title: Improved diagnosis of pancreatic adenocarcinoma using haptoglobin and serum amyloid A in a panel screen.
abstract: BACKGROUND
  Timely, accurate diagnosis of pancreatic adenocarcinoma (PA) is hampered by the lack of effective circulating biomarkers. No single test has emerged that improves upon the commonly used biomarker cancer antigen 19-9 (CA 19-9) to discriminate PA from benign conditions effectively. The goals of this study were to validate two acute-phase proteins, haptoglobin and serum amyloid A (SAA), as biomarkers for PA and determine if the combination of haptoglobin, SAA, and CA 19-9 would improve PA diagnosis over CA 19-9 alone.
  
  
  METHODS
  Levels of haptoglobin, SAA, and CA 19-9 were measured in pretreatment sera from 75 PA patients, 32 patients with chronic pancreatitis, 42 patients with other benign pancreatic disease or biliary stricture, and 150 healthy control subjects by enzyme-linked immunosorbent assay or colorimetric binding assay. Relative levels of haptoglobin or SAA were compared between groups using analysis of variance. The diagnostic accuracy of serum haptoglobin and SAA levels were investigated using receiver operating characteristics (ROC) analysis. Using classification tree analysis, an algorithm was developed that used haptoglobin, SAA, and CA 19-9 in a diagnostic screening panel.
  
  
  RESULTS
  Both haptoglobin and SAA were significantly elevated in sera from PA patients compared to healthy control subjects (p<0.0001) and patients with chronic pancreatitis (p=0.01). Haptoglobin was significantly elevated in sera from PA patients relative to patients with other benign diseases (p=0.0015), whereas SAA fell short of significance in the same comparison (p=0.0508). ROC analysis indicated that haptoglobin [area under the curve (AUC)=0.792] was a better diagnostic marker than SAA (AUC=0.691) over multiple threshold cutoffs. Using specific cutoffs that minimized overall misclassification, haptoglobin yielded a sensitivity of 82.7% and a specificity of 71.1%, and SAA yielded a sensitivity of 34.7% and a specificity of 90.2% when discriminating PA cases from all non-PA controls. In the same sample set, CA 19-9 yielded a sensitivity of 77.3% and a specificity of 91.1%. Combining data from haptoglobin, SAA, and CA 19-9 in a diagnostic screening panel improved the overall accuracy when compared to CA 19-9 alone, yielding a sensitivity of 81.3% and a specificity of 95.5%.
  
  
  CONCLUSIONS
  These data demonstrate that haptoglobin and SAA are useful for discriminating PA from benign conditions as well as healthy controls when used in a diagnostic screening panel. This study supports the use of combined biomarkers for improved accuracy in the diagnosis of PA.
authors.affiliation: Department of Surgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA. matt.firpo@hsc.utah.edu
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Firpo
authors.forename: David Z
authors.initials: DZ
authors.lastname: Gay
authors.forename: Steven R
authors.initials: SR
authors.lastname: Granger
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Scaife
authors.forename: James A
authors.initials: JA
authors.lastname: DiSario
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Boucher
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Mulvihill
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis*; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000097:blood*; D018395:CA-19-9 Antigen / Q000097:blood; D005260:Female; D006242:Haptoglobins / Q000032:analysis*; D006801:Humans; D008297:Male; D010190:Pancreatic Neoplasms / Q000175:diagnosis*; D012372:ROC Curve; D012680:Sensitivity and Specificity; D000685:Serum Amyloid A Protein / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; D018395:CA-19-9 Antigen; D006242:Haptoglobins; D000685:Serum Amyloid A Protein