Abstract
Recurrence after curative-intent surgery for colorectal cancer is a major cause of cancer-related death. Circulating cell-free tumor DNA (ctDNA) is increasingly used in the perioperative setting to detect residual disease. However, the association between preoperative ctDNA, the tumor microenvironment, including tumor-infiltrating lymphocytes, and recurrence is unknown. We explored the association between ctDNA and the tumor microenvironment in patients with non-metastatic CRC undergoing curative-intent surgery. ctDNA was assessed using a tumor-agnostic hypermethylated cfDNA test. Among 140 patients, ctDNA tested positive in 102 (72.9%) before surgery, with 38 (27.1%) tumors classified as immune infiltration high. ctDNA was associated with expression of cancer-metastasis pathways, while immune active phenotypes were associated with immune infiltration high tumors. ctDNA status could identify deficient mismatch repair tumors with an active immune phenotype. The results suggest that a positive ctDNA analysis before surgery is associated with a metastatic tumor microenvironment.
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Acknowledgements
Biorender.com and Adobe Illustrator was used for figure preparation. This study was funded by the Misse and Valdemar Risoms Foundation (IG, no grant number), the Toyota Foundation (IG, no grant number), the Novo Nordic Foundation (CLA grants no. NNF17OC0025052 and NNF22OC0074415), and the Danish Cancer Society (CLA grant no. R231-A13845).
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Conceptualization: M.G. and I.G. Methodology: M.G., I.G., and C.A. Investigation: M.G., S.J., N.Ø., I.L., M.B., R.D.B., and A.F. Visualization: M.G. and L.B. Funding acquisition: M.G., I.G., and C.L.A. Supervision: I.G. and C.A. Writing—original draft: M.G. Writing—review and editing: All authors.
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Gögenur, M., Balsevicius, L., Jensen, S.Ø. et al. Preoperative positive ctDNA analysis is associated with the tumor microenvironment, and the risk of recurrence in non-metastatic colorectal cancer. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01288-2
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DOI: https://doi.org/10.1038/s41698-026-01288-2
