Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma.
Humans
Carcinoma, Pancreatic Ductal
/ genetics
Circulating Tumor DNA
/ genetics
Male
Female
Pancreatic Neoplasms
/ genetics
Aged
Middle Aged
Prognosis
Biomarkers, Tumor
/ genetics
High-Throughput Nucleotide Sequencing
/ methods
Gene Frequency
Proto-Oncogene Proteins p21(ras)
/ genetics
Aged, 80 and over
Tumor Suppressor Protein p53
/ genetics
Mutation
Biomarkers
Gastrointestinal neoplasms
Genomics
Liquid biopsy
Precision medicine
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
13 Jul 2024
13 Jul 2024
Historique:
received:
19
04
2024
accepted:
09
07
2024
medline:
14
7
2024
pubmed:
14
7
2024
entrez:
13
7
2024
Statut:
epublish
Résumé
Pancreatic ductal adenocarcinoma represents one of the solid tumors showing the worst prognosis worldwide, with a high recurrence rate after adjuvant or neoadjuvant therapy. Circulating tumor DNA analysis raised as a promising non-invasive tool to characterize tumor genomics and to assess treatment response. In this study, surgical tumor tissue and sequential blood samples were analyzed by next-generation sequencing and were correlated with clinical and pathological characteristics. Thirty resectable/borderline pancreatic ductal adenocarcinoma patients treated at the Hospital Universitario de Navarra were included. Circulating tumoral DNA sequencing identified pathogenic variants in KRAS and TP53, and in other cancer-associated genes. Pathogenic variants at diagnosis were detected in patients with a poorer outcome, and were correlated with response to neoadjuvant therapy in borderline pancreatic ductal adneocarcinoma patients. Higher variant allele frequency at diagnosis was associated with worse prognosis, and thesum of variant allele frequency was greater in samples at progression. Our results build on the potential value of circulating tumor DNA for non-metastatic pancreatic ductal adenocarcinoma patients, by complementing tissue genetic information and as a non-invasive tool for treatment decision. Confirmatory studies are needed to corroborate these findings.
Identifiants
pubmed: 39003322
doi: 10.1038/s41598-024-67235-y
pii: 10.1038/s41598-024-67235-y
doi:
Substances chimiques
Circulating Tumor DNA
0
Biomarkers, Tumor
0
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Tumor Suppressor Protein p53
0
KRAS protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
16203Subventions
Organisme : Spanish National Agency of Research (AEI)
ID : FJC2021-046521-I
Organisme : Clínico Junior 2019 scholarship from the Spanish Association Against Cancer (AECC)
ID : CLJUN19010ARAS
Organisme : Clinico Junior 2023 scholarship from the Spanish Association Against Cancer (AECC)
ID : CLJUN234885LECU
Organisme : Department of Economic Development of Navarre
ID : 0011-1408-2017-000026
Informations de copyright
© 2024. The Author(s).
Références
Taieb, J. & Abdallah, R. How I treat pancreatic cancer. ESMO Open 4(Suppl 2), e000818. https://doi.org/10.1136/esmoopen-2020-000818 (2020).
doi: 10.1136/esmoopen-2020-000818
pubmed: 32817138
pmcid: 7451467
Wood, L. D., Canto, M. I., Jaffee, E. M. & Simeone, D. M. Pancreatic cancer: Pathogenesis, screening, diagnosis, and treatment. Gastroenterology 163(2), 386-402.e1. https://doi.org/10.1053/j.gastro.2022.03.056 (2022).
doi: 10.1053/j.gastro.2022.03.056
pubmed: 35398344
Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3), 209–249. https://doi.org/10.3322/caac.21660 (2021).
doi: 10.3322/caac.21660
pubmed: 33538338
Ferlay, J., Partensky, C. & Bray, F. More deaths from pancreatic cancer than breast cancer in the EU by 2017. Acta Oncol. 55(9–10), 1158–1160. https://doi.org/10.1080/0284186X.2016.1197419 (2016).
doi: 10.1080/0284186X.2016.1197419
pubmed: 27551890
Neoptolemos, J. 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 389(10073), 1011–1024. https://doi.org/10.1016/S0140-6736(16)32409-6 (2017).
doi: 10.1016/S0140-6736(16)32409-6
pubmed: 28129987
Conroy, T. et al. Five-year outcomes of FOLFIRINOX vs gemcitabine as adjuvant therapy for pancreatic cancer: A randomized clinical trial. JAMA Oncol. 8(11), 1571–1578. https://doi.org/10.1001/jamaoncol.2022.3829 (2022).
doi: 10.1001/jamaoncol.2022.3829
pubmed: 36048453
pmcid: 9437831
Isaji, S. et al. International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017. Pancreatology 18(1), 2–11. https://doi.org/10.1016/j.pan.2017.11.011 (2018).
doi: 10.1016/j.pan.2017.11.011
pubmed: 29191513
Nappo, G., Donisi, G. & Zerbi, A. Borderline resectable pancreatic cancer: Certainties and controversies. World J. Gastrointest. Surg. 13(6), 516–528. https://doi.org/10.4240/wjgs.v13.i6.516 (2021).
doi: 10.4240/wjgs.v13.i6.516
pubmed: 34194610
pmcid: 8223708
Sohal, D. P. S. et al. Efficacy of perioperative chemotherapy for resectable pancreatic adenocarcinoma: A phase 2 randomized clinical trial. JAMA Oncol. 7(3), 421–427. https://doi.org/10.1001/jamaoncol.2020.7328 (2021).
doi: 10.1001/jamaoncol.2020.7328
pubmed: 33475684
Versteijne, E. et al. Neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer: Long-term results of the Dutch randomized PREOPANC trial. J. Clin. Oncol. 40(11), 1220–1230. https://doi.org/10.1200/JCO.21.02233 (2022).
doi: 10.1200/JCO.21.02233
pubmed: 35084987
Wattenberg, M. M. et al. Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation. Br. J. Cancer 122(3), 333–339. https://doi.org/10.1038/s41416-019-0582-7 (2020).
doi: 10.1038/s41416-019-0582-7
pubmed: 31787751
García-Pardo, M., Makarem, M., Li, J. J. N., Kelly, D. & Leighl, N. B. Integrating circulating-free DNA (cfDNA) analysis into clinical practice: Opportunities and challenges. Br. J. Cancer 127(4), 592–602. https://doi.org/10.1038/s41416-022-01776-9 (2022).
doi: 10.1038/s41416-022-01776-9
pubmed: 35347327
pmcid: 9381753
Labiano, I. et al. State of the art: ctDNA in upper gastrointestinal malignancies. Cancers (Basel) https://doi.org/10.3390/cancers15051379 (2023).
doi: 10.3390/cancers15051379
pubmed: 36900172
Reichert, Z. R. et al. Prognostic value of plasma circulating tumor DNA fraction across four common cancer types: A real-world outcomes study. Ann. Oncol. 34(1), 111–120. https://doi.org/10.1016/j.annonc.2022.09.163 (2023).
doi: 10.1016/j.annonc.2022.09.163
pubmed: 36208697
Sausen, M. et al. Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. Nat. Commun. 6, 7686. https://doi.org/10.1038/ncomms8686 (2015).
doi: 10.1038/ncomms8686
pubmed: 26154128
Pietrasz, D. et al. Plasma circulating tumor DNA in pancreatic cancer patients is a prognostic marker. Clin. Cancer Res. 23(1), 116–123. https://doi.org/10.1158/1078-0432.CCR-16-0806 (2017).
doi: 10.1158/1078-0432.CCR-16-0806
pubmed: 27993964
Wei, T. et al. Monitoring tumor burden in response to FOLFIRINOX chemotherapy via profiling circulating cell-free DNA in pancreatic cancer. Mol. Cancer Ther. 18(1), 196–203. https://doi.org/10.1158/1535-7163.MCT-17-1298 (2019).
doi: 10.1158/1535-7163.MCT-17-1298
pubmed: 30301865
Strijker, M. et al. Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma. Int. J. Cancer 146(5), 1445–1456. https://doi.org/10.1002/ijc.32586 (2020).
doi: 10.1002/ijc.32586
pubmed: 31340061
Adamo, P. et al. Profiling tumour heterogeneity through circulating tumour DNA in patients with pancreatic cancer. Oncotarget 8(50), 87221–87233. https://doi.org/10.18632/oncotarget.20250 (2017).
doi: 10.18632/oncotarget.20250
pubmed: 29152076
pmcid: 5675628
Chen, H. et al. K-ras mutational status predicts poor prognosis in unresectable pancreatic cancer. Eur. J. Surg. Oncol. 36(7), 657–662. https://doi.org/10.1016/j.ejso.2010.05.014 (2010).
doi: 10.1016/j.ejso.2010.05.014
pubmed: 20542658
Jiang, J. et al. Circulating tumor DNA as a potential marker to detect minimal residual disease and predict recurrence in pancreatic cancer. Front. Oncol. 10, 1220. https://doi.org/10.3389/fonc.2020.01220 (2020).
doi: 10.3389/fonc.2020.01220
pubmed: 32850360
pmcid: 7406781
Toledano-Fonseca, M. et al. Circulating cell-free DNA-based liquid biopsy markers for the non-invasive prognosis and monitoring of metastatic pancreatic cancer. Cancers (Basel) https://doi.org/10.3390/cancers12071754 (2020).
doi: 10.3390/cancers12071754
pubmed: 32630266
Lee, B. et al. Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localized pancreatic cancer. Ann. Oncol. 30(9), 1472–1478. https://doi.org/10.1093/annonc/mdz200 (2019).
doi: 10.1093/annonc/mdz200
pubmed: 31250894
pmcid: 6771221
Pascual, J. et al. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: A report from the ESMO Precision Medicine Working Group. Ann. Oncol. 33(8), 750–768. https://doi.org/10.1016/j.annonc.2022.05.520 (2022).
doi: 10.1016/j.annonc.2022.05.520
pubmed: 35809752
Horak, P. et al. Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of clinical genome resource (ClinGen), cancer genomics consortium (CGC), and variant interpretation for cancer consortium (VICC). Genet. Med. 24(5), 986–998. https://doi.org/10.1016/j.gim.2022.01.001 (2022).
doi: 10.1016/j.gim.2022.01.001
pubmed: 35101336
pmcid: 9081216
Niroula, A. et al. Distinction of lymphoid and myeloid clonal hematopoiesis. Nat. Med. 27(11), 1921–1927. https://doi.org/10.1038/s41591-021-01521-4 (2021).
doi: 10.1038/s41591-021-01521-4
pubmed: 34663986
pmcid: 8621497
Gómez-España, M. A. et al. SEOM clinical guidelines for pancreatic and biliary tract cancer (2020). Clin. Transl. Oncol. 23(5), 988–1000. https://doi.org/10.1007/s12094-021-02573-1 (2021).
doi: 10.1007/s12094-021-02573-1
pubmed: 33660222
pmcid: 8058005
Miller-Phillips, L. & Collisson, E. A. RAS and other molecular targets in pancreatic cancer: The next wave is coming. Curr. Treat. Options Oncol. 24(8), 1088–1101. https://doi.org/10.1007/s11864-023-01096-x (2023).
doi: 10.1007/s11864-023-01096-x
pubmed: 37296367
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503(7477), 548–551. https://doi.org/10.1038/nature12796 (2013).
doi: 10.1038/nature12796
pubmed: 24256730
pmcid: 4274051
Golan, T. et al. Maintenance olaparib for germline. N. Engl. J. Med. 381(4), 317–327. https://doi.org/10.1056/NEJMoa1903387 (2019).
doi: 10.1056/NEJMoa1903387
pubmed: 31157963
pmcid: 6810605
Schram, A. M. et al. Zenocutuzumab, a HER2xHER3 bispecific antibody, is effective therapy for tumors driven by NRG1 gene rearrangements. Cancer Discov. 12(5), 1233–1247. https://doi.org/10.1158/2159-8290.CD-21-1119 (2022).
doi: 10.1158/2159-8290.CD-21-1119
pubmed: 35135829
pmcid: 9394398
Gouda, M. A. & Subbiah, V. Precision oncology with selective RET inhibitor selpercatinib in. Ther. Adv. Med. Oncol. 15, 17588359231177016. https://doi.org/10.1177/17588359231177015 (2023).
doi: 10.1177/17588359231177015
pubmed: 37360768
pmcid: 10288430
Hong, D. S. et al. Larotrectinib in patients with TRK fusion-positive solid tumours: A pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 21(4), 531–540. https://doi.org/10.1016/S1470-2045(19)30856-3 (2020).
doi: 10.1016/S1470-2045(19)30856-3
pubmed: 32105622
pmcid: 7497841
Okamura, R. et al. Comprehensive genomic landscape and precision therapeutic approach in biliary tract cancers. Int. J. Cancer 148(3), 702–712. https://doi.org/10.1002/ijc.33230 (2021).
doi: 10.1002/ijc.33230
pubmed: 32700810
Lamarca, A. et al. Molecular profiling in daily clinical practice: Practicalities in advanced cholangiocarcinoma and other biliary tract cancers. J. Clin. Med. https://doi.org/10.3390/jcm9092854 (2020).
doi: 10.3390/jcm9092854
pubmed: 32899345
pmcid: 7563385
Mohan, S. 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. 9(1), 11610. https://doi.org/10.1038/s41598-019-47489-7 (2019).
doi: 10.1038/s41598-019-47489-7
pubmed: 31406261
pmcid: 6690979
Kitahata, Y. et al. Circulating tumor DNA as a potential prognostic marker in patients with borderline-resectable pancreatic cancer undergoing neoadjuvant chemotherapy followed by pancreatectomy. Ann. Surg. Oncol. 29(3), 1596–1605. https://doi.org/10.1245/s10434-021-10985-0 (2022).
doi: 10.1245/s10434-021-10985-0
pubmed: 34724126
Lim, D. H. et al. Analysis of plasma circulating tumor DNA in borderline resectable pancreatic cancer treated with neoadjuvant modified FOLFIRINOX: Clinical relevance of DNA damage repair gene alteration detection. Cancer Res. Treat. 55(4), 1313–1320. https://doi.org/10.4143/crt.2023.452 (2023).
doi: 10.4143/crt.2023.452
pubmed: 37139665
pmcid: 10582539
Caliez, O. et al. Circulating tumor DNA: A help to guide therapeutic strategy in patients with borderline and locally advanced pancreatic adenocarcinoma?. Dig. Liver Dis. 54(10), 1428–1436. https://doi.org/10.1016/j.dld.2022.01.126 (2022).
doi: 10.1016/j.dld.2022.01.126
pubmed: 35120842
Yin, L. et al. Improved assessment of response status in patients with pancreatic cancer treated with neoadjuvant therapy using somatic mutations and liquid biopsy analysis. Clin. Cancer Res. 27(3), 740–748. https://doi.org/10.1158/1078-0432.CCR-20-1746 (2021).
doi: 10.1158/1078-0432.CCR-20-1746
pubmed: 33082211
Shah, D. et al. Prospective evaluation of circulating tumor DNA using next generation sequencing as a biomarker during neoadjuvant chemotherapy in localized pancreatic cancer. Ann. Surg. https://doi.org/10.1097/SLA.0000000000006209 (2024).
doi: 10.1097/SLA.0000000000006209
pubmed: 38979600
Arisi, M. F., Dotan, E. & Fernandez, S. V. Circulating tumor DNA in precision oncology and its applications in colorectal cancer. Int. J. Mol. Sci. https://doi.org/10.3390/ijms23084441 (2022).
doi: 10.3390/ijms23084441
pubmed: 36362235
pmcid: 9654348
Bettegowda, C. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl. Med. 6(224), 224ra24. https://doi.org/10.1126/scitranslmed.3007094 (2014).
doi: 10.1126/scitranslmed.3007094
pubmed: 24553385
pmcid: 4017867
Edland, K. H. et al. Monitoring of circulating tumour DNA in advanced pancreatic ductal adenocarcinoma predicts clinical outcome and reveals disease progression earlier than radiological imaging. Mol. Oncol. 17(9), 1857–1870. https://doi.org/10.1002/1878-0261.13472 (2023).
doi: 10.1002/1878-0261.13472
pubmed: 37341038
pmcid: 10483602
Tjensvoll, K. et al. Clinical relevance of circulating KRAS mutated DNA in plasma from patients with advanced pancreatic cancer. Mol. Oncol. 10(4), 635–643. https://doi.org/10.1016/j.molonc.2015.11.012 (2016).
doi: 10.1016/j.molonc.2015.11.012
pubmed: 26725968