Accuracy of Cytologic vs Histologic Specimens for Assessment of Programmed Cell Death Ligand-1 Expression in Non-Small Cell Lung Cancer
Pattraporn Tajarernmuang, Felipe Aliaga, Amr J. Alwakeel, Gamuchirai Tavaziva, Kimberly A. Turner, Dick Menzies, Hangjun Wang, Linda Ofiara, Andrea Benedetti, Anne V. Gonzalez
Abstract
BackgroundProgrammed death ligand 1 (PD-L1) expression on tumor cells, evaluated by immunohistochemistry, guides the use of immunotherapy in advanced non-small cell lung cancer (NSCLC).Research QuestionWhat is the sensitivity and specificity of PD-L1 testing performed in cytologic vs paired histologic specimens in patients with NSCLC?Study Design and MethodsThe MEDLINE, Embase, Web of Science, and Cochrane Registry databases were searched through June 1, 2021. The primary outcome was pooled sensitivity and specificity of PD-L1 testing performed on cytologic specimens compared with the reference standard of histologic specimens, analyzed at the PD-L1 expression cutoffs (tumor proportion score) ≥ 1% and ≥ 50%. Pooled sensitivity and specificity, and associated 95% CIs, were estimated using bivariate generalized linear mixed models.ResultsTwenty-six articles were included, encompassing a total of 1,064 pairs of histology specimens and cytology cell blocks, and 267 pairs of histology specimens and direct smears. Among these, 946 paired specimens were acquired without interval treatment between the collection of histology and cytology samples. The pooled sensitivity and specificity of cytology specimens compared with paired histology specimens at the PD-L1 expression cutoff ≥ 1% were 0.84 (95% CI, 0.77-0.89) and 0.88 (95% CI, 0.82-0.93), respectively, whereas the pooled sensitivity and specificity at cutoff ≥ 50% were 0.78 (95% CI, 0.69-0.86) and 0.94 (95% CI, 0.91-0.96), respectively. When only paired specimens acquired without interval treatment were considered, the pooled sensitivity and specificity of cytology specimens at PD-L1 expression cutoff ≥ 1% were 0.84 (95% CI, 0.76-0.90) and 0.89 (95% CI, 0.82-0.94), respectively, whereas the pooled sensitivity and specificity at cutoff ≥ 50% were 0.80 (95% CI, 0.71-0.89) and 0.94 (95% CI, 0.91-0.96), respectively.InterpretationCytologic specimens provide an accurate assessment of PD-L1 expression in most patients with NSCLC, at both ≥ 1% and ≥ 50% cutoffs, when compared with histologic specimens.Trial RegistrationPROSPERO; No.: CRD42020153279; URL: https://www.crd.york.ac.uk/prospero/ Programmed death ligand 1 (PD-L1) expression on tumor cells, evaluated by immunohistochemistry, guides the use of immunotherapy in advanced non-small cell lung cancer (NSCLC). What is the sensitivity and specificity of PD-L1 testing performed in cytologic vs paired histologic specimens in patients with NSCLC? The MEDLINE, Embase, Web of Science, and Cochrane Registry databases were searched through June 1, 2021. The primary outcome was pooled sensitivity and specificity of PD-L1 testing performed on cytologic specimens compared with the reference standard of histologic specimens, analyzed at the PD-L1 expression cutoffs (tumor proportion score) ≥ 1% and ≥ 50%. Pooled sensitivity and specificity, and associated 95% CIs, were estimated using bivariate generalized linear mixed models. Twenty-six articles were included, encompassing a total of 1,064 pairs of histology specimens and cytology cell blocks, and 267 pairs of histology specimens and direct smears. Among these, 946 paired specimens were acquired without interval treatment between the collection of histology and cytology samples. The pooled sensitivity and specificity of cytology specimens compared with paired histology specimens at the PD-L1 expression cutoff ≥ 1% were 0.84 (95% CI, 0.77-0.89) and 0.88 (95% CI, 0.82-0.93), respectively, whereas the pooled sensitivity and specificity at cutoff ≥ 50% were 0.78 (95% CI, 0.69-0.86) and 0.94 (95% CI, 0.91-0.96), respectively. When only paired specimens acquired without interval treatment were considered, the pooled sensitivity and specificity of cytology specimens at PD-L1 expression cutoff ≥ 1% were 0.84 (95% CI, 0.76-0.90) and 0.89 (95% CI, 0.82-0.94), respectively, whereas the pooled sensitivity and specificity at cutoff ≥ 50% were 0.80 (95% CI, 0.71-0.89) and 0.94 (95% CI, 0.91-0.96), respectively. Cytologic specimens provide an accurate assessment of PD-L1 expression in most patients with NSCLC, at both ≥ 1% and ≥ 50% cutoffs, when compared with histologic specimens. PROSPERO; No.: CRD42020153279; URL: https://www.crd.york.ac.uk/prospero/ Take-home PointsStudy Question: What is the diagnostic accuracy of cytologic vs paired histologic specimens for assessment of programmed cell death ligand-1 (PD-L1) expression in patients with non-small cell lung cancer?Results: The pooled sensitivity values of cytologic specimens at the clinically relevant PD-L1 expression cutoffs of ≥ 1% and ≥ 50% were 84% and 78%, respectively, whereas specificity values of cytologic specimens at these same cutoffs were 88% and 94%, respectively. When only paired specimens acquired in the absence of interval treatment were considered, the pooled sensitivity of cytologic specimens compared with paired histologic specimens at the ≥ 50% PD-L1 expression cutoff was 80%, with similar specificity.Interpretation: Cytologic specimens provide an accurate assessment of PD-L1 expression in most patients with non-small cell lung cancer, at both ≥ 1% and ≥ 50% cutoffs, when compared with histologic specimens. Study Question: What is the diagnostic accuracy of cytologic vs paired histologic specimens for assessment of programmed cell death ligand-1 (PD-L1) expression in patients with non-small cell lung cancer? Results: The pooled sensitivity values of cytologic specimens at the clinically relevant PD-L1 expression cutoffs of ≥ 1% and ≥ 50% were 84% and 78%, respectively, whereas specificity values of cytologic specimens at these same cutoffs were 88% and 94%, respectively. When only paired specimens acquired in the absence of interval treatment were considered, the pooled sensitivity of cytologic specimens compared with paired histologic specimens at the ≥ 50% PD-L1 expression cutoff was 80%, with similar specificity. Interpretation: Cytologic specimens provide an accurate assessment of PD-L1 expression in most patients with non-small cell lung cancer, at both ≥ 1% and ≥ 50% cutoffs, when compared with histologic specimens. The introduction of immune checkpoint inhibitors (ICIs) into clinical practice has transformed the care of patients with non-small cell lung cancer (NSCLC). Programmed cell death protein-1 (PD-1) is a transmembrane receptor expressed on T cells. Interaction with programmed death ligand-1 (PD-L1), a transmembrane protein on tumor cells, inhibits the immune system’s ability to destroy cancer cells. ICIs, whether targeting the PD-1 receptor or its ligand PD-L1, break this inhibitory system and allow T cells to attack cancer cells.1Ohaegbulam K.C. Assal A. Lazar-Molnar E. Yao Y. Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway.Trends Mol Med. 2015; 21: 24-33Abstract Full Text Full Text PDF PubMed Scopus (563) Google Scholar,2Ichikawa M. Chen L. Role of B7-H1 and B7-H4 molecules in down-regulating effector phase of T-cell immunity: novel cancer escaping mechanisms.Front Biosci. 2005; 10: 2856-2860Crossref PubMed Scopus (56) Google Scholar Patients whose tumors demonstrate higher levels of PD-L1 expression derive greater clinical benefit from immunotherapy.3Brody R. Zhang Y. Ballas M. et al.PD-L1 expression in advanced NSCLC: insights into risk stratification and treatment selection from a systematic literature review.Lung Cancer. 2017; 112: 200-215Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, 4Reck M. Rodriguez-Abreu D. 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Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (7040) Google L. Rodriguez-Abreu D. et al.Pembrolizumab chemotherapy in non-small-cell lung cancer.N Engl J Med. PubMed Scopus Google cell lung cancer Scholar The clinical of PD-L1 expression using histologic samples. the to of patients with advanced with cytologic specimens Y. of PD-L1 in Cancer. for the Study of Scholar a in the of patients with NSCLC, and and and in the of patients with lung and of lung cancer, of clinical practice Full Text Full Text PDF PubMed Scopus Google et for non-small cell lung and of lung cancer, of clinical practice Full Text Full Text PDF PubMed Scopus Google Scholar The of PD-L1 expression has in specimens, in cytologic Y. of PD-L1 in Cancer. for the Study of L. M. et immune of non-small-cell lung of cytologic and histologic through J Med. 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