Annals of Laboratory Medicine

Korean Society for Laboratory Medicine (대한진단검사의학회)
권호 표지
DOI QR코드

DOI QR Code

Prognostic Value of Residual Circulating Tumor DNA in Metastatic Pancreatic Ductal Adenocarcinoma

  • Hongkyung Kim (Department of Laboratory Medicine, Chung-Ang University College of Medicine) ;
  • Jinho Lee (Department of Laboratory Medicine, Yonsei University College of Medicine, Severance Hospital) ;
  • Mi Ri Park (Department of Laboratory Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine) ;
  • Zisun Choi (Dxome Co., Ltd.) ;
  • Seung Jung Han (Dxome Co., Ltd.) ;
  • Dongha Kim (Dxome Co., Ltd.) ;
  • Saeam Shin (Department of Laboratory Medicine, Yonsei University College of Medicine, Severance Hospital) ;
  • Seung-Tae Lee (Department of Laboratory Medicine, Yonsei University College of Medicine, Severance Hospital) ;
  • Jong Rak Choi (Department of Laboratory Medicine, Yonsei University College of Medicine, Severance Hospital) ;
  • Seung Woo Park (Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital)
  • Received : 2024.07.04
  • Accepted : 2024.12.20
  • Published : 2025.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Circulating tumor DNA (ctDNA) is a potential biomarker in pancreatic ductal adenocarcinoma (PDAC). However, studies on residual ctDNA in patients post-chemotherapy are limited. We assessed the prognostic value of residual ctDNA in metastatic PDAC relative to that of carbohydrate antigen 19-9 (CA19-9). Methods: ctDNA analysis using a targeted next-generation sequencing panel was performed at baseline and during chemotherapy response evaluation in 53 patients. Progression-free survival (PFS) and overall survival (OS) were first evaluated based on ctDNA positivity at baseline. For further comparison, patients testing ctDNA-positive at baseline were subdivided based on residual ctDNA into ctDNA responders (no residual ctDNA post-chemotherapy) and ctDNA non-responders (residual ctDNA post-chemotherapy). Additional survival analysis was performed based on CA19-9 levels. Results: The baseline ctDNA detection rate was 56.6%. Although clinical outcomes tended to be poorer in patients with baseline ctDNA positivity than in those without, the differences were not significant. Residual ctDNA post-chemotherapy was associated with reduced PFS and OS. The prognosis of ctDNA responders was better than that of non-responders but did not significantly differ from that of ctDNA-negative individuals (no ctDNA both at baseline and during post-chemotherapy). Compared with ctDNA responses to chemotherapy, a ≥50% decrease in the CA19-9 level had less effect on both PFS and OS based on hazard ratios and significance levels. ctDNA could be monitored in half of the patients whose baseline CA19-9 levels were within the reference range. Conclusions: Residual ctDNA analysis post-chemotherapy is a promising approach for predicting the clinical outcomes of patients with metastatic PDAC.

Keywords

Acknowledgement

We thank the patients who participated in this study and their families.

References

  1. 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. https://doi.org/10.3322/caac.21660
  2. Ilic I and Ilic M. International patterns in incidence and mortality trends of pancreatic cancer in the last three decades: a joinpoint regression analysis. World J Gastroenterol 2022;28:4698–715. https://doi.org/10.3748/wjg.v28.i32.4698
  3. Quante AS, Ming C, Rottmann M, Engel J, Boeck S, Heinemann V, et al. Projections of cancer incidence and cancer-related deaths in Germany by 2020 and 2030. Cancer Med 2016;5:2649–56. https://doi.org/10.1002/cam4.767
  4. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913–21. https://doi.org/10.1158/0008-5472.CAN-14-0155
  5. Wood LD, Canto MI, Jaffee EM, Simeone DM. Pancreatic cancer: pathogenesis, screening, diagnosis, and treatment. Gastroenterology 2022;163:386–402.e1. https://doi.org/10.1053/j.gastro.2022.03.056
  6. 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. https://doi.org/10.1056/NEJMoa1011923
  7. 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. https://doi.org/10.1056/NEJMoa1304369
  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. https://doi.org/10.1093/annonc/mdy417
  9. Orth M, Metzger P, Gerum S, Mayerle J, Schneider G, Belka C, et al. Pancreatic ductal adenocarcinoma: biological hallmarks, current status, and future perspectives of combined modality treatment approaches. Radiat Oncol 2019;14:141. https://doi.org/10.1186/s13014-019-1345-6
  10. Hess V, Glimelius B, Grawe P, Dietrich D, Bodoky G, Ruhstaller T, et al. CA 19-9 tumour-marker response to chemotherapy in patients with advanced pancreatic cancer enrolled in a randomised controlled trial. Lancet Oncol 2008;9:132–8. https://doi.org/10.1016/S1470-2045(08)70001-9
  11. Morris-Stiff G and Taylor MA. Ca19-9 and pancreatic cancer: is it really that good? J Gastrointest Oncol 2012;3:88–9
  12. Ballehaninna UK and 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.
  13. Tempero MA, Uchida E, Takasaki H, Burnett DA, Steplewski Z, Pour PM. Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer. Cancer Res 1987;47:5501–3.
  14. 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.
  15. Reichert ZR, Morgan TM, Li G, Castellanos E, Snow T, Dall'Olio FG, et al. Prognostic value of plasma circulating tumor DNA fraction across four common cancer types: a real-world outcomes study. Ann Oncol 2023;34:111–20. https://doi.org/10.1016/j.annonc.2022.09.163
  16. Bachet JB, Blons H, Hammel P, Hariry IE, Portales F, Mineur L, et al. Circulating tumor DNA is prognostic and potentially predictive of eryaspase efficacy in second-line in patients with advanced pancreatic adenocarcinoma. Clin Cancer Res 2020;26:5208–16. https://doi.org/10.1158/1078-0432.CCR-20-0950
  17. Lapin M, Edland KH, Tjensvoll K, Oltedal S, Austdal M, Garresori H, et al. Comprehensive ctDNA measurements improve prediction of clinical outcomes and enable dynamic tracking of disease progression in advanced pancreatic cancer. Clin Cancer Res 2023;29:1267–78. https://doi.org/10.1158/1078-0432.CCR-22-3526
  18. Kirchweger P, Kupferthaler A, Burghofer J, Webersinke G, Jukic E, Schwendinger S, et al. Prediction of response to systemic treatment by kinetics of circulating tumor DNA in metastatic pancreatic cancer. Front Oncol 2022;12:902177. https://doi.org/10.3389/fonc.2022.902177
  19. Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, et al. Standards and guidelines for the interpretation and reporting of se-quence variants in cancer: a joint consensus recommendation of the association for molecular pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn 2017;19:4–23. https://doi.org/10.1016/j.jmoldx.2016.10.002
  20. Lee KS, Seo J, Lee CK, Shin S, Choi Z, Min S, et al. Analytical and clinical validation of cell-free circulating tumor DNA assay for the estimation of tumor mutational burden. Clin Chem 2022;68:1519–28. https://doi.org/10.1093/clinchem/hvac146
  21. Elazezy M and Joosse SA. Techniques of using circulating tumor DNA as a liquid biopsy component in cancer management. Comput Struct Biotechnol J 2018;16:370–8. https://doi.org/10.1016/j.csbj.2018.10.002
  22. Hasenleithner SO and Speicher MR. A clinician's handbook for using ctDNA throughout the patient journey. Mol Cancer 2022;21:81. https://doi.org/10.1186/s12943-022-01551-7
  23. Sivapalan L, Kocher HM, Ross-Adams H, Chelala C. Molecular profiling of ctDNA in pancreatic cancer: opportunities and challenges for clinical application. Pancreatology 2021;21:363–78. https://doi.org/10.1016/j.pan.2020.12.017
  24. Reni M, Cereda S, Balzano G, Passoni P, Rognone A, Fugazza C, et al. Carbohydrate antigen 19-9 change during chemotherapy for advanced pancreatic adenocarcinoma. Cancer 2009;115:2630–9. https://doi.org/10.1002/cncr.24302