Elevated levels of cleaved soluble forms of urokinase-type plasminogen activator receptor are associated with poor survival in advanced pancreatic cancer

Abstract

Purpose: Different forms of urokinase plasminogen activator receptor (uPAR) in tissues and plasma are associated with poor prognosis in several types of cancers. This study aimed to determine whether different forms of soluble uPAR (suPAR) in pretreatment plasma samples from patients with advanced pancreatic adenocarcinoma (PDAC) have prognostic potential.

Patients and methods: Plasma samples were collected at diagnosis and before treatment from 344 patients with advanced PDAC who were enrolled in the Danish BIOPAC study from to 2008-2014. The patients were divided into a training cohort (n = 229) and a validation cohort (n = 115). Plasma levels of suPAR were determined using time-resolved fluorescence immunoassays measuring uPAR domain I (uPAR(I)) and total suPAR (intact and cleaved forms: suPAR(I-III+II-III)). Cox proportional hazards models adjusted for suPAR forms, age, performance status, sex, CA19-9, and Charlson comorbidity score were used for univariate and multivariate analyses.

Results: Elevated pretreatment uPAR(I) was an independent predictor of overall survival (hazard ratio [HR] =1.39, 95 % confidence interval (CI) 1.17-1.66, p < 0.05, c-index= 0.70). Comparable results were observed for suPAR(I-III+II-III) (HR=1.48, 1.17-1.88, p < 0.0001, c-index 0.69). These findings were confirmed in the validation cohort, uPAR(I), p < 0.0001, c-index 0.65; suPAR(I-III+II-III), p < 0.0001, c-index 0.65. by using CA19-9 as an independent prognostic marker.

Conclusions: Elevated plasma levels of uPAR(I) and suPAR(I-III+II-III) were associated with poor survival in patients with advanced PDAC independent of CA19-9 levels. These biomarkers have a potential prognostic value in this population.

Keywords: Pancreatic cancer; Plasminogen activation system; Prognostic biomarker; SuPAR.