Skip to main content
SpringerLink
Log in

Circulating Tumor DNA as a Novel Biomarker for Pancreatic Cancer

  • Chapter
  • First Online:
Translational Pancreatic Cancer Research

Part of the book series: Molecular and Translational Medicine ((MOLEMED))

  • 361 Accesses

Abstract

Despite some therapeutic advances in the past years, pancreatic ductal adenocarcinoma (PDAC) still has a dismal prognosis. One explanation is the lack of reliable biomarkers wherefore screening has been hampered. In turn, early tumor detection is still the exception. The sole clinically established tumor marker is the serum carbohydrate antigen 19-9 (CA19-9), but its use is due to only moderate sensitivity and specificity restricted to patients’ follow-up. The use of biomarkers in basic and clinical research as well as in clinical practice has become common in a variety of tumors, and even study endpoints nowadays operate based on their outcome. However, no clinical used biomarkers exist in the case of PDAC. Circulating tumor DNA (ctDNA) derived either from exosomes or directly from the bloodstream originating from a given cancer might have the capacity to circumvent this hurdle. Eventually ctDNA can in the future provide (i) a diagnostic tool for early diagnosis allowing cure in case of primary disease but also relapse, (ii) the opportunity to monitor and detect the disease progression, (iii) therapeutic decision guide based on the mutational makeup of the primary PDAC, and (iv) guidance to react chemotherapy-driven tumor evolution.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Kleger A, Perkhofer L, Seufferlein T. Smarter drugs emerging in pancreatic cancer therapy. Ann Oncol. 2014;25:1260–70.

    Article  CAS  PubMed  Google Scholar 

  2. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tomasello G, Petrelli F, Barni S. Risk of primary tumor sidedness as a criterion for screening, diagnostic colonoscopy, and surveillance intervals-reply. JAMA Oncol. 2017;3(10):1427.

    Article  PubMed  Google Scholar 

  4. Berger AW, Schwerdel D, Costa IG, et al. Detection of hot-spot mutations in circulating cell-free DNA from patients with intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology. 2016;151:267–70.

    Article  CAS  PubMed  Google Scholar 

  5. Boj SF, Hwang CI, Baker LA, et al. Organoid models of human and mouse ductal pancreatic cancer. Cell. 2015;160:324–38.

    Article  CAS  PubMed  Google Scholar 

  6. Costello E, Greenhalf W, Neoptolemos JP. New biomarkers and targets in pancreatic cancer and their application to treatment. Nat Rev Gastroenterol Hepatol. 2012;9:435–44.

    Article  CAS  PubMed  Google Scholar 

  7. Morris JP, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer. 2010;10:683–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11:426–37.

    Article  CAS  PubMed  Google Scholar 

  9. Pisetsky DS, Fairhurst AM. The origin of extracellular DNA during the clearance of dead and dying cells. Autoimmunity. 2007;40:281–4.

    Article  CAS  PubMed  Google Scholar 

  10. Anker P, Stroun M, Maurice PA. Spontaneous release of DNA by human blood lymphocytes as shown in an in vitro system. Cancer Res. 1975;35:2375–82.

    CAS  PubMed  Google Scholar 

  11. Rogers JC, Boldt D, Kornfeld S, et al. Excretion of deoxyribonucleic acid by lymphocytes stimulated with phytohemagglutinin or antigen. Proc Natl Acad Sci U S A. 1972;69:1685–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Stroun M, Anker P. Nucleic acids spontaneously released by living frog auricles. Biochem J. 1972;128:100P–1P.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stroun M, Lyautey J, Lederrey C, et al. About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clin Chim Acta. 2001;313:139–42.

    Article  CAS  PubMed  Google Scholar 

  14. Murtaza M, Dawson SJ, Tsui DW, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013;497:108–12.

    Article  CAS  PubMed  Google Scholar 

  15. Pantel K, Diaz LA Jr, Polyak K. Tracking tumor resistance using ‘liquid biopsies’. Nat Med. 2013;19:676–7.

    Article  PubMed  CAS  Google Scholar 

  16. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra224.

    Article  CAS  Google Scholar 

  17. Speicher MR, Pantel K. Tumor signatures in the blood. Nat Biotechnol. 2014;32:441–3.

    Article  CAS  PubMed  Google Scholar 

  18. Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32:579–86.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Gall TM, Frampton AE, Krell J, et al. Circulating molecular markers in pancreatic cancer: ready for clinical use? Future Oncol. 2013;9:141–4.

    Article  CAS  PubMed  Google Scholar 

  20. Diehl F, Li M, Dressman D, et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A. 2005;102:16368–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14:985–90.

    Article  CAS  PubMed  Google Scholar 

  22. Holdhoff M, Schmidt K, Donehower R, Diaz LA Jr. Analysis of circulating tumor DNA to confirm somatic KRAS mutations. J Natl Cancer Inst. 2009;101:1284–5.

    Article  PubMed  Google Scholar 

  23. Spindler KG, Boysen AK, Pallisgard N, et al. Cell-free DNA in metastatic colorectal cancer: a systematic review and meta-analysis. Oncologist. 2017;22:1049–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shen SY, Singhania R, Fehringer G, et al. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature. 2018;563:579–83.

    Article  CAS  PubMed  Google Scholar 

  25. Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015;523:177–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kahlert C, Melo SA, Protopopov A, et al. Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem. 2014;289:3869–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nuzhat Z, Kinhal V, Sharma S, et al. Tumour-derived exosomes as a signature of pancreatic cancer – liquid biopsies as indicators of tumour progression. Oncotarget. 2017;8:17279–91.

    Article  PubMed  Google Scholar 

  28. Kamerkar S, LeBleu VS, Sugimoto H, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature. 2017;546:498–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Oellerich M, Schutz E, Beck J, et al. Using circulating cell-free DNA to monitor personalized cancer therapy. Crit Rev Clin Lab Sci. 2017;54:205–18.

    Article  CAS  PubMed  Google Scholar 

  30. Riva F, Dronov OI, Khomenko DI, et al. Clinical applications of circulating tumor DNA and circulating tumor cells in pancreatic cancer. Mol Oncol. 2016;10:481–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Berger AW, Schwerdel D, Welz H, et al. Treatment monitoring in metastatic colorectal cancer patients by quantification and KRAS genotyping of circulating cell-free DNA. PLoS One. 2017;12:e0174308.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Berger AW, Schwerdel D, Ettrich TJ, et al. Targeted deep sequencing of circulating tumor DNA in metastatic pancreatic cancer. Oncotarget. 2018;9:2076–85.

    Article  PubMed  Google Scholar 

  33. Cohen JD, Li L, Wang Y, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359:926–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Phallen J, Sausen M, Adleff V, et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med. 2017;9(403):eaan2415.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379:2395–406.

    Article  CAS  PubMed  Google Scholar 

  37. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389:1011–24.

    Article  CAS  PubMed  Google Scholar 

  38. European Study Group on Cystic Tumours of the P. European evidence-based guidelines on pancreatic cystic neoplasms. Gut. 2018;67:789–804.

    Article  Google Scholar 

  39. Tanaka M, Fernandez-Del Castillo C, Kamisawa T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology. 2017;17:738–53.

    Article  PubMed  Google Scholar 

  40. Del Chiaro M, Segersvard R, Lohr M, Verbeke C. Early detection and prevention of pancreatic cancer: is it really possible today? World J Gastroenterol. 2014;20:12118–31.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Hawighorst T, Velasco P, Streit M, et al. Thrombospondin-2 plays a protective role in multistep carcinogenesis: a novel host anti-tumor defense mechanism. EMBO J. 2001;20:2631–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kim J, Hoffman JP, Alpaugh RK, et al. An iPSC line from human pancreatic ductal adenocarcinoma undergoes early to invasive stages of pancreatic cancer progression. Cell Rep. 2013;3:2088–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim J, Bamlet WR, Oberg AL, et al. Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers. Sci Transl Med. 2017;9(398):eaah5583.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Berger AW, Schwerdel D, Reinacher-Schick A, et al. A blood-based multi marker assay supports the differential diagnosis of early-stage pancreatic cancer. Theranostics. 2019;9(5):1280–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52.

    Article  CAS  PubMed  Google Scholar 

  46. Mishra NK, Guda C. Genome-wide DNA methylation analysis reveals molecular subtypes of pancreatic cancer. Oncotarget. 2017;8:28990–9012.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Huang MH, Chou YW, Li MH, et al. Epigenetic targeting DNMT1 of pancreatic ductal adenocarcinoma using interstitial control release biodegrading polymer reduced tumor growth through hedgehog pathway inhibition. Pharmacol Res. 2018;139:50–61.

    Article  PubMed  CAS  Google Scholar 

  48. Aravanis AM, Lee M, Klausner RD. Next-generation sequencing of circulating tumor DNA for early cancer detection. Cell. 2017;168:571–4.

    Article  CAS  PubMed  Google Scholar 

  49. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20:548–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pietrasz D, Pecuchet N, Garlan F, et al. Plasma circulating tumor DNA in pancreatic cancer patients is a prognostic marker. Clin Cancer Res. 2017;23:116–23.

    Article  CAS  PubMed  Google Scholar 

  51. Chen H, Tu H, Meng ZQ, et al. K-ras mutational status predicts poor prognosis in unresectable pancreatic cancer. Eur J Surg Oncol. 2010;36:657–62.

    Article  CAS  PubMed  Google Scholar 

  52. Sausen M, Phallen J, Adleff V, et al. Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. Nat Commun. 2015;6:7686.

    Article  PubMed  Google Scholar 

  53. Hadano N, Murakami Y, Uemura K, et al. Prognostic value of circulating tumour DNA in patients undergoing curative resection for pancreatic cancer. Br J Cancer. 2016;115:59–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bernard V, Kim DU, San Lucas FA, et al. Circulating nucleic acids are associated with outcomes of patients with pancreatic cancer. Gastroenterology. 2019;156:108–18.. e104

    Article  CAS  PubMed  Google Scholar 

  55. Kinde I, Wu J, Papadopoulos N, et al. Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108:9530–5.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Takai E, Totoki Y, Nakamura H, et al. Clinical utility of circulating tumor DNA for molecular assessment and precision medicine in pancreatic cancer. Adv Exp Med Biol. 2016;924:13–7.

    Article  CAS  PubMed  Google Scholar 

  57. Zill OA, Greene C, Sebisanovic D, et al. Cell-free DNA next-generation sequencing in pancreatobiliary carcinomas. Cancer Discov. 2015;5:1040–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kruger S, Heinemann V, Ross C, et al. Repeated mutKRAS ctDNA measurements represent a novel and promising tool for early response prediction and therapy monitoring in advanced pancreatic cancer. Ann Oncol. 2018;29:2348–55.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Gastrointestinal Oncology and Interventional Endoscopy, Vivantes Klinikum Im Friedrichshain, Berlin, Germany

    Andreas W. Berger

  2. Department of Internal Medicine I, Ulm University, Ulm, Germany

    Andreas W. Berger & Alexander Kleger

Authors
  1. Andreas W. Berger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander Kleger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander Kleger .

Editor information

Editors and Affiliations

  1. Department of Visceral, Vascular and Endocrine Surgery, University Hospital Halle (Saale), Halle (Saale), Sachsen-Anhalt, Germany

    Christoph W. Michalski

  2. Department of Internal Medicine I, University Hospital Halle (Saale), Halle (Saale), Sachsen-Anhalt, Germany

    Jonas Rosendahl

  3. Department of Internal Medicine I, University Hospital Halle (Saale), Halle (Saale), Sachsen-Anhalt, Germany

    Patrick Michl

  4. Department of Visceral, Vascular and Endocrine Surgery, University Hospital Halle (Saale), Halle (Saale), Sachsen-Anhalt, Germany

    Jörg Kleeff

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Berger, A.W., Kleger, A. (2020). Circulating Tumor DNA as a Novel Biomarker for Pancreatic Cancer. In: Michalski, C., Rosendahl, J., Michl, P., Kleeff, J. (eds) Translational Pancreatic Cancer Research. Molecular and Translational Medicine. Humana, Cham. https://doi.org/10.1007/978-3-030-49476-6_7

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-49476-6_7

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-030-49475-9

  • Online ISBN: 978-3-030-49476-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation