Validation of biomarkers that complement CA19.9 in detecting early pancreatic cancer

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer mortality. Carbohydrate antigen 19.9 (CA19.9), the only tumor marker available to detect and monitor PDAC, is not sufficiently sensitive and specific to consistently differentiate early cancer from benign disease. In this study, we aimed to validate recently discovered serum protein biomarkers for the early detection of PDAC and ultimately develop a biomarker panel that could discriminate PDAC from other benign disease better than the existing marker CA19.9.

Patients and methods: We performed a retrospective blinded evaluation of 400 serum samples collected from individuals recruited on a consecutive basis. The sample population consisted of 250 individuals with PDAC at various stages, 130 individuals with benign conditions and 20 healthy individuals. The serum levels of each biomarker were determined by ELISAs or automated immunoassay.

Results: By randomly splitting matched samples into a training (n = 186) and validation (n = 214) set, we were able to develop and validate a biomarker panel consisting of CA19.9, CA125, and LAMC2 that significantly improved the performance of CA19.9 alone. Improved discrimination was observed in the validation set between all PDAC and benign conditions (AUCCA19.9 = 0.80 vs. AUCCA19.9+CA125+LAMC2 = 0.87; P < 0.005) as well as between early-stage PDAC and benign conditions (AUCCA19.9 = 0.69 vs. AUCCA19.9+CA125+LAMC2 = 0.76; P < 0.05) and between early-stage PDAC and chronic pancreatitis (CP; AUCCA19.9 = 0.59 vs. AUCCA19.9+CA125+LAMC2 = 0.74; P < 0.05).

Conclusions: The data demonstrate that a serum protein biomarker panel consisting of CA125, CA19.9, and LAMC2 is able to significantly improve upon the performance of CA19.9 alone in detecting PDAC.

Figure 1. Scatter plots of CA19.9, CA125 and LAMC2 in the training and validation cohorts

CA19.9 (A, B), CA125 (C, D) and LAMC2 (E, F) for training and validation cohorts, respectively. Black horizontal lines are medians. PDAC=pancreatic ductal adenocarcinoma. The clinical groups are shown on the x-axis and further described in the text.

Figure 2. Diagnostic performances of CA19.9, CA125, LAMC2, AGR2, SYCN and REG1B for all PDAC patients versus benign patients, as individual markers

Receiver operator characteristics (ROC) curves for CA19.9, CA125, LAMC2, AGR2, SYCN and REG1B for all patients with pancreatic ductal adenocarcinoma (PDAC) versus all benign patients as individual markers in the training cohort (A) and validation cohort (B). The area under the curve (AUC) for each marker is provided along with its associated 95% confidence intervals in brackets.

Figure 3. Complementarity of CA19.9, CA125 and LAMC2 in differentiating all patients with PDAC versus all benign patients

Receiver operator characteristics (ROC) curves for CA19.9, CA125+CA19.9, CA19.9+LAMC2 and CA125+CA19.9+LAMC2 multiple markers models for all patients with pancreatic ductal adenocarcinoma (PDAC) versus all benign patients in the training (A) and validation cohort (B). The area under the curve (AUC) for each marker is provided along with its associated 95% confidence intervals in brackets.