Analysis of angiogenic and stromal biomarkers in a large malignant mesothelioma cohort

Our plain-English summary of Analysis of angiogenic and stromal biomarkers in a large malignant mesothelioma cohort, by P.L. Chia, P. Russell, K. Asadi, et al (Lung Cancer, 2020).

The study

• Authors: P.L. Chia, P. Russell, K. Asadi, B. Thapa, V. Gebski, C. Murone, M. Walkiewicz, U. Eriksson, A.M. Scott, T. John
• Journal: Lung Cancer
• Published: 2020;150:1-8
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Malignant mesothelioma (MM) is an aggressive malignancy of the pleura and other mesothelial membranes. Agents targeting vascular endothelial growth factor (VEGF) such as bevacizumab; and multi-kinase inhibitors such as nintedanib [angiokinase inhibitor of VEGF, platelet-derived growth factor (PDGF) receptor and fibroblast growth factor receptor (FGFR)] have recently demonstrated efficacy in MM.

Methods: Tissue microarrays (TMAs) were created from formalin-fixed, paraffin-embedded tissue samples obtained from 326 patients with MM who were treated surgically. PDGF-CC, FGFR-1, VEGF and CD31 expression were analysed by immunohistochemical (IHC) staining. The H-score method assigned a score of 0-300 to each sample, based on the percentage of cells stained at different intensities. CD31 was evaluated via Chalkley's method to evaluate microvessel density. We evaluated the association between expression of the biomarkers, clinicopathological factors and outcomes, in patients with MM.

Results: CD31 high (≥5) was seen in only 31/302 (10.3%) irrespective of histology. PDGF-CC high (≥150) was seen in 203 /310 (65%) of all samples. VEGF high (≥80) was seen in 219/322 (68%) of all MM with 143/209 (68%) of epithelioid histology. FGFR-1 high (≥40) was seen in 127/310 (41%) of all MM. There was no association of VEGF and FGFR-1 IHC with survival nor differences between histological subtypes. There was a non-significant trend towards poorer survival in epithelioid tumours with increased PDGF-CC expression (OS 18.5 vs 13.2 months; HR 0.7928; 95% CI 0.5958 to 1.055, P = 0.1110). High CD31 score was associated with significantly poorer survival (OS 12 vs 8.6 months; HR 0.48; 95% CI 0.2873 to 0.7941, P = 0.0044). Of the 31 patients with high CD31 scores; 23/31 (74%) were also high for PDGF-CC and 20/31 (64%) with high VEGF scores. CD31 was found to be an independent prognostic factor in multivariate analysis (HR 1.540; 95% CI 1.018 to 2.330; p = 0.041).

Conclusions: High CD31 was an independent poor prognostic factor and high PDGF-CC expression was associated with poor survival in MM. Abrogating these pathways may have prognostic implications.

Copyright © 2020 Elsevier B.V. All rights reserved.

In plain English

This study examined tumour tissue from 326 patients with malignant mesothelioma who had surgery or a biopsy between 1988 and 2014. It did not examine asbestos exposure. The authors stained the samples for four markers linked to blood-vessel growth and tumour-supporting tissue (VEGF, PDGF-CC, FGFR-1 and CD31) and compared them with survival. High CD31 (a score of 5 or more, indicating many small blood vessels) was seen in 31 of 302 samples (10.3%). Median overall survival was 8.6 months with high CD31, against 12 months with low CD31. In an analysis of 269 patients with complete data, CD31 remained linked to survival after adjusting for other factors (HR 1.540; 95% CI 1.018 to 2.330). In epithelioid tumours, median overall survival was 13.2 months with high PDGF-CC and 18.5 months with low PDGF-CC, but this difference was not statistically significant. VEGF and FGFR-1 levels showed no association with survival. The authors concluded that high CD31 was an independent poor prognostic factor. They noted that multiple testing was not corrected for and that tissue processing and observer variation were limitations.

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: Retrospective laboratory study of archived tumour tissue (tissue microarrays stained by immunohistochemistry), with survival analysis
• Who was studied: 326 patients with malignant mesothelioma who had clinical data available, out of 329 sampled. They had surgical resection or biopsy between 1988 and 2014. Histology was 70% epithelioid, 22.8% biphasic, 4.6% sarcomatoid and under 1% desmoplastic. 83% were male and the median age was 67 years.
• Exposure: No asbestos exposure was studied. The factors examined were tumour levels of VEGF, PDGF-CC and FGFR-1 (scored 0 to 300 by the H-score method) and microvessel density measured by CD31 staining using Chalkley's method.
• Main results:
  • High CD31 (score of 5 or more) was found in 31 of 302 samples (10.3%), regardless of histology.
  • Median overall survival was 8.6 months for patients with high CD31 vs 12 months for those with low CD31 (HR 0.48; 95% CI 0.287 to 0.794, p = 0.004).
  • In the multivariate analysis of 269 cases with complete data, CD31 was an independent prognostic factor (HR 1.540; 95% CI 1.018 to 2.330; p = 0.041). Neutrophil-lymphocyte ratio, epithelioid subtype and stage 4 disease were also significant.
  • High PDGF-CC (H-score of 150 or more) was seen in 203 of 310 samples (65%).
  • In epithelioid tumours, median overall survival was 13.2 months with high PDGF-CC vs 18.5 months with low PDGF-CC. The difference was not statistically significant (HR 0.793; 95% CI 0.596 to 1.055; p = 0.110).
  • High VEGF was seen in 219 of 322 samples (68%). VEGF was not associated with survival: 12 months with high VEGF vs 11.5 months with low VEGF (HR 0.975; 95% CI 0.780 to 1.218; p = 0.820).
  • High FGFR-1 was seen in 120 of 300 samples (40%). FGFR-1 showed no survival association: 11.1 months with high FGFR-1 vs 11.8 months with low FGFR-1 (p = 0.984).
  • Of the 31 patients with high CD31, 23 (74%) also had high PDGF-CC and 20 (64%) had high VEGF.
• The authors' conclusion: The authors concluded that high CD31 was an independent poor prognostic factor and that high PDGF-CC was associated with poor survival. In the results, the PDGF-CC finding was reported as a non-significant trend.
• Limitations the authors state:
  • Matching blood (serum) levels of these markers were not available for this cohort.
  • Because the study was exploratory, statistical significance was not corrected for multiple testing.
  • Results may be affected by differences in tissue processing, a lack of reference standards for measuring the proteins, and variation within and between observers.
  • Tumour-rich samples were chosen, so the stromal PDGF-CC findings may not reflect true stromal expression.
  • Response to treatment was not assessed.

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: Biomarker, Malignant Mesothelioma, Pleura, Bevacizumab, Platelet-Derived Growth Factor (PDGF), Fibroblast, Histology, Epithelioid.

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