Circulating Cell-Free DNA-Based Liquid Biopsy Markers for the Non-Invasive Prognosis and Monitoring of Metastatic Pancreatic Cancer

Cancers - Tập 12 Số 7 - Trang 1754
Marta Toledano‐Fonseca1,2, María Teresa Cano3, Elizabeth Inga3, Rosa María Rodríguez-Alonso3, María Auxiliadora Gómez‐España1,3, Silvia Guil‐Luna1,2, Rafael Mena‐Osuna2, Juan de la Haba1,2,3, Antonio Rodríguez‐Ariza1,2,3, Enrique Aranda1,4,2,3
1Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain
2Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain
3Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain
4Department of Medicine, Faculty of Medicine, University of Córdoba, E14004 Córdoba, Spain

Tóm tắt

Liquid biopsy may assist in the management of cancer patients, which can be particularly applicable in pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated the utility of circulating cell-free DNA (cfDNA)-based markers as prognostic tools in metastatic PDAC. Plasma was obtained from 61 metastatic PDAC patients, and cfDNA levels and fragmentation were determined. BEAMing technique was used for quantitative determination of RAS mutation allele fraction (MAF) in cfDNA. We found that the prognosis was more accurately predicted by RAS mutation detection in plasma than in tissue. RAS mutation status in plasma was a strong independent prognostic factor for both overall survival (OS) and progression-free survival (PFS). Moreover, RAS MAF in cfDNA was also an independent risk factor for poor OS, and was strongly associated with primary tumours in the body/tail of the pancreas and liver metastases. Higher cfDNA levels and fragmentation were also associated with poorer OS and shorter PFS, body/tail tumors, and hepatic metastases, whereas cfDNA fragmentation positively correlated with RAS MAF. Remarkably, the combination of CA19-9 with MAF, cfDNA levels and fragmentation improved the prognostic stratification of patients. Furthermore, dynamics of RAS MAF better correlated with patients’ outcome than standard CA19-9 marker. In conclusion, our study supports the use of cfDNA-based liquid biopsy markers as clinical tools for the non-invasive prognosis and monitoring of metastatic PDAC patients.

Từ khóa


Tài liệu tham khảo

Bray, 2018, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin., 68, 394, 10.3322/caac.21492

Ferlay, 2018, Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018, Eur J. Cancer, 103, 356, 10.1016/j.ejca.2018.07.005

Rahib, 2014, Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States, Cancer Res., 74, 2913, 10.1158/0008-5472.CAN-14-0155

Ryan, 2014, Pancreatic adenocarcinoma, N. Engl. J. Med., 371, 1039, 10.1056/NEJMra1404198

Waters, A.M., and Der, C.J. (2018). KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb. Perspect. Med., 8.

Baek, 2015, Diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration cytology of pancreatic lesions, J. Pathol. Transl. Med., 49, 52, 10.4132/jptm.2014.10.26

Luchini, C., Veronese, N., Nottegar, A., Cappelletti, V., Daidone, M.G., Smith, L., Parris, C., Brosens, L.A.A., Caruso, M.G., and Cheng, L. (2019). Liquid Biopsy as Surrogate for Tissue for Molecular Profiling in Pancreatic Cancer: A Meta-Analysis Towards Precision Medicine. Cancers, 11.

Tjensvoll, 2016, Clinical relevance of circulating KRAS mutated DNA in plasma from patients with advanced pancreatic cancer, Mol. Oncol., 10, 635, 10.1016/j.molonc.2015.11.012

Mouliere, 2016, Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care, Clin. Cancer Res., 22, 3067, 10.1158/1078-0432.CCR-15-0297

Tabernero, 2015, Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: A retrospective, exploratory analysis of the CORRECT trial, Lancet Oncol., 16, 937, 10.1016/S1470-2045(15)00138-2

Kinugasa, 2015, Detection of K-ras gene mutation by liquid biopsy in patients with pancreatic cancer, Cancer, 121, 2271, 10.1002/cncr.29364

Park, 2018, Utility of targeted deep sequencing for detecting circulating tumor DNA in pancreatic cancer patients, Sci. Rep., 8, 11631, 10.1038/s41598-018-30100-w

Wang, 2019, KRAS Mutant Allele Fraction in Circulating Cell-Free DNA Correlates With Clinical Stage in Pancreatic Cancer Patients, Front. Oncol., 9, 1295, 10.3389/fonc.2019.01295

Chen, 2017, Ultrasensitive plasma ctDNA KRAS assay for detection, prognosis, and assessment of therapeutic response in patients with unresectable pancreatic ductal adenocarcinoma, Oncotarget, 8, 97769, 10.18632/oncotarget.22080

Perets, 2018, Mutant KRAS Circulating Tumor DNA Is an Accurate Tool for Pancreatic Cancer Monitoring, Oncologist, 23, 566, 10.1634/theoncologist.2017-0467

Hadano, 2016, Prognostic value of circulating tumour DNA in patients undergoing curative resection for pancreatic cancer, Br. J. Cancer, 115, 59, 10.1038/bjc.2016.175

Gall, 2019, Circulating Tumor Cells and Cell-Free DNA in Pancreatic Ductal Adenocarcinoma, Am. J. Pathol., 189, 71, 10.1016/j.ajpath.2018.03.020

Lennerz, 2015, Allelic ratio of KRAS mutations in pancreatic cancer, Oncologist, 20, e8, 10.1634/theoncologist.2014-0408

Bernard, 2019, Circulating Nucleic Acids Are Associated With Outcomes of Patients With Pancreatic Cancer, Gastroenterology, 156, 108, 10.1053/j.gastro.2018.09.022

Mueller, 2018, Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes, Nature, 554, 62, 10.1038/nature25459

Birnbaum, D.J., Bertucci, F., Finetti, P., Birnbaum, D., and Mamessier, E. (2019). Head and Body/Tail Pancreatic Carcinomas Are Not the Same Tumors. Cancers, 11.

Dreyer, S.B., Jamieson, N.B., Upstill-Goddard, R., Bailey, P.J., McKay, C.J., Biankin, A.V., and Chang, D.K. (2018). Defining the molecular pathology of pancreatic body and tail adenocarcinoma. Br. J. Surg.

Mackay, 2018, Association of the location of pancreatic ductal adenocarcinoma (head, body, tail) with tumor stage, treatment, and survival: A population-based analysis, Acta Oncol., 57, 1655, 10.1080/0284186X.2018.1518593

Tomasello, 2019, Outcome of head compared to body and tail pancreatic cancer: A systematic review and meta-analysis of 93 studies, J. Gastrointest. Oncol., 10, 259, 10.21037/jgo.2018.12.08

Artinyan, 2008, The anatomic location of pancreatic cancer is a prognostic factor for survival, HPB, 10, 371, 10.1080/13651820802291233

Valpione, 2018, Plasma total cell-free DNA (cfDNA) is a surrogate biomarker for tumour burden and a prognostic biomarker for survival in metastatic melanoma patients, Eur. J. Cancer, 88, 1, 10.1016/j.ejca.2017.10.029

Lapin, 2018, Fragment size and level of cell-free DNA provide prognostic information in patients with advanced pancreatic cancer, J. Transl. Med., 16, 300, 10.1186/s12967-018-1677-2

Heitzer, 2020, Cell-Free DNA and Apoptosis: How Dead Cells Inform About the Living, Trends Mol. Med., 26, 519, 10.1016/j.molmed.2020.01.012

Zvereva, M., Roberti, G., Durand, G., Voegele, C., Nguyen, M.D., Delhomme, T.M., Chopard, P., Fabianova, E., Adamcakova, Z., and Holcatova, I. (2020). Circulating tumour-derived KRAS mutations in pancreatic cancer cases are predominantly carried by very short fragments of cell-free DNA. EBioMedicine, 102462.

Saad, 2002, Pretreatment CA 19-9 level as a prognostic factor in patients with advanced pancreatic cancer treated with gemcitabine, Int. J. Gastrointest. Cancer, 32, 35, 10.1385/IJGC:32:1:35

Maisey, 2005, CA19-9 as a prognostic factor in inoperable pancreatic cancer: The implication for clinical trials, Br. J. Cancer, 93, 740, 10.1038/sj.bjc.6602760

Scara, 2015, CA 19-9: Biochemical and Clinical Aspects, Adv. Exp. Med. Biol., 867, 247, 10.1007/978-94-017-7215-0_15

Bauer, 2013, Carbohydrate antigen 19-9 is a prognostic and predictive biomarker in patients with advanced pancreatic cancer who receive gemcitabine-containing chemotherapy: A pooled analysis of 6 prospective trials, Cancer, 119, 285, 10.1002/cncr.27734

van der Sijde, F., Vietsch, E.E., Mustafa, D.A.M., Besselink, M.G., Groot Koerkamp, B., and van Eijck, C.H.J. (2019). Circulating Biomarkers for Prediction of Objective Response to Chemotherapy in Pancreatic Cancer Patients. Cancers, 11.

Vivancos, 2019, Comparison of the Clinical Sensitivity of the Idylla Platform and the OncoBEAM RAS CRC Assay for KRAS Mutation Detection in Liquid Biopsy Samples, Sci. Rep., 9, 8976, 10.1038/s41598-019-45616-y

Thông tin
Thông tin xuất bản

Cancers

Tập 12 Số 7

1754

Thông tin tác giả