Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis
Julia Mayerle, Holger Kalthoff, Regina Reszka, Beate Kamlage, Erik Peter, Bodo Schniewind, Sandra González Maldonado, Christian Pilarsky, Claus-Dieter Heidecke, Philipp Schatz, Marius Distler, Jonas A Scheiber, Ujjwal M Mahajan, F Ulrich Weiss, Robert Grützmann, Markus M Lerch, Julia Mayerle, Holger Kalthoff, Regina Reszka, Beate Kamlage, Erik Peter, Bodo Schniewind, Sandra González Maldonado, Christian Pilarsky, Claus-Dieter Heidecke, Philipp Schatz, Marius Distler, Jonas A Scheiber, Ujjwal M Mahajan, F Ulrich Weiss, Robert Grützmann, Markus M Lerch
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.
Keywords: PANCREATIC CANCER; PANCREATITIS.
Conflict of interest statement
Competing interests: None declared.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Figures
References
- Rahib L, Smith BD, Aizenberg R, et al. . Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913–21. 10.1158/0008-5472.CAN-14-0155
- Peery AF, Dellon ES, Lund J, et al. . Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology 2012;143:1179–87 e1–3.
- Lowenfels AB, Maisonneuve P, Cavallini G, et al. . Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993;328:1433–7. 10.1056/NEJM199305203282001
- Duffy MJ, Sturgeon C, Lamerz R, et al. . Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report. Ann Oncol 2010;21:441–7.
- Gui JC, Yan WL, Liu XD. CA19-9 and CA242 as tumor markers for the diagnosis of pancreatic cancer: a meta-analysis. Clin Exp Med 2013;14:225–33.
- Poruk KE, Gay DZ, Brown K, et al. . The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates. Curr Mol Med 2013;13:340–51.
- de Icaza E, Lopez-Cervantes M, Arredondo A, et al. . Likelihood ratios of clinical, laboratory and image data of pancreatic cancer: Bayesian approach. J Eval Clin Pract 2009;15:62–8. 10.1111/j.1365-2753.2008.00955.x
- Ghatnekar O, Andersson R, Svensson M, et al. . Modelling the benefits of early diagnosis of pancreatic cancer using a biomarker signature. Int J Cancer 2013;133:2392–7. 10.1002/ijc.28256
- Talamini G, Falconi M, Bassi C, et al. . Incidence of cancer in the course of chronic pancreatitis. Am J Gastroenterol 1999;94:1253–60. 10.1111/j.1572-0241.1999.01075.x
- Del Chiaro M, Segersvard R, Lohr M, et al. . Early detection and prevention of pancreatic cancer: is it really possible today? World J Gastroenterol 2014;20:12118–31. 10.3748/wjg.v20.i34.12118
- Simeone DM, Ji B, Banerjee M, et al. . CEACAM1, a novel serum biomarker for pancreatic cancer. Pancreas 2007;34:436–43. 10.1097/MPA.0b013e3180333ae3
- Canto MI, Harinck F, Hruban RH, et al. . International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 2013;62:339–47. 10.1136/gutjnl-2012-303108
- Jenkinson C, Earl J, Ghaneh P, et al. . Biomarkers for early diagnosis of pancreatic cancer. Expert Rev Gastroenterol Hepatol 2015;9:305–15. 10.1586/17474124.2015.965145
- Majumder S, Chari ST, Ahlquist DA. Molecular detection of pancreatic neoplasia: current status and future promise. World J Gastroenterol 2015;21:11387–95. 10.3748/wjg.v21.i40.11387
- Gerdtsson AS, Malats N, Säll A, et al. . A multicenter trial defining a serum protein signature associated with pancreatic ductal adenocarcinoma. Int J Proteomics 2015;2015:587250 10.1155/2015/587250
- Fiedler GM, Leichtle AB, Kase J, et al. . Serum peptidome profiling revealed platelet factor 4 as a potential discriminating Peptide associated with pancreatic cancer. Clin Cancer Res 2009;15:3812–19. 10.1158/1078-0432.CCR-08-2701
- Jiang JT, Wu CP, Deng HF, et al. . Serum level of TSGF, CA242 and CA19-9 in pancreatic cancer. World J Gastroenterol 2004;10:1675–7. 10.3748/wjg.v10.i11.1675
- Kawa S, Tokoo M, Hasebe O, et al. . Comparative study of CA242 and CA19-9 for the diagnosis of pancreatic cancer. Br J Cancer 1994;70:481–6. 10.1038/bjc.1994.331
- Chari ST, Leibson CL, Rabe KG, et al. . Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 2005;129:504–11. 10.1016/j.gastro.2005.05.007
- Schultz NA, Dehlendorff C, Jensen BV, et al. . MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA 2014;311:392–404. 10.1001/jama.2013.284664
- Kobayashi T, Nishiumi S, Ikeda A, et al. . A novel serum metabolomics-based diagnostic approach to pancreatic cancer. Cancer Epidemiol Biomark Prev 2013;22:571–9.
- Nishiumi S, Shinohara M, Ikeda A, et al. . Serum metabolomics as a novel diagnostic approach for pancreatic cancer. Metabolomics 2010;6:518–28.
- Ritchie SA, Chitou B, Zheng Q, et al. . Pancreatic cancer serum biomarker PC-594: Diagnostic performance and comparison to CA19-9. World J Gastroenterol 2015;21:6604–12. 10.3748/wjg.v21.i21.6604
- Pepe MS, Etzioni R, Feng Z, et al. . Phases of biomarker development for early detection of cancer. J Natl Cancer Inst 2001;93:1054–61. 10.1093/jnci/93.14.1054
- Morad SA, Messner MC, Levin JC, et al. . Potential role of acid ceramidase in conversion of cytostatic to cytotoxic end-point in pancreatic cancer cells. Cancer Chemother Pharmacol 2013;71:635–45.
- Christie WW. Rapid separation and quantification of lipid classes by high performance liquid chromatography and mass (light-scattering) detection. J Lipid Res 1985;26:507–12.
- Schmidt H, Schmidt R, Geisslinger G. LC-MS/MS-analysis of sphingosine-1-phosphate and related compounds in plasma samples. Prostaglandins Other Lipid Mediat 2006;81:162–70. 10.1016/j.prostaglandins.2006.09.003
- van Ravenzwaay B, Cunha GC, Leibold E, et al. . The use of metabolomics for the discovery of new biomarkers of effect. Toxicol Lett 2007;172:21–8. 10.1016/j.toxlet.2007.05.021
- Friedman J, Hastie T, Tibshirani R. Regularization Paths for Generalized Linear Models via Coordinate Descent. J Stat Softw 2010;33:1–22. 10.18637/jss.v033.i01
- Grossjohann HS, Rappeport ED, Jensen C, et al. . Usefulness of contrast-enhanced transabdominal ultrasound for tumor classification and tumor staging in the pancreatic head. Scand J Gastroenterol 2010;45:917–24. 10.3109/00365521003702718
- Rösch T, Schusdziarra V, Born P, et al. . Modern imaging methods versus clinical assessment in the evaluation of hospital in-patients with suspected pancreatic disease. Am J Gastroenterol 2000;95:2261–70. 10.1111/j.1572-0241.2000.02312.x
- Chari ST, Leibson CL, Rabe KG, et al. . Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 2008;134:95–101. 10.1053/j.gastro.2007.10.040
- Aggarwal G, Rabe KG, Petersen GM, et al. . New-onset diabetes in pancreatic cancer: a study in the primary care setting. Pancreatology 2012;12:156–61. 10.1016/j.pan.2012.02.003
- Howes N, Lerch MM, Greenhalf W, et al. . Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004;2:252–61. 10.1016/S1542-3565(04)00013-8
- Rebours V, Boutron-Ruault MC, Schnee M, et al. . Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series. Am J Gastroenterol 2008;103:111–19. 10.1111/j.1572-0241.2007.01597.x
- Bathe OF, Shaykhutdinov R, Kopciuk K, et al. . Feasibility of identifying pancreatic cancer based on serum metabolomics. Cancer Epidemiol Biomarkers Prev 2011;20:140–7.
- Ritchie SA, Akita H, Takemasa I, et al. . Metabolic system alterations in pancreatic cancer patient serum: potential for early detection. BMC Cancer 2013;13:416 10.1186/1471-2407-13-416
- Leichtle AB, Ceglarek U, Weinert P, et al. . Pancreatic carcinoma, pancreatitis, and healthy controls: metabolite models in a three-class diagnostic dilemma. Metabolomics 2013;9:677–87.
- Di Gangi IM, Mazza T, Fontana A, et al. . Metabolomic profile in pancreatic cancer patients: a consensus-based approach to identify highly discriminating metabolites. Oncotarget 2016;7:5815–29.
- Birkmeyer JD, Sun Y, Wong SL, et al. . Hospital volume and late survival after cancer surgery. Ann Surg 2007;245:777–83. 10.1097/01.sla.0000252402.33814.dd
- Kamlage B, Maldonado SG, Bethan B, et al. . Quality markers addressing preanalytical variations of blood and plasma processing identified by broad and targeted metabolite profiling. Clin Chem 2014;60:399–412. 10.1373/clinchem.2013.211979
- Mayers JR, Wu C, Clish CB, et al. . Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med 2014;20:1193–8. 10.1038/nm.3686
- Yuan C, Clish CB, Wu C, et al. . Circulating metabolites and survival among patients with pancreatic cancer. J Natl Cancer Inst 2016;108:djv409 10.1093/jnci/djv409
- Mayerle J, Hoffmeister A, Werner J, et al. . Chronic pancreatitis—definition, etiology, investigation and treatment. Dtsch Arztebl Int 2013;110:387–93.
- Morad SA, Cabot MC. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer 2013;13:51–65.
- Wymann MP, Schneiter R. Lipid signalling in disease. Nat Rev Mol Cell Biol 2008;9:162–76. 10.1038/nrm2335
- Guillermet-Guibert J, Davenne L, Pchejetski D, et al. . Targeting the sphingolipid metabolism to defeat pancreatic cancer cell resistance to the chemotherapeutic gemcitabine drug. Mol Cancer Ther 2009;8:809–20. 10.1158/1535-7163.MCT-08-1096
- Modrak DE, Leon E, Goldenberg DM, et al. . Ceramide regulates gemcitabine-induced senescence and apoptosis in human pancreatic cancer cell lines. Mol Cancer Res 2009;7:890–6. 10.1158/1541-7786.MCR-08-0457
Source: PubMed