A Plasma Biomarker Panel to Identify Surgically Resectable Early-Stage Pancreatic Cancer

Abstract

Background: Blood-based biomarkers for early detection of pancreatic ductal adenocarcinoma (PDAC) are urgently needed. Current biomarkers lack high sensitivity and specificity for population screening. The gold-standard biomarker, CA 19-9, also fails to demonstrate the predictive value necessary for early detection.

Methods: To validate a functional genomics-based plasma migration signature biomarker panel, plasma tissue factor pathway inhibitor (TFPI), tenascin C (TNC-FN III-C), and CA 19-9 levels were measured by enzyme-linked immunosorbent assays in three early-stage PDAC plasma cohorts, including two independent blinded validation cohorts containing a total of 43 stage I, 163 stage II, 86 chronic pancreatitis, 31 acute biliary obstruction, and 108 controls. Logistic regression models developed classification rules combining TFPI and/or TNC-FN III-C with CA 19-9 for patient cases and control subjects, with or without adjustment for age and diabetes status. Model classification performance was evaluated and analyses repeated among subpopulations without diabetes and pancreatitis history. Two-sided P values were calculated using bootstrap method.

Results: The TFPI/TNC-FN III-C/CA 19-9 panel improved CA 19-9 performance in all early-stage cohorts, including discriminating stage IA/IB/IIA, stage IIB, and all early-stage cancer from healthy controls. Statistical significance was reached for a number of subcohorts, including for all early-stage cancer vs healthy controls (cohort 1 AUC = 0.92, 95% CI = 0.86 to 0.96, P = .04; cohort 3 AUC = 0.83, 95% CI = 0.76 to 0.89, P = .045). Among subcohorts without diabetes and pancreatitis history, the panel approaches potential clinical utility for early detection to discriminate early-stage PDAC from healthy controls including an area under the curve (AUC) of 0.87 (95% CI = 0.77 to 0.95) for stage I/IIA, an AUC of 0.93 (95% CI = 0.87 to 0.98) for stage IIB, and a statistically significant AUC of 0.89 (95% CI = 0.82 to 0.95) for all early-stage cancer ( P = .03).

Conclusions: TFPI/TNC-FN III-C migration signature adds statistically significantly to CA 19-9's predictive power to detect early-stage PDAC and may have clinical utility for early detection of surgically resectable PDAC, as well as for enhanced survival from this routinely lethal cancer.

Figure 1.

Biomarker panel performance in the TexGen cohort 1. Receiver operating characteristic (ROC) curves of the biomarker panel in differentiating stage I/IIA (A), stage IIB (B), all stage II (C) and all early-stage cancer (D) from healthy controls in the TexGen cohort. Area under the curve was calculated, and its 95% confidence interval was estimated using bootstrapping method. The P values were two-sided and are based on bootstrapping. CI = confidence interval; TFPI = tissue factor pathway inhibitor; TNC = tenascin C.

Figure 2.

Biomarker panel performance in the National Cancer Institute Early Detection Research Network reference set cohort 3. A) Receiver operating characteristic (ROC) curves of the biomarker panel in differentiating stage IA/IB/IIA from healthy controls. B) ROC curves of the biomarker panel in differentiating stage IA/IB/IIA from healthy controls in cohort without history of diabetes and pancreatitis. C) ROC curves of the biomarker panel in differentiating stage IIB from healthy controls. D) ROC curves of the biomarker panel in differentiating stage IIB from healthy controls in samples without history of diabetes and chronic pancreatitis. Area under the curve was calculated, and its 95% confidence interval was estimated using bootstrapping method. P values are two-sided and based on z test using bootstrap standard error estimate. AUC = area under the curve; CI = confidence interval; TFPI = tissue factor pathway inhibitor; TNC = tenascin C.

Figure 3.

Biomarker panel performance in the National Cancer Institute Early Detection Research Network (NCI EDRN) reference set cohort 3. A) Receiver operating characteristic (ROC) curves of the biomarker panel model for differentiating all early-stage cancer from healthy controls in the EDRN reference set (A). B) ROC curves of the biomarker panel in differentiating all cancer from healthy controls in samples without history of diabetes and chronic pancreatitis. The area under the curve was calculated, and its 95% confidence interval was estimated using bootstrapping method. P values are two-sided and based on z test using bootstrap standard error estimate. CI = confidence interval; TFPI = tissue factor pathway inhibitor; TNC = tenascin C.