Artificial intelligence for detection of microsatellite instability in colorectal cancer—a multicentric analysis of a pre-screening tool for clinical application

ESMO Open, vol. 7, pp. 100400

Abstract

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

Authors 38

1. Amelie Echle Aachen Department of Medicine III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

2. Narmin Ghaffari Laleh Aachen Department of Medicine III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

3. Philip Quirke

   University of Leeds

   Affiliation as printed

   Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK

4. Heike Irmgard Grabsch

   University of Leeds · Maastricht University Medical Centre · Maastricht University

   Affiliation as printed

   Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK; Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands

   Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands

   Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK

5. Hannah Sophie Muti Aachen Department of Medicine III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

6. Oliver Lester Saldanha Aachen Department of Medicine III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

7. Scarlet Fiona Brockmoeller

   University of Leeds

   Affiliation as printed

   Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK

8. Piet A. van den Brandt

   Maastricht University Medical Centre · Maastricht University

   Affiliation as printed

   Department of Epidemiology, Maastricht University Medical Center+, Maastricht, The Netherlands

9. Gordon G. A. Hutchins

   University of Leeds

   Affiliation as printed

   Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK

10. Susan D. Richman

    University of Leeds

    Affiliation as printed

    Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK

11. Karoline Horisberger

    University of Zurich · University Hospital Zurich

    Affiliation as printed

    Department of Abdominal and Transplantation Surgery, University Hospital of Zurich, Zurich, Switzerland

12. Christian L. Galata

    Johannes Gutenberg University Mainz · Heidelberg University · University Medical Center of the Johannes Gutenberg University Mainz · University Medical Centre Mannheim · Medizinische Fakultät Mannheim

    Affiliation as printed

    Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Division of Thoracic Surgery, Academic Thoracic Center Mainz, University Medical Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany

    Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Division of Thoracic Surgery, Academic Thoracic Center Mainz, University Medical Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany

13. M. Ebert

    Heidelberg University · University Medical Centre Mannheim · Medizinische Fakultät Mannheim

    Affiliation as printed

    Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Mannheim Institute for Innate Immunoscience (MI3) and Clinical Cooperation Unit Healthy Metabolism, Center of Preventive Medicine and Digital Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Mannheim Institute for Innate Immunoscience (MI3) and Clinical Cooperation Unit Healthy Metabolism, Center of Preventive Medicine and Digital Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

14. Maximilian Eckardt

    Heidelberg University · University Medical Centre Mannheim · Medizinische Fakultät Mannheim

    Affiliation as printed

    Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

15. Michael Boutros

    German Cancer Research Center

    Affiliation as printed

    Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany

16. David A. Horst

    Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Institut für Pathologie Charité, Berlin, Germany

17. Christoph Reißfelder

    Heidelberg University · University Medical Centre Mannheim · Medizinische Fakultät Mannheim

    Affiliation as printed

    Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

18. Elizabeth Alwers

    German Cancer Research Center

    Affiliation as printed

    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany

19. Titus Josef Brinker

    German Cancer Research Center · National Center for Tumor Diseases

    Affiliation as printed

    Digital Biomarkers for Oncology Group, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany

20. Rupert Langer

    University of Bern · University Hospital of Bern

    Affiliation as printed

    Institute of Pathology, Inselspital, University of Bern, Bern, Switzerland

21. Josien C.A. Jenniskens

    Maastricht University Medical Centre · Maastricht University

    Affiliation as printed

    Department of Epidemiology, Maastricht University Medical Center+, Maastricht, The Netherlands

22. Kelly Offermans

    Maastricht University Medical Centre · Maastricht University

    Affiliation as printed

    Department of Epidemiology, Maastricht University Medical Center+, Maastricht, The Netherlands

23. Wolfram Mueller
    Affiliation as printed

    Gemeinschaftspraxis Pathologie, Starnberg, Germany

24. Richard G. Gray

    University of Oxford

    Affiliation as printed

    Clinical Trial Service Unit, University of Oxford, Oxford, UK

25. Stephen B. Gruber

    City Of Hope National Medical Center

    Affiliation as printed

    Center for Precision Medicine and Department of Medical Oncology, City of Hope National Medical Center, Duarte, USA

26. Joel K. Greenson

    City Of Hope National Medical Center · City of Hope

    Affiliation as printed

    Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, USA

27. Gad Rennert

    Technion – Israel Institute of Technology · Carmel Medical Center

    Affiliation as printed

    Department of Community Medicine & Epidemiology, Lady Davis Carmel Medical Center, Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Steve and Cindy Rasmussen Institute for Genomic Medicine, Lady Davis Carmel Medical Center and Technion Faculty of Medicine, Clalit National Cancer Control Center, Haifa, Israel

    Department of Community Medicine & Epidemiology, Lady Davis Carmel Medical Center, Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

    Steve and Cindy Rasmussen Institute for Genomic Medicine, Lady Davis Carmel Medical Center and Technion Faculty of Medicine, Clalit National Cancer Control Center, Haifa, Israel

28. Joseph D. Bonner

    City Of Hope National Medical Center

    Affiliation as printed

    Center for Precision Medicine and Department of Medical Oncology, City of Hope National Medical Center, Duarte, USA

29. Daniel B. Schmolze

    City Of Hope National Medical Center · City of Hope

    Affiliation as printed

    Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, USA

30. Jenny C. Chang-Claude

    Universität Hamburg · German Cancer Research Center · University Medical Center Hamburg-Eppendorf · University Cancer Center Hamburg

    Affiliation as printed

    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

31. Hermann Brenner

    German Cancer Research Center · National Center for Tumor Diseases · Deutsches Konsortium für Translationale Krebsforschung

    Affiliation as printed

    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany

    Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany

    German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

32. Christian Trautwein Aachen Department of Medicine III

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

33. Peter Boor Aachen Institute of Pathology Department of Nephrology and Immunology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany; Department of Nephrology and Immunology, University Hospital RWTH Aachen, Aachen, Germany

    Department of Nephrology and Immunology, University Hospital RWTH Aachen, Aachen, Germany

    Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany

34. D. Jaeger

    University Hospital Heidelberg · National Center for Tumor Diseases

    Affiliation as printed

    Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany

35. Nadine Therese Gaisa Aachen Institute of Pathology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany

36. Michael Hoffmeister

    German Cancer Research Center

    Affiliation as printed

    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany

37. Nicholas Paul West

    University of Leeds

    Affiliation as printed

    Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK

38. Jakob Nikolas Kather corresponding Aachen Department of Medicine III

    University of Leeds · Heidelberg University · University Hospital Heidelberg · National Center for Tumor Diseases · Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK; Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany. Electronic address: jkather@ukaachen.de

    Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany

    Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK

    Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany