Combined CA125 and Mesothelin Levels for the Diagnosis of Malignant Mesothelioma

doi:10.1378/chest.07-0013

Chest

Volume 132, Issue 4, October 2007, Pages 1239-1246

https://doi.org/10.1378/chest.07-0013 Get rights and content

Background

Malignant mesothelioma is an aggressive, uniformly fatal tumor. Serum markers would be useful for the diagnosis of this disease. One potential marker is mesothelin. The purpose of this study was to study the mesothelin biomarker in a large patient cohort and to determine if another biomarker, CA125, improves on the sensitivity of mesothelin in the diagnosis of mesothelioma.

Methods

Serum levels of mesothelin and CA125 were determined by commercially available assays in 117 samples obtained at diagnosis from patients with pleural malignant mesothelioma, 33 healthy, asbestos-exposed individuals, 53 patients with asbestos-related lung or pleural disease, and 30 patients presenting with benign pleural effusions. Cross-validated sensitivities were determined, and receiver operator characteristic curves were generated to compare the diagnostic accuracy of the biomarkers.

Results

CA125 had a cross-validated sensitivity of 27% for mesothelioma patients at a specificity of 95% relative to asbestos-exposed individuals, or 50% relative to individuals with benign pleural effusions. Mesothelin had a cross-validated sensitivity of 52% for mesothelioma patients, at a sensitivity of 95% relative to individuals with benign lung or pleural disease. CA125 and mesothelin levels were discordant in > 50% of mesothelioma patients. Combining the data from the two biomarkers using a logistic regression model did not improve sensitivity for detecting mesothelioma above that of the mesothelin marker alone.

Conclusion

Combining mesothelin and CA125 data does not improve the sensitivity of mesothelioma diagnosis over mesothelin alone. The use of both markers potentially increases the number of patients who can be monitored.

Section snippets

Sample Population

We studied sera from four groups of patients: (1) 117 consecutive patients with pleural malignant mesothelioma; the diagnosis of malignant mesothelioma was confirmed with published criteria using cytologic or histopathologic samples¹²; samples were obtained at diagnosis (within 6 weeks before or after pathologically confirmed diagnosis); (2) 53 individuals with benign asbestos-related disease (asbestosis, or asbestosis and pleural plaques): (3) 30 patients with benign pleural effusions

Patient Characteristics

Serum samples were collected from 117 patients with pleural malignant mesothelioma: 35 patients with predominantly epithelioid histology, 15 patients with sarcomatoid, 18 patients with mixed histology, and 49 patients with a diagnosis made on immunocytology grounds.¹² Premorbid serum samples were analyzed from four individuals with mesothelioma developing approximately 1, 2, 5, and 7 years after serum sampling, respectively. Sera were collected from 30 patients with nonmalignant effusions (10

Discussion

Combining markers often improves the diagnostic performance of diagnosis and screening strategies, and the use of independent (or nonredundant) biomarkers can significantly enhance sensitivity.¹⁵ This study shows that combining CA125 and mesothelin serum levels does not improve the accuracy of diagnosis of malignant mesothelioma over the mesothelin marker used alone.

Although CA125 has previously been reported to be elevated in a small number of patients with mesothelioma, particularly those

ACKNOWLEDGMENT

We thank the staff of PathWest Laboratory Medicine, Sir Charles Gairdner Hospital, Hollywood Hospital, and St John of God Pathology for their assistance with this study. We would specifically like to acknowledge the assistance and advice of Nola Olsen, Michael Platen, and Steve Fletcher.

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Malignant Mesothelioma
2018, IASLC Thoracic Oncology
Malignant mesothelioma as an oxidative stress-induced cancer: An update
2015, Free Radical Biology and Medicine
Malignant mesothelioma (MM) is a relatively rare cancer that occurs almost exclusively following respiratory exposure to asbestos in humans. Its pathogenesis is closely associated with iron overload and oxidative stress in mesothelial cells. On fiber exposure, mesothelial cells accumulate fibers simultaneously with iron, which either performs physical scissor function or catalyzes free radical generation, leading to oxidative DNA damage such as strand breaks and base modifications, followed by activation of intracellular signaling pathways. Chrysotile, per se without iron, causes massive hemolysis and further adsorbs hemoglobin. Exposure to indigestible foreign materials also induces chronic inflammation, involving consistent generation of free radicals and subsequent activation of NALP3 inflammasomes in macrophages. All of these contribute to mesothelial carcinogenesis. Genomic alterations most frequently involve homozygous deletion of INK4A/4B, and other pathways such as Hippo and TGF-β pathways are also affected in MM. Recently, analyses of familial MM sorted out BAP1 as a novel responsible tumor suppressor gene, whose function is not fully elucidated. Five-year survival of mesothelioma is still ~8%, and this cancer is increasing worldwide. Connective tissue growth factor, a secretory protein creating a vicious cycle mediated by β-catenin, has been recognized as a hopeful target for therapy, especially in sarcomatoid subtype. Recent research outcomes related to microRNAs and cancer stem cells also offer additional novel targets for the treatment of MM. Iron reduction as chemoprevention of mesothelioma is helpful at least in an animal preclinical study. Integrated approaches to fiber-induced oxidative stress would be necessary to overcome this currently fatal disease.
Does CA125 binding to mesothelin impact the detection of malignant mesothelioma?
2013, Lung Cancer
Citation Excerpt :
Multivariate analysis demonstrated that mesothelin concentrations were an independent prognostic indicator (Table 2), whilst overlapping prognostic information was supplied by the CA125 and bound mesothelin–CA125 data (Table 2). Mesothelin levels are useful in MM diagnosis but because CA125 can bind to mesothelin, and because both of these molecules are often elevated in the serum of MM patients [7], it was crucial to determine if this binding had any potential effect on mesothelin levels in patient samples. In this study we show that binding is only observed in patients with relatively high CA125 and mesothelin levels and that disruption of this binding with the chelating agent DTPA and the anionic surfactant SDS did not alter the amount of mesothelin detected in clinical samples.
The biomarker mesothelin is a useful diagnostic tool in malignant mesothelioma (MM) patients. It has high specificity but a sensitivity of only 50%. As mesothelin binds CA125, and as CA125 is often elevated in MM, we asked whether this binding affected measurable mesothelin levels in a relevant clinical setting. Mesothelin and CA125 concentrations were measured in the serum of 41 patients with MM. An assay was developed to detect mesothelin bound to CA125. Mesothelin was demonstrated to be bound by CA125 in 9 of 41 MM patients. This binding could be broken by the addition of sodium dodecyl sulphate and diethylenetriaminepenta acetic acid (DTPA) to the samples, however this did not lead to any change in the mesothelin level measured. We therefore conclude that binding of mesothelin to CA125 does not alter the measurement of mesothelin for the detection of MM.
Peritoneal Mesothelioma. Current Status and Future Directions
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A phase ii study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma
2012, Journal of Thoracic Oncology
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In a subset of patients, samples were taken more frequently. Serum mesothelin was measured by enzyme-linked immunosorbant assay (ELISA; Fujirebio, Malvern, PA) as previously described.24 Serum VEGF-A, VEGF-C, VEGFR2, VEGFR3, c-kit, and interleukin-8 (IL-8) concentrations were determined using ELISA (R&D Systems, Minneapolis, MN) according to the manufacturer's instructions.
There is no accepted second-line therapy for patients with advanced malignant pleural mesothelioma (MPM), whose disease has progressed after first-line chemotherapy. The multitargeted tyrosine kinase inhibitor sunitinib malate targets several pathways overexpressed in mesothelioma. This phase II study assessed objective response to sunitinib and correlative biomarkers in patients with progressive pretreated MPM.
Eligible patients had confirmed MPM, radiological progression after chemotherapy, Eastern Cooperative Oncology Group performance status 0 to 1, and measurable disease. Patients received oral sunitinib 50 mg daily for 28 of every 42 days. The primary endpoint was objective radiological response. Patients without prior pleurodesis had fluorodeoxyglucose positron emission tomographic response assessed by total glycolytic volume criteria. Correlative biomarkers included serum mesothelin, vascular endothelial growth factor (VEGF)-A, VEGF-C, interleukin-8, sVEGFR-2, sVEGFR-3, and s-kit.
Fifty-three patients received sunitinib between July 2006 and December 2009; 51 were assessable for response. Patients received a median of two cycles (range, 1–12); 40% required dose reduction. Fatigue was the most prominent toxicity. Six patients (12%) had a confirmed radiological partial response, 34 (65%) had stable disease, and 11 (22%) had progressive disease as best response. Six of 20 patients had a decrease in fluorodeoxyglucose positron emission tomographic total glycolytic volume of 15% or more. Median overall survival was 6.1 months, and median time to progression was 3.5 months. Correlative biomarkers did not predict treatment response.
Sunitinib has activity in a subset of patients with pretreated MPM. Consideration should be given to different treatment schedules and examination of other biomarkers for further study of sunitinib in MPM.
Clinical utility of diagnostic biomarkers in malignant pleural mesothelioma: a systematic review and meta-analysis
2021, European Respiratory Review

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This work was performed at the National Research Centre for Asbestos Related Diseases, Western Australian Institute of Medical Research, University of Western Australia.

This work was supported in part by research grants from the National Health and Medical Council of Australia and the Insurance Commission of Western Australia, and in part by Fujirebio Diagnostic Incorporated, Malvern, PA.

Dr. Creaney and Dr. Robinson have received consultancy fees from Fujirebio Diagnostic Incorporated. The remaining authors have no conflicts of interest to disclose.

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ORIGINAL RESEARCHNEOPLASTIC DISEASESCombined CA125 and Mesothelin Levels for the Diagnosis of Malignant Mesothelioma

Background

Methods

Results

Conclusion

Section snippets

Sample Population

Patient Characteristics

Discussion

ACKNOWLEDGMENT

Lancet

J Biol Chem

Lancet

Hematol Oncol Clin North Am

Gynecol Oncol

Prostate cancer: epidemiology, screening, and biomarkers

Rev Urol

ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer

J Clin Oncol

Biomolecular markers of breast cancer

Front Biosci

CA 125: the past and the future

Int J Biol Markers

Tissue distribution of a coelomic-epithelium-related antigen recognized by the monoclonal antibody OC125

Int J Gynecol Pathol