Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma

Our plain-English summary of Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma, by J. Creaney, I.M. Dick, T.M. Meniawy, et al (Thorax, 2014).

The study

• Authors: J. Creaney, I.M. Dick, T.M. Meniawy, S.L. Leong, J.S. Leon, Y. Demelker, A. Segal, A.W. Musk, Y.C. Lee, S.J. Skates, A.K. Nowak, B.W. Robinson
• Journal: Thorax
• Published: 2014;69(10):895-902
• Cited by: 110 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Pleural malignant mesothelioma (MM) is a deadly tumour predominantly associated with asbestos exposure. A reliable diagnostic and prognostic marker for MM will significantly enhance clinical care and is an area of intense research. Soluble mesothelin is the most studied and an FDA-approved biomarker for MM. A recent report showed promising results using fibulin-3 as a new diagnostic marker. The aim of this study was to compare the utility of fibulin-3 versus mesothelin, singly or in combination.

Methods: Fibulin-3 and soluble mesothelin were determined by ELISA in the plasma and pleural fluid of 153 patients presenting with a pleural effusion including 82 with MM, 36 with non-MM malignant effusions and 35 with benign effusions. Biomarker concentrations were determined in the plasma of an additional 49 cases with benign asbestos-related disease.

Results: Mesothelin provides better diagnostic accuracy than fibulin-3 for MM whether measured in plasma or pleural effusion: area under the curve (AUC) for plasma was 0.822 (95% CI 0.76 to 0.87) compared with 0.671 (0.61 to 0.73), respectively, and for pleural fluid AUC was 0.815 (0.74 to 0.87) compared with 0.588 (0.51 to 0.67), respectively. Effusion fibulin-3 was an independent significant prognostic factor for survival in MM patients; HR 2.08 (1.14 to 3.82), p=0.017. MM patients with effusion fibulin-3 levels below the median survived significantly longer than those with levels above the median (14.1 vs 7.9 months, p=0.012). Mesothelin and neutrophil to lymphocyte ratio were not significant prognostic markers.

Conclusions: Soluble mesothelin is a superior diagnostic biomarker for MM compared with fibulin-3, whereas fibulin-3 provides superior prognostic information compared with mesothelin.

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In plain English

This Western Australian study compared fibulin-3 and soluble mesothelin as markers for pleural malignant mesothelioma. The authors measured both in plasma and pleural fluid from 82 patients with newly diagnosed pleural mesothelioma, 36 with effusions (fluid around the lung) from other cancers and 35 with benign effusions. Plasma from 49 people with benign asbestos-related disease (asbestosis and/or pleural plaques) was also tested. Mesothelin separated mesothelioma from other patients better than fibulin-3: the area under the curve (a test-accuracy measure) was 0.816 (95% CI 0.755 to 0.867) versus 0.671 (0.606 to 0.732) in plasma, and 0.815 (0.743 to 0.874) versus 0.588 (0.505 to 0.668) in pleural fluid. Fibulin-3 in pleural fluid exceeded its cut-off in 63% of benign effusions; combining the markers in plasma added nothing over mesothelin alone. Mesothelioma patients with pleural fluid fibulin-3 below 467 ng/mL survived 14.1 months as a group (95% CI 10.5 to 17.7), versus 7.9 months (4.9 to 10.9) for those above (p=0.012). Mesothelin did not significantly predict survival. The authors concluded mesothelin was the better diagnostic marker and fibulin-3 the better prognostic one.

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: Diagnostic and prognostic biomarker comparison study using stored samples from a prospective tissue bank. Cases and controls were randomly selected, and laboratory staff were blinded to diagnosis.
• Who was studied: 153 patients presenting with a pleural effusion: 82 with newly diagnosed pleural malignant mesothelioma, 36 with effusions from other cancers and 35 with benign effusions. A further 49 people had benign asbestos-related disease (asbestosis and/or pleural plaques). Samples came from the Australian Mesothelioma Tissue Bank (Sir Charles Gairdner and Hollywood Hospitals, Western Australia) and were collected October 2007 to September 2012.
• Exposure: Not a study of asbestos exposure levels. It measured levels of two biomarkers, fibulin-3 and soluble mesothelin, by ELISA in plasma and pleural fluid.
• Main results:
  • Plasma fibulin-3 at the previously reported threshold detected 22% (18/82) of mesothelioma patients, with 95% (114/120) specificity.
  • Plasma mesothelin at the 2.5 nM threshold detected 56% (46/82) of mesothelioma patients, with 96% (115/120) specificity.
  • In plasma, the area under the curve was 0.816 (0.755 to 0.867) for mesothelin, significantly higher than the 0.671 (95% CI 0.606 to 0.732) for fibulin-3 (p=0.003).
  • Combining fibulin-3 and mesothelin in plasma (area under the curve 0.822, 95% CI 0.762 to 0.872) gave no diagnostic advantage over mesothelin alone. A combination in pleural fluid is not reported.
  • Pleural fluid fibulin-3 did not differ significantly between diagnostic groups, and 63% of benign effusions were above the 346 ng/mL cut-off.
  • In pleural fluid, fibulin-3 at 346 ng/mL had 59% sensitivity and 52% specificity. Its area under the curve for distinguishing mesothelioma from all other patients was 0.588 (0.505 to 0.668).
  • In pleural fluid, mesothelin at 20 nM had 58% sensitivity and 96% specificity, with an area under the curve of 0.815 (0.743 to 0.874).
  • Mesothelioma patients with biphasic or sarcomatoid histology had higher pleural fluid fibulin-3 (median 1331 ng/mL) than those with epithelioid histology (426 ng/mL, p=0.018) or those diagnosed by cytology (298 ng/mL, p=0.002).
  • In mesothelioma patients, pleural fluid fibulin-3 was a significant predictor of survival in multivariable analysis: HR 2.08 (1.14 to 3.82), p=0.017, per log(10) unit increase, with 13 cases missing data. In a model using only variables with complete data, the HR was 2.05 (1.24 to 3.39), p=0.005.
  • As groups, mesothelioma patients with low pleural fluid fibulin-3 (below 467 ng/mL) survived 14.1 months (95% CI 10.5 to 17.7), compared with 7.9 months (95% CI 4.9 to 10.9) for those with high levels (p=0.012).
  • Plasma fibulin-3, plasma mesothelin and pleural fluid mesothelin were not significant predictors of survival in univariable analyses.
• The authors' conclusion: The authors concluded that soluble mesothelin was a superior diagnostic biomarker for mesothelioma compared with fibulin-3, whereas fibulin-3 provided superior prognostic information compared with mesothelin.
• Limitations the authors state:
  • Missing clinical data excluded nearly 16% of cases from the multivariable survival analysis.
  • The EORTC and CALGB prognostic groups were not significant, which the authors attributed possibly to small numbers and missing data.

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: Fibulin-3, Mesothelin, Malignant Mesothelioma, Asbestos Exposure, Biomarker, Pleural Effusion.

Related studies

• Comparison of mesothelin and fibulin-3 in pleural fluid and serum as markers in malignant mesothelioma — J. Creaney, I.M. Dick, et al. (2015)
• Comparison of osteopontin, megakaryocyte potentiating factor, and mesothelin proteins as markers in the serum of patients with malignant mesothelioma — J. Creaney, D. Yeoman, et al. (2008)
• Mesothelin and osteopontin as circulating markers of diffuse malignant peritoneal mesothelioma: A preliminary study — F. Bruno, D. Baratti, et al. (2018)
• Pleural fluid mesothelin as an adjunct to the diagnosis of pleural malignant mesothelioma — J. Creaney, A. Segal, et al. (2014)
• Comparison of the diagnostic accuracy of the MSLN gene products, mesothelin and megakaryocyte potentiating factor, as biomarkers for mesothelioma in pleural effusions and serum — J. Creaney, S. Sneddon, et al. (2013)
• Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma (DIAPHRAGM) study: protocol of a prospective, multicentre, observational study — S. Tsim, C. Kelly, et al. (2016)

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