Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool

Our plain-English summary of Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool, by R.M. Ostroff, M.R. Mehan, A. Stewart, et al (PloS One, 2012).

The study

• Authors: R.M. Ostroff, M.R. Mehan, A. Stewart, D. Ayers, E.N. Brody, S.A. Williams, S. Levin, B. Black, M. Harbut, M. Carbone, C. Goparaju, H.I. Pass
• Journal: PloS One
• Published: 2012;7(10):e46091
• Cited by: 107 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MM) is an aggressive, asbestos-related pulmonary cancer that is increasing in incidence. Because diagnosis is difficult and the disease is relatively rare, most patients present at a clinically advanced stage where possibility of cure is minimal. To improve surveillance and detection of MM in the high-risk population, we completed a series of clinical studies to develop a noninvasive test for early detection.

Methodology/principal Findings: We conducted multi-center case-control studies in serum from 117 MM cases and 142 asbestos-exposed control individuals. Biomarker discovery, verification, and validation were performed using SOMAmer proteomic technology, which simultaneously measures over 1000 proteins in unfractionated biologic samples. Using univariate and multivariate approaches we discovered 64 candidate protein biomarkers and derived a 13-marker random forest classifier with an AUC of 0.99±0.01 in training, 0.98±0.04 in independent blinded verification and 0.95±0.04 in blinded validation studies. Sensitivity and specificity at our pre-specified decision threshold were 97%/92% in training and 90%/95% in blinded verification. This classifier accuracy was maintained in a second blinded validation set with a sensitivity/specificity of 90%/89% and combined accuracy of 92%. Sensitivity correlated with pathologic stage; 77% of Stage I, 93% of Stage II, 96% of Stage III and 96% of Stage IV cases were detected. An alternative decision threshold in the validation study yielding 98% specificity would still detect 60% of MM cases. In a paired sample set the classifier AUC of 0.99 and 91%/94% sensitivity/specificity was superior to that of mesothelin with an AUC of 0.82 and 66%/88% sensitivity/specificity. The candidate biomarker panel consists of both inflammatory and proliferative proteins, processes strongly associated with asbestos-induced malignancy.

Significance: The SOMAmer biomarker panel discovered and validated in these studies provides a solid foundation for surveillance and diagnosis of MM in those at highest risk for this disease.

In plain English

This study tested whether a blood test measuring many proteins could tell people with malignant pleural mesothelioma apart from asbestos-exposed people without the disease. The authors used stored serum from 117 mesothelioma patients and 142 high-risk controls at four U.S. centers. The controls included insulators and Libby, Montana workers who mined or processed tremolite-contaminated vermiculite. From 64 candidate proteins the authors built a 13-protein classifier. In the final blinded validation set of 38 cases and 62 controls, it detected 89.5% of cases (95% confidence interval 79.7 to 99.2) and correctly classed 88.7% of controls as negative (80.8 to 96.6). Across all sets it detected 10 of 13 Stage I and 25 of 27 Stage II cases. In a paired set of 32 cases and 34 controls, its sensitivity and specificity were 91% and 94%, against 66% and 88% for the blood marker mesothelin. It classified all 6 benign and 24 of 26 other malignant pleural effusion samples as disease, which the authors listed as a limitation. The authors concluded the markers have potential to improve surveillance and early detection.

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: Multi-center case-control diagnostic biomarker study using archived serum samples, with separate training, blinded verification and blinded validation sets
• Who was studied: 117 malignant pleural mesothelioma (MM) cases and 142 high-risk controls, 94% of whom had documented asbestos exposure. Samples came from four U.S. institutions: New York University, Mount Sinai Medical Center, the Center for Asbestos Related Diseases in Libby, Montana, and Karmanos Cancer Institute. Cases were collected 1996 to 2005 (Karmanos) and 2005 to 2011 (NYU). Controls included people with asbestosis, pulmonary fibrosis and pulmonary plaques. The samples were split into training (60 cases, 60 controls), verification (19 cases, 20 controls) and validation (38 cases, 62 controls) sets.
• Exposure: Asbestos exposure in the control groups. At Karmanos it covered various occupations, such as foundry workers, pipe fitters, brake work and boiler repair. The Mount Sinai group were active and retired insulators. The Libby group mined or processed tremolite-contaminated vermiculite. No exposure doses were given. The test studied was a 13-protein serum classifier.
• Main results:
  • Analysis of the training set produced 64 candidate protein biomarkers, from which a 13-protein random forest classifier was built
  • Sensitivity and specificity were 97% and 92% in training and 90% and 95% in blinded verification
  • In the blinded validation set, sensitivity was 89.5% (95% CI 79.7 to 99.2), specificity 88.7% (80.8 to 96.6) and accuracy 89.0% (82.9 to 95.1)
  • For all sets combined, sensitivity was 93.2% (95% CI 88.6 to 97.7), specificity 90.8% (86.1 to 95.6) and accuracy 91.9% (88.6 to 95.2)
  • Detection varied by stage: 77% of Stage I (10/13), 93% of Stage II (25/27), 96% of Stage III (47/49) and 96% of Stage IV (25/26) MM cases were detected
  • Sensitivity for local disease (Stages I and II combined) was 88%
  • All 6 benign pleural effusion samples and 24 of 26 non-mesothelioma malignant pleural effusion samples were classified as disease
  • In a paired sample set of 32 MM cases and 34 asbestos-exposed controls, mesothelin had sensitivity and specificity of 66% and 88%, compared with 91% and 94% for the classifier
  • In the validation study, an alternative decision threshold giving 98% specificity would still detect 60% of MM cases
  • Of 10 patients who received neoadjuvant therapy before the blood draw, 8 were correctly identified as MM
• The authors' conclusion: The authors concluded that the candidate markers and classifier have the potential to improve surveillance and early detection of MM. They reported that they had begun further validation studies.
• Limitations the authors state:
  • The classifier did not discriminate MM from other conditions in patients with pleural effusion
  • Because most MM cases present with pleural effusion, the test's use for diagnosing symptomatic people with effusion is limited without further refinement
  • The assay changed versions partway through, so the classifier had to be retrained on the same sample set, with seven samples depleted

Mines named here

Asbestos mines this study is about. Each mine's page says who ran it, when it worked, and what it produced.

• Libby vermiculite mine, Montana

All asbestos mines

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, Biomarker, Discovery, Mesothelin.

Related studies

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• A Proteomic Analysis of the Malignant Mesothelioma Secretome Using iTRAQ — J. Creaney, I.M. Dick, et al. (2017)
• Comparative proteomic analysis of malignant pleural mesothelioma evidences an altered expression of nuclear lamin and filament-related proteins — L. Giusti, Y. Da Valle, et al. (2014)
• Chest ultrasonography in health surveillance of asbestos related pleural disease — S. Scarlata, P. Finamore, et al. (2017)
• Noninvasive detection of early asbestos-related disease of the thorax: algorithmic analysis of radiographic, nuclear, and serologic tests — S.D. Rockoff, A.M. Schwartz (1991)
• Profiling tumor-associated markers for early detection of malignant mesothelioma: an epidemiologic study — M. Amati, M. Tomasetti, et al. (2008)

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