Early Detection of Malignant Pleural Mesothelioma in Asbestos-Exposed Individuals with a Noninvasive Proteomics-Based Surveillance Tool

Abstract

BackgroundMalignant pleural mesothelioma (MM) is an aggressive, asbestos-related pulmonary cancer that is increasing in incidence. Because diagnosis is difficult and the disease is relatively rare, most patients present at a clinically advanced stage where possibility of cure is minimal. To improve surveillance and detection of MM in the high-risk population, we completed a series of clinical studies to develop a noninvasive test for early detection.Methodology/Principal FindingsWe conducted multi-center case-control studies in serum from 117 MM cases and 142 asbestos-exposed control individuals. Biomarker discovery, verification, and validation were performed using SOMAmer proteomic technology, which simultaneously measures over 1000 proteins in unfractionated biologic samples. Using univariate and multivariate approaches we discovered 64 candidate protein biomarkers and derived a 13-marker random forest classifier with an AUC of 0.99±0.01 in training, 0.98±0.04 in independent blinded verification and 0.95±0.04 in blinded validation studies. Sensitivity and specificity at our pre-specified decision threshold were 97%/92% in training and 90%/95% in blinded verification. This classifier accuracy was maintained in a second blinded validation set with a sensitivity/specificity of 90%/89% and combined accuracy of 92%. Sensitivity correlated with pathologic stage; 77% of Stage I, 93% of Stage II, 96% of Stage III and 96% of Stage IV cases were detected. An alternative decision threshold in the validation study yielding 98% specificity would still detect 60% of MM cases. In a paired sample set the classifier AUC of 0.99 and 91%/94% sensitivity/specificity was superior to that of mesothelin with an AUC of 0.82 and 66%/88% sensitivity/specificity. The candidate biomarker panel consists of both inflammatory and proliferative proteins, processes strongly associated with asbestos-induced malignancy.SignificanceThe SOMAmer biomarker panel discovered and validated in these studies provides a solid foundation for surveillance and diagnosis of MM in those at highest risk for this disease.

Mesothelioma: recent highlights

“…A clinical trial will start in 2017 to validate these findings and to validate other biomarkers discovered by our collaborator Dr. Harvey I. Pass (19,20). The availability of biomarkers to identify asbestos-exposed individuals and mesothelioma patients would represent a major step forward to prevent and treat this deadly cancer.…”

Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic

“…When compared to mesothelin in a paired sample set, the 13-protein classifier AUC of 0.99 and 91%/94% sensitivity/specificity were superior to those of mesothelin, with an AUC of 0.82 and a 66%/88% sensitivity/specificity. The candidate biomarker panel consisted of both inflammatory and proliferative proteins that could be associated with asbestos-induced malignancy [128]. However, there have been no prospective studies on asbestos-exposed cohorts to verify their value for early diagnosis and survival.…”

Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model

“…Malignant pleural mesothelioma (MPM) is an aggressively growing neoplasm, which disseminates into the thoracic cavity and frequency produces a malignant pleural effusion (1,2). MPM is most often caused by asbestos exposure with a long latency period, often exceeding 20 years between the first exposure to asbestos and a diagnosis of the disease (3,4).…”