Objective Current non-invasive diagnostic tests can distinguish between pancreatic cancer (pancreatic ductal adenocarcinoma (PDAC)) and chronic pancreatitis (CP) in only about two thirds of patients. We have searched for blood-derived metabolite biomarkers for this diagnostic purpose.
Design For a case–control study in three tertiary referral centres, 914 subjects were prospectively recruited with PDAC (n=271), CP (n=282), liver cirrhosis (n=100) or healthy as well as non-pancreatic disease controls (n=261) in three consecutive studies. Metabolomic profiles of plasma and serum samples were generated from 477 metabolites identified by gas chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry.
Results A biomarker signature (nine metabolites and additionally CA19-9) was identified for the differential diagnosis between PDAC and CP. The biomarker signature distinguished PDAC from CP in the training set with an area under the curve (AUC) of 0.96 (95% CI 0.93–0.98). The biomarker signature cut-off of 0.384 at 85% fixed specificity showed a sensitivity of 94.9% (95% CI 87.0%–97.0%). In the test set, an AUC of 0.94 (95% CI 0.91–0.97) and, using the same cut-off, a sensitivity of 89.9% (95% CI 81.0%–95.5%) and a specificity of 91.3% (95% CI 82.8%–96.4%) were achieved, successfully validating the biomarker signature.
Conclusions In patients with CP with an increased risk for pancreatic cancer (cumulative incidence 1.95%), the performance of this biomarker signature results in a negative predictive value of 99.9% (95% CI 99.7%–99.9%) (training set) and 99.8% (95% CI 99.6%–99.9%) (test set). In one third of our patients, the clinical use of this biomarker signature would have improved diagnosis and treatment stratification in comparison to CA19-9.
- PANCREATIC CANCER
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JM and HK shared first co-authorship.
RG and MML shared senior authorship.
Contributors Study design: JM, HK, RR, BK, MML; patient and biomaterial recruitment: JM, HK, CP, JAS, C-DH, FUW, RG, UMM; data acquisition: RR, BK, EP, BS, SGM, PS; statistical analysis: EP, SGM; writing committee: JM, RR, BK, MML; manuscript revision and approval: HK, EP, BS, SGM, CP, PS, JAS, C-DH, FUW, RG, MD,UMM.
Funding Supported by the Deutsche Krebshilfe/Dr. Mildred-Scheel-Stiftung (109102), the Deutsche Forschungsgemeinschaft (DFG MA 4115/1-2/3), the Federal Ministry of Education and Research (BMBF GANI-MED 03IS2061A and BMBF 0314107, 01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012) the European Union (EU-FP-7: EPC-TM), the Wilhelm Sander Stiftung (2009.039.2) and EFRE-State Ministry of Economics MV (V-630-S-150-2012/132/133), the popgen 2.0 network is supported by a grant from the German Ministry for Education and Research (01EY1103), Patent applications have been filed for the identified biomarkers under accession numbers WO 2011/151252 and WO 2013/079594 by Metanomics Health GmbH.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Az. 110/99, ethics committee Greifswald.
Provenance and peer review Not commissioned; externally peer reviewed.
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