A126: Decreased Serum Thrombospondin-1 Levels in Pancreatic Ductal Adenocarcinoma Patients: An Early Indicator of Disease or Diabetes Mellitus Development?

Claire Jenkinson1,2,Victoria Elliott1,2,Anthony Evans1,2,Lucy Oldfield1,2,Rosalind Jenkins3,John Timms4,Darragh O’Brien4,Sophia Apostolidou4,Aleksandra Gentry-aharaj4,Evangelia Fourkala4,Ian Jacobs4,5,Usha Menon4,Trevor Cox1,Fiona Campbell6,Robert Sutton1,2,Stephen Pereira7,David Tuveson8,Kevin Park3,William Greenhalf1,2,John Neoptolemos1,2

1Department of Molecular and Clinical Cancer Medicine, Liverpool, UK,2National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, Liverpool, UK,3MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, Liverpool, UK,4Department of Women’s Cancer, Institute for Women’s Health, London, UK,5Faculty of Medical & Human Sciences, 1.018 Core Technology Facility, Manchester, UK,6Department of Pathology, Liverpool, UK,7Institute for Liver and Digestive Health, London, UK,8Cold Spring Harbor Laboratory, New York, USA

Presenting date: Monday 2 November

Background

Pancreatic ductal adenocarcinoma (PDAC) is almost always detected at an advanced stage when effective treatment options are limited. Late diagnosis, coupled with a poor response to chemotherapy, mean overall survival is poor. Identification of serum biomarkers enabling earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) could improve outcome. Serum protein profiles in patients with pre-clinical disease and at diagnosis were investigated.

Method

Serum from cases up to 4 years prior to diagnosis of PDAC and controls enrolled on the UK Collaborative Trial of Ovarian Cancer Screening (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 MRM and/or western blotting in all 472 human samples.

Results

 

iTRAQ identified thrombospondin-1 (TSP-1) as down-regulated pre-clinically and in diagnosed samples. MRM confirmed significant down-regulation 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 & 0.77 respectively; P<0.01). TSP-1 was also decreased in PDAC patients compared to healthy controls (P<0.05) and patients with benign biliary obstruction (P<0.01). Low levels of TSP-1 correlated with poorer survival, pre-clinically (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 to individuals with type 2 DM (P=0.01).

Conclusion

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 behaviour should be considered in future studies.