Elevated PDGFRB gene copy number gain is prognostic for improved survival outcomes in resected malignant pleural mesothelioma

Our plain-English summary of Elevated PDGFRB gene copy number gain is prognostic for improved survival outcomes in resected malignant pleural mesothelioma, by A.S. Tsao, N. Harun, J. Fujimoto, et al (Annals of Diagnostic Pathology, 2014).

The study

• Authors: A.S. Tsao, N. Harun, J. Fujimoto, V. Devito, J.J. Lee, E. Kuhn, R. Mehran, D. Rice, C. Moran, W.K. Hong, L. Shen, M. Suraokar, I. Wistuba
• Journal: Annals of Diagnostic Pathology
• Published: 2014;18(3):140-5
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

PDGF/PDGFR pathway has been implicated in malignant pleural mesothelioma (MPM) carcinogenesis, and evidence suggests autocrine mechanisms of proliferation. We sought to evaluate the incidence of PDGFRB gene copy number gain (CNG) by fluorescence in situ hybridization and PDGFR pathway protein expression by immunohistochemistry (IHC) and correlate it to patient clinical outcome. Eighty-eight archived tumor blocks from resected MPM with full clinical information were used to perform IHC biomarkers (PDGFRα, PDGFRβ, p-PDGFRβ) and fluorescence in situ hybridization analysis of PDGFRB gene CNG. Spearman rank correlation, Wilcoxon rank-sum test, Kruskal-Wallis test, BLiP plots, and Kaplan-Meier method were used to analyze the biomarkers and correlation to clinical outcome. Several correlations between the IHC biomarkers were seen; however, none correlated to clinically relevant patient demographics or histology. In the CNG analysis, PDGFRB gene CNG in >10% of tumor cells had lower cytoplasmic p-PDGFRβ (P=.029), while PDGFRB gene CNG in >40% of tumor cells had a higher cytoplasmic PDGFRβ (P=.04). PDGFRB gene CNG status did not associate with patient demographics or tumor characteristics. PDGFR pathway IHC biomarkers did not associate with survival outcomes. However, patients with PDGFRB CNG >40% of tumor cells had improved relapse-free survival (HR 0.25 [95% CI 0.09-0.72], P=.0096) and improved overall survival (HR 0.32 [95% CI 0.11-0.89], P=.029). PDGFRB CNG >40% of MPM tumor cells is a potential prognostic biomarker for surgery and may identify a unique population of mesothelioma patients. Future validation of this biomarker in prospective trials is needed. From a retrospective review of archived tissue specimens from patients with resected malignant pleural mesothelioma tumors, we show that patients with PDGFRB CNG >40% of tumor cells had improved relapse-free survival (HR 0.25 [95% CI 0.09-0.72], P=.0096) and improved overall survival (HR 0.32 [95% CI 0.11-0.89], P=.029). PDGFRB CNG >40% of MPM tumor cells is a potential prognostic biomarker for surgery and may identify a unique population of mesothelioma patients.

Copyright © 2014 Elsevier Inc. All rights reserved.

In plain English

This retrospective study examined archived tumor tissue from 88 surgically treated malignant pleural mesothelioma patients at M.D. Anderson Cancer Center, from 1986 to 2006. The authors measured three PDGFR pathway proteins and used a gene test (FISH) for extra PDGFRB copies. They compared results with overall survival and relapse-free survival, where death from any cause also counted as an event and residual disease counted as relapse at surgery. The gene test was completed in 61 patients. Five epithelioid and one sarcomatoid patient had at least four PDGFRB copies per cell in more than 40% of tumor cells. Compared with patients below that level, they had better relapse-free survival (HR 0.25, 95% CI 0.09 to 0.72) and overall survival (HR 0.32, 95% CI 0.11 to 0.89). The protein measures were not linked to survival. Of all patients, 66% had known asbestos exposure; those without it had better unadjusted relapse-free survival (HR 0.58, 95% CI 0.36 to 0.94). The authors called the gene gain a potential prognostic marker needing prospective validation. They cited the small sample, 20-year span and varied treatments.

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 analysis of archived surgical tumor tissue (laboratory biomarker study linked to clinical outcomes)
• Who was studied: 88 archived tumor blocks from patients with surgically resected malignant pleural mesothelioma (extrapleural pneumonectomy, pleurectomy/decortication, or debulking), from the M.D. Anderson Cancer Center Thoracic Tissue Bank, Houston, 1986 to 2006. The PDGFRB gene test was completed in 61 patients.
• Exposure: The study did not measure asbestos exposure. It studied tumor biomarkers: PDGFRB gene copy number gain and PDGFR pathway protein expression. Asbestos exposure was recorded only as a patient characteristic (66% known asbestos exposure). No fiber types or doses were reported.
• Main results:
  • Definition used: relapse-free survival ran from surgery to relapse, death from any cause, or last contact. Patients with residual disease were counted as having relapsed on the surgery date.
  • Definition used: PDGFRB copy number gain meant at least four gene copies per cell, assessed at two cutoffs, in more than 10% of cells and in more than 40% of cells.
  • The PDGFRB gene copy number test was completed for 61 patients.
  • Five epithelioid patients and one sarcomatoid patient had PDGFRB gene copy number gain (at least four copies) in more than 40% of tumor cells.
  • Patients with PDGFRB gain in more than 40% of cells had improved relapse-free survival compared with patients below 40%: HR 0.25 (95% CI 0.09 to 0.72), P = .0096.
  • After adjusting for gender, known asbestos exposure, EPP and adjuvant chemotherapy, patients with PDGFRB gain in more than 40% of cells still had improved relapse-free survival: HR 0.27 (95% CI 0.09 to 0.80), P = .018.
  • PDGFRB gain in more than 40% of cells was associated with improved overall survival: HR 0.32 (95% CI 0.11 to 0.89), P = .029. In the multi-covariate analysis the HR was 0.29, P = .02.
  • The PDGFR pathway protein (immunohistochemistry) biomarkers were not associated with survival outcomes.
  • In univariate analysis of relapse-free survival, patients with no known asbestos exposure had better outcomes: HR 0.58 (95% CI 0.36 to 0.94), P = .027.
  • Patients with no known asbestos exposure had higher levels of cytoplasmic PDGFR-alpha protein (P = .029).
  • In the multi-covariate overall survival model, biphasic histology (HR 2.74, 95% CI 1.41 to 5.33) and sarcomatoid histology (HR 2.83, 95% CI 1.19 to 6.68) had lower median overall survival than epithelioid histology.
• The authors' conclusion: The authors concluded that PDGFRB copy number gain in more than 40% of tumor cells is a potential prognostic biomarker in surgically resected malignant pleural mesothelioma, and that it needs validation in prospective trials.
• Limitations the authors state:
  • The analysis was retrospective, spanned 20 years, and included a heterogeneous group of patients with varied treatments.
  • The sample size was small and the tissue had been archived over a long period.
  • Later treatments, including systemic therapy, were inconsistent and could have affected the survival results.

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, Platelet-Derived Growth Factor (PDGF), Carcinogenesis, Fluorescence In Situ Hybridization (FISH), Immunohistochemistry, Biomarker, Histology, Overall Survival.

Related studies

• Gene expression profiling and gene copy-number changes in malignant mesothelioma cell lines — C. Zanazzi, R. Hersmus, et al. (2007)
• Genomic copy number alterations in 33 malignant peritoneal mesothelioma analyzed by comparative genomic hybridization array — P. Chirac, D. Maillet, et al. (2016)
• DNA copy number changes in familial malignant mesothelioma — V. Ascoli, Y. Aalto, et al. (2001)
• Copy number gains on 5p15, 6p11-q11, 7p12, and 8q24 are rare in sputum cells of individuals at high risk of lung cancer — E. Kettunen, K. Salmenkivi, et al. (2006)
• DNA copy number gains in malignant pleural mesothelioma — M. Furukawa, S. Toyooka, et al. (2015)
• High tumor cell platelet-derived growth factor receptor beta expression is associated with shorter survival in malignant pleural epithelioid mesothelioma — H. Ollila, J. Paajanen, et al. (2021)

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