Pleural mesothelioma (PM) is a rare disease with dismal outcome. Systemic treatment
options include chemotherapy and immunotherapy, but biomarkers for treatment personalization
are missing. The only FDA-approved diagnostic biomarker is the soluble mesothelin-related
protein (SMRP). Krebs von den Lungen-6 (KL-6) is a human mucin 1 (MUC1) glycoprotein,
which has shown diagnostic and prognostic value as a biomarker in other malignancies.
The present study investigated whether KL-6 can serve as a diagnostic and/or prognostic
biomarker in PM.Using a fully-automated chemiluminescence enzyme immunoassay (CLEIA)
for KL-6 and SMRP, pleural effusion samples from 87 consecutive patients with PM and
25 patients with non-malignant pleural disorders were studied. In addition, KL-6 and
SMRP levels were determined in corresponding patient sera, and in an independent validation
cohort (n = 122). MUC1 mRNA and protein expression, and KL-6 levels in cell line supernatants
were investigated in PM primary cell lines in vitro.PM patients had significantly
higher KL-6 levels in pleural effusion than non-malignant controls (AUC 0.78, p <
0.0001). Among PM patients, levels were highest in those with epithelioid or biphasic
histologies. There was a strong positive correlation between pleural effusion levels
of KL-6 and SMRP (p < 0.0001). KL-6 levels in sera similarly associated with diagnosis
of PM, however, to a lesser extent (AUC 0.71, p = 0.008). PM patients with high pleural
effusion KL-6 levels (≥303 IU/mL) had significantly better overall survival (OS) compared
to those with low KL-6 levels (HR 0.51, p = 0.004). Congruently, high tumor cell MUC1
mRNA expression in primary cell lines associated with prolonged corresponding patient
OS (HR 0.35, p = 0.004). These findings were confirmed in an independent validation
cohort.This is the first study demonstrating KL-6 as a potential novel liquid-based
diagnostic and prognostic biomarker in PM.
