October 17, 2012
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Biomarkers detected mesothelioma after asbestos exposure

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A novel blood-based proteomics assay identified malignant pleural mesothelioma in individuals exposed to asbestos, according to study findings published in PloS One.

“In the next 25 years, it is estimated that the diagnosis of [malignant mesothelioma] will increase 5% to 10% each year until 2020 in most industrialized countries, at a cost of $200 billion in the US and nearly $300 billion worldwide,” Rachel M. Ostroff, PhD, clinical research director at SomaLogic in Boulder, Colo., and colleagues wrote. “The interval between asbestos exposure and the development of [malignant mesothelioma] ranges from 25 to 71 years, yet this disease is often fatal within 1 year of diagnosis. The large gap between asbestos exposure and disease lends itself to surveillance in the high-risk population with the goal of detecting early, treatable disease.”

Recent studies have identified that blood-based biomarkers — including mesothelin and its proteolytic products, and osteopontin — could be used for differential diagnosis and monitoring treatment response of malignant mesothelioma.

Mesothelin is reported to have low sensitivity for early disease, but early detection may be improved with serial sampling in a high-risk population. Osteopontin has shown promise for early detection, but serum protein instability has led to variable results.

“Since malignant mesothelioma is a low-incidence disease even in the asbestos-exposed population, a need still exists for a highly specific test for risk surveillance and early detection while avoiding false positive results and unnecessary invasive procedures,” Ostroff and colleagues wrote.

To improve surveillance and detection of malignant mesothelioma in the high-risk population, the researchers conducted multicenter case-control studies in serum from 117 malignant mesothelioma cases and 142 asbestos-exposed control participants.

All malignant mesothelioma cases were pathologically confirmed by cytology and/or resection by an expert in mesothelioma pathology, and consenting patients were eligible for inclusion in the study regardless of exhibited symptoms.

In addition, investigators collected blood samples from most cases before treatment. Control blood was obtained from study participants with a history of asbestos exposure. The control group contained those with pulmonary fibrosis, pulmonary plaques and asbestosis, and it embodied the population most at risk for malignant mesothelioma.

Biomarker discovery, confirmation and validation were performed using Slow Off-rate Modified Aptamer (SOMAmer) proteomic technology from SomaLogic, which simultaneously measures more than 1,000 proteins in unfractionated biologic samples.

Using univariate and multivariate approaches, the researchers observed 64 candidate protein biomarkers and derived a 13-marker random forest classifier with an area under the curve of 0.99 ± 0.01 in training, 0.98 ± 0.04 in independent masked verification, and 0.95 ± 0.04 in masked validation studies. The candidate biomarker panel consisted of both inflammatory and proliferative proteins, processes strongly associated with asbestos-induced malignancy.

Researchers who used the SOMAscan proteomic assay discovered and validated a highly sensitive candidate 13-biomarker panel for the detection of malignant mesothelioma in the asbestos-exposed population, with an accuracy of 92% and detection of 88% of stage I/II disease, according to study results.

“Our data suggest that the candidate markers and classifier described in this series of discovery, verification, and validation studies have the potential to improve [malignant mesothelioma] surveillance and early detection, leading to more effective treatment and the potential for prolonged survival,” Ostroff and colleagues wrote. “The high specificity reduces unnecessary treatment for this rare disease, thus saving cost and reducing patient anxiety. Based on the discoveries reported here, we have initiated further validation studies in high-risk individuals for both screening and diagnosis.”