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. 2019 Feb 12;9(5):1280-1287.
doi: 10.7150/thno.29247. eCollection 2019.

A Blood-Based Multi Marker Assay Supports the Differential Diagnosis of Early-Stage Pancreatic Cancer

Andreas W Berger  1 , Daniel Schwerdel  1 , Anke Reinacher-Schick  2 , Waldemar Uhl  3 , Hana Algül  4 , Helmut Friess  5 , Klaus-Peter Janssen  5 , Alexander König  6 , Michael Ghadimi  7 , Eike Gallmeier  8 , Detlef K Bartsch  9 , Michael Geissler  10 , Ludger Staib  11 , Andrea Tannapfel  12 , Alexander Kleger  1 , Alica Beutel  1 , Lucas-Alexander Schulte  1 , Marko Kornmann  13 , Thomas J Ettrich  1 , Thomas Seufferlein  1
Affiliations

A Blood-Based Multi Marker Assay Supports the Differential Diagnosis of Early-Stage Pancreatic Cancer

Andreas W Berger et al. Theranostics. .

Abstract

The most frequent malignancy of the pancreas is the pancreatic ductal adenocarcinoma (PDAC). Despite many efforts PDAC has still a dismal prognosis. Biomarkers for early disease stage diagnosis as a prerequisite for a potentially curative treatment are still missing. Novel blood-based markers may help to overcome this limitation. Methods: Prior to surgery plasma levels of thrombospondin-2 (THBS2), which was recently published as a novel biomarker, and CA19-9 from 52 patients with histologically proven PDAC were determined, circulating cell-free (cfDNA) was quantified. 15 patients with side-branch IPMNs without worrisome features and 32 patients with chronic pancreatitis served for comparison. Logit (logistic regression) models were used to test the performance of single biomarkers and biomarker combinations. Results: CA19-9 and THBS2 alone showed comparable c-statistics of 0.80 and 0.73, respectively, improving to 0.87 when combining these two markers. The c-statistic was further increased to 0.94 when combining CA19-9 and THBS2 with cfDNA quantification. This marker combination performed best for all PDAC stages but also for PDACs grouped by stage. The greatest improvement over CA19-9 was seen in the group of stage I PDAC, from 0.69 to 0.90 for the three marker combination. Conclusion:These data establish the combination of CA19-9, THBS2 and cfDNA as a composite liquid biomarker for non-invasive diagnosis of early-stage PDAC.

Keywords: CA19-9; circulating tumor DNA; liquid biopsy; pancreatic cancer; thrombospondin-2.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Scatter plot of (A) cfDNA concentrations (IPMN vs. PDAC: p<0.0001; pancreatitis vs. PDAC: p<0.0001), (B) CA19-9 concentrations (IPMN vs. PDAC: p<0.0001; pancreatitis vs. PDAC: p<0.0001), (C) THBS2 concentrations (IPMN vs. PDAC: p=0.0007; pancreatitis vs. PDAC: p=0.0001), and (D) three-dimensional plot of log-transformed cfDNA, THBS2 and CA19-9 concentrations of patients with PDAC (n=52), IPMN (n=15) and chronic pancreatitis (n=32). cfDNA=Circulating cell-free DNA, IPMN=Intraductal papillary mucinous neoplasia, PDAC=Pancreatic ductal adenocarcinoma, CA19-9=Carbohydrate antigen 19-9, THBS2=Thrombospondin-2.
Figure 2
Figure 2
ROC-curves (validation sample set) of (A) univariate analysis of THBS2, CA19-9 and cfDNA concentrations and (B) multivariable analysis of CA19-9+THBS2 and CA19‑9+THBS2+cfDNA concentrations in plasma samples from patients with all stages of PDAC versus patients with IPMN or pancreatitis. ROC=Receiver operating characteristics, THBS2=Thrombospondin-2, CA19-9=Carbohydrate antigen 19-9, cfDNA=Circulating cell-free DNA.
Figure 3
Figure 3
Venn diagram showing the number of PDAC patients (n=52) tested positive for each marker/marker combination. CA19-9=Carbohydrate antigen 19-9, cfDNA=Circulating cell-free DNA, THBS2=Thrombospondin-2.
See this image and copyright information in PMC

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