Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the third leading cause of cancer-related mortality within the next decade. Management of PDAC remains challenging with limited effective treatment options and a dismal long-term prognosis. Liquid biopsy and circulating biomarkers seem to be promising to improve the multidisciplinary approach in PDAC treatment. Circulating tumour DNA (ctDNA) is the most studied blood liquid biopsy analyte and can provide insight into the molecular profile and individual characteristics of the tumour in real-time and in advance of standard imaging modalities. This could pave the way for identifying new therapeutic targets and markers of tumour response to supplement diagnostic and provide enhanced stratified treatment. Although its specificity seems excellent, the current sensitivity of ctDNA remains a limitation for clinical use, especially in patients with a low tumour burden. Increasing evidence suggests that ctDNA is a pertinent candidate biomarker to assess minimal residual disease after surgery but also a strong independent prognostic biomarker. This review explores the current knowledge and recent developments in ctDNA as a screening, diagnostic, prognostic and predictive biomarker in the management of resectable PDAC but also technical and analytical challenges that must be overcome to move toward “precision onco-surgery.”
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Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.
Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J Oncol. 2019;10:10–27.
Ferlay J, Partensky C, Bray F. More deaths from pancreatic cancer than breast cancer in the EU by 2017. Acta Oncol. 2016;55:1158–60.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.
Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379:2395–406.
Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: An evidence based appraisal. J Gastrointest Oncol. 2012;3:105–19.
Goggins M. Molecular markers of early pancreatic cancer. J Clin Oncol. 2005;23:4524–31.
Kondo N, Murakami Y, Uemura K, Nakagawa N, Takahashi S, Ohge H, et al. Comparison of the prognostic impact of pre- and post-operative CA19-9, SPan-1, and DUPAN-II levels in patients with pancreatic carcinoma. Pancreatology. 2017;17:95–102.
Ishii H, Okada S, Sato T, Wakasugi H, Saisho H, Furuse J, et al. CA 19-9 in evaluating the response to chemotherapy in advanced pancreatic cancer. Hepato Gastroenterol. 1997;44:279–83.
Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17:223–38.
Ignatiadis M, Sledge GW, Jeffrey SS. Liquid biopsy enters the clinic—implementation issues and future challenges. Nat Rev Clin Oncol. 2021;18:297–312.
Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002;2:897–909.
Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52.
Bournet B, Buscail C, Muscari F, Cordelier P, Buscail L. Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: hopes and realities. Eur J Cancer. 2016;54:75–83.
Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11:761–74.
Maitra A, Hruban RH. Pancreatic cancer. Annu Rev Pathol. 2008;3:157–88.
Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci. 2014;39:91–100.
Hruban RH, Maitra A, Schulick R, Laheru D, Herman J, Kern SE, et al. Emerging molecular biology of pancreatic cancer. Gastrointest Cancer Res. 2008;2(Suppl):S10–5.
Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495–501.
Puleo F, Nicolle R, Blum Y, Cros J, Marisa L, Demetter P, et al. Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features. Gastroenterology. 2018;155:1999–2013 e3.
Cancer Genome Atlas Research Network. Electronic address aadhe, Cancer Genome Atlas Research N. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2017;32:185–203 e13.
de Santiago I, Yau C, Heij L, Middleton MR, Markowetz F, Grabsch HI, et al. Immunophenotypes of pancreatic ductal adenocarcinoma: meta-analysis of transcriptional subtypes. Int J Cancer. 2019;145:1125–37.
Sausen M, Phallen J, Adleff V, Jones S, Leary RJ, Barrett MT, et al. Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. Nat Commun. 2015;6:7686.
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.
Zill OA, Greene C, Sebisanovic D, Siew LM, Leng J, Vu M, et al. Cell-free DNA next-generation sequencing in pancreatobiliary carcinomas. Cancer Discov. 2015;5:1040–8.
Shapiro B, Chakrabarty M, Cohn EM, Leon SA. Determination of circulating DNA levels in patients with benign or malignant gastrointestinal disease. Cancer. 1983;51:2116–20.
Diaz LA Jr., Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32:579–86.
Thierry AR, El Messaoudi S, Gahan PB, Anker P, Stroun M. Origins, structures, and functions of circulating DNA in oncology. Cancer Metastasis Rev. 2016;35:347–76.
Jeppesen DK, Fenix AM, Franklin JL, Higginbotham JN, Zhang Q, Zimmerman LJ, et al. Reassessment of exosome composition. Cell. 2019;177:428–45.e18.
Yong E. Cancer biomarkers: written in blood. Nature. 2014;511:524–6.
Taly V, Pekin D, El Abed A, Laurent-Puig P. Detecting biomarkers with microdroplet technology. Trends Mol Med. 2012;18:405–16.
Pecuchet N, Zonta E, Didelot A, Combe P, Thibault C, Gibault L, et al. Base-position error rate analysis of next-generation sequencing applied to circulating tumor DNA in non-small cell lung cancer: a prospective study. PLoS Med. 2016;13:e1002199.
Newman AM, Bratman SV, Wynne J, Eclov JF, Modlin NC. LA, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20:548–54.
Newman AM, Lovejoy AF, Klass DM, Kurtz DM, Chabon JJ, Scherer F, et al. Integrated digital error suppression for improved detection of circulating tumor DNA. Nat Biotechnol. 2016;34:547–55.
Dabritz J, Preston R, Hanfler J, Oettle H. Follow-up study of K-ras mutations in the plasma of patients with pancreatic cancer: correlation with clinical features and carbohydrate antigen 19-9. Pancreas. 2009;38:534–41.
Maire F, Micard S, Hammel P, Voitot H, Levy P, Cugnenc PH, et al. Differential diagnosis between chronic pancreatitis and pancreatic cancer: value of the detection of KRAS2 mutations in circulating DNA. Br J Cancer. 2002;87:551–4.
Kinugasa H, Nouso K, Miyahara K, Morimoto Y, Dohi C, Tsutsumi K, et al. Detection of K-ras gene mutation by liquid biopsy in patients with pancreatic cancer. Cancer. 2015;121:2271–80.
Takai E, Totoki Y, Nakamura H, Morizane C, Nara S, Hama N, et al. Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer. Sci Rep. 2015;5:18425.
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.
Pietrasz D, Pecuchet 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.
Earl J, Garcia-Nieto S, Martinez-Avila JC, Montans J, Sanjuanbenito A, Rodriguez-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.
Buscail E, Chauvet A, Quincy P, Degrandi O, Buscail C, Lamrissi I, et al. CD63-GPC1-positive exosomes coupled with CA19-9 offer good diagnostic potential for resectable pancreatic ductal adenocarcinoma. Transl Oncol. 2019;12:1395–403.
Le Calvez-Kelm F, Foll M, Wozniak MB, Delhomme TM, Durand G, Chopard P, et al. KRAS mutations in blood circulating cell-free DNA: a pancreatic cancer case-control. Oncotarget. 2016;7:78827–40.
Van Paemel R, De Koker A, Caggiano C, Morlion A, Mestdagh P, De Wilde B, et al. Genome-wide study of the effect of blood collection tubes on the cell-free DNA methylome. Epigenetics. 2020:16;797–807.
Greytak SR, Engel KB, Parpart-Li S, Murtaza M, Bronkhorst AJ, Pertile MD, et al. Harmonizing cell-free DNA collection and processing practices through evidence-based guidance. Clin Cancer Res. 2020;26:3104–9.
Eissa MAL, Lerner L, Abdelfatah E, Shankar N, Canner JK, Hasan NM, et al. Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood. Clin Epigenetics. 2019;11:59.
Singh N, Rashid S, Rashid S, Dash NR, Gupta S, Saraya A. Clinical significance of promoter methylation status of tumor suppressor genes in circulating DNA of pancreatic cancer patients. J Cancer Res Clin Oncol. 2020;146:897–907.
Feinberg AP, Cui H, Ohlsson R. DNA methylation and genomic imprinting: insights from cancer into epigenetic mechanisms. Semin Cancer Biol. 2002;12:389–98.
Liggett T, Melnikov A, Yi Q-l, Replogle C, Brand R, Kaul K, et al. Differential methylation of cell-free circulating DNA among patients with pancreatic cancer versus chronic pancreatitis. Cancer 2010;116:1674–80.
Melnikov AA, Scholtens D, Talamonti MS, Bentrem DJ, Levenson VV. Methylation profile of circulating plasma DNA in patients with pancreatic cancer. J Surg Oncol. 2009;99:119–22.
Henriksen SD, Madsen PH, Larsen AC, Johansen MB, Pedersen IS, Krarup H, et al. Cell-free DNA promoter hypermethylation in plasma as a predictive marker for survival of patients with pancreatic adenocarcinoma. Oncotarget. 2017;8:93942–56.
Pedersen KS, Bamlet WR, Oberg AL, de Andrade M, Matsumoto ME, Tang H, et al. Leukocyte DNA methylation signature differentiates pancreatic cancer patients from healthy controls. PLoS ONE. 2011;6:e18223.
Majumder S, Taylor W, Foote PH, Berger CK, Wu CW, Mahoney DW, et al. High detection rates of pancreatic cancer across stages by plasma assay of novel methylated DNA markers and CA 19-9. Clin Cancer Res. 2021;27:2523–32.
Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467:1114–7.
Springer S, Wang Y, Dal Molin M, Masica DL, Jiao Y, Kinde I, et al. A combination of molecular markers and clinical features improve the classification of pancreatic cysts. Gastroenterology. 2015;149:1501–10.
Singhi AD, McGrath K, Brand RE, Khalid A, Zeh HJ, Chennat JS, et al. Preoperative next-generation sequencing of pancreatic cyst fluid is highly accurate in cyst classification and detection of advanced neoplasia. Gut. 2018;67:2131–41.
Berger AW, Schwerdel D, Costa IG, Hackert T, Strobel O, Lam S, 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.
Hata T, Mizuma M, Motoi F, Omori Y, Ishida M, Nakagawa K, et al. GNAS mutation detection in circulating cell-free DNA is a specific predictor for intraductal papillary mucinous neoplasms of the pancreas, especially for intestinal subtype. Sci Rep. 2020;10:17761.
Buscail E, Maulat C, Muscari F, Chiche L, Cordelier P, Dabernat S, et al. Liquid biopsy approach for pancreatic ductal adenocarcinoma. Cancers. 2019;11;852.
Cohen JD, Javed AA, Thoburn C, Wong F, Tie J, Gibbs P, et al. Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. Proc Natl Acad Sci USA. 2017;114:10202–7.
Guo S, Shi X, Shen J, Gao S, Wang H, Shen S, et al. Preoperative detection of KRAS G12D mutation in ctDNA is a powerful predictor for early recurrence of resectable PDAC patients. Br J Cancer. 2020;122:857–67.
Allenson K, Castillo J, San Lucas FA, Scelo G, Kim DU, Bernard V, et al. High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients. Ann Oncol. 2017;28:741–7.
Kato S, Honda K. Use of biomarkers and imaging for early detection of pancreatic cancer. Cancers. 2020;12:1965.
Shen SY, Singhania R, Fehringer G, Chakravarthy A, Roehrl MHA, Chadwick D, et al. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature. 2018;563:579–83.
Fujimoto Y, Suehiro Y, Kaino S, Suenaga S, Tsuyama T, Matsui H, et al. Combination of CA19-9 and blood free-circulating methylated RUNX3 may be useful to diagnose stage I pancreatic cancer. Oncology. 2021;99:234–9.
Shinjo K, Hara K, Nagae G, Umeda T, Katsushima K, Suzuki M, et al. A novel sensitive detection method for DNA methylation in circulating free DNA of pancreatic cancer. PLoS ONE. 2020;15:e0233782.
Cohen JD, Li L, Wang Y, Thoburn C, Afsari B, Danilova L, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359:926–30.
Delpero JR, Sauvanet A. Vascular resection for pancreatic cancer: 2019 French Recommendations Based on a Literature Review From 2008 to 6-2019. Front Oncol. 2020;10:40.
Cassinotto C, Cortade J, Belleannee G, Lapuyade B, Terrebonne E, Vendrely V, et al. An evaluation of the accuracy of CT when determining resectability of pancreatic head adenocarcinoma after neoadjuvant treatment. Eur J Radiol. 2013;82:589–93.
Ferrone CR, Marchegiani G, Hong TS, Ryan DP, Deshpande V, McDonnell EI, et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. Ann Surg. 2015;261:12–7.
Wagner M, Antunes C, Pietrasz D, Cassinotto C, Zappa M, Sa Cunha A, et al. CT evaluation after neoadjuvant FOLFIRINOX chemotherapy for borderline and locally advanced pancreatic adenocarcinoma. Eur Radiol. 2017;27:3104–16.
Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra24.
Lee B, Lipton L, Cohen J, Tie J, Javed AA, Li L, et al. Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer. Ann Oncol. 2019;30:1472–8.
Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.
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.
Groot VP, Mosier S, Javed AA, Teinor JA, Gemenetzis G, Ding D, et al. Circulating tumor DNA as a clinical test in resected pancreatic cancer. Clin Cancer Res. 2019;25:4973–84.
Nakano Y, Kitago M, Matsuda S, Nakamura Y, Fujita Y, Imai S, et al. KRAS mutations in cell-free DNA from preoperative and postoperative sera as a pancreatic cancer marker: a retrospective study. Br J Cancer. 2018;118:662–9.
Watanabe F, Suzuki K, Tamaki S, Abe I, Endo Y, Takayama Y, et al. Longitudinal monitoring of KRAS-mutated circulating tumor DNA enables the prediction of prognosis and therapeutic responses in patients with pancreatic cancer. PLoS ONE. 2019;14:e0227366.
Mohan S, Ayub M, Rothwell DG, Gulati S, Kilerci B, Hollebecque A, et al. Analysis of circulating cell-free DNA identifies KRAS copy number gain and mutation as a novel prognostic marker in Pancreatic cancer. Sci Rep. 2019;9:11610.
Kim MK, Woo SM, Park B, Yoon KA, Kim YH, 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.
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.
Wang SE, Shyr BU, Shyr BS, Chen SC, Chang SC, Shyr YM. Circulating cell-free DNA in pancreatic head adenocarcinoma undergoing pancreaticoduodenectomy. Pancreas. 2021;50:214–8.
Kruger S, Heinemann V, Ross C, Diehl F, Nagel D, Ormanns S, 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.
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. International journal of cancer. J Int du Cancer. 2020;146:1445–56.
Yamaguchi T, Uemura K, Murakami Y, Kondo N, Nakagawa N, Okada K, et al. Clinical implications of pre- and postoperative circulating tumor DNA in patients with resected pancreatic ductal adenocarcinoma. Ann Surg Oncol. 2021;28:3135–44.
Hussung S, Akhoundova D, Hipp J, Follo M, Klar RFU, Philipp U, et al. Longitudinal analysis of cell-free mutated KRAS and CA 19-9 predicts survival following curative resection of pancreatic cancer. BMC Cancer. 2021;21:49.
Chen K, Sun J, Zhao H, Jiang R, Zheng J, Li Z, et al. Non-invasive lung cancer diagnosis and prognosis based on multi-analyte liquid biopsy. Mol Cancer. 2021;20:23.
Hofmann L, Sallinger K, Haudum C, Smolle M, Heitzer E, Moser T, et al. A multi-analyte approach for improved sensitivity of liquid biopsies in prostate cancer. Cancers. 2020;12;2247.
Buscail E, Alix-Panabières C, Quincy P, Cauvin T, Chauvet A, Degrandi O, et al. High clinical value of liquid biopsy to detect circulating tumor cells and tumor exosomes in pancreatic ductal adenocarcinoma patients eligible for up-front surgery. Cancers. 2019;11:1656.
Lee B. Circulating Tumour DNA Analysis Informing Adjuvant Chemotherapy in Early Stage Pancreatic Cancer: A Multicentre Randomised Study (DYNAMIC- Pancreas): ANZCTR. 2018. https://anzctr.org.au/ACTRN12618000335291.aspx.
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Pietrasz, D., Sereni, E., Lancelotti, F. et al. Circulating tumour DNA: a challenging innovation to develop “precision onco-surgery” in pancreatic adenocarcinoma. Br J Cancer 126, 1676–1683 (2022). https://doi.org/10.1038/s41416-022-01745-2