High sensitivity of PD-L1 analysis from pleural effusion in nonsmall cell lung cancer

Our plain-English summary of High sensitivity of PD-L1 analysis from pleural effusion in nonsmall cell lung cancer, by L. Hagmeyer, S. Schäfer, M. Engels, et al (ERJ Open Research, 2021).

The study

• Authors: L. Hagmeyer, S. Schäfer, M. Engels, A. Pietzke-Calcagnile, M. Treml, S.D. Herkenrath, M. Heldwein, K. Hekmat, S. Matthes, A. Scheel, J. Wolf, R. Büttner, W. Randerath
• Journal: ERJ Open Research
• Published: 2021;7(1)
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) immune checkpoint inhibitors have been approved for monotherapy of metastatic nonsmall cell lung cancer (mNSCLC) depending on tumour cells' PD-L1 expression. Pleural effusion is common in mNSCLC. The significance of immunocytochemistry PD-L1 analysis from pleural effusion samples is unclear. Aim: The aim of the study was to analyse the sensitivity regarding immunocytochemistry PD-L1 analysis of pleural effusion in NSCLC as compared to immunohistochemistry of pleural biopsies. Patients and Methods: Fifty consecutive subjects (17 female, median age 72.5 years, seven never-smokers) were enrolled in this prospective controlled two-centre study. Inclusion criteria were pleural effusion, suspected or known lung cancer, indication for pleural puncture and thoracoscopy, and written informed consent. Immunocytochemistry and immunohistochemistry PD-L1 analyses were performed with the Dako-PDL1-IHC-22C3pharmDx assay. Analysis for sensitivity, specificity, and positive and negative predictive value was performed for PD-L1 detection from pleural effusion. Results: 50 subjects underwent pleural puncture and thoracoscopy. Pathological diagnoses were lung cancer (48), lymphoma (1) and mesothelioma (1). Sensitivity, specificity, positive predictive value and negative predictive value of PD-L1-testing with expression ≥50% defined as positive were 100% (95% CI 46-100%), 63% (36-84%), 45% (18-75%) and 100% (66-100%), and with expression ≥1% defined as positive 86% (56-97%), 43% (12-80%), 75% (47-92%) and 60% (17-93%). Conclusion: PD-L1 analysis in tumour-positive pleural effusion samples shows a very high sensitivity and negative predictive value, especially regarding PD-L1 expression levels ≥50% (European Medicines Agency approval). Negative results are reliable and help in the decision against a first-line checkpoint inhibitor monotherapy. However, a 1% cut-off level (United States Food and Drug Administration approval) leads to a markedly lower negative predictive value, making other invasive procedures necessary (NCT02855281).

Copyright ©ERS 2021.

In plain English

This was a prospective pilot study at two hospitals in Germany. It did not examine asbestos exposure. The authors compared PD-L1 testing of cancer cells in fluid around the lung (pleural effusion) with pleural tissue biopsies, the reference standard. Fifty patients with pleural effusion and suspected or known lung cancer were enrolled (2016 to 2018); 41 had nonsmall cell lung cancer, one sarcomatoid mesothelioma. Mostly because samples held too few tumour cells, PD-L1 testing succeeded in 25 fluid and 35 tissue samples. In the 21 cases where both succeeded, using a cut-off of 50% of tumour cells, the fluid test's sensitivity was 100% (95% CI 46 to 100%, based on 5 biopsy-positive cases), negative predictive value 100% (66 to 100%, based on 10 fluid-negative cases) and specificity 63% (36 to 84%). With a 1% cut-off, sensitivity was 86% (56 to 97%), negative predictive value 60% (17 to 93%) and specificity 43% (12 to 80%). The authors concluded that negative fluid results at the 50% cut-off seem very reliable; the 1% cut-off gave a markedly lower negative predictive value.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Prospective controlled pilot diagnostic study at two centres. It compared PD-L1 testing of pleural effusion (immunocytochemistry) with PD-L1 testing of pleural biopsies (immunohistochemistry), which served as the reference standard.
• Who was studied: 50 patients (17 female, median age 72.5 years) with pleural effusion and suspected or known lung cancer at two tertiary care centres in Germany (Solingen and Cologne), October 2016 to November 2018. 41 had nonsmall cell lung cancer. The others had small cell lung cancer (4), mixed carcinoma (3), non-Hodgkin lymphoma (1) and sarcomatoid mesothelioma (1).
• Exposure: Not applicable: the study did not examine asbestos or any other exposure. It evaluated a diagnostic test, PD-L1 staining with the Dako PD-L1 IHC 22C3 pharmDx assay, at two cut-offs: 50% or more and 1% or more of tumour cells.
• Main results:
  • PD-L1 analysis could actually be performed in 25 pleural effusion cases and 35 pleural tissue cases. The main reason was insufficient sample material (low tumour cell count), especially in pleural effusion.
  • In the 21 cases where PD-L1 analysis of both samples succeeded, with 50% or more of tumour cells defined as positive, the pleural effusion test had sensitivity 100% (95% CI 46 to 100%; 5 biopsy-positive cases). Specificity was 63% (36 to 84%), positive predictive value 45% (18 to 75%), negative predictive value 100% (66 to 100%; 10 fluid-negative cases) and negative likelihood ratio 0.00.
  • At the 50% cut-off, no false negative results were documented among tumour cell-positive effusions where PD-L1 analysis was feasible.
  • In the same 21 cases, with 1% or more of tumour cells defined as positive, sensitivity was 86% (95% CI 56 to 97%), positive predictive value 75% (47 to 92%), negative predictive value 60% (17 to 93%) and specificity 43% (12 to 80%).
  • In the analysis based on all cases where PD-L1 testing was indicated, at the 50% cut-off, the effusion test had sensitivity 71% (95% CI 30 to 95%), specificity 71% (49 to 87%), positive predictive value 42% (16 to 71%) and negative predictive value 89% (65 to 98%).
  • In the analysis based on all cases where PD-L1 testing was indicated, at the 1% cut-off, sensitivity was 71% (95% CI 44 to 89%) and specificity 64% (95% CI 36 to 86%).
  • Compared with pleural biopsies, detection of tumour cells in pleural effusion had sensitivity 83% (95% CI 67 to 89%), specificity 70% (35 to 92%), positive predictive value 92% (76 to 98%) and negative predictive value 50% (24 to 76%).
  • Specificity was only moderate at both cut-offs. The authors said this means there may be a relevant proportion of false-positive results, so positive effusion results need confirmation by more specific tests.
• The authors' conclusion: The authors concluded that PD-L1 analysis in tumour-positive pleural effusion samples has very high sensitivity and negative predictive value at the 50% cut-off. They said negative results at that cut-off seem very reliable for deciding against first-line checkpoint inhibitor monotherapy in the European Medicines Agency region. Under the 1% cut-off used in the US Food and Drug Administration region, the negative predictive value is markedly lower, so pleural tissue analysis would be needed.
• Limitations the authors state:
  • Pleural effusion did not always yield enough material for full evaluation, including PD-L1 analysis. This in part led to inconclusive results regarding malignancy.
  • Mesothelial cells can also stain for PD-L1 and cannot always be told apart from tumour cells in fluid samples, which may produce false-positive results.
  • Tumour heterogeneity may cause differences in PD-L1 expression between the test sample and the reference standard sample.
  • Further studies are needed to strengthen confidence in the results and to investigate false-positive immunocytochemistry results.

Topics

Medical terms in this study, explained in our Lexicon: PD-L1, Pleural Effusion, Lung Cancer, checkpoint inhibitors, Immunohistochemistry, Thoracoscopy, Informed Consent, Mesothelioma.

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