20
  18. Baharun NB21
  19. Balslev E22
  20. Bellolio ER23
  21. Bheemaraju V24
  22. Blenman KRM25, 26
  23. Botinelly Mendonca Fujimoto L27
  24. Bouchmaa N28
  25. Burgues O29
  26. Chardas A30
  27. Chon U Cheang M31
  28. Ciompi F32
  29. Cooper LAD33
  30. Coosemans A34
  31. Corredor G35
  32. Dahl AB1
  33. Dantas Portela FL36
  34. Deman F3
  35. Demaria S37, 38
  36. Dore Hansen J2
  37. Dudgeon SN39
  38. Ebstrup T2
  39. Elghazawy M40, 41
  40. Fernandezmartin C42
  41. Fox SB43
  42. Gallagher WM6
  43. Giltnane JM44
  44. Gnjatic S45
  45. Gonzalezericsson PI46
  46. Grigoriadis A47, 48
  47. Halama N49
  48. Hanna MG50
  49. Harbhajanka A51
  50. Hart SN52
  51. Hartman J13, 14
  52. Hauberg S1
  53. Hewitt S53
  54. Hida AI54
  55. Horlings HM55
  56. Husain Z56
  57. Hytopoulos E57
  58. Irshad S58
  59. Janssen EAM59, 60
  60. Kahila M61
  61. Kataoka TR62
  62. Kawaguchi K63
  63. Kharidehal D24
  64. Khramtsov AI64
  65. Kiraz U59, 60
  66. Kirtani P65
  67. Kodach LL66
  68. Korski K67
  69. Kovacs A68, 69
  70. Laenkholm AV70, 71
  71. Langschwarz C72
  72. Larsimont D73
  73. Lennerz JK74
  74. Lerousseau M75, 76, 77
  75. Li X78
  76. Ly A79
  77. Madabhushi A80
  78. Maley SK81
  79. Manur Narasimhamurthy V82
  80. Marks DK83
  81. Mcdonald ES84
  82. Mehrotra R85, 86
  83. Michiels S87
  84. Minhas FUAA88
  85. Mittal S89
  86. Moore DA90
  87. Mushtaq S91
  88. Nighat H92
  89. Papathomas T93, 94
  90. Penaultllorca F95
  91. Perera RD96, 97
  92. Pinard CJ98, 99, 100, 101
  93. Pintocardenas JC102
  94. Pruneri G103, 104
  95. Pusztai L105, 106
  96. Rahman A6
  97. Rajpoot NM107
  98. Rapoport BL108, 109
  99. Rau TT110
  100. Reisfilho JS111
  101. Ribeiro JM112
  102. Rimm D113, 114
  103. Roslind A22
  104. Vincentsalomon A115
  105. Saltotellez M116, 117
  106. Saltz J9
  107. Sayed S118
  108. Scott E119
  109. Siziopikou KP120
  110. Sotiriou C121, 122
  111. Stenzinger A123, 124
  112. Sughayer MA125
  113. Sur D126
  114. Fineberg S127, 128
  115. Symmans F129
  116. Tanaka S130
  117. Taxter T131
  118. Tejpar S7
  119. Teuwen J132
  120. Thompson EA133
  121. Tramm T134, 135
  122. Tran WT136
  123. Van Der Laak J137
  124. Van Diest PJ138, 139
  125. Verghese GE47, 48
  126. Viale G140, 141
  127. Vieth M72
  128. Wahab N142
  129. Walter T75, 76, 77
  130. Waumans Y143
  131. Wen HY50
  132. Yang W144
  133. Yuan Y145
  134. Zin RM146
  135. Adams S83, 147
  136. Bartlett J148
  137. Loibl S149
  138. Denkert C150
  139. Savas P97, 151
  140. Loi S97, 151
  141. Salgado R3, 97
  142. Specht Stovgaard E22, 152
Show Affiliations
Authors Affiliations
  1. 1. Technical University of Denmark, Kongens Lyngby, Denmark
  2. 2. Visiopharm A/S, Horsholm, Denmark
  3. 3. Department of Pathology, GZA-ZNA Hospitals, Antwerp, Belgium
  4. 4. Centre for Oncological Research (CORE), MIPPRO, Faculty of Medicine, Antwerp University, Antwerp, Belgium
  5. 5. Earle A Chiles Research Institute, Providence Cancer Institute, Portland, OR, United States
  6. 6. UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland
  7. 7. Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
  8. 8. Department of Pathology and Laboratory Medicine, BC Cancer Vancouver Centre, University of British Columbia, Vancouver, BC, Canada
  9. 9. Department of Biomedical Informatics, Stony Brook University, Stony Brook, NY, United States
  10. 10. Department of Cellular Pathology, University College Hospital London, London, United Kingdom
  11. 11. Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
  12. 12. Hospital Maria Curie, Buenos Aires, Argentina
  13. 13. Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
  14. 14. Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden
  15. 15. Translational Molecular Biomarkers, Merck & Co Inc, Rahway, NJ, United States
  16. 16. Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Rockville, MD, United States
  17. 17. Oncology Hospital, Star Medica Centro, Ciudad de Mexico, Mexico
  18. 18. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
  19. 19. Tehran University of Medical Sciences, Tehran, Iran
  20. 20. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Emory University Winship Cancer Institute, Atlanta, GA, United States
  21. 21. The National University of Malaysia, Kuala Lumpur, Malaysia
  22. 22. Department of Pathology, Herlev and Gentofte Hospital, Herlev, Denmark
  23. 23. Departamento de Anatomia Patologica, Facultad de Medicina, Universidad de La Frontera, Temuco, Chile
  24. 24. Department of Pathology, Narayana Medical College, Nellore, India
  25. 25. Department of Internal Medicine Section of Medical Oncology and Yale Cancer Center, Yale School of Medicine, New Haven, CT, United States
  26. 26. Department of Computer Science, Yale School of Engineering and Applied Science, New Haven, CT, United States
  27. 27. Department of Pathology and Legal Medicine, Amazonas Federal University, Manaus, Brazil
  28. 28. Institute of Biological Sciences, Faculty of Medical Sciences, Mohammed VI Polytechnic University (UM6P), Ben-Guerir, Morocco
  29. 29. Pathology Department, Hospital Clinico Universitario de Valencia/Incliva, Valencia, Spain
  30. 30. Department of Pathobiology & Population Sciences, The Royal Veterinary College, London, United Kingdom
  31. 31. Head of Integrative Genomics Analysis in Clinical Trials, ICR-CTSU, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom
  32. 32. Radboud University Medical Center, Department of Pathology, Nijmegen, Netherlands
  33. 33. Department of Pathology, Northwestern Feinberg School of Medicine, Chicago, IL, United States
  34. 34. Department of Oncology, Laboratory of Tumor Immunology and Immunotherapy, KU Leuven, Leuven, Belgium
  35. 35. Biomedical Engineering Department, Emory University, Atlanta, GA, United States
  36. 36. Hospital Universitario Getulio Vargas, Manaus, Brazil
  37. 37. Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, United States
  38. 38. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, United States
  39. 39. Conputational Biology and Bioinformatics, Yale University, New Haven, CT, United States
  40. 40. University of Surrey, Guildford, United Kingdom
  41. 41. Ain Shams University, Cairo, Egypt
  42. 42. Instituto Universitario de Investigacion en Tecnologia Centrada en el Ser Humano, HUMAN-tech, Universitat Politecnica de Valencia, Valencia, Spain
  43. 43. Pathology, Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  44. 44. Genentech, San Francisco, CA, United States
  45. 45. Department of Oncological Sciences, Medicine Hem/Onc, and Pathology, Tisch Cancer Institute – Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
  46. 46. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
  47. 47. Cancer Bioinformatics, School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
  48. 48. The Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
  49. 49. Department of Translational Immunotherapy, German Cancer Research Center, Heidelberg, Germany
  50. 50. Department of Pathology, Memorial Sloan Kettering Cancer Center, NY, United States
  51. 51. Case Western University, Cleveland, OH, United States
  52. 52. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
  53. 53. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
  54. 54. Department of Pathology, Matsuyama Shimin Hospital, Matsuyama, Japan
  55. 55. Division of Pathology, Netherlands Cancer Institute (NKI), Amsterdam, Netherlands
  56. 56. Praava Health, Dhaka, Bangladesh
  57. 57. iRhythm Technologies, San Francisco, CA, United States
  58. 58. King's College London & Guy's & St Thomas’ NHS Trust, London, United Kingdom
  59. 59. Department of Pathology, Stavanger University Hospital, Stavanger, Norway
  60. 60. Department of Chemistry, Bioscience and Environmental Technology, University of Stavanger, Stavanger, Norway
  61. 61. Department of Pathology, Yale University, New Haven, CT, United States
  62. 62. Department of Pathology, Iwate Medical University, Morioka, Japan
  63. 63. Department of Breast Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
  64. 64. Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States
  65. 65. Department of Histopathology, Aakash Healthcare Super Speciality Hospital, New Delhi, India
  66. 66. Department of Pathology, Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
  67. 67. Data, Analytics and Imaging, Product Development, F. Hoffmann-La Roche AG, Basel, Switzerland
  68. 68. Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden
  69. 69. Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  70. 70. Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark
  71. 71. Department of Surgical Pathology, University of Copenhagen, Copenhagen, Denmark
  72. 72. Institute of Pathology, Klinikum Bayreuth GmbH, Friedrich-Alexander-University Erlangen-Nuremberg, Bayreuth, Germany
  73. 73. Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium
  74. 74. Center for Integrated Diagnostics, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
  75. 75. Centre for Computational Biology (CBIO), Mines Paris, PSL University, Paris, France
  76. 76. Institut Curie, PSL University, Paris, France
  77. 77. INSERM, Paris, France
  78. 78. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States
  79. 79. Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
  80. 80. Department of Biomedical Engineering, Radiology and Imaging Sciences, Biomedical Informatics, Pathology, Georgia Institute of Technology and Emory University, Atlanta, GA, United States
  81. 81. NRG Oncology/NSABP Foundation, Pittsburgh, PA, United States
  82. 82. Manipal Hospitals, Bangalore, India
  83. 83. Perlmutter Cancer Center, NYU Langone Health, New York, NY, United States
  84. 84. Breast Cancer Translational Research Group, University of Pennsylvania, Philadelphia, PA, United States
  85. 85. Indian Cancer Genomic Atlas, Pune, India
  86. 86. Centre for Health, Innovation and Policy Foundation, Noida, India
  87. 87. Office of Biostatistics and Epidemiology, Gustave Roussy, Oncostat U1018, Inserm, University Paris-Saclay, Ligue Contre le Cancer labeled Team, Villejuif, France
  88. 88. Tissue Image Analytics Centre, Warwick Cancer Research Centre, PathLAKE Consortium, Department of Computer Science, University of Warwick, Coventry, United Kingdom
  89. 89. Department of Chemical Engineering, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States
  90. 90. CRUK Lung Cancer Centre of Excellence, UCL and Cellular Pathology Department, UCLH, London, United Kingdom
  91. 91. Department of Biochemistry, Ziauddin University, Karachi, Pakistan
  92. 92. Pathology and Laboratory Medicine, All India Institute of Medical sciences, Raipur, India
  93. 93. Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
  94. 94. Department of Clinical Pathology, Drammen Sykehus, Vestre Viken HF, Drammen, Norway
  95. 95. Centre Jean Perrin, Universite Clermont Auvergne, INSERM, U1240 Imagerie Moleculaire et Strategies Theranostiques, Clermont Ferrand, France
  96. 96. School of Electrical, Mechanical and Infrastructure Engineering, University of Melbourne, Melbourne, VIC, Australia
  97. 97. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  98. 98. Radiogenomics Laboratory, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
  99. 99. Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
  100. 100. Department of Oncology, Lakeshore Animal Health Partners, Mississauga, ON, Canada
  101. 101. Centre for Advancing Responsible and Ethical Artificial Intelligence (CARE-AI), University of Guelph, Guelph, ON, Canada
  102. 102. Diagnostico de Salud Animal SA, Ciudad de Mexico, Mexico
  103. 103. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  104. 104. Faculty of Medicine and Surgery, University of Milan, Milan, Italy
  105. 105. Yale Cancer Center, Yale University, New Haven, CT, United States
  106. 106. Department of Medical Oncology, Yale School of Medicine, Yale University, New Haven, CT, United States
  107. 107. University of Warwick, Coventry, United Kingdom
  108. 108. The Medical Oncology Centre of Rosebank, Johannesburg, South Africa
  109. 109. Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
  110. 110. Institute of Pathology, University Hospital Dusseldorf and Heinrich-Heine-University Dusseldorf, Dusseldorf, Germany
  111. 111. Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
  112. 112. Departement de Medecine Oncologique, Gustave Roussy, Villejuif, France
  113. 113. Department of Pathology, Yale University School of Medicine, New Haven, CT, United States
  114. 114. Department of Medicine, Yale University School of Medicine, New Haven, CT, United States
  115. 115. Department of Diagnostic and Theranostic Medicine, Institut Curie, University Paris-Sciences et Lettres, Paris, France
  116. 116. Integrated Pathology Unit, The Institute of Cancer Research, London, United Kingdom
  117. 117. Precision Medicine Centre, Queen's University Belfast, Belfast, United Kingdom
  118. 118. Department of Pathology, Aga Khan University, Nairobi, Kenya
  119. 119. Translational Pathology, Translational Sciences and Diagnostics/Translational Medicine/R&D, Bristol Myers Squibb, Princeton, NJ, United States
  120. 120. Department of Pathology, Section of Breast Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
  121. 121. Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Hopital Universitaire de Bruxelles (HUB), Universite Libre de Bruxelles (ULB), Brussels, Belgium
  122. 122. Medical Oncology Department, Institut Jules Bordet, Hopital Universitaire de Bruxelles (HUB), Universite Libre de Bruxelles (ULB), Brussels, Belgium
  123. 123. Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
  124. 124. Centers for Personalized Medicine (ZPM), Heidelberg, Germany
  125. 125. King Hussein Cancer Center, Amman, Jordan
  126. 126. Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu�, Cluj-Napoca, Romania
  127. 127. Montefiore Medical Center, Bronx, NY, United States
  128. 128. Albert Einstein College of Medicine, Bronx, NY, United States
  129. 129. University of Texas MD Anderson Cancer Center, Houston, TX, United States
  130. 130. Kyoto University, Kyoto, Japan
  131. 131. Tempus Labs, Chicago, IL, United States
  132. 132. AI for Oncology Lab, The Netherlands Cancer Institute, Amsterdam, Netherlands
  133. 133. Mayo Clinic Florida, Jacksonville, FL, United States
  134. 134. Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
  135. 135. Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
  136. 136. Department of Radiation Oncology, University of Toronto and Sunnybrook Health Sciences Centre, Toronto, ON, Canada
  137. 137. Department of Pathology, Radboud University Medical Center, Nijmegen, Netherlands
  138. 138. Department of Pathology, University Medical Center Utrecht, Netherlands
  139. 139. Johns Hopkins Oncology Center, Baltimore, MD, United States
  140. 140. Department of Pathology, European Institute of Oncology, Milan, Italy
  141. 141. Department of Pathology, University of Milan, Milan, Italy
  142. 142. Tissue Image Analytics Centre, Department of Computer Science, University of Warwick, Coventry, United Kingdom
  143. 143. CellCarta NV, Antwerp, Belgium
  144. 144. Fudan Medical University Shanghai Cancer Center, Shanghai, China
  145. 145. Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
  146. 146. Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
  147. 147. Department of Medicine, NYU Grossman School of Medicine, Manhattan, NY, United States
  148. 148. University of Edinburgh, Edinburgh, United Kingdom
  149. 149. Department of Medicine and Research, German Breast Group, Neu-Isenburg, Germany
  150. 150. Institut fur Pathologie, Philipps-Universitat Marburg und Universitatsklinikum Marburg, Marburg, Germany
  151. 151. The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia
  152. 152. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

Source: Journal of Pathology Published:2023


Abstract

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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