title: PO-28 - Protein C levels are associated with mortality in patients with advanced cancer.
abstract: BACKGROUND
  In cancer, tumor progression and metastasis are promoted by prohemostatic activity. Protein C (PC) is involved in hemostasis, inflammation and signal transduction, and has a protective effect on the endothelial barrier. In mice, administration of activated PC reduced experimental metastasis. It is unclear whether PC level is associated with mortality in patients with cancer.
  
  
  OBJECTIVE
  To assess the relation between PC level and survival in patients with advanced cancer.
  
  
  METHODS
  A multicenter, randomized, open-label study was performed in 11 countries between May 2006 and August 2008 (INPACT study, van Doormaal et al, JCO 2011). Patients (n=503) with hormone-refractory prostate cancer, non-small cell lung cancer stage IIIB and locally advanced pancreatic cancer were randomized to receive nadroparin or placebo for 6 to 46 weeks following a specific schedule. Patients were followed till death or the end of the study in May 2009. PC activity levels were measured at baseline and categorized in tertiles. The association between PC level and mortality was evaluated with Cox proportional hazard models, adjustments were made by multivariate Cox proportional hazard models.
  
  
  RESULTS
  PC activity could be measured in 479 (95%) patients (tertiles: <97, 97-120 and >120%). Two patients with missing information on type of cancer were excluded. Mean age was 65±10 years; 87 (18%) were female; and 161 patients had lung cancer, 125 pancreatic cancer and 191 prostate cancer. During median follow-up of 10.5 months, 291 (61%) patients died. Median PC activity was 107% (IQR 92-129). There was a clear inverse relation between PC activity and mortality (p for trend=0.036). In the lowest tertile, mortality was 66%, in the middle and high tertile 61% and 56%, respectively. Compared to the highest tertile, the lowest tertile was associated with a HR on mortality of 1.36 (95% CI 1.02-1.80). Adjustment for age, gender and nadroparin use did not affect this association. The association appeared to be strongest in the patients with lung cancer, HR 0.818 (p=0.11) as compared to the patients with prostate cancer, HR 0.972 (p=0.83) and pancreatic cancer, HR 0.950 (p=0.68).
  
  
  CONCLUSIONS
  Lower PC activity is associated with increased mortality in patients with advanced cancer. However, validation of our findings in a larger cohort is necessary. When the association of PC and mortality has been proven to be consistent, we would suggest a trial on suppletion of PC in cancer patients.
authors.affiliation: Dept. of Vascular Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: I T
authors.initials: IT
authors.lastname: Wilts
authors.affiliation: Dept. of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Medical Center.
authors.forename: B A
authors.initials: BA
authors.lastname: Hutten
authors.affiliation: Dept. of Vascular Medicine, Amsterdam Medical Center; Dept. of Plasma Proteins, Sanquin Blood Supply.
authors.forename: J C
authors.initials: JC
authors.lastname: Meijers
authors.affiliation: Center for Experimental and Molecular Medicine, Amsterdam Medical Center, Amsterdam, The Netherlands.
authors.forename: C A
authors.initials: CA
authors.lastname: Spek
authors.affiliation: Center for Experimental and Molecular Medicine, Amsterdam Medical Center, Amsterdam, The Netherlands.
authors.forename: H R
authors.initials: HR
authors.lastname: Büller
authors.affiliation: Dept. of Vascular Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: P W
authors.initials: PW
authors.lastname: Kamphuisen