Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma.
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.).
Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, NY 10016, USA. harvey.pass@med.nyu.edu
Harvey I
HI
Pass
Stephen M
SM
Levin
Michael R
MR
Harbut
Jonathan
J
Melamed
Luis
L
Chiriboga
Jessica
J
Donington
Margaret
M
Huflejt
Michele
M
Carbone
David
D
Chia
Lee
L
Goodglick
Gary E
GE
Goodman
Mark D
MD
Thornquist
Geoffrey
G
Liu
Marc
M
de Perrot
Ming-Sound
MS
Tsao
Chandra
C
Goparaju
D000368:Aged; D001194:Asbestos / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003937:Diagnosis, Differential; D016326:Extracellular Matrix Proteins / Q000097:blood*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008654:Mesothelioma / Q000097:blood / Q000175:diagnosis*; D008875:Middle Aged; D016273:Occupational Exposure; D010996:Pleural Effusion / Q000097:blood / Q000175:diagnosis; D016066:Pleural Effusion, Malignant / Q000097:blood / Q000175:diagnosis; D010997:Pleural Neoplasms / Q000097:blood / Q000175:diagnosis*; D012372:ROC Curve; D012680:Sensitivity and Specificity
D015415:Biomarkers; C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; D001194:Asbestos