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Original article
Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis
  1. Julia Mayerle1,2,
  2. Holger Kalthoff3,
  3. Regina Reszka4,
  4. Beate Kamlage4,
  5. Erik Peter4,
  6. Bodo Schniewind3,
  7. Sandra González Maldonado5,
  8. Christian Pilarsky6,
  9. Claus-Dieter Heidecke7,
  10. Philipp Schatz4,
  11. Marius Distler8,
  12. Jonas A Scheiber1,
  13. Ujjwal M Mahajan1,2,
  14. F Ulrich Weiss1,
  15. Robert Grützmann6,
  16. Markus M Lerch1
  1. 1Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
  2. 2Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern, München, Germany
  3. 3Section for Molecular Oncology, Institut for Experimental Cancer Research (IET), UKSH, Kiel, Germany
  4. 4Metanomics Health GmbH, Berlin, Germany
  5. 5metanomics GmbH, Berlin, Germany
  6. 6Department of Surgery, University Hospital, Erlangen, Germany
  7. 7Department of General, Visceral, Thoracic and Vascular Surgery University Medicine Greifswald, Ernst-Moritz-Arndt University, Greifswald, Germany
  8. 8Clinic and Outpatient Clinic for Visceral-, Thorax- and Vascular Surgery, Medizinische Fakultät, TU Dresden, Dresden, Germany
  1. Correspondence to Professor Markus M Lerch, Department of Medicine A, University Medicine Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald 17475, Germany; lerch{at}uni-greifswald.de

Abstract

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
  • PANCREATITIS

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • 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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