Prediagnostic detection of mesothelioma by circulating calretinin and mesothelin - a case-control comparison nested into a prospective cohort of asbestos-exposed workers

Our plain-English summary of Prediagnostic detection of mesothelioma by circulating calretinin and mesothelin - a case-control comparison nested into a prospective cohort of asbestos-exposed workers, by G. Johnen, K. Burek, I. Raiko, et al (Scientific Reports, 2018).

The study

• Authors: G. Johnen, K. Burek, I. Raiko, K. Wichert, B. Pesch, D.G. Weber, M. Lehnert, S. Casjens, O. Hagemeyer, D. Taeger, T. Brüning, MoMar Study Group
• Journal: Scientific Reports
• Published: 2018;8(1):14321
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is strongly associated with a previous asbestos exposure. To improve timely detection of MM in asbestos workers, better screening tools - like minimally-invasive biomarkers - are desirable. Between 2008 and 2018 2,769 patients with benign asbestos-related diseases were recruited to participate in annual screens. Using a nested case-control design the protein markers calretinin and mesothelin were determined by enzyme-linked immunosorbent assays in prediagnostic plasma samples of 34 MM cases as well as 136 matched controls from the cohort. Conditional on a pre-defined specificity of 98% for calretinin and 99% for mesothelin the markers reached individual sensitivities of 31% and 23%, respectively, when including the incident cases with samples taken between one and 15 months before diagnosis. The combination of both markers increased the sensitivity to 46% at 98% specificity. Marker complementation increased with earlier sampling. The marker combination improves the sensitivity of the individual markers, indicating a useful complementation and suggesting that additional markers may further improve the performance. This is the first prospective cohort study to evaluate a detection of MM by calretinin and its combination with mesothelin up to about a year before clinical diagnosis. Whether an earlier diagnosis will result in reduced mortality has yet to be demonstrated.

In plain English

This German study used the MoMar cohort of 2,769 former asbestos workers with benign asbestos-related diseases, recruited from 2008 to 2018 for yearly blood draws. By December 2017, 34 men in the cohort had been diagnosed with malignant mesothelioma. The authors measured two blood proteins, calretinin and mesothelin, in stored samples from 31 of them, taken 1 to 44 months before diagnosis. They compared these with samples from 136 cancer-free men matched by age and sampling time. Median levels of both proteins were higher in cases. The cutoffs were set so that 2% of controls tested positive for calretinin and 1% for mesothelin. Among the 26 cases sampled within 15 months of diagnosis, calretinin flagged 31% and mesothelin 23%. In a best-case calculation, testing calretinin first, then mesothelin in calretinin-negative men, flagged 46% of these cases, with 2% of controls testing positive. None of the three sarcomatoid cases was detected. The authors concluded calretinin can detect mesothelioma up to about a year before diagnosis. They noted few cases as a limitation and called for confirmation in another cohort.

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: Nested case-control comparison within a prospective cohort, using stored blood samples taken before diagnosis
• Who was studied: 2,769 participants of a German Social Accident Insurance surveillance program for asbestos workers, recruited November 2008 to February 2018 at 26 medical centers in Germany. 34 malignant mesothelioma cases were diagnosed by December 2017, all male, and 31 were eligible for analysis. They were matched 1:4 by age and time of blood sampling to 136 cancer-free controls. The article does not report whether the tumors were pleural or peritoneal.
• Exposure: Former asbestos workers with a recognized occupational disease (asbestosis and/or nonmalignant pleural disease caused by asbestos). Fiber types were not reported. Exposure was rated by experts as moderate, high or very high from at-risk occupations, because no fiber measurements or job-exposure matrix were available.
• Main results:
  • Median plasma calretinin was 0.359 ng/ml in the mesothelioma cases and 0.187 ng/ml in the controls (p less than 0.0001).
  • Median plasma mesothelin was 1.349 nM in the mesothelioma cases and 0.963 nM in the controls (p = 0.0043).
  • Across all 31 cases (samples taken 1 to 44 months before diagnosis), at a pre-defined specificity of 98%, calretinin detected 26% of cases and mesothelin 19%.
  • For the 26 cases sampled 1 to 15 months before diagnosis, calretinin detected 31% at 98% specificity and mesothelin 23% at 99% specificity.
  • For the same 1 to 15 month group, a sequential combination of both markers detected 46% of cases at a pre-set specificity of 98%. In this combination, calretinin was tested first and mesothelin was then tested only in calretinin-negative subjects, and the authors describe it as a 'best case' sequential combination.
  • For cases sampled 1 to 6 months before diagnosis (9 cases), the marker combination detected 56%.
  • At 98% specificity, 12 of the 31 eligible cases were detected by at least one marker.
  • None of the 3 sarcomatoid mesotheliomas was detected by either marker, while 5 of the 6 biphasic cases were detected by at least one.
  • Among controls, levels of neither marker were associated with the expert-rated asbestos exposure level (calretinin p = 0.32; mesothelin p = 0.57).
• The authors' conclusion: The authors concluded that calretinin can detect malignant mesothelioma with high specificity in plasma samples taken up to about a year before diagnosis, and that combining it with mesothelin markedly increases its moderate sensitivity. They said the results must be confirmed in an independent cohort, and that any reduction in deaths from earlier detection has yet to be shown.
• Limitations the authors state:
  • The number of mesothelioma cases that arose during follow-up was low.
  • The small number of cases limits conclusions about tumor subtype or tumor location.
  • The shorter time intervals contained few cases, which limits statistical power.
  • Data on duration of exposure and individual fiber-years were lacking.
  • The results need confirmation in an independent cohort with serial samples taken before diagnosis.
  • Whether early detection reduces deaths cannot be assessed until better therapies are available.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Calretinin, Mesothelin, Malignant Mesothelioma, Asbestos Exposure, Biomarker, Cohort Study.

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• Are circulating microRNAs suitable for the early detection of malignant mesothelioma? Results from a nested case-control study — D.G. Weber, A. Brik, et al. (2019)
• Biomarkers for Predicting Malignant Pleural Mesothelioma in a Mexican Population — G. Aguilar-Madrid, B. Pesch, et al. (2018)
• Calretinin as a blood-based biomarker for mesothelioma — G. Johnen, K. Gawrych, et al. (2017)
• Is soluble mesothelin-related protein an upfront predictive marker of pleural mesothelioma? A prospective study on Italian workers exposed to asbestos — R. Filiberti, P. Marroni, et al. (2014)
• Combination of MiR-103a-3p and mesothelin improves the biomarker performance of malignant mesothelioma diagnosis — D.G. Weber, S. Casjens, et al. (2014)

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