Zaret, Kenneth S.

Abstract Purpose: The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded Early Detection Research Network–defined phase II biomarker bakeoff study of blood-based biomarker panels. The aims were to evaluate panel performance, to compare the panels’ performance with that of cancer antigen 19-9 (CA19-9) alone, and to evaluate the performance of new combinations of the individual biomarkers. Experimental Design: Ten biomarkers representing eight biomarker panels and CA19-9 were evaluated using plasma, serum, and germline DNA from 140 stage I to IV pancreatic ductal adenocarcinoma (PDAC) cases and 140 controls from three tertiary care institutions, with controls frequency matched to cases on age and sex. LASSO regression was employed to explore new biomarker combinations. The primary metric was area under the receiver operating characteristic curve (AUC). Results: The study population was 51% female, with median age 67.3 (minimum: 45, maximum: 90) years. Biomarker panel AUCs ranged from 89.9 to 96.3; the AUC for serum CA19-9 alone was 91.7 [95% confidence interval (CI), 87.8–95.6]. Two panels had significantly higher AUCs than serum CA19-9 alone, the CA19-9/FUT2/3 panel (AUC = 96.3, P = 0.002), and the tissue factor pathway inhibitor/tenascin C (TFPI/TNC-FNIII-C) panel (AUC = 95, P = 0.01). Exploratory models to recombine biomarkers retained all but two biomarkers [optimism-corrected AUC = 96.4 (94–98.9)]. Conclusions: The CA19-9/FUT2/3 panel was the best performing panel in this biomarker bakeoff. Its evaluation in larger studies is warranted. Biomarker bakeoffs are an effective strategy for comparing the performance of promising biomarkers for pancreatic cancer early detection, and the PCDC is well poised to conduct such studies. Recommendations for performing such studies are provided.

Abstract 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.