Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy associated with dismal prognosis. In order to support diagnosis and to risk stratify patients, more reliable biomarkers are urgently needed. Emerging evidence suggests a functional role of transforming growth factor-β (TGF-β) in MPM tumorigenesis, however, its clinical implementation remains unknown.
Pleural effusion samples from 48 consecutively diagnosed MPM patients and 24 patients with non-malignant pleural disease (NMPD) at diagnosis were measured by ELISA for TGF-β and by chemiluminescence enzyme immunoassay for mesothelin (SMRP). In 22 of those MPM and 19 of those NMPD patients, TGF-β and SMRP were also measured in corresponding sera.
Effusion TGF-β levels were significantly higher in MPM patients than in NMPD patients (p < 0.0001), with an AUC of 0.78 (p = 0.0001). Both epithelioid and non-epithelioid MPM patients had significantly higher effusion TGF-β levels than NMPD patients (NMPD vs epithelioid: p < 0.05; NMPD vs non-epithelioid: p < 0.0001) and within the MPM patient cohort elevated effusion TGF-β levels were seen in patients with advanced disease (p < 0.005). Strikingly, patients with high effusion TGF-β levels ( > =14.36ng/mL) had significantly worse overall survival (HR 3.30, p < 0.0005) which was confirmed by a multivariate cox regression model yielding effusion TGF-β and multimodality treatment to be independently prognostic. In contrary, circulating TGF-β was neither diagnostic nor prognostic and did not correlate with matched effusion TGF-β. Of note, effusion SMRP performed similar to effusion TGF-β as diagnostic marker (AUC: 0.71, p = 0.005), but was only elevated in epithelioid tumors and not prognostic in our MPM cohort. However, there was a significant negative correlation between effusion TGF-β and SMRP and by combining both biomarkers we could remarkably increase sensitivity to 93.4%.
Our data is the first evidence showing pleural effusion TGF-β to be a novel highly diagnostic and prognostic biomarker in MPM applicable for epithelioid and non-epithelioid MPM. Those findings may pave the way for future clinical trials targeting TGF-β in MPM and beyond.
Clinical trial identification
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Has not received any funding.
S. Langer: Full / Part-time employment, Employed at Fujirebio Germany, which provided non-financial support in terms of SMRP measurements: Fujirebio Germany GmbH. All other authors have declared no conflicts of interest.