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Molecular Diagnostics

Prognostic value of circulating tumour DNA in metastatic pancreatic cancer patients: post-hoc analyses of two clinical trials



The prognostication of metastatic pancreatic adenocarcinoma (mPDAC) patients remains uncertain, mainly based on carbohydrate antigen 19-9 (CA19-9), with limited utility. Circulating tumour DNA (ctDNA) has been suggested as a prognostic factor, but its added value has been poorly explored. The objective was to determine whether ctDNA is an independent factor for the prognostication of mPDAC.


Translational study based on two prospective collections of plasma samples of mPDAC patients naïve for chemotherapy. One used as a test series and the other as validation series coming from two randomised trials (Prodige 35 and Prodige 37). CtDNA was assessed by digital droplet PCR targeting two methylated markers (HOXD8 and POU4F1) according to a newly developed and validated method. Univariate and multivariate analyses were performed according to ctDNA status.


Of 372 plasma samples available, 354 patients were analyzed for survival. In the validation series, 145 of 255 patients were found ctDNA positive (56.8%), Median PFS and OS were 5.3 and 8.2 months in ctDNA-positive and 6.2 and 12.6 months in ctDNA-negative patients, respectively. ctDNA positivity was more often associated with young age, high CA19-9 level and neutrophils lymphocytes ratio. In multivariate analysis including these previous markers, ctDNA was confirmed as an independent prognostic marker for PFS (adjusted hazard ratio (HR) 1.5, CI 95% [1.03–2.18], p = 0.034) and OS (HR 1.62, CI 95% [1.05–2.5], p = 0.029).


In this first ctDNA assessment in a large series of mPDAC derived from clinical trials, ctDNA was detectable in 56.8% of patients and confirmed as an independent prognostic marker.

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Fig. 1: Test cohort.
Fig. 2: Validation cohort.
Fig. 3: Overall survival according to CA.19.9 concentration and ctDNA status.

Data availability

PLP and DP have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.


  1. Henley SJ, Ward EM, Scott S, Ma J, Anderson RN, Firth AU, et al. Annual Report to the Nation on the Status of Cancer, part I: National cancer statistics. Cancer. 2020;126:2225–49.

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Article  Google Scholar 

  3. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.

    CAS  Article  Google Scholar 

  4. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.

    Article  Google Scholar 

  5. Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul J-L, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379:2395–406.

    CAS  Article  Google Scholar 

  6. Poruk KE, Gay DZ, Brown K, Mulvihill JD, Boucher KM, Scaife CL, et al. The clinical utility of CA 19-9 in pancreatic adenocarcinoma: diagnostic and prognostic updates. Curr Mol Med. 2013;13:340–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Corcoran RB, Chabner BA. Application of cell-free DNA analysis to cancer treatment. N Engl J Med. 2018;379:1754–65.

    CAS  Article  Google Scholar 

  8. Kim MK, Woo SM, Park B, Yoon K-A, Kim Y-H, Joo J, et al. Prognostic implications of multiplex detection of KRAS mutations in cell-free DNA from patients with pancreatic ductal adenocarcinoma. Clin Chem. 2018;64:726–34.

    CAS  Article  Google Scholar 

  9. Chen L, Zhang Y, Cheng Y, Zhang D, Zhu S, Ma X. Prognostic value of circulating cell-free DNA in patients with pancreatic cancer: a systemic review and meta-analysis. Gene. 2018;679:328–34.

    CAS  Article  Google Scholar 

  10. Strijker M, Soer EC, de Pastena M, Creemers A, Balduzzi A, Beagan JJ, et al. Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma. Int J Cancer. 2020;146:1445–56.

    CAS  Article  Google Scholar 

  11. Sugimori M, Sugimori K, Tsuchiya H, Suzuki Y, Tsuyuki S, Kaneta Y, et al. Quantitative monitoring of circulating tumor DNA in patients with advanced pancreatic cancer undergoing chemotherapy. Cancer Sci. 2020;111:266–78.

    CAS  Article  Google Scholar 

  12. Pietrasz D, Pécuchet N, Garlan F, Didelot A, Dubreuil O, Doat S, et al. Plasma circulating tumor DNA in pancreatic cancer patients is a prognostic marker. Clin Cancer Res. 2017;23:116–23.

    CAS  Article  Google Scholar 

  13. Dahan L, Phelip JM, Le Malicot K, Williet N, Desrame J, Volet J, et al. FOLFIRINOX until progression, FOLFIRINOX with maintenance treatment, or sequential treatment with gemcitabine and FOLFIRI.3 for first-line treatment of metastatic pancreatic cancer: a randomized phase II trial (PRODIGE 35-PANOPTIMOX). J Clin Oncol Am Soc Clin Oncol. 2018;36:4000–4000.

    Article  Google Scholar 

  14. Taieb J, Rinaldi Y, Pointet A-L, Barbier E, Khemissa F, Gratet A, et al. gemcitabine plus nab-paclitaxel until progression or given sequentially with 5-fluorouracile plus irinotecan (FOLFIRI.3) for first-line treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC): A randomized phase II study (PRODIGE 37-FIRGEMAX). J Clin Oncol Am Soc Clin Oncol. 2018;36:4107–4107.

    Article  Google Scholar 

  15. dMIQE Group, Huggett JF. The Digital MIQE Guidelines Update: Minimum Information for Publication of Quantitative Digital PCR Experiments for 2020. Clin Chem. 2020;66:1012–29.

    Article  Google Scholar 

  16. Bernard V, Kim DU, San Lucas FA, Castillo J, Allenson K, Mulu FC, et al. Circulating nucleic acids are associated with outcomes of patients with pancreatic cancer. Gastroenterology. 2019;156:108–118.e4.

    CAS  Article  Google Scholar 

  17. Singh N, Gupta S, Pandey RM, Chauhan SS, Saraya A. High levels of cell-free circulating nucleic acids in pancreatic cancer are associated with vascular encasement, metastasis and poor survival. Cancer Invest. 2015;33:78–85.

    CAS  Article  Google Scholar 

  18. Perets R, Greenberg O, Shentzer T, Semenisty V, Epelbaum R, Bick T, et al. Mutant KRAS circulating tumor DNA is an accurate tool for pancreatic cancer monitoring. Oncologist. 2018;23:566–72.

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  20. Wang Z-Y, Ding X-Q, Zhu H, Wang R-X, Pan X-R, Tong J-H. KRAS mutant allele fraction in circulating cell-free DNA correlates with clinical stage in pancreatic cancer patients. Front Oncol. 2019;9:1295.

    Article  Google Scholar 

  21. Uesato Y, Sasahira N, Ozaka M, Sasaki T, Takatsuki M, Zembutsu H. Evaluation of circulating tumor DNA as a biomarker in pancreatic cancer with liver metastasis. PLoS ONE. 2020;15:e0235623.

    CAS  Article  Google Scholar 

  22. Earl J, Garcia-Nieto S, Martinez-Avila JC, Montans J, Sanjuanbenito A, Rodríguez-Garrote M, et al. Circulating tumor cells (Ctc) and kras mutant circulating free Dna (cfdna) detection in peripheral blood as biomarkers in patients diagnosed with exocrine pancreatic cancer. BMC Cancer. 2015;15:797.

    Article  Google Scholar 

  23. Del ReM, Vivaldi C, Rofi E, Vasile E, Miccoli M, Caparello C, et al. Early changes in plasma DNA levels of mutant KRAS as a sensitive marker of response to chemotherapy in pancreatic cancer. Sci Rep. 2017;7:7931.

    Article  Google Scholar 

  24. Postel M, Roosen A, Laurent-Puig P, Taly V, Wang-Renault S-F. Droplet-based digital PCR and next generation sequencing for monitoring circulating tumor DNA: a cancer diagnostic perspective. Expert Rev Mol Diagn. 2018;18:7–17.

    CAS  Article  Google Scholar 

  25. Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, et al. COSMIC: the Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 2019;47:D941–7.

    CAS  Article  Google Scholar 

  26. Garrigou S, Perkins G, Garlan F, Normand C, Didelot A, Le Corre D, et al. A study of hypermethylated circulating tumor DNA as a universal colorectal cancer biomarker. Clin Chem. 2016;62:1129–39.

    CAS  Article  Google Scholar 

  27. Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science. 2017;357:eaal2380.

  28. Barault L, Amatu A, Siravegna G, Ponzetti A, Moran S, Cassingena A, et al. Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer. Gut. 2018;67:1995–2005.

    CAS  Article  Google Scholar 

  29. Xu R-H, Wei W, Krawczyk M, Wang W, Luo H, Flagg K, et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma. Nat Mater. 2017;16:1155–61.

    CAS  Article  Google Scholar 

  30. Brancaccio M, Natale F, Falco G, Angrisano T. Cell-free DNA methylation: the new frontiers of pancreatic cancer biomarkers’ discovery. Genes. 2019;11:14.

  31. Zhou Y, Wei Q, Fan J, Cheng S, Ding W, Hua Z. Prognostic role of the neutrophil-to-lymphocyte ratio in pancreatic cancer: a meta-analysis containing 8252 patients. Clin Chim Acta. 2018;479:181–9.

    CAS  Article  Google Scholar 

  32. Patel H, Okamura R, Fanta P, Patel C, Lanman RB, Raymond VM, et al. Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer. J Hematol Oncol. 2019;12:130.

    CAS  Article  Google Scholar 

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DP, SWR, JBB, VT and PLP are inventors of HOXD8 and POU4F1 methylated markers and owners of the European Patent n°19305695.9-1111 “Detection of hypermethylated genes for diagnosing pancreatic cancer” (Faculté Paris Descartes, INSERM, CNRS, AP-HP, IDF INNOV’).


This work was supported by the Ministère de l’Enseignement Supérieur et de la Recherche, the Université de Paris, the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the SIRIC CARPEM (Inca_DGOS_Inserm-12561), the (LNCC, Program “Equipe labelisée LIGUE”; no. EL2016.LNCC). Collection of plasma samples was supported by Celgene and Fédération Francophone de Cancérologie Digestive (FFCD). A part of this work has been supported by the Fondation Roche.

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Authors and Affiliations



DP: Conceptualisation, Methodology, Formal analysis, investigation, Writing Original Draft Review and Editing, Project administration; SWR: Conceptualisation, Methodology, Resources; JT: Investigation, Writing Original draft Review and Editing, Supervision; LD: investigation, Writing Review and Editing, Project administration; MP: Methodology, Investigation, Resources; JDL: Methodology, Investigation, Resources; KLM: Methodology, Investigation, Data curation; CM: Investigation, Resources; YR: Investigation, Resources; JMP: Investigation, Resources; SD: Investigation, Resources; MD; HB: Validation, Resources; AdR: Formal analysis, Software, Data curation; JBB: Conceptualisation, Methodology, investigation, Writing Review and Editing, Project administration, Funding acquisition, Visualisation; VT: Conceptualisation, Methodology, Formal analysis, Writing Review and Editing, Project administration, Funding acquisition; PLP: Conceptualisation, Formal analysis, Software, Writing Original Draft Review and Editing, Project administration, Funding acquisition.

Corresponding authors

Correspondence to Valérie Taly or Pierre Laurent-Puig.

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Competing interests

JT has received honoraria for speaker or advisory roles from AMGEN, Roche, MERCKKGaA, MSD, Lilly, Servier, Sanofi, Pierre Fabre, AstraZeneca, Samsung Bioepis, HallioDx. JBB has received personal fees from Amgen, AstraZeneca, Bayer, Merck Serono, Pierre Fabre, Roche, Sanofi, Servier, Shire, and non-financial support from Amgen, Merck Serono, and Roche. PLP declares consulting for or personal fees from Amgen, AstraZeneca, Biocartis, BMS, Boehringer-Ingelheim, Lilly, Merck Serono, MSD, Sanofi, Servier, Roche.

Ethics approval and consent to participate

All the patients included in the PLAPAN cohort signed an informed consent form approved by the ethics committee (CPP Ile-de-France 2014/59NICB). PRODIGE 35 PANOPTIMOX trial (NCT02352337) PRODIGE 37 FIRGEMAX (NCT 02827201) trials were approved by the ethics committee.

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Pietrasz, D., Wang-Renault, S., Taieb, J. et al. Prognostic value of circulating tumour DNA in metastatic pancreatic cancer patients: post-hoc analyses of two clinical trials. Br J Cancer 126, 440–448 (2022).

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