{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:58:36Z","timestamp":1790744316031,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"IMBdx Inc."},{"name":"National Research Foundation"},{"DOI":"10.13039\/501100003725","name":"Korean government","doi-asserted-by":"publisher","award":["RS-2025-19542979"],"award-info":[{"award-number":["RS-2025-19542979"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Circulating tumor DNA (ctDNA) is a minimally invasive biomarker in pancreatic ductal adenocarcinoma (PDAC), but the prognostic information added by multigene ctDNA metrics beyond KRAS and carbohydrate antigen 19-9 (CA19-9) is uncertain. In this prospective observational pilot study, 51 patients with advanced PDAC receiving 5-fluorouracil-based chemotherapy underwent 118-gene ctDNA profiling at baseline and 4 and 8 weeks after treatment initiation. ctDNA burden was summarized with variant allele frequency (VAF) metrics: Sum VAF and Top4 VAF (KRAS, TP53, CDKN2A, SMAD4). Twelve-month progression-free survival (PFS) areas under the curve were 0.816 for Top4 VAF, 0.812 for Sum VAF, 0.788 for KRAS VAF, and 0.687 for CA19-9; the Top4\u2013KRAS difference was not statistically significant (95% confidence interval, \u22120.120 to 0.131). Baseline ctDNA detection and high Top4 VAF remained associated with shorter PFS and overall survival after adjustment for clinical covariates. Detectable Top4 VAF at 4 weeks was associated with shorter PFS (hazard ratio, 5.739; p &lt; 0.001). Top4 VAF changes differed across radiologic response categories at 8 but not 4 weeks; CA19-9 showed no significant paired change. These exploratory findings suggest that baseline and early on-treatment multigene ctDNA carries prognostic information in advanced PDAC, although superiority over KRAS or CA19-9 was not established.<\/jats:p>","DOI":"10.3390\/ijms27198668","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:50:54Z","timestamp":1790614254000},"page":"8668","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prognostic Value and Longitudinal Dynamics of Multigene Circulating Tumor DNA in Advanced Pancreatic Cancer Treated with 5-Fluorouracil-Based Chemotherapy"],"prefix":"10.3390","volume":"27","author":[{"given":"Gi Yeon","family":"Lee","sequence":"first","affiliation":[{"name":"Targeted Therapy Branch, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, Republic of Korea"},{"name":"Department of Laboratory Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1964-7501","authenticated-orcid":false,"given":"Jung Won","family":"Chun","sequence":"additional","affiliation":[{"name":"Center for Liver and Pancreatobiliary Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Dong-eun","family":"Lee","sequence":"additional","affiliation":[{"name":"Biostatistics Collaboration Team, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"software","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4972-2306","authenticated-orcid":false,"given":"Jun-Ha","family":"Jang","sequence":"additional","affiliation":[{"name":"Targeted Therapy Branch, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, Republic of Korea"},{"name":"Department of Public Health & AI, National Cancer Center Graduate School of Cancer Science and Policy, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2115-6701","authenticated-orcid":false,"given":"Woo Jin","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Liver and Pancreatobiliary Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"given":"Hwang-Phill","family":"Kim","sequence":"additional","affiliation":[{"name":"IMBdx, 38 Teheran-ro 113-gil, Gangnam-gu, Seoul 06173, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1047-1415","authenticated-orcid":false,"given":"Seung-Tae","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3786-4403","authenticated-orcid":false,"given":"Sang Myung","family":"Woo","sequence":"additional","affiliation":[{"name":"Center for Liver and Pancreatobiliary Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0620-4058","authenticated-orcid":false,"given":"Sun-Young","family":"Kong","sequence":"additional","affiliation":[{"name":"Targeted Therapy Branch, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, Republic of Korea"},{"name":"Department of Laboratory Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, Republic of Korea"},{"name":"Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7686","DOI":"10.1038\/ncomms8686","article-title":"Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients","volume":"6","author":"Sausen","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1126\/science.aar3247","article-title":"Detection and localization of surgically resectable cancers with a multi-analyte blood test","volume":"359","author":"Cohen","year":"2018","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1039\/C8LC00100F","article-title":"Circulating tumor DNA and liquid biopsy: Opportunities, challenges, and recent advances in detection technologies","volume":"18","author":"Gorgannezhad","year":"2018","journal-title":"Lab Chip"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1158\/2159-8290.CD-15-0274","article-title":"Cell-Free DNA Next-Generation Sequencing in Pancreatobiliary Carcinomas","volume":"5","author":"Zill","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"78827","DOI":"10.18632\/oncotarget.12386","article-title":"KRAS mutations in blood circulating cell-free DNA: A pancreatic cancer case-control","volume":"7","author":"Foll","year":"2016","journal-title":"Oncotarget"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1093\/annonc\/mdy417","article-title":"Repeated mutKRAS ctDNA measurements represent a novel and promising tool for early response prediction and therapy monitoring in advanced pancreatic cancer","volume":"29","author":"Kruger","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.pan.2020.12.017","article-title":"Molecular profiling of ctDNA in pancreatic cancer: Opportunities and challenges for clinical application","volume":"21","author":"Sivapalan","year":"2021","journal-title":"Pancreatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41576-018-0071-5","article-title":"Current and future perspectives of liquid biopsies in genomics-driven oncology","volume":"20","author":"Heitzer","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1002\/ijc.30650","article-title":"Analysis of ctDNA to predict prognosis and monitor treatment responses in metastatic pancreatic cancer patients","volume":"140","author":"Cheng","year":"2017","journal-title":"Int. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"765","DOI":"10.4143\/crt.2023.1294","article-title":"Analytical and Clinical Validation of a Highly Sensitive NGS-Based ctDNA Assay with Real-World Concordance in Non-Small Cell Lung Cancer","volume":"56","author":"Yi","year":"2024","journal-title":"Cancer Res. Treat."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1002\/ijc.32586","article-title":"Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma","volume":"146","author":"Strijker","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1200\/JCO.2025.43.4_suppl.684","article-title":"Utility of circulating tumor DNA in patients with unresectable pancreatic cancer using a patient-specific panel: ARTEMIS-PC study","volume":"43","author":"Shibuki","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1002\/1878-0261.13472","article-title":"Monitoring of circulating tumour DNA in advanced pancreatic ductal adenocarcinoma predicts clinical outcome and reveals disease progression earlier than radiological imaging","volume":"17","author":"Edland","year":"2023","journal-title":"Mol. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1158\/1078-0432.CCR-22-3526","article-title":"Comprehensive ctDNA Measurements Improve Prediction of Clinical Outcomes and Enable Dynamic Tracking of Disease Progression in Advanced Pancreatic Cancer","volume":"29","author":"Lapin","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Guan, S., Deng, G., Sun, J., Han, Q., Lv, Y., Xue, T., Ding, L., Yang, T., Qian, N., and Dai, G. (2022). Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.926260"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hussung, S., Hess, M.E., Haghighi, E.B., Wittel, U.A., Boerries, M., and Fritsch, R.M. (2025). Integrated Analysis of Cell-Free DNA and Novel Protein Biomarkers for Stratification and Therapy Monitoring in Stage IV Pancreatic Cancer: A Preliminary Study. Diagnostics, 15.","DOI":"10.20944\/preprints202412.0461.v1"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"199","DOI":"10.3343\/alm.2024.0345","article-title":"Prognostic Value of Residual Circulating Tumor DNA in Metastatic Pancreatic Ductal Adenocarcinoma","volume":"45","author":"Kim","year":"2025","journal-title":"Ann. Lab. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)","volume":"45","author":"Eisenhauer","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4720","DOI":"10.1158\/1078-0432.CCR-25-0758","article-title":"The Prognostic Impact of Early ctDNA Kinetics in Metastatic Pancreatic Cancer Using the ctDNA-RECIST","volume":"31","author":"Steiniche","year":"2025","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1093\/oncolo\/oyae155","article-title":"Association of personalized and tumor-informed ctDNA with patient survival outcomes in pancreatic adenocarcinoma","volume":"29","author":"Botta","year":"2024","journal-title":"Oncologist"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s00432-023-05594-1","article-title":"Short-term serial circulating tumor DNA assessment predicts therapeutic efficacy for patients with advanced pancreatic cancer","volume":"150","author":"Motobayashi","year":"2024","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s12967-024-04989-z","article-title":"High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: Prospective study","volume":"22","author":"Huang","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Sivapalan, L., Thorn, G.J., Gadaleta, E., Kocher, H.M., Ross-Adams, H., and Chelala, C. (2022). Longitudinal profiling of circulating tumour DNA for tracking tumour dynamics in pancreatic cancer. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-09387-6"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"34481","DOI":"10.1038\/s41598-025-22369-5","article-title":"Reliable on-treatment prognostication and target identification with a customized assay for circulating tumor DNA in patients with newly diagnosed pancreatic cancer","volume":"15","author":"Petersson","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1158\/1535-7163.MCT-17-1298","article-title":"Monitoring Tumor Burden in Response to FOLFIRINOX Chemotherapy via Profiling Circulating Cell-Free DNA in Pancreatic Cancer","volume":"18","author":"Wei","year":"2019","journal-title":"Mol. Cancer Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.trsl.2024.05.003","article-title":"ctDNA whole exome sequencing in pancreatic ductal adenocarcinoma unveils organ-dependent metastatic mechanisms and identifies actionable alterations in fast progressing patients","volume":"271","author":"Huerta","year":"2024","journal-title":"Transl. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ojha, S., Sessions, W., Zhou, Y., and Aung, K.L. (2025). ctDNA in Pancreatic Adenocarcinoma: A Critical Appraisal. Curr. Oncol., 32.","DOI":"10.3390\/curroncol32110589"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/nrclinonc.2017.14","article-title":"Integrating liquid biopsies into the management of cancer","volume":"14","author":"Siravegna","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nrc.2017.7","article-title":"Liquid biopsies come of age: Towards implementation of circulating tumour DNA","volume":"17","author":"Wan","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1016\/j.ccell.2025.09.006","article-title":"Cell-free DNA fragmentomics in cancer","volume":"43","author":"Tsui","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8801","DOI":"10.1038\/s41467-024-53017-7","article-title":"Cancer treatment monitoring using cell-free DNA fragmentomes","volume":"15","author":"Alipanahi","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.18632\/oncotarget.23330","article-title":"Targeted deep sequencing of circulating tumor DNA in metastatic pancreatic cancer","volume":"9","author":"Berger","year":"2018","journal-title":"Oncotarget"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1373\/clinchem.2018.298323","article-title":"Guidelines for the Preanalytical Conditions for Analyzing Circulating Cell-Free DNA","volume":"65","author":"Meddeb","year":"2019","journal-title":"Clin. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1038\/s41416-022-01837-z","article-title":"Dynamic changes in longitudinal circulating tumour DNA profile during metastatic colorectal cancer treatment","volume":"127","author":"Kim","year":"2022","journal-title":"Br. J. Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8668\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:25:10Z","timestamp":1790742310000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8668"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":34,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198668"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198668","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,28]]}}}