A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases

Modern Pathology volume 34, pages252–263(2021)Cite this article

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Abstract

PD-L1 immunohistochemistry (IHC) currently has the most Food and Drug Administration (FDA) approvals as a companion diagnostic (CDx) for immunotherapies in specific tumor types; however, multiple other immunotherapy biomarkers exist. We performed this study to examine and report the prevalence of PD-L1 expression in a wide variety of tumor types and examine its relationship to microsatellite instability (MSI), tumor mutational burden (TMB), and CD274 (PD-L1) gene amplification. We performed a retrospective analysis of all cases in which both PD-L1 IHC (using the DAKO 22C3 IHC assay with either tumor proportion score (TPS) or combined positive score (CPS); or the VENTANA SP142 assay with infiltrating immune cell score (IC)) and comprehensive genomic profiling (CGP) were tested at Foundation Medicine between January 2016 and November 2019. Of note, PD-L1 positivity is defined per the CDx indication and tumor proportion score (TPS ≥ 1) for indications without a CDx claim; and TMB positivity is defined as ≥10 mutations/Mb. A total of 48,782 cases were tested for PD-L1 IHC and CGP. Immune cell expression of PD-L1 was more frequently identified than tumor cell expression of PD-L1. We saw a high correlation between PD-L1 expression and CD274 gene amplification (p < 0.0001), MSI and TMB (p < 0.0001), and PD-L1 and TMB (p < 0.0001). In addition, the combination of PD-L1 and TMB identified four unique disease subsets PD-L1−/TMB−, PD-L1+/TMB−, PD-L1−/TMB+, and PD-L1+/TMB+ with varying prevalence dependent on tumor type. Lastly, 50.3% (24527/48782) of the overall cohort was positive for at least one of the CDx or exploratory biomarkers described above. This is the largest pan-cancer analysis of relevant biomarkers associated with response to checkpoint inhibitors to date, including more than 48,000 cases. Additional clinical trials with treatment outcome data in individual tumor types are needed to determine whether the double positive PD-L1+/TMB+ disease subset would respond best to immunotherapy.

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Fig. 1: Examples of a PD-L1 expression in different tumor types using different PD-L1 immunohistochemistry (IHC) assay.
Fig. 2: Prevalence rates of various tumor types.
Fig. 3: The prevalence of rates of TMB, MSI-H, and CD274 gene amplification in individual tumor types.
Fig. 4: Immunotherapy biomarker correlation of PD-L1 IHC, MSI, TMB, and CD274 gene amplification.
Fig. 5: Patients potentially eligible for checkpoint inhibitors (CPIs).

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Acknowledgements

We thank Cierra Smith, Bethany Thompson, Natasha Oakley, and Panhia Vang for their contribution in processing all the PD-L1 IHC specimens.

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Affiliations

  1. Foundation Medicine, Inc., Morrisville, NC, USA

    Richard S. P. Huang, James Haberberger, Eric Severson, Daniel L. Duncan, Amanda Hemmerich, Claire Edgerly, Naomi Lynn Ferguson, Clarence Owens & Shakti H. Ramkissoon

  2. Foundation Medicine, Inc., Cambridge, MA, USA

    Erik Williams, Julia Elvin, Jo-Anne Vergilio, Jonathan Keith Killian, Douglas I. Lin, Julie Tse, Matthew Hiemenz, Natalie Danziger, Priti S. Hegde, Jeffrey Venstrom, Brian Alexander & Jeffrey S. Ross

  3. Department of Pathology, State University of New York (SUNY) Upstate Medical University, Syracuse, NY, USA

    Jeffrey S. Ross

  4. Wake Forest Comprehensive Cancer Center and Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Shakti H. Ramkissoon

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  1. Richard S. P. Huang
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Correspondence to Richard S. P. Huang.

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All authors are Foundation Medicine employees and receive a salary and/or stock equity from Foundation Medicine.

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Huang, R.S.P., Haberberger, J., Severson, E. et al. A pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases. Mod Pathol 34, 252–263 (2021). https://doi.org/10.1038/s41379-020-00664-y

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