Malignant mesothelioma (MM) is an aggressive cancer of serosal surfaces such as the pleura, peritoneum and rarely the pericardium. It is causally linked to asbestos exposure with a lag time of 15–60 years and has an incidence of approximately 2500 cases/year in the UK [
1]. Diagnosis of MM is challenging as symptoms and early radiographic signs are often non-specific and their significance can be masked by multiple co-morbidities of this normally older patient. Typically, histological features of MM include positive immunohistochemical staining for epithelial membrane antigen, WT1, cytokeratin 5/6 and HBME-1 [
2]. Expression of several proteins detected by immunochemistry have been suggested to correlate with survival such as IL4Rα [
3], c-MET [
4], aquaporin1 [
5], calretinin [
6], and HtrA1 [
7]. The optimal surgical approach is debated and includes palliative support with or without chemotherapy contingent on co-morbidities.
The identification of a robust serological biomarker for mesothelioma could have a significant impact in this disease in helping with early diagnosis, avoiding multiple invasive procedures, providing prognostic and/or predictive information and aid in treatment response assessment. The latter is particularly important, since the response evaluation criteria in sold tumours (RECIST) and the modified RECIST criteria for mesothelioma are associated with significant variability [
8,
9]. Several candidates have shown promise as predictive/prognostic biomarkers such as LDH [
10], C-Reactive Protein (CRP) levels (≥1 mg/dL, predicting a poorer outcome) [
11], neutrophil/lymphocyte ratio [
6], platelet count (>400,000/microL, predicting a poorer outcome) [
12], osteopontin [
13], and fibulin-3 [
14]. However, the most extensively studied is mesothelin, which has been shown to potentially differentiate between mesothelioma and other conditions, both benign and malignant [
2,
15‐
17], and also potentially correlates with response to therapy [
18]. Mesothelin is a 40 kDa membrane-localised protein that along with the 31 kDa megakaryocyte potentiation factor (MPF) are cleavage products of a 69 kDa precursor protein encoded by
MSLN on chromosome 16. Mesothelin is proposed to play a role in cell adhesion as it binds to the cell adhesion molecule Ca125 (Muc16) and forced over-expression of
MSLN in NIH3T3 cells leads to increased adhesion to a plastic substrate. In tissue culture, mesothelin also promotes ERK dependent proliferation [
19], apoptosis resistance, anoikis resistance and invasion [
20]. Mesothelin may therefore be involved in cancer metastasis and its role as a potential therapeutic target is being actively pursued [
21]. It is predominantly expressed in epithelioid subtype mesotheliomas, with little/no expression in sarcomatoid sub-types. MPF and mesothelin isoforms 1 and 3 can be detected as soluble proteins in plasma or serum, which may be detected using a validated commercial dual antibody ELISA platform [
16]. Mesothelin level seems to correlate with MM disease bulk and can potentially predict relapse in patients who had previously resected mesothelioma [
22]. Additionally, several studies have provided some evidence for an association between high mesothelin level and poorer survival [
13,
15,
23]. While the absolute baseline serum mesothelin level has not been reported to predict for treatment response a number of trials have demonstrated that a fall in the mesothelin level with treatment correlates well with radiological response rate and overall survival [
24,
25].
We therefore conducted this exploratory study of serum mesothelin testing in patients with MM in routine clinical practice.