Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus

• Published in: Clinical cancer research Vol. 22; no. 7; pp. 1734 - 1743
• Main Authors: Jenkinson, Claire, Elliott, Victoria L., Evans, Anthony, Oldfield, Lucy, Jenkins, Rosalind E., O'Brien, Darragh P., Apostolidou, Sophia, Gentry-Maharaj, Aleksandra, Fourkala, Evangelia-O, Jacobs, Ian J., Menon, Usha, Cox, Trevor, Campbell, Fiona, Pereira, Stephen P., Tuveson, David A., Park, B. Kevin, Greenhalf, William, Sutton, Robert, Timms, John F., Neoptolemos, John P., Costello, Eithne
• Format: Journal Article
• Language: English
• Published: United States 01.04.2016
• Subjects: Aged; Animals; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal - blood; Carcinoma, Pancreatic Ductal - complications; Carcinoma, Pancreatic Ductal - diagnosis; Case-Control Studies; Diabetes Mellitus, Type 2 - complications; Disease Models, Animal; Early Detection of Cancer; Female; Humans; Male; Mice; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms - blood; Pancreatic Neoplasms - complications; Pancreatic Neoplasms - diagnosis; Pancreatic Neoplasms - mortality; Patient Outcome Assessment; Platelet Count; Proteomics - methods; Reproducibility of Results; Thrombospondin 1 - blood; Time Factors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-15-0879

Purpose: Identification of serum biomarkers enabling earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) could improve outcome. Serum protein profiles in patients with preclinical disease and at diagnosis were investigated. Experimental Design: Serum from cases up to 4 years prior to PDAC diagnosis and controls (UKCTOCS, n = 174) were studied, alongside samples from patients diagnosed with PDAC, chronic pancreatitis, benign biliary disease, type 2 diabetes mellitus, and healthy subjects (n = 298). Isobaric tags for relative and absolute quantification (iTRAQ) enabled comparisons of pooled serum from a test set (n = 150). Validation was undertaken using multiple reaction monitoring (MRM) and/or Western blotting in all 472 human samples and samples from a KPC mouse model. Results: iTRAQ identified thrombospondin-1 (TSP-1) as reduced preclinically and in diagnosed samples. MRM confirmed significant reduction in levels of TSP-1 up to 24 months prior to diagnosis. A combination of TSP-1 and CA19-9 gave an AUC of 0.86, significantly outperforming both markers alone (0.69 and 0.77, respectively; P < 0.01). TSP-1 was also decreased in PDAC patients compared with healthy controls (P < 0.05) and patients with benign biliary obstruction (P < 0.01). Low levels of TSP-1 correlated with poorer survival, preclinically (P < 0.05) and at clinical diagnosis (P < 0.02). In PDAC patients, reduced TSP-1 levels were more frequently observed in those with confirmed diabetes mellitus (P < 0.01). Significantly lower levels were also observed in PDAC patients with diabetes compared with individuals with type 2 diabetes mellitus (P = 0.01). Conclusions: Circulating TSP-1 levels decrease up to 24 months prior to diagnosis of PDAC and significantly enhance the diagnostic performance of CA19-9. The influence of diabetes mellitus on biomarker behavior should be considered in future studies. Clin Cancer Res; 22(7); 1734–43. ©2015 AACR.