Analysis of expression of PTEN/PI3K pathway and programmed cell death ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM)

Our plain-English summary of Analysis of expression of PTEN/PI3K pathway and programmed cell death ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM), by S. Cedrés, S. Ponce-Aix, N. Pardo-Aranda, et al (Lung Cancer, 2016).

The study

• Authors: S. Cedrés, S. Ponce-Aix, N. Pardo-Aranda, A. Navarro-Mendivil, A. Martinez-Marti, J. Zugazagoitia, I. Sansano, M.A. Montoro, A. Enguita, E. Felip
• Journal: Lung Cancer
• Published: 2016;96:1-6
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant pleural mesothelioma (MPM) frequently express elevated AKT/mTOR activity. Previous reports in gliomas, colon, breast and prostate cancer suggest that PTEN/PI3K pathway may be important for the induction of PD-L1 expression. This study explored the expression of PTEN/PI3K pathway and PD-L1 in MPM and its relationship with the patient́s prognosis

Material And Methods: Twenty seven consecutive MPM patients were reviewed. Formalin-fixed, paraffin-embedded tissue biopsies were used for immunohistochemical analysis of PTEN/PI3K pathway and PD-L1 RESULTS: Expression of PTEN, mTOR, pAKT, p4EBP1, peif4E, pS6 and FOXO3a was found in 88.5%, 92.3%, 78.3%, 38.5%, 100%, 52.2% and 100% of tumors and PD-L1 in 23%. We found a significant correlation between pAKT, FOXO3a and PD-L1 expression and longer overall survival (p <0.05). We did not identify significant association between the level of PD-L1 expression and alterations in PI3K pathway

Conclusions: This study shows PTEN/PI3K pathway and PD-L1 in MPM are frequently activated. Our results suggests that there is not association between PD-L1 and the involvement of the PI3K pathway in MPM.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In plain English

This study looked at tumor tissue from 27 consecutive patients with malignant pleural mesothelioma seen at Vall d'Hebron University Hospital in Barcelona, Spain, between January 2000 and April 2014. Using stored biopsy samples taken at diagnosis, the authors stained for proteins of the PTEN/PI3K signaling pathway and for PD-L1, a protein that can dampen the immune response. Pathway proteins were found in most tumors. PD-L1 was positive in 6 of 26 tested patients. PD-L1 was not significantly linked to any pathway protein. In single-factor analyses, patients with PD-L1-positive tumors had shorter median survival (5 versus 20 months), while high pAKT and high FOXO3a were linked to longer survival. None of these remained significant in a combined (multivariate) analysis. PD-L1 was more often positive in non-epithelioid than in epithelioid tumors. Asbestos exposure was recorded but did not correlate with protein expression, and the article gives conflicting figures for how many patients were exposed. The authors concluded they could not show an association between the two pathways, and noted the small number of cases.

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: Single-hospital series of consecutive patients. Laboratory (immunohistochemistry) analysis of stored tumor biopsies taken at diagnosis, compared with clinical data and survival.
• Who was studied: 27 consecutive patients with histologically proven malignant pleural mesothelioma at Vall d'Hebron University Hospital, Barcelona, Spain, January 2000 to April 2014. There were 19 epithelioid, 5 biphasic, 1 sarcomatoid and 2 unspecified histology. Median age was 68.
• Exposure: This is not an asbestos exposure study. What was measured was tumor expression of PTEN/PI3K pathway proteins and PD-L1. Asbestos exposure was recorded only as a yes/no clinical variable, with no fiber types, jobs or doses given. Table 1 lists 9 of 27 (33.3%) as exposed, but the results text says 66.7% had previous asbestos exposure.
• Main results:
  • PD-L1 was positive in 6 patients (22.2%) and negative in 20 patients (77.7%) of those tested. The article's abstract gives 23%.
  • Pathway proteins were found in these percentages of tumors: PTEN 88.5%, mTOR 92.3%, pAKT 78.3%, p4EBP1 38.5%, peIF4E 100%, pS6 52.2% and FOXO3a 100%.
  • No significant association was found between PD-L1 and the PI3K pathway proteins. Table 3 p values ranged from 0.141 to 0.653.
  • Median survival for the whole group of 27 patients was 16.6 months (95% CI 6.4 to 19.3).
  • Patients with PD-L1-positive tumors had a median survival of 5 months, against 20 months for PD-L1-negative patients (p = 0.009; HR 3.91; 95% CI 1.2 to 11.8). This was a single-factor analysis.
  • Median survival was 30.9 months with high pAKT and 6 months with low pAKT (p = 0.040; HR 0.42; 95% CI 0.18 to 0.98). This was a single-factor analysis.
  • Median survival was 22.1 months with high FOXO3a and 6 months with low FOXO3a (p = 0.018; HR 0.34; 95% CI 0.14 to 0.86). This was a single-factor analysis.
  • In the multivariate Cox model, none of the variables remained a significant prognostic factor for survival.
  • PD-L1 was positive in 4 of 7 patients (57%) with non-epithelioid histology and in 2 of 17 patients (12%) with epithelioid histology (p = 0.028).
  • Expression of PI3K pathway proteins and PD-L1 did not correlate with gender, asbestos exposure or clinical stage.
  • No association was found between PD-L1 expression and tumor-infiltrating lymphocytes (p = 0.075).
• The authors' conclusion: The authors concluded that their results support a role for PI3K pathway dysregulation in the development of malignant pleural mesothelioma, and that PD-L1 is expressed in about a quarter of patients. They were unable to demonstrate an association between the two pathways.
• Limitations the authors state:
  • The series had a limited number of cases and used archival tissue.
  • The median score was used as the cutoff, and both pathways were measured only in samples taken at diagnosis.
  • PD-L1 expression may change during the disease and after treatment. No repeat biopsies were analyzed.
  • Different PD-L1 antibodies could change the percentage of tumors counted as positive.
  • Not every test could be done for every patient because of limited tissue.
  • The authors suggest longer follow-up is needed to detect biological prognostic factors.

Topics

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

Medical terms in this study, explained in our Lexicon: PD-L1, Pleural Mesothelioma, Prognosis, Overall Survival.

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• 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)
• Prognostic and clinicopathological utility of programmed death-ligand 1 in malignant pleural mesothelioma: A meta-analysis — F. Zhang, W. Gong (2020)

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