Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma

Our plain-English summary of Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma, by H.I. Pass, S.M. Levin, M.R. Harbut, et al (The New England Journal of Medicine, 2012).

The study

• Authors: H.I. Pass, S.M. Levin, M.R. Harbut, J. Melamed, L. Chiriboga, J. Donington, M. Huflejt, M. Carbone, D. Chia, L. Goodglick, G.E. Goodman, M.D. Thornquist, G. Liu, M. de Perrot, M.S. Tsao, C. Goparaju
• Journal: The New England Journal of Medicine
• Published: 2012;367(15):1417-27
• Cited by: 219 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: New biomarkers are needed to detect pleural mesothelioma at an earlier stage and to individualize treatment strategies. We investigated whether fibulin-3 in plasma and pleural effusions could meet sensitivity and specificity criteria for a robust biomarker.

Methods: We measured fibulin-3 levels in plasma (from 92 patients with mesothelioma, 136 asbestos-exposed persons without cancer, 93 patients with effusions not due to mesothelioma, and 43 healthy controls), effusions (from 74 patients with mesothelioma, 39 with benign effusions, and 54 with malignant effusions not due to mesothelioma), or both. A blinded validation was subsequently performed. Tumor tissue was examined for fibulin-3 by immunohistochemical analysis, and levels of fibulin-3 in plasma and effusions were measured with an enzyme-linked immunosorbent assay.

Results: Plasma fibulin-3 levels did not vary according to age, sex, duration of asbestos exposure, or degree of radiographic changes and were significantly higher in patients with pleural mesothelioma (105±7 ng per milliliter in the Detroit cohort and 113±8 ng per milliliter in the New York cohort) than in asbestos-exposed persons without mesothelioma (14±1 ng per milliliter and 24±1 ng per milliliter, respectively; P<0.001). Effusion fibulin-3 levels were significantly higher in patients with pleural mesothelioma (694±37 ng per milliliter in the Detroit cohort and 636±92 ng per milliliter in the New York cohort) than in patients with effusions not due to mesothelioma (212±25 and 151±23 ng per milliliter, respectively; P<0.001). Fibulin-3 preferentially stained tumor cells in 26 of 26 samples. In an overall comparison of patients with and those without mesothelioma, the receiver-operating-characteristic curve for plasma fibulin-3 levels had a sensitivity of 96.7% and a specificity of 95.5% at a cutoff value of 52.8 ng of fibulin-3 per milliliter. In a comparison of patients with early-stage mesothelioma with asbestos-exposed persons, the sensitivity was 100% and the specificity was 94.1% at a cutoff value of 46.0 ng of fibulin-3 per milliliter. Blinded validation revealed an area under the curve of 0.87 for plasma specimens from 96 asbestos-exposed persons as compared with 48 patients with mesothelioma.

Conclusions: Plasma fibulin-3 levels can distinguish healthy persons with exposure to asbestos from patients with mesothelioma. In conjunction with effusion fibulin-3 levels, plasma fibulin-3 levels can further differentiate mesothelioma effusions from other malignant and benign effusions. (Funded by the Early Detection Research Network, National Institutes of Health, and others.).

In plain English

This study tested whether fibulin-3, a protein measured in blood plasma and in pleural effusions (fluid around the lungs), could identify pleural mesothelioma. Samples came from Detroit and New York, where 142 patients had mesothelioma: plasma was measured in 92 of them and effusion fluid in 74. The comparison groups were 136 asbestos-exposed people without cancer, people with effusions from other causes, and 43 healthy controls. The authors then tested blinded samples from Toronto and from the CARET trial. Average plasma levels were 105 and 113 ng per milliliter in the two mesothelioma groups, compared with 14 and 24 ng per milliliter in the asbestos-exposed groups. At a cutoff of 52.8 ng per milliliter, the test correctly identified 96.7% of mesothelioma patients and correctly cleared 95.5% of controls. In the blinded Toronto plasma samples, the area under the curve was 0.87. In old CARET serum samples, the test failed to tell the groups apart. Higher effusion levels were associated with later stage and poorer survival after surgery. The authors concluded that plasma fibulin-3 can distinguish asbestos-exposed healthy persons from mesothelioma patients. They stated that their data cannot support its use as an early-detection marker.

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 biomarker study comparing fibulin-3 levels between patient groups, followed by blinded validation on samples from other centers. Tumor tissue was also examined by immunohistochemistry.
• Who was studied: The Detroit cohort (Wayne State University, 1998 through 2005) had 78 patients with mesothelioma. The New York cohort (NYU Langone, 2005 through 2011) had 64 patients with mesothelioma. Plasma was measured from 92 patients with mesothelioma, 136 asbestos-exposed persons without cancer, 93 patients with effusions not due to mesothelioma, and 43 healthy controls. Effusions were measured from 74 patients with mesothelioma, 39 with benign effusions, and 54 with malignant effusions not due to mesothelioma. Blinded validation used two further sample sets: plasma from 48 mesothelioma patients and 96 asbestos-exposed cancer-free persons in Toronto, and serum from 49 asbestos-exposed persons who developed mesothelioma and 96 cancer-free controls in CARET.
• Exposure: Asbestos exposure; no fiber type is specified. The Detroit asbestos-exposed group included foundry workers, pipe fitters, construction workers, brake and boiler workers, people exposed to vermiculite insulation, and others. The New York asbestos-exposed group was 95 steamfitters. The factor measured was the fibulin-3 level in plasma and effusions.
• Main results:
  • Average plasma fibulin-3 was higher in patients with pleural mesothelioma (105±7 ng per milliliter in Detroit, 113±8 in New York) than in asbestos-exposed persons without mesothelioma (14±1 and 24±1 ng per milliliter); P<0.001
  • Comparing all 92 mesothelioma patients with all 290 controls, plasma fibulin-3 had a sensitivity of 96.7% and a specificity of 95.5% at a cutoff of 52.8 ng per milliliter (AUC 0.99).
  • Comparing 28 patients with stage I or II mesothelioma with asbestos-exposed controls, the AUC was 0.99 at a cutoff of 46.0 ng per milliliter, with sensitivity 100% and specificity 94.1%.
  • Plasma fibulin-3 levels were not related to duration of asbestos exposure or radiographic score in the asbestos-exposed groups.
  • Blinded validation with old serum samples from CARET participants failed to discriminate between those with and without malignant pleural mesothelioma (AUC 0.56 and 0.52 in the two laboratories).
  • Blinded validation with Toronto plasma samples gave an AUC of 0.87 for 48 mesothelioma patients versus 96 asbestos-exposed controls. At 100% specificity, sensitivity was 33%.
  • Effusion fibulin-3 distinguished mesothelioma effusions from all other effusions (AUC 0.93).
  • Among patients who had cytoreductive surgery and pathological staging, effusion levels were higher in the 33 patients with stage III or IV disease than in the 21 with stage I or II (765±55 vs 576±67 ng per milliliter, P = 0.04).
  • Among patients with mesothelioma who had cytoreductive surgery, those with effusion fibulin-3 at or above the median (733.4 ng per milliliter) had poorer survival than those below it, with a hazard ratio of 2.70 (95% CI 1.46 to 4.98).
  • Fibulin-3 staining was seen in mesothelioma cells in all 26 tumor specimens examined.
• The authors' conclusion: The authors concluded that plasma fibulin-3 levels can distinguish healthy asbestos-exposed persons from patients with mesothelioma. They also concluded that plasma levels, used together with effusion levels, can help tell mesothelioma effusions apart from other malignant and benign effusions.
• Limitations the authors state:
  • The data cannot support a conclusion that fibulin-3 is an early-detection marker, because there were no prospective, plasma-based longitudinal sample collections.
  • The best cutoff values differed between the two geographic cohorts, so their precision needs further study.
  • Serum may give inaccurate results, and the authors suggest that plasma, not serum, be used.
  • More asbestos-exposed patients with benign effusions need to be tested, which would require a prospective trial.

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, Biomarker, Pleural Mesothelioma, Pleural Effusion, Mesothelioma, Asbestos Exposure.

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• Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma — J. Creaney, I.M. Dick, et al. (2014)
• Fibulin-3 as a biomarker for pleural mesothelioma — H.I. Pass, C. Goparaju (2013)
• Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis — M.B. Kirschner, E. Pulford, et al. (2015)
• 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)

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