Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases

Selina Tsim,Holly Hall,Matthew Neilson,Anthony J Chalmers,Angela Wright,Caroline Kelly,Dipak Mukherjee,Ioannis Psallidas,Alina Ionescu,Douglas Grieve,David P Breen,John Edwards,Carol Mccormick,Kevin G Blyth,Elankumaran Paramasivam,Samantha Hinsley,Cyrus Daneshvar,Davand Sharma,Crispin Miller,Rachel Ostroff,Mohammed Munavvar,Leigh Alexander,Mahendran Chetty,Matthew Evison,Jayne Holme,Rakesh Panchal,Ann Shaw,Seamus Grundy,Alan Hart-Thomas,R Naseer ,Fiona T Thomson ,G Cox ,Euan Cameron ,Laura E Crotty Alexander ,Stephen W Clark ,Nick Maskell

doi:10.1016/j.jtho.2021.05.018

Abstract

IntroductionMalignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory. MethodsA multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure. ResultsA total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557–0.664], p = 0.0015) and 0.516 [0.443–0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume. ConclusionsSOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.

Highlights

Malignant pleural mesothelioma (MPM) is difficult to diagnose
Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification
MPM diagnoses were based on histological features in 129 of 152 (84.9%), radiology and cytology in 10 of 152 (6.6%), radiology in 9 of 152 (5.9%), and postmortem findings in 1 of 152 (0.7%)

Summary

Introduction

Malignant pleural mesothelioma (MPM) is difficult to diagnose. SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory. The diagnosis of MPM is often difficult because the disease presents nonspecifically with a pleural effusion or mass, and tumors are not biopsied in earlystage disease.[1] An accurate blood biomarker would be a considerable clinical advancement but would require high sensitivity and high specificity given the low incidence of MPM in most settings. The secreted glycoprotein fibulin-3 had 96.7% sensitivity at 95.5% specificity for MPM,[2] but subsequent studies have reported conflicting results,[3,4,5,6] leaving uncertainty regarding its value.[7,8] The SOMAscan proteomic assay

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Discussion

Conclusion