Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis

Our plain-English summary of Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis, by M.B. Kirschner, E. Pulford, M.A. Hoda, et al (British Journal of Cancer, 2015).

The study

• Authors: M.B. Kirschner, E. Pulford, M.A. Hoda, A. Rozsas, K. Griggs, Y.Y. Cheng, J.J. Edelman, S.C. Kao, R. Hyland, Y. Dong, V. László, T. Klikovits, M.P. Vallely, M. Grusch, B. Hegedus, B. Dome, W. Klepetko, N. van Zandwijk, S. Klebe, G. Reid
• Journal: British Journal of Cancer
• Published: 2015;113(6):963-9
• Cited by: 65 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Fibulin-3 (FBLN3) was recently presented as a promising novel biomarker for malignant pleural mesothelioma (MPM), warranting independent validation studies.

Methods: ELISA was used to measure cellular and secreted FBLN3 in cell lines, in plasma of xenograft tumour-bearing mice, in plasma from two independent series of MPM and non-MPM patients and in pleural fluid from a third series. Diagnostic and prognostic potential of FBLN3 was assessed by receiver operating characteristics curve analysis and Kaplan-Meier method, respectively.

Results: FBLN3 was expressed in all MPM and benign mesothelial cell lines tested, and a correlation was observed between cellular protein expression and secreted levels. Human FBLN3 was detectable in plasma of tumour-bearing mice, suggesting that MPM cells contribute to levels of circulating FBLN3. Plasma FBLN3 was significantly elevated in MPM patients from the Sydney cohort, but not the Vienna cohort, but the diagnostic accuracy was low (63%, (95% CI: 50.1-76.4) and 56% (95% CI: 41.5-71.0), respectively). Although FBLN3 levels in pleural effusions were not significantly different between cases and controls, FBLN3 levels in pleural effusion fluid were found to be independently associated with prognosis (hazard ratio of 9.92 (95% CI: 2.14-45.93)).

Conclusions: These data confirm the potential prognostic value of pleural effusion FBLN3, but question the diagnostic value of this protein in MPM patients.

In plain English

This study tested whether the protein fibulin-3 could help diagnose malignant pleural mesothelioma or predict survival. It was measured in cell lines, in tumour-bearing mice, in plasma from two patient groups (Sydney: 37 with mesothelioma, 32 without; Vienna: 47 and 24) and in pleural fluid from a third (30 with mesothelioma, 60 without). Fibulin-3 was found in all mesothelioma and benign mesothelial cell lines and in plasma from 5 of 6 mice. Plasma levels were modestly but significantly higher in Sydney mesothelioma patients than controls (16.10 vs 10.92 ng/ml), but not in Vienna. Their diagnostic accuracy in receiver operating characteristic analysis was 63.2% (95% CI 50.1 to 76.4%) and 56.2% (95% CI 41.5 to 71.0%) respectively. Pleural fluid levels did not differ significantly by diagnosis. Among mesothelioma patients, low pleural fluid levels were linked with longer survival, independent of histology, age and gender (hazard ratio 9.92, 95% CI 2.14 to 45.93, at a previously published cut-off). Asbestos exposure was not reported. The authors concluded that pleural fluid fibulin-3 may have prognostic value but questioned its diagnostic value.

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: Laboratory study (cell lines and mouse xenografts) combined with a retrospective analysis of stored patient blood plasma and pleural effusion samples, testing fibulin-3 as a diagnostic and prognostic biomarker
• Who was studied: Human mesothelioma and benign mesothelial cell lines; nude mice with H226 or MSTO tumour xenografts (3 each); Sydney plasma cohort (37 malignant pleural mesothelioma, 32 non-mesothelioma: 27 coronary artery disease, 5 pleural plaques/pleuritis); Vienna plasma cohort (47 mesothelioma, 24 non-mesothelioma including pleural plaques/pleuritis, lung cancer and coronary artery disease); Adelaide pleural effusion cohort (30 mesothelioma from consecutive patients at Flinders Medical Centre, August 2011 to June 2014, and 60 non-mesothelioma)
• Exposure: Individual asbestos exposure was not reported. The study measured fibulin-3 protein levels by ELISA. The authors note that controls were not people with proven asbestos exposure. They assumed that low-level, often unknown asbestos exposure was reflected in their control series, especially the Sydney cardiac patients.
• Main results:
  • Fibulin-3 was detected in all benign mesothelial and all mesothelioma cell lines; the difference in levels between the two groups was not statistically significant (P = 0.093)
  • In tumour-bearing mice, human fibulin-3 was not detectable in serum but was found in plasma from 3 of 3 H226-xenograft mice and 2 of 3 MSTO-xenograft mice
  • Sydney cohort: plasma fibulin-3 was modestly but significantly higher in mesothelioma patients than in patients with pleural plaques or coronary artery disease (16.10 vs 10.92 ng/ml, P = 0.039). Vienna cohort: no significant difference (11.51 vs 11.97 ng/ml, P = 0.897).
  • In receiver operating characteristic curve analysis, overall accuracy of plasma fibulin-3 for correctly classifying mesothelioma was 63.2% (95% CI: 50.1 to 76.4%) in the Sydney cohort and 56.2% (95% CI: 41.5 to 71.0%) in the Vienna cohort
  • At the previously published lower cut-off of 29 ng/ml, plasma fibulin-3 had a sensitivity of 13.5% and a specificity of 96.9% in Sydney, and a sensitivity of 12.7% and a specificity of 87.5% in Vienna
  • Plasma fibulin-3 levels did not differ by histological subtype and were not associated with survival (data not shown)
  • Pleural effusion cohort: mean fibulin-3 in mesothelioma effusions was 628.9 ng/ml, but levels did not differ significantly between mesothelioma patients and patients with other conditions
  • Among mesothelioma patients, low pleural effusion fibulin-3 was significantly associated with longer survival. In multivariate analysis including histological subtype, age and gender, the hazard ratio was 4.03 (95% CI: 1.215 to 13.36) using the group median as cut-off and 9.92 (95% CI: 2.14 to 45.93) using the previously published cut-off.
• The authors' conclusion: The authors concluded that their data further confirm the prognostic value of fibulin-3 in pleural effusion but question its diagnostic value in the plasma of mesothelioma patients, and that prospective validation is needed
• Limitations the authors state:
  • The mouse xenograft experiments used a relatively small number of samples
  • The patient cohorts were relatively small
  • The study was retrospective
  • Using cardiac surgery patients as controls could be a weakness; patients with proven asbestos exposure would be more appropriate controls
  • Small subgroup numbers may explain why clinical prognostic factors (histological subtype, age, gender) showed no correlation with survival

Topics

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

Medical terms in this study, explained in our Lexicon: Fibulin-3, Pleural Mesothelioma, Prognosis, Biomarker, Mesothelial Cells, Pleural Effusion, Hazard Ratio.

Related studies

• Overexpression of fibulin-3 in tumor tissue predicts poor survival of malignant mesothelioma patients from hand-spinning asbestos exposed area in eastern China — Z. Jiang, W. Shen, et al. (2020)
• Fibulin-3 as biomarker of malignant mesothelioma — C. Ledda, R. Caltabiano, et al. (2019)
• Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma — J. Creaney, I.M. Dick, et al. (2014)
• Fibulin-3 immunoexpression in malignant mesothelioma due to fluoro-edenite: a preliminary report — R. Caltabiano, C. Loreto, et al. (2018)
• Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma — H.I. Pass, S.M. Levin, et al. (2012)
• Plasma Fibulin-3 as a Potential Biomarker for Patients with Asbestos-Related Diseases in the Han Population — Z. Jiang, S. Ying, et al. (2017)

Browse more research in British Journal of Cancer, or return to medical research.