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Scoring PD-L1 Expression in Urothelial Carcinoma: An International Multi-Institutional Study on Comparison of Manual and Artificial Intelligence Measurement Model (AIM-PD-L1) Pathology Assessments

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Abstract

Assessing programmed death ligand 1 (PD-L1) expression on tumor cells (TCs) using Food and Drug Administration-approved, validated immunoassays can guide the use of immune checkpoint inhibitor (ICI) therapy in cancer treatment. However, substantial interobserver variability has been reported using these immunoassays. Artificial intelligence (AI) has the potential to accurately measure biomarker expression in tissue samples, but its reliability and comparability to standard manual scoring remain to be evaluated. This multinational study sought to compare the %TC scoring of PD-L1 expression in advanced urothelial carcinoma, assessed by either an AI Measurement Model (AIM-PD-L1) or expert pathologists. The concordance among pathologists and between pathologists and AIM-PD-L1 was determined. The positivity rate of ≥ 1%TC PD-L1 was between 20–30% for 8/10 pathologists, and the degree of agreement and scoring distribution for among pathologists and between pathologists and AIM-PD-L1 was similar both scored as a continuous variable or using the pre-defined cutoff. Numerically higher score variation was observed with the 22C3 assay than with the 28–8 assay. A 2-h training module on the 28–8 assay did not significantly impact manual assessment. Cases exhibiting significantly higher variability in the assessment of PD-L1 expression (mean absolute deviation > 10) were found to have patterns of PD-L1 staining that were more challenging to interpret. An improved understanding of sources of manual scoring variability can be applied to PD-L1 expression analysis in the clinical setting. In the future, the application of AI algorithms could serve as a valuable reference guide for pathologists while scoring PD-L1.

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Acknowledgements

The authors would like to thank Jennifer Schroeder and the Pharmalex team for their help with the statistical analysis; CellCarta, especially Elizabeth Ross, Senne Carpentier, and Pablo Reclusa, for managing sample staining and digitization; and Discovery Life Sciences, especially Gudrun Baenfer and Rolf Diezko, for managing sample selection and provisioning. Writing and editorial assistance were provided by Emily Motola, PharmD, Allyson Koyen Malashevich, PhD, and Agata Shodeke, PhD, of Spark (a division of Prime, New York, USA), funded by Bristol Myers Squibb, according to Good Publication Practice guidelines.

Funding

This study was sponsored by Bristol Myers Squibb.

Author information

Author notes

  1. Josef Rüschoff, George Kumar and Sunil Badve contributed equally to this work.

Authors and Affiliations

  1. Discovery Life Sciences and Pathology Nordhessen, Kassel, Germany

    Josef Rüschoff & Bharat Jasani

  2. Bristol Myers Squibb, Princeton, NJ, USA

    George Kumar, Vipul Baxi, Zulfia Babadjanova, James Pratt & Maria Karasarides

  3. Emory University School of Medicine, Atlanta, GA, USA

    Sunil Badve

  4. University of Cardiff, Cardiff, Wales, UK

    Bharat Jasani

  5. PathAI, Boston, MA, USA

    Emma Krause, Darren Fahy, Mike Pyle, Quang Le, Limin Yu, Benjamin Glass & Sergine Brutus

  6. CHU de RENNES, Rennes, France

    Nathalie Rioux-Leclercq

  7. IIS-Fundacion Jimenez Diaz CIBERONC (Madrid), Madrid, Spain

    Federico Rojo

  8. Università Degli Studi Di Messina, Messina, Italy

    Maurizio Martini

  9. Brown University Warren Alpert Medical School and the Legorreta Cancer Center at Brown University, Providence, RI, USA

    Liang Cheng

  10. University of Washington, Seattle, WA, USA

    Maria Tretiakova

  11. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Catherine Mitchell

  12. John Hopkins University, Baltimore, MD, USA

    Robert A. Anders

  13. Yale University School of Medicine, New Haven, CT, USA

    Marie E. Robert

  14. Comprehensive Cancer Center EMN, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, Germany

    Arndt Hartmann

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  1. Josef Rüschoff
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  2. George Kumar
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Contributions

Authors contributions are as follows: study conception/design: Drs Kumar, Badve, Babadjanova, Karasarides and Hartmann; data acquisition: Drs Rüschoff, Kumar, Badve, Jasani, Rioux-Leclercq, Rojo, Martini, Cheng, Tretiakova, Mitchell, Anders, Robert, Brutus, Karasarides, and Hartmann, and Mr Glass; data analysis: Drs Kumar, Badve, Krause, Babadjanova, Pratt, and Karasarides, and Mr Fahy, Pyle, Le, and Baxi; data interpretation: Drs Rüschoff, Kumar, Badve, Jasani, Krause, Rioux-Leclercq, Rojo, Martini, Cheng, Tretiakova, Mitchell, Anders, Robert, Yu, Pratt, Brutus, Karasarides, and Hartmann, and Mr Baxi. All authors contributed to the writing and editing of this manuscript.

Corresponding authors

Correspondence to Josef Rüschoff or Arndt Hartmann.

Ethics declarations

The study was conducted in compliance with BMS Bioethics Policy (https://www.bms.com/about-us/responsibility/position-on-key-issues/bioethics-policy-statement.html). The samples procured from Discovery Life Sciences were processed in accordance with all applicable EU and US regulations as specified on the company’s website (https://www.dls.com/resource-hub/faqs).

Conflict of Interest

Dr. Rüschoff has received support for travel and participation in advisory boards from Agilent, AstraZeneca, Bristol Myers Squibb, DSI, and Merck/MSD. Dr Badve has received grants or contracts from Agilent, Lilly, the National Institutes of Health (NIH), and the National Cancer Institute; consulting fees from Agendia, Dako-Agilent, Ventana, Roche, and Daiichi-Sankyo; and honoraria from Medscape, Targos-Discovery, and PER; and is the Director of the Indian Cancer Genome Atlas Foundation. Dr. Jasani has received consulting fees from Bristol Myers Squibb. Dr Rojo has received grants or contracts from AstraZeneca, Roche, and Pfizer; consulting fees and honoraria from Roche, AstraZeneca, Novartis, MSD, Bristol Myers Squibb, Lilly, Amgen, Astellas, Glaxo-Smith Kline, and Daiichi Sankyo; and support for meeting attendance and travel from MSD, Roche, and AstraZeneca. Dr Martini has received funding from the University of Washington and Bristol Myers Squibb. Dr Anders has received grants or contracts from BMS, RAPT Therapeutics, Stand Up2Cancer, the NIH, and Mark Foundation; consulting fees from Bristol Myers Squibb, Merck SD, and AstraZeneca; and support for attending meetings from Bristol Myers Squibb. Dr Robert has received consulting fees from Takeda Pharmaceuticals and Bristol Myers Squibb. Drs Babadjanova, Pratt, Karasarides, and Kumar are employees of, and hold stock in, Bristol Myers Squibb. Dr. Brutus is a former employee of PathAI and holds stock in PathAI. Dr Hartmann has received consulting fees from Bristol Myers Squibb, MSD, Roche, Cepheid, Qiagen, Janssen, AstraZeneca, Agilent, Eli Lilly, Phäon, Ipsen, Diaceutics, Illumina, Abbvie, and Nanostring; receives travel support/support for attending meetings for, and participates in, advisory boards for Bristol Myers Squibb, MSD, Roche, Cepheid, Qiagen, Janssen, AstraZeneca, Agilent, Lilly, Phäon, Ipsen, and Diaceutics; and has received other research support from AstraZeneca, Biocartis, Cepheid, Gilead, Illumina, Janssen, Nanostring, Novartis, Owkin, Qiagen, QUIP GmbH, Roche, and Sanofi. Drs Krause, Rioux-Leclercq, Cheng, Tretiakova, Mitchell and Yu, and Mr Fahy, Pyle, Le, Glass and Baxi have no competing interests to declare.

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Josef Rüschoff and George Kumar co-lead authors.

George Kumar, Sergine Brutus and Maria Karasarides affiliation pertains to the time the study was conducted.

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Rüschoff, J., Kumar, G., Badve, S. et al. Scoring PD-L1 Expression in Urothelial Carcinoma: An International Multi-Institutional Study on Comparison of Manual and Artificial Intelligence Measurement Model (AIM-PD-L1) Pathology Assessments. Virchows Arch (2024). https://doi.org/10.1007/s00428-024-03795-8

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