Prognostic Role of Programmed Cell Death 1 Ligand 1 in Resectable Pleural Mesothelioma

Our plain-English summary of Prognostic Role of Programmed Cell Death 1 Ligand 1 in Resectable Pleural Mesothelioma, by H.S. Lee, M. Hamaji, N. Palivela, et al (The Annals of Thoracic Surgery, 2021).

The study

• Authors: H.S. Lee, M. Hamaji, N. Palivela, H.J. Jang, T. Splawn, D. Ramos, A.K. Lee, A.C. Raghuram, M. Ramineni, C.I. Amos, R.T. Ripley, B.M. Burt
• Journal: The Annals of Thoracic Surgery
• Published: 2021;112(5):1575-1583
• Type of article: Meta-analysis
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: The prognostic role of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM) is incompletely understood. Our objectives were to evaluate the evidence for tumor PD-L1 as a prognostic biomarker in MPM through meta-analysis and to determine whether tumor PD-L1 expression is associated with survival in MPM patients undergoing macroscopic complete resection.

Methods: Meta-analysis was performed to determine the association of PD-L1 with overall survival in MPM (n = 1655) from 14 studies containing overall survival and tumor PD-L1 expression. Univariable and multivariable analyses tested the relationship of tumor PD-L1 with overall survival and recurrence-free survival in an institutional cohort of MPM patients treated by macroscopic complete resection (n = 75). To validate the association of PD-L1 with overall survival, we utilized two independent MPM cohorts (n = 284).

Results: Meta-analysis demonstrated that high tumor PD-L1 expression was associated with poor overall survival. Among 75 patients undergoing macroscopic complete resection, 49 tumors (65%) expressed PD-L1 (1% or more), and high PD-L1 (50% or greater) was more commonly expressed on nonepithelial (29%) compared with epithelial tumors (14%). High tumor PD-L1 expression was independently associated with poor overall survival (P < .001, hazard ratio 5.67) and recurrence-free survival (P = .003, hazard ratio 3.28). The association of PD-L1 overexpression with unfavorable survival was more significant in epithelial MPMs than nonepithelial MPMs. These findings were validated in RNA sequencing analyses in two independent cohorts. Exploratory transcriptome analysis revealed that MPM tumors with PD-L1 overexpression displayed coexpression of other immune regulatory molecules, programmed cell death 1 ligand 2 and T-cell immunoglobulin mucin receptor 3.

Conclusions: Tumor PD-L1 expression is a prognostic biomarker in patients undergoing surgical resection for MPM and may be useful in perioperative decision making.

Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

In plain English

This study, from Baylor College of Medicine in Houston, asked whether the amount of a protein called PD-L1 on tumor cells is linked to survival in malignant pleural mesothelioma. It did not study asbestos exposure. The authors first pooled 14 published studies of 1,655 patients, mostly treated without surgery. In the 10 studies giving unadjusted figures, high PD-L1 was associated with poorer overall survival (pooled hazard ratio 1.55, 95% CI 1.28-1.88). They then reviewed 75 patients whose visible tumor was fully removed by surgery between 2014 and 2018. Of these, 49 (65%) had tumors with any PD-L1 (1% or more of tumor cells). After accounting for factors including tumor cell type, high PD-L1 (50% or more) was associated with worse overall survival (hazard ratio 5.67, 95% CI 2.11-15.2) and worse recurrence-free survival (hazard ratio 3.28, 95% CI 1.48-7.25). In gene data from two other groups of 211 and 73 patients, high-PD-L1 tumors also had significantly worse survival, but only among epithelial tumors. The authors concluded that PD-L1 marks aggressive tumors and may help surgical decisions. They noted possible selection bias and limited generalizability.

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: Meta-analysis of published retrospective studies, plus a retrospective review of a single-institution database. Findings were checked in two outside cohorts using RNA sequencing data.
• Who was studied: Meta-analysis: 1,655 patients with malignant pleural mesothelioma from 14 studies, mostly treated non-surgically. Institutional cohort: 75 patients at Baylor College of Medicine who had macroscopic complete resection by extrapleural pneumonectomy or pleurectomy/decortication from 2014 to 2018 and had PD-L1 testing. Validation cohorts: Brigham and Women's Hospital (n=211) and The Cancer Genome Atlas (n=73).
• Exposure: No asbestos exposure was studied. The factor examined was tumor PD-L1 protein expression, measured as the percentage of tumor cells staining. It was counted as positive at 1% or more and as high at 50% or more.
• Main results:
  • Meta-analysis, 10 studies giving unadjusted hazard ratios (1,047 patients): the pooled hazard ratio for overall survival with high PD-L1 was 1.55 (95% CI 1.28-1.88, P less than 0.001).
  • Meta-analysis, 5 studies giving adjusted hazard ratios (638 patients): the pooled hazard ratio was 1.77 (95% CI 1.22-2.57, P=0.002), with high heterogeneity among studies.
  • Institutional cohort: 49 of 75 tumors (65%) expressed PD-L1 at 1% or more, and 26 (35%) did not.
  • Institutional cohort: high PD-L1 (50% or more) was found in 8 of 58 epithelial tumors (14%) and 3 of 6 sarcomatoid tumors (50%).
  • Institutional cohort: PD-L1 cutoffs of 1% and 5% did not statistically separate good from poor survival.
  • Institutional cohort, multivariable analysis including histology: PD-L1 at 50% or more was independently associated with worse overall survival (hazard ratio 5.67, P less than 0.001) and worse recurrence-free survival (hazard ratio 3.28, P=0.003).
  • Table 2: the 95% confidence interval for the multivariable overall-survival hazard ratio of 5.67 was 2.11-15.2.
  • Table 2: the 95% confidence interval for the multivariable recurrence-free-survival hazard ratio of 3.28 was 1.48-7.25.
  • Validation cohorts (BWH n=211, TCGA n=73): patients with high-PD-L1 tumors, classified by a gene-expression signature, had significantly worse overall survival. The prognostic value was significant only for epithelial tumors.
  • Exploratory analysis of the 20 institutional patients given anti-PD-1 drugs (nivolumab or pembrolizumab) after recurrence: splitting them by PD-L1 level at 5%, 10% or 50% showed no significant difference in overall survival.
  • In the validation cohorts, PD-L1 gene expression was highly correlated with expression of two other immune regulatory molecules, PD-L2 and TIM-3.
• The authors' conclusion: The authors concluded that tumor PD-L1 expression is a biomarker for tumors with aggressive clinical behavior in patients undergoing surgical resection for malignant pleural mesothelioma, and that it may be useful in perioperative decision making.
• Limitations the authors state:
  • Selection bias and unmeasured confounders are inherent to the meta-analytic and retrospective designs.
  • The strict inclusion criteria for the institutional cohort limit how far the results can be generalized.
  • PD-L1 testing used three different antibody clones, although the authors cite evidence that these give comparable staining.
  • The analysis of patients treated with anti-PD-1 therapy was exploratory and needs larger cohorts.
  • Treatment in the meta-analysis studies varied widely, which the authors say clouds how the biomarker performs and likely added to heterogeneity.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, PD-L1, Biomarker, Meta-Analysis, Overall Survival, Recurrence-Free Survival, Hazard Ratio, Surgical Resection.

Related studies

• Prognostic and clinicopathological utility of programmed death-ligand 1 in malignant pleural mesothelioma: A meta-analysis — F. Zhang, W. Gong (2020)
• Analysis of expression of PTEN/PI3K pathway and programmed cell death ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM) — S. Cedrés, S. Ponce-Aix, et al. (2016)
• Prognosis of patients with malignant mesothelioma by expression of programmed cell death 1 ligand 1 and mesothelin in a contemporary cohort in Finland — D. Vizcaya, B. Farahmand, et al. (2020)
• Programmed cell death 1 ligand 1 (PD-L1) expression is associated with poor prognosis of malignant pleural mesothelioma patients with good performance status — E. Rrapaj, L. Giacometti, et al. (2021)
• Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation — A.J. Currie, A. Prosser, et al. (2009)
• Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malignant mesothelioma: A RENAPE study — S. Valmary-Degano, P. Colpart, et al. (2017)

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