Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer

Modern Pathology volume 33, pages1746–1752(2020)Cite this article

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Abstract

The US Food and Drug Administration (FDA) approved the PD-L1 immunohistochemical assay, SP142, as a companion test to determine eligibility for atezolizumab therapy in patients with advanced triple negative breast cancer (TNBC) but data in lung cancer studies suggest the assay suffers from poor reproducibility. We sought to evaluate reproducibility and concordance in PD-L1 scoring across multiple pathologists. Full TNBC sections were stained with SP142 and SP263 assays and interpreted for percentage (%) immune cell (IC) staining by 19 pathologists from 14 academic institutions. Proportion of PD-L1 positive cases (defined as ≥1% IC) was determined for each assay as well as concordance across observers. We utilized a new method we call Observers Needed to Evaluate Subjective Tests (ONEST) to determine the minimum number of evaluators needed to estimate concordance between large numbers of readers, as occurs in the real-world setting. PD-L1 was interpreted as positive with the SP142 assay in an average 58% of cases compared with 78% with SP263 (p < 0.0001). IC positive continuous scores ranged from 1 to 95% (mean = 20%) and 1 to 90% (mean = 10%) for SP263 and SP142, respectively. With SP142, 26 cases (38%) showed complete two category (<1% vs. ≥1%) concordance; with SP263, 38 cases (50%) showed complete agreement. The intraclass correlation coefficient (ICC) for two category scoring of SP263 and SP142 was 0.513 and 0.560. ONEST plots showed decreasing overall percent agreement (OPA) as observer number increased, reaching a low plateau of 0.46 at ten observers for SP263 and 0.41 at eight observers for SP142. IC scoring with both assays showed poor reproducibility across multiple pathologists with ONEST analysis suggesting more than half of pathologists will disagree about IC scores. This could lead to many patients either receiving atezolizumab when they are unlikely to benefit, or not receiving atezolizumab when they may benefit.

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Fig. 1: Distribution of assigned continuous percentage scores.
Fig. 2: Percentage of cases designated as positive by pathologists.
Fig. 3: ONEST plots showing overall percent agreement (OPA) or proportion of identical reads between pathologists as a function of the number of observers.
Fig. 4: Example cases with high discordance in immune cell scoring across observers.

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Acknowledgements

This research was supported by the Breast Cancer Research Foundation (DLR and LP) and an NCI R01 grant (R01CA219647) to LP.

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Affiliations

  1. Yale School of Medicine, New Haven, CT, USA

    Emily S. Reisenbichler, Kimberly Cole, Vasiliki Pelekanou, Vesal Yaghoobi, Fahad Ahmed, Lajos Pusztai & David L. Rimm

  2. Texas A&M University, College Station, TX, USA

    Gang Han

  3. University of Iowa, Iowa City, IA, USA

    Andrew Bellizzi

  4. Massachusetts General Hospital, Boston, MA, USA

    Veerle Bossuyt & Amy Ly

  5. Brigham and Women’s Hospital, Boston, MA, USA

    Jane Brock & Beth T. Harrison

  6. University of California San Diego, San Diego, CA, USA

    Oluwole Fadare

  7. Forward Pathology Solutions, Kansas City, MO, USA

    Omar Hameed

  8. Vanderbilt University Medical Center, Nashville, TN, USA

    Omar Hameed & Mirna Podoll

  9. Emory University, Atlanta, GA, USA

    Krisztina Hanley & Hannah Wen

  10. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    M. Gabriela Kuba

  11. Intermountain Healthcare, Salt Lake City, UT, USA

    Dylan Miller

  12. University of Utah, Salt Lake City, UT, USA

    Dylan Miller

  13. Mayo Clinic, Rochester, MN, USA

    Anja C. Roden

  14. Brown University, Providence, RI, USA

    Kamaljeet Singh

  15. University of Louisville, Louisville, KY, USA

    Mary Ann Sanders

  16. University of Alabama at Birmingham, Birmingham, AL, USA

    Shi Wei

  17. Sanofi Oncology US, Cambridge, MA, USA

    Vasiliki Pelekanou

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  1. Emily S. Reisenbichler
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Correspondence to David L. Rimm.

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Conflict of interest

LP has received consulting fees and honoraria from Astra Zeneca, Merck, Novartis, Genentech, Eisai, Pieris, Immunomedics, Seattle Genetics, Almac and Syndax. DLR has served as an advisor for Astra Zeneca, Agendia, Amgen, BMS, Cell Signaling Technology, Cepheid, Daiichi Sankyo, Genoptix/Novartis, GSK, Konica Minolta, Merck, NanoString, PAIGE.AI, Perkin Elmer, Roche, Sanofi, Ventana and Ultivue. Astra Zeneca, Cepheid, NavigateBP, NextCure, Nanostring, Lilly, and Ultivue fund research in DLRs lab. VP is now an employee of Sanofi Aventis.

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Reisenbichler, E.S., Han, G., Bellizzi, A. et al. Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer. Mod Pathol 33, 1746–1752 (2020). https://doi.org/10.1038/s41379-020-0544-x

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