Utility of progranulin and serum leukocyte protease inhibitor as diagnostic and prognostic biomarkers in ovarian cancer

Abstract

Background: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer-related death in females and leading gynecologic cause of cancer-related death. Despite the identification of a number of serum biomarkers, methods to identify early-stage disease and predict prognosis remain scarce. We have evaluated two biologically connected serum biomarkers, serum leukocyte protease inhibitor (SLPI) and progranulin (PGRN).

Methods: Two-hundred frozen plasma samples were acquired from the Mayo Clinic Biospecimen Repository for Ovarian Cancer Research. Samples were obtained from 50 patients with benign conditions, 50 with American Joint Committee on Cancer (AJCC) stage I and II EOC, and 100 with AJCC stage III and IV EOC. Samples were obtained before surgical resection of a mass and were analyzed for absolute levels of SLPI and PGRN using ELISA assays. Receiver-operator characteristic curves were generated for SLPI and PGRN. Median follow-up was 48 months.

Results: Absolute levels of SLPI were significantly elevated in patients with EOC compared with benign disease and predicted the presence of EOC (AUC of 0.812; P = 0.04); SLPI remained elevated in the subset of patients with normal CA-125. PGRN levels were not significantly increased in patients with early-stage or late-stage EOC as a whole, but an increase in PGRN levels was associated with decreased overall survival in advanced EOC.

Conclusions: SLPI levels are elevated in EOC, and SLPI shows promise as a diagnostic biomarker for patients with both elevated and normal CA-125 levels. An increase in PGRN is associated with decreased overall survival.

Impact: SLPI is elevated in EOC and warrants investigation in a screening study in women at risk for EOC.

Figure 1

Jit-plots showing the range of plasma concentrations of SLPI (A) and PGRN (B). Absolute levels of SLPI were significantly higher in both early stage and advanced stage EOC patients relative to control patients. There was no significant difference in PGRN levels between groups.

Figure 2

Receiver-operator curves for both SLPI (A) and PGRN (B). SLPI demonstrated good predictive ability for EOC, with an area under the curve (AUC) of 0.812 for ovarian cancer patients versus controls; PGRN demonstrated poor predictive ability, with an AUC of 0.535. SLPI retained its ability to predict the presence of EOC in patients with normal (< 35 U/ml) CA-125 levels (C), with an AUC of 0.760.

Figure 3

Smoothing spline showing the nature of association between serum concentration and overall survival across the range of observed values for PGRN.