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

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).

References

  1. 1.

    Li Y, Li F, Jiang F, Lv X, Zhang R, Lu A, et al. A mini-review for cancer immunotherapy: molecular understanding of PD-1/PD-L1 pathway & translational blockade of immune checkpoints. Int J Mol Sci. 2016;17:1151.

    Article  Google Scholar 

  2. 2.

    Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet. 2017;390:1853–62.

    CAS  Article  Google Scholar 

  3. 3.

    Pai-Scherf L, Blumenthal GM, Li H, Subramaniam S, Mishra-Kalyani PS, He K, et al. FDA approval summary: pembrolizumab for treatment of metastatic non-small cell lung cancer: first-line therapy and beyond. Oncologist. 2017;22:1392–9.

    CAS  Article  Google Scholar 

  4. 4.

    Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108–21.

    CAS  Article  Google Scholar 

  5. 5.

    Heimes AS, Schmidt M. Atezolizumab for the treatment of triple-negative breast cancer. Expert Opin Investig Drugs. 2019;28:1–5.

    CAS  Article  Google Scholar 

  6. 6.

    Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220–9.

    CAS  Article  Google Scholar 

  7. 7.

    Pacheco J, Bunn PA. Advancements in small-cell lung cancer: the changing landscape following IMpower-133. Clin Lung Cancer. 2019;20:148–60.e2.

    Article  Google Scholar 

  8. 8.

    FDA. List of cleared or approved companion diagnostic devices (In Vitro and Imaging Tools). 2020. https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools.

  9. 9.

    Scheerens H, Malong A, Bassett K, Boyd Z, Gupta V, Harris J, et al. Current status of companion and complementary diagnostics: strategic considerations for development and launch. Clin Transl Sci. 2017;10:84–92.

    CAS  Article  Google Scholar 

  10. 10.

    FDA. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. 2020. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication.

  11. 11.

    Wu Y, Xu J, Du C, Wu Y, Xia D, Lv W, et al. The predictive value of tumor mutation burden on efficacy of immune checkpoint inhibitors in cancers: a systematic review and meta-analysis. Front Oncol. 2019;9:1161.

    Article  Google Scholar 

  12. 12.

    Marabelle A, Fakih MG, Lopez J, Shah M, Shapira-Frommer R, Nakagawa KC, et al. Association of tumor mutational burden with outcomes in patients with select advanced solid tumors treated with pembrolizumab in KEYNOTE-158. Ann Oncol. 2019;30:477–8.

    Article  Google Scholar 

  13. 13.

    Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9.

    Article  Google Scholar 

  14. 14.

    Armand P, Shipp MA, Ribrag V, Michot JM, Zinzani PL, Kuruvilla J, et al. Programmed death-1 blockade with pembrolizumab in patients with classical hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016;34:3733–9.

    CAS  Article  Google Scholar 

  15. 15.

    Goodman AM, Piccioni D, Kato S, Boichard A, Wang HY, Frampton G, et al. Prevalence of PDL1 amplification and preliminary response to immune checkpoint blockade in solid tumors. JAMA Oncol. 2018;4:1237–44.

    Article  Google Scholar 

  16. 16.

    Kowanetz M, Zou W, Gettinger SN, Koeppen H, Kockx M, Schmid P, et al. Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1). Proc Natl Acad Sci USA. 2018;115:E10119–26.

    CAS  Article  Google Scholar 

  17. 17.

    Hegde PS, Chen DS. Top 10 challenges in cancer immunotherapy. Immunity. 2020;52:17–35.

    CAS  Article  Google Scholar 

  18. 18.

    Hegde PS, Karanikas V, Evers S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res. 2016;22:1865–74.

    CAS  Article  Google Scholar 

  19. 19.

    Li K, Luo H, Huang L, Luo H, Zhu X. Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int. 2020;20:16.

    Article  Google Scholar 

  20. 20.

    Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8.

    CAS  Article  Google Scholar 

  21. 21.

    Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–99.

    Article  Google Scholar 

  22. 22.

    Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9:34.

    Article  Google Scholar 

  23. 23.

    Merino DM, McShane LM, Fabrizio D, Funari V, Chen SJ, White JR, et al. Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project. J Immunother Cancer. 2020;8:e000147.

    Article  Google Scholar 

  24. 24.

    Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202–6.

    CAS  Article  Google Scholar 

  25. 25.

    FDA. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors.

  26. 26.

    Goeman JJ, Solari A. Multiple hypothesis testing in genomics. Stat Med. 2014;33:1946–78.

    Article  Google Scholar 

  27. 27.

    VENTANA Medical Systems. VENTANA PD-L1 (SP142) assay interpretation guide for triple-negative breast carcinoma (TNBC). 2020. https://diagnostics.roche.com/content/dam/diagnostics/us/en/resource-center/VENTANA-PD-L1-(SP142)-Assay-Interpretation-Guide.pdf.

  28. 28.

    DAKO. PD-L1 IHC 22C3 pharmDx interpretation manual—NSCLC. 2020. https://www.agilent.com/cs/library/usermanuals/public/29158_pd-l1-ihc-22C3-pharmdx-nsclc-interpretation-manual.pdf.

  29. 29.

    DAKO. PD-L1 IHC 22C3 pharmDx interpretation manual—urothelial carcinoma. 2020. https://www.agilent.com/cs/library/usermanuals/public/29276_22C3_pharmdx_uc_interpretation_manual_us.pdf.

  30. 30.

    Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013;31:1023–31.

    CAS  Article  Google Scholar 

  31. 31.

    Trabucco SE, Gowen K, Maund SL, Sanford E, Fabrizio DA, Hall MJ, et al. A novel next-generation sequencing approach to detecting microsatellite instability and pan-tumor characterization of 1000 microsatellite instability-high cases in 67,000 patient samples. J Mol Diagn. 2019;21:1053–66.

    CAS  Article  Google Scholar 

  32. 32.

    Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21:44–59.

    CAS  Article  Google Scholar 

  33. 33.

    Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019;37:1470–8.

    CAS  Article  Google Scholar 

  34. 34.

    Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr. et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394:1915–28.

    CAS  Article  Google Scholar 

  35. 35.

    Schrock AB, Ouyang C, Sandhu J, Sokol E, Jin D, Ross JS, et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol. 2019;30:1096–103.

    CAS  Article  Google Scholar 

  36. 36.

    Hamza A, Roberts D, Su S, Weber RS, Bell D, Ferrarotto R. PD-L1 expression by immunohistochemistry in salivary duct carcinoma. Ann Diagn Pathol. 2019;40:49–52.

    Article  Google Scholar 

  37. 37.

    Vigliar E, Malapelle U, Iaccarino A, Acanfora G, Pisapia P, Clery E, et al. PD-L1 expression on routine samples of non-small cell lung cancer: results and critical issues from a 1-year experience of a centralised laboratory. J Clin Pathol. 2019;72:412–7.

    CAS  Article  Google Scholar 

  38. 38.

    Takeda M, Kasai T, Naito M, Tamiya A, Taniguchi Y, Saijo N, et al. Programmed death-ligand 1 expression with clone 22C3 in non-small cell lung cancer: a single institution experience. Clin Med Insights Oncol. 2019;13:1–5.

    Article  Google Scholar 

  39. 39.

    Velcheti V, Rimm DL, Schalper KA. Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1). J Thorac Oncol. 2013;8:803–5.

    CAS  Article  Google Scholar 

  40. 40.

    Joseph RW, Millis SZ, Carballido EM, Bryant D, Gatalica Z, Reddy S, et al. PD-1 and PD-L1 expression in renal cell carcinoma with sarcomatoid differentiation. Cancer Immunol Res. 2015;3:1303–7.

    CAS  Article  Google Scholar 

  41. 41.

    Hanif A, Pandey M, Khan S, Attwood K, George S. Metastatic sarcomatoid renal cell carcinoma treated with immune checkpoint inhibitors. OncoImmunology. 2019;8:1606639.

    Article  Google Scholar 

  42. 42.

    Kotlowska MP, Rueda AG, Olmedo ME, Benito A, Roldán AS, Fernandez Méndez MA, et al. Efficacy of immunotherapy in sarcomatoid lung cancer, a case report and literature review. Respir Med Case Rep. 2019;26:310–4.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Domblides C, Leroy K, Monnet I, Mazières J, Barlesi F, Gounant V, et al. Efficacy of immune checkpoint inhibitors in lung sarcomatoid carcinoma. J Thorac Oncol. 2020;15:460–6.

    Article  Google Scholar 

  44. 44.

    O’Malley DP, Yang Y, Boisot S, Sudarsanam S, Wang JF, Chizhevsky V, et al. Immunohistochemical detection of PD-L1 among diverse human neoplasms in a reference laboratory: observations based upon 62,896 cases. Mod Pathol. 2019;32:929–42.

    Article  Google Scholar 

  45. 45.

    FDA. FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS ≥ 1%). 2020. Available from: https://www.fda.gov/drugs/fda-expands-pembrolizumab-indication-first-line-treatment-nsclc-tps-1#:~:text=On%20April%2011%2C%202019%2C%20the,definitive%20chemoradiation%20or%20metastatic%20NSCLC.

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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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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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