Fibulin-3 as a Blood and Effusion Biomarker for Pleural Mesothelioma

Abstract

BACKGROUND New biomarkers are needed to detect pleural mesothelioma at an earlier stage and to individualize treatment strategies. We investigated whether fibulin-3 in plasma and pleural effusions could meet sensitivity and specificity criteria for a robust biomarker. METHODS We measured fibulin-3 levels in plasma (from 92 patients with mesothelioma, 136 asbestos-exposed persons without cancer, 93 patients with effusions not due to mesothelioma, and 43 healthy controls), effusions (from 74 patients with mesothelioma, 39 with benign effusions, and 54 with malignant effusions not due to mesothelioma), or both. A blinded validation was subsequently performed. Tumor tissue was examined for fibulin-3 by immunohistochemical analysis, and levels of fibulin-3 in plasma and effusions were measured with an enzyme-linked immunosorbent assay. RESULTS Plasma fibulin-3 levels did not vary according to age, sex, duration of asbestos exposure, or degree of radiographic changes and were significantly higher in patients with pleural mesothelioma (105±7 ng per milliliter in the Detroit cohort and 113±8 ng per milliliter in the New York cohort) than in asbestos-exposed persons without mesothelioma (14±1 ng per milliliter and 24±1 ng per milliliter, respectively; P<0.001). Effusion fibulin-3 levels were significantly higher in patients with pleural mesothelioma (694±37 ng per milliliter in the Detroit cohort and 636±92 ng per milliliter in the New York cohort) than in patients with effusions not due to mesothelioma (212±25 and 151±23 ng per milliliter, respectively; P<0.001). Fibulin-3 preferentially stained tumor cells in 26 of 26 samples. In an overall comparison of patients with and those without mesothelioma, the receiver-operating-characteristic curve for plasma fibulin-3 levels had a sensitivity of 96.7% and a specificity of 95.5% at a cutoff value of 52.8 ng of fibulin-3 per milliliter. In a comparison of patients with early-stage mesothelioma with asbestos-exposed persons, the sensitivity was 100% and the specificity was 94.1% at a cutoff value of 46.0 ng of fibulin-3 per milliliter. Blinded validation revealed an area under the curve of 0.87 for plasma specimens from 96 asbestos-exposed persons as compared with 48 patients with mesothelioma. CONCLUSIONS Plasma fibulin-3 levels can distinguish healthy persons with exposure to asbestos from patients with mesothelioma. In conjunction with effusion fibulin-3 levels, plasma fibulin-3 levels can further differentiate mesothelioma effusions from other malignant and benign effusions. (Funded by the Early Detection Research Network, National Institutes of Health, and others.)

Role of fibulin-3 in lung cancer: In vivo and in vitro analyses

“…The results indicate that upregulated expression of fibulin-3 can be used as a therapeutic strategy for NSCLC. In addition, levels of fibulin-3 in plasma and effusions may aid in determining the diagnosis and prognosis of pleural mesothelioma (23). Our results were lacking healthy controls, thus we could not conclude that fibulin-3 is a marker for lung cancer.…”

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.…”

Overexpression of fibulin-4 is associated with tumor progression and poor prognosis in patients with cervical carcinoma

“…Fibulin-3 and fibulin-4 may play pathogenic roles in osteoarthritis (32,43). The plasma fibulin-3 and fibulin-1 levels were found to be elevated in patients with mesothelioma and breast carcinoma, respectively (44,45). Novel specific biomarkers can help detect diseases at an earlier stage and tailor treatment strategies for individualized management.…”