Mesothelioma Biomarkers: A Review Highlighting Contributions from the Early Detection Research Network

Our plain-English summary of Mesothelioma Biomarkers: A Review Highlighting Contributions from the Early Detection Research Network, by H.I. Pass, M. Alimi, M. Carbone, et al (Cancer Epidemiology, Biomarkers & Prevention, 2020).

The study

• Authors: H.I. Pass, M. Alimi, M. Carbone, H. Yang, C.M. Goparaju
• Journal: Cancer Epidemiology, Biomarkers & Prevention
• Published: 2020;29(12):2524-2540
• Type of article: Review
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an asbestos-related neoplasm, which can be treated successfully only if correctly diagnosed and treated in early stages. The asbestos-exposed population serves as a high-risk group that could benefit from sensitive and specific blood- or tissue-based biomarkers. This review details the recent work with biomarker development in MPM and the contributions of the NCI Early Detection Research Network Biomarker Developmental Laboratory of NYU Langone Medical Center. The literature of the last 20 years was reviewed to comment on the most promising of the blood- and tissue-based biomarkers. Proteomic, genomic, and epigenomic platforms as well as novel studies such as "breath testing" are covered. Soluble mesothelin-related proteins (SMRP) have been characterized extensively and constitute an FDA-approved biomarker in plasma with diagnostic, monitoring, and prognostic value in MPM. Osteopontin is found to be a valuable prognostic biomarker for MPM, while its utility in diagnosis is slightly lower. Other biomarkers, such as calretinin, fibulin 3, and High-Mobility Group Box 1 (HMGB1), remain under study and need international validation trials with large cohorts of cases and controls to demonstrate any utility. The EDRN has played a key role in the development and testing of MPM biomarkers by enlisting collaborations all over the world. A comprehensive understanding of previously investigated biomarkers and their utility in screening and early diagnosis of MPM will provide guidance for further future research.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

©2020 American Association for Cancer Research.

In plain English

This article was a review, not new research. The authors reviewed 20 years of research on blood and tissue tests (biomarkers) for malignant pleural mesothelioma (MPM), highlighting work by the NCI Early Detection Research Network (EDRN). They reported that soluble mesothelin-related protein (SMRP) remained the only FDA-approved biomarker for diagnosing MPM, with high specificity but low sensitivity. In an EDRN-sponsored analysis of 49 MPM cases and 96 matched controls from a trial of heavily asbestos-exposed US men, SMRP's accuracy (AUC) was 0.604 (95% confidence interval 0.489 to 0.699) for all cases. It was 0.720 (0.562 to 0.853) when measured under one year before diagnosis, which the authors called statistically significant. In patients from the US (83) and Canada (111), a model combining osteopontin with clinical factors improved survival prediction, raising the C-index from 0.718 (0.67 to 0.77) to 0.801 (0.77 to 0.84). Fibulin-3, calretinin and HMGB1 were described as still under study, and fibulin-3 as one of the most controversial markers. The authors called it disappointing that only one validated blood test remained, and named osteopontin the standard for prognosis.

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: narrative review of the literature on mesothelioma biomarkers, highlighting EDRN-funded work
• Who was studied: Published research from the previous 20 years on biomarker development in malignant pleural mesothelioma. The studies described include MPM patients, asbestos-exposed controls and other comparison groups.
• Exposure: Not an exposure study. It reviewed blood- and tissue-based biomarkers, including proteomic, genomic and epigenomic platforms and breath testing, in MPM patients and asbestos-exposed people. No specific fiber types were studied.
• Main results:
  • SMRP was described as the only FDA-approved biomarker for diagnosis of MPM.
  • The authors summarized the evidence on mesothelin as showing high specificity but low sensitivity, which limits its use as a screening test.
  • An EDRN-sponsored international blinded trial measured MESOMARK (SMRP) in 652 asbestos-exposed controls and 165 MPM cases from Australia and North America. The figure with the results was not included in the text.
  • In the EDRN investigation of 49 MPM cases and 96 matched controls from the CARET trial (4,060 heavily asbestos-exposed US men followed for 9-17 years), SMRP had an overall AUC of 0.604 (95% CI 0.489 to 0.699).
  • In the same CARET analysis, SMRP measured less than one year before diagnosis had an AUC of 0.720 (95% CI 0.562 to 0.853), which the authors described as statistically significant evidence that SMRP can be elevated in the year before diagnosis. The AUC was not statistically significant for the 1-2 year interval, where the number of cases was small.
  • In 28 patients treated with tetrathiomolybdate, MESOMARK levels fell immediately after surgery and rose during disease progression in 82.4% of patients with progressive disease.
  • In an EDRN-sponsored blinded prognosis study (83 US MPM patients in a discovery set, 111 Canadian MPM patients in a validation set), higher osteopontin and mesothelin levels were each associated with worse prognosis in both sets.
  • In that study, a combined biomarker and clinical model improved Harrell's C-index from 0.718 (0.67-0.77) for the clinical model to 0.801 (0.77-0.84).
  • In the authors' laboratory's 2012 fibulin-3 study, a plasma fibulin-3 cutoff of 52.8 ng/mL showed 96.7% sensitivity and 95.5% specificity in distinguishing patients with and without MPM. Accuracy was slightly lower in a blinded validation cohort.
  • The authors described fibulin-3 as one of the most controversial MPM markers, because other studies from Europe and Australia did not confirm its diagnostic value.
  • In a SOMAmer proteomics case-control study of 117 MPM patients and 142 asbestos-exposed controls, a 13-marker classifier had sensitivity and specificity above 90% (AUC 0.99).
  • In a study by other researchers cited in the review, blood calretinin identified mesothelioma in an asbestos-exposed population 1-15 months before definitive diagnosis with an AUC of 0.77, improved to 0.85 when combined with serum mesothelin.
• The authors' conclusion: The authors concluded it was disappointing that only one blood-based test (MesoMark) remained validated for MPM despite many studies. They considered fibulin-3 still intriguing, and osteopontin the standard for prognosis because it had been externally validated.
• Limitations the authors state:
  • About the evidence reviewed, not the review itself: the authors said failure to validate biomarkers has several causes. These include a lack of large archives of high-quality, prospectively collected specimens, limited funding for large validation trials, and the need for a more unified approach among investigators.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Biomarker, Pleural Mesothelioma, Neoplasm, Mesothelin, Soluble Mesothelin-Related Peptides (SMRP), Osteopontin, Calretinin.

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