Improving a Plasma Biomarker Panel for Early Detection of Pancreatic Ductal Adenocarcinoma with Aminopeptidase N (ANPEP) and Polymeric Immunoglobulin Receptor (PIGR)

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is typically detected too late for useful therapeutic interventions; hence, we sought blood biomarkers to detect early-stage disease. EXPERIMENTAL DESIGN: Using mass spectrometry and ELISA on plasma pools from the University of Pennsylvania (Penn) and the Mayo Clinic (Mayo), we identified aminopeptidase N (ANPEP) and polymeric immunoglobulin receptor (PIGR) as increased in early-stage (stage I/II) PDAC plasma compared with controls. We tested ANPEP and PIGR, along with prior data for thrombospondin 2 (THBS2) and carbohydrate antigen 19-9 (CA19-9), in retrospective phase II studies using separate cohorts of PDAC plasmas at different stages versus healthy or nonmalignant disease controls (DC) from Penn (n = 135) and Mayo (n = 537). RESULTS: Comparing healthy controls with stage I/II PDAC, we obtained area under the receiver-operating characteristic curves (AUC) of 0.78 [95% confidence interval (CI), 0.68-0.86]/0.80 (95% CI, 0.74-0.85; ANPEP) and 0.81 (95% CI, 0.70-0.88)/0.86 (95% CI, 0.82-0.90; PIGR) for the Penn/Mayo phase II studies, respectively. In multivariable models, CA19-9/THBS2/ANPEP, CA19-9/THBS2/PIGR, and CA19-9/THBS2/ANPEP/PIGR elicited AUC of 0.94 to 0.96 for Penn and 0.97 for Mayo. Notably, the four-marker panel elicited AUC of 0.87 for the Mayo stage I/II versus DC and 0.91 for stages I to IV versus DC. At a specificity of 95%, a plasma biomarker panel composed of CA19-9 (≥35 U/mL), THBS2 (≥42 ng/mL), ANPEP (≥2,995 ng/mL), and PIGR (≥1,800 ng/mL) yielded a sensitivity of 91.9% for PDAC stages I to IV and 87.5% for PDAC stage I/II. CONCLUSIONS: Adding ANPEP and PIGR to a plasma biomarker panel of CA19-9 and THBS2 enhances the detection of early-stage PDAC when comparing cancer versus healthy or nonmalignant DC. Given the concordance of our data in two retrospective phase II studies, assessments in prediagnostic cases are warranted.