Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jan;28(1):83-95.
doi: 10.1007/s10120-024-01556-9. Epub 2024 Oct 5.

Circulating tumor DNA predicts recurrence and survival in patients with resectable gastric and gastroesophageal junction cancer

Cecilie Riis Iden #  1 , Salah Mohammad Mustafa #  2   3 , Nadia Øgaard  2   3 , Tenna Henriksen  2   3 , Sarah Østrup Jensen  2   3 , Lise Barlebo Ahlborn  4 , Kristian Egebjerg  1 , Lene Baeksgaard  1 , Rajendra Singh Garbyal  5 , Mette Kjølhede Nedergaard  5 , Michael Patrick Achiam  6 , Claus Lindbjerg Andersen #  2   3 , Morten Mau-Sørensen #  7
Affiliations

Circulating tumor DNA predicts recurrence and survival in patients with resectable gastric and gastroesophageal junction cancer

Cecilie Riis Iden et al. Gastric Cancer. 2025 Jan.

Abstract

Background: Gastric and gastroesophageal junction (GEJ) cancer represents a significant global health challenge, with high recurrence rates and poor survival outcomes. This study investigates circulating tumor DNA (ctDNA) as a biomarker for assessing recurrence risk in patients with resectable gastric and GEJ adenocarcinomas (AC).

Methods: Patients with resectable gastric and GEJ AC, undergoing perioperative chemotherapy and surgery, were prospectively enrolled. Serial plasma samples were collected at baseline, after one cycle of chemotherapy, after preoperative chemotherapy, and after surgery. ctDNA was assessed by a ddPCR test (TriMeth), which targets the gastrointestinal cancer-specific methylation patterns of the genes C9orf50, KCNQ5, and CLIP4.

Results: ctDNA analysis was performed on 229 plasma samples from 86 patients. At baseline, ctDNA was detected in 56% of patients, which decreased to 37% following one cycle of chemotherapy, 25% after preoperative chemotherapy and 15% after surgical resection. The presence of ctDNA after one cycle of chemotherapy was associated with reduced recurrence-free survival (RFS) (HR = 2.54, 95% confidence interval (CI) 1.33-4.85, p = 0.005) and overall survival (OS) (HR = 2.23, 95% CI 1.07-4.62, p = 0.032). Similarly, ctDNA after surgery was associated with significantly shorter RFS (HR = 6.22, 95% CI 2.39-16.2, p < 0.001) and OS (HR = 6.37, 95% CI 2.10-19.3, p = 0.001). Multivariable regression analysis confirmed ctDNA after surgery as an independent prognostic factor (p < 0.001).

Conclusion: ctDNA analysis has the potential to identify patients at elevated risk of recurrence, thus providing personalized treatment strategies for patients with resectable gastric and GEJ cancer. Further validation in larger cohorts and ctDNA-guided interventions are needed for future clinical use.

Keywords: Circulating tumor DNA; Curative treatment; DNA methylation; Gastroesophageal cancer; Tumor biomarkers.

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval and informed consent: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. This study was performed in line with the principles of the Declaration of Helsinki. Approvals were granted from The Ethics Committee of the Capital Region Denmark for the collection and use of biological samples and the capture of clinical data from patient journals. Informed consent was obtained from all participating patients. The Danish Data Protection Agency approved the study.

Figures

Fig. 1
Fig. 1
Study design. a Plasma samples from 86 patients with resectable gastric GEJ cancer, were collected at baseline, after one cycle of chemotherapy (CT), after preoperative CT and 2–4 weeks following surgical resection. Cell-free DNA was extracted from plasma prior to bisulfite conversion, and subsequently analyzed using a DNA methylation-specific ddPCR assay (TriMeth). Plasma samples were classified as ctDNA positive (detected) or ctDNA negative (not detected). b Consort diagram illustrating the patient and plasma selection process for ctDNA analysis. Figure created using BioRender.com. GEJ gastroesophageal junction; CT chemotherapy; ddPCR droplet digital polymerase chain reaction; ctDNA circulating tumor DNA, Me methylation
Fig. 2
Fig. 2
Serial plasma sampling and clinical outcomes in the 86 patients with plasma samples analyzed for ctDNA. a Follow-up time is indicated by the gray horizontal line. The absence or presence of circulating tumor DNA (ctDNA) is denoted by white and black dots, respectively. Surgical resection is marked with a steel blue asterisk (*), clinical or radiological recurrence with a red line (I), and death with a black "X". b Time to recurrence in ctDNA-positive and -negative patients after one cycle of chemotherapy (c) and after surgical resection, in recurrent patients (n = 38), presented in boxplots and a density plots. ctDNA circulating tumor DNA
Fig. 3
Fig. 3
Kaplan–Meier analysis in the 86 patients with plasma analyzed for ctDNA. Red curves represent patients with detected ctDNA, while blue curves show patients without detected ctDNA. Vertical tick-marks indicate censoring. Number of events and at-risk patients are provided below each graph. a, c, e, f Recurrence-free survival (RFS) and b, d, f, g overall survival (OS) for patients with ctDNA analyses available at a, b baseline, c, d after one cycle of chemotherapy (CT), e, f after preoperative CT, and g, h after surgery. HR Hazard Ratio; ctDNA circulating tumor DNA; CT chemotherapy
Fig. 4
Fig. 4
Kaplan–Meier analysis in four patient groups based on changes in ctDNA status during treatment: ‘negative to negative’ (green); ‘negative to positive’ (blue); ‘positive to negative’ (purple); ‘positive to positive’ (orange). a, c Recurrence-free survival (RFS) and overall survival (OS) (b, d) for ctDNA status transitions from baseline to after one cycle of chemotherapy (CT) (a, b) and ctDNA status transitions from after one cycle of CT to after surgical resection (c, d). Number of events and at-risk patients are provided below each graph. Vertical tick-marks indicate censoring. ctDNA circulating tumor DNA; CT chemotherapy
See this image and copyright information in PMC

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(3):209–49. - PubMed
    1. GLOBOCAN [Internet]. Lyon: World Health Organization, International Agency for Research on Cancer; c2024 [cited 2024 Feb 10]. Available from: https://gco.iarc.fr/
    1. Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev. 2014;23(5):700–13. - PMC - PubMed
    1. Obermannová R, Alsina M, Cervantes A, Leong T, Lordick F, Nilsson M, et al. Oesophageal cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(10):992–1004. - PubMed
    1. Lordick F, Carneiro F, Cascinu S, Fleitas T, Haustermans K, Piessen G, et al. Gastric cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(10):1005–20. - PubMed

MeSH terms

LinkOut - more resources