Liquid Biopsy in Malignant Pleural Mesothelioma: State of the Art, Pitfalls, and Perspectives

Our plain-English summary of Liquid Biopsy in Malignant Pleural Mesothelioma: State of the Art, Pitfalls, and Perspectives, by I. Cavallari, L. Urso, E. Sharova, et al (Frontiers in Oncology, 2019).

The study

• Authors: I. Cavallari, L. Urso, E. Sharova, G. Pasello, V. Ciminale
• Journal: Frontiers in Oncology
• Published: 2019;9:740
• Type of article: Review
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor linked to asbestos exposure. Although the risk factors for MPM are well-known, the majority of MPM patients are diagnosed at an advanced stage and have a very poor prognosis. Circulating biomarkers for early diagnosis remain to be identified, and the current standard for MPM diagnosis relies on pleural biopsies. Robust non-invasive tests for the screening of asbestos-exposed subjects are therefore an important unmet clinical need. This review provides a critical summary of recent liquid biopsy-based studies aimed at discovering novel blood-based circulating biomarkers for the early diagnosis and prognostic stratification of MPM patients.

In plain English

This article is a review, not a new study. The authors summarized published research on "liquid biopsy" tests, mostly of blood, that might detect malignant pleural mesothelioma early or predict outcome, especially in asbestos-exposed people. They covered proteins such as mesothelin (SMRP), osteopontin, fibulin-3, HMGB1 and VEGF, plus microRNAs, tumor DNA, DNA methylation and circulating tumor cells. In the review's account, a meta-analysis of 16 studies found that SMRP had low accuracy for early diagnosis because of low sensitivity. High SMRP levels were linked with shorter survival in three studies of mesothelioma patients. Fibulin-3 scored an accuracy (AUC) of 0.99 in a first report but 0.87 in a validation group. One study used blood taken a median of 8.9 months before diagnosis, from 17 people later diagnosed with mesothelioma and 34 asbestos-exposed controls. It found 0% sensitivity for three microRNAs at a specificity of 98%. The authors concluded that there is at present no reliable marker for monitoring asbestos-exposed people. They noted that most markers were tested in limited groups of patients with differing laboratory methods, and that they need validation in large prospective studies.

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 published studies on blood-based and other body-fluid (liquid biopsy) biomarkers for malignant pleural mesothelioma
• Who was studied: Published studies comparing malignant pleural mesothelioma (MPM) patients with asbestos-exposed people, people with benign asbestos-related disease, patients with other diseases or cancers, and healthy controls. Group sizes differed from study to study. The review does not say how studies were selected.
• Exposure: Asbestos exposure in general (no fiber types specified), described as the main cause of MPM. The review is about candidate biomarkers rather than about exposure measurement.
• Main results:
  • SMRP (soluble mesothelin): the review reports that a meta-analysis of data from 16 studies found low accuracy for early diagnosis because of low sensitivity.
  • SMRP and outcome: in three prospective studies enrolling 96, 107 and 100 MPM patients, high baseline SMRP levels significantly correlated with shorter survival (as reported by the review).
  • Osteopontin: in a study of 69 asbestos-exposed subjects, 45 smokers and 75 MPM patients, the best cut-off for stage I disease was 62.4 ng/ml, with 84.6% sensitivity and 88.4% specificity. Another study found that serum osteopontin failed to distinguish MPM from pleural metastasis of other carcinomas or from non-tumoral asbestos-related diseases.
  • Fibulin-3: the first report gave an AUC of 0.99 (92 MPM patients, 136 healthy asbestos-exposed controls, 93 patients with other cancers). In a validation cohort of 48 MPM patients and 96 asbestos-exposed controls, the AUC was 0.87, which did not differ from that reported for mesothelin.
  • Acetylated HMGB1: one study of 22 MPM patients and 20 healthy exposed individuals reported an AUC of 1 (100% sensitivity, 100% specificity, cut-off 2 ng/ml). The review notes this was a small number of subjects.
  • MicroRNAs: in plasma taken a median of 8.9 months before MPM diagnosis (17 cases vs 34 asbestos-exposed controls), miR-126-3p, miR-132-3p and miR-103a-3p showed 0% sensitivity at a specificity of 98%. That study's authors concluded these miRNAs are unsuitable for early detection.
  • Circulating tumor DNA: in one study of ten MPM patients, an NF2 mutation was clearly and reproducibly detectable in serum in only one patient (fraction of mutated DNA = 0.8%).
  • Circulating tumor cells: the standard CellSearch technique showed very low diagnostic sensitivity for MPM.
• The authors' conclusion: The authors concluded that there is at present no reliable marker for longitudinal monitoring and risk assessment of asbestos-exposed individuals. In their view, liquid biopsy is still far from replacing tissue biopsy for MPM diagnosis, although it holds promise for following up asbestos-exposed people.
• Limitations the authors state:
  • Most markers were studied in restricted patient cohorts and await validation in large prospective studies.
  • The reviewed studies were highly heterogeneous in their pre-analytical and analytical protocols.
  • Studies of circulating microRNAs face major problems with data normalization (the choice of reference RNA).

Topics

Medical terms in this study, explained in our Lexicon: Liquid Biopsy, Pleural Mesothelioma, State-of-the-Art Defense, Asbestos Exposure, Prognosis, Biomarker.

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• Novel platinum agents and mesenchymal stromal cells for thoracic malignancies: state of the art and future perspectives — F. Petrella, I. Rimoldi, et al. (2018)
• Perspectives on the knowledge of asbestos disease in the United States - what was known, by whom, and when — W.H. Bullock (2020)
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