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Peer-reviewedCC BY 4.0Cancers

Circulating Tumor DNA in Resected Colorectal Liver Metastases: From Minimal Residual Disease Detection to Treatment Guidance—A Systematic Review

  • Melina Yerolatsite1,2
  • Nanteznta Torounidou2
  • Loizos Hadjigeorgiou3
  • Anna-Lea Amylidi1
  • Evangeli Lampri4
  • Georgios D. Lianos3
  • Angeliki Magklara5,6
  • George Zarkavelis1,7
7 affiliations
  1. 1Department of Medical Oncology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece
  2. 2Department of Medical Oncology, University Hospital of Ioannina, 45500 Ioannina, Greece
  3. 3Department of General Surgery, University Hospital of Ioannina, 45500 Ioannina, Greece
  4. 4Department of Pathology, University of Ioannina, 45110 Ioannina, Greece
  5. 5Department of Clinical Chemistry, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
  6. 6Biomedical Research Institute-Foundation for Research and Technology, 45110 Ioannina, Greece
  7. 7Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45444 Ioannina, Greece
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Abstract

Background: Circulating tumor DNA (ctDNA) has emerged as a potential marker of minimal residual disease (MRD) after resection of colorectal liver metastases (CRLM), but its prognostic value and possible role in guiding postoperative management remain uncertain. This systematic review evaluated the available evidence on ctDNA for predicting recurrence and survival after CRLM resection, with particular attention to perioperative and serial ctDNA measurements and their potential value in guiding adjuvant treatment. Methods: PubMed/MEDLINE, Scopus, and the Cochrane Library were searched from inception to 21 July 2026 for studies evaluating ctDNA in patients undergoing resection of CRLM. Prospective and retrospective cohort studies and relevant randomized trial sub-studies were eligible. The primary outcome was the association between ctDNA status and recurrence, while secondary outcomes included recurrence-free survival (RFS), disease-free survival (DFS), overall survival (OS), serial ctDNA dynamics, and the potential predictive value of ctDNA for adjuvant chemotherapy. Risk of bias was assessed using the QUIPS tool. Findings were synthesized narratively, with an additional exploratory random-effects meta-analysis of early postoperative tissue-informed ctDNA positivity and RFS/DFS. Unadjusted and adjusted HRs were pooled separately. Results: Twenty-eight studies published between 2018 and 2026 were included, representing 2079 unique patients after accounting for overlapping cohorts. In six studies, postoperative ctDNA positivity was associated with poorer RFS/DFS (pooled unadjusted HR 5.15, 95% CI 3.65–7.27; I2 = 0%). Five studies provided adjusted estimates (pooled HR 4.95, 95% CI 2.45–10.01; I2 = 60.5%). Serial monitoring provided additional prognostic information: persistent ctDNA positivity or conversion from negative to positive during follow-up was associated with poor outcomes, whereas ctDNA clearance was generally associated with a lower risk of recurrence. ctDNA could precede radiological recurrence by approximately 2.5 to >20 months, although detection was less reliable in patients with small-volume pulmonary recurrence. In contrast, the prognostic value of preoperative ctDNA was less consistent and appeared to depend on assay methodology, quantitative ctDNA burden, and previous systemic treatment. Observational studies reported associations between postoperative MRD status and outcomes following adjuvant chemotherapy, but non-randomized treatment allocation and potential time-related bias limit conclusions about treatment benefit. Considerable variation in assay platforms and postoperative sampling schedules remained across studies. Conclusions: Postoperative ctDNA positivity is associated with poorer recurrence-related outcomes after CRLM resection. However, the moderate-to-high risk of bias and differences between studies limit confidence in the evidence. The predictive value of ctDNA for adjuvant chemotherapy benefit remains unproven. Prospective randomized trials are needed to determine whether ctDNA-guided management improves patient outcomes.

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Cite

BibTeXRIS
BibTeX
@article{yerolatsite2026circulating,
  title = {{Circulating Tumor DNA in Resected Colorectal Liver Metastases: From Minimal Residual Disease Detection to Treatment Guidance—A Systematic Review}},
  author = {Melina Yerolatsite and Nanteznta Torounidou and Loizos Hadjigeorgiou and Anna-Lea Amylidi and Evangeli Lampri and Georgios D. Lianos and Angeliki Magklara and George Zarkavelis},
  journal = {Cancers},
  year = {2026},
  month = oct,
  doi = {10.3390/cancers18203304},
  url = {https://www.mdpi.com/2072-6694/18/20/3304},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Circulating Tumor DNA in Resected Colorectal Liver Metastases: From Minimal Residual Disease Detection to Treatment Guidance—A Systematic Review
AU  - Melina Yerolatsite
AU  - Nanteznta Torounidou
AU  - Loizos Hadjigeorgiou
AU  - Anna-Lea Amylidi
AU  - Evangeli Lampri
AU  - Georgios D. Lianos
AU  - Angeliki Magklara
AU  - George Zarkavelis
PY  - 2026
DA  - 2026/10/01
JO  - Cancers
DO  - 10.3390/cancers18203304
UR  - https://www.mdpi.com/2072-6694/18/20/3304
AB  - Background: Circulating tumor DNA (ctDNA) has emerged as a potential marker of minimal residual disease (MRD) after resection of colorectal liver metastases (CRLM), but its prognostic value and possible role in guiding postoperative management remain uncertain. This systematic review evaluated the available evidence on ctDNA for predicting recurrence and survival after CRLM resection, with particular attention to perioperative and serial ctDNA measurements and their potential value in guiding adjuvant treatment. Methods: PubMed/MEDLINE, Scopus, and the Cochrane Library were searched from inception to 21 July 2026 for studies evaluating ctDNA in patients undergoing resection of CRLM. Prospective and retrospective cohort studies and relevant randomized trial sub-studies were eligible. The primary outcome was the association between ctDNA status and recurrence, while secondary outcomes included recurrence-free survival (RFS), disease-free survival (DFS), overall survival (OS), serial ctDNA dynamics, and the potential predictive value of ctDNA for adjuvant chemotherapy. Risk of bias was assessed using the QUIPS tool. Findings were synthesized narratively, with an additional exploratory random-effects meta-analysis of early postoperative tissue-informed ctDNA positivity and RFS/DFS. Unadjusted and adjusted HRs were pooled separately. Results: Twenty-eight studies published between 2018 and 2026 were included, representing 2079 unique patients after accounting for overlapping cohorts. In six studies, postoperative ctDNA positivity was associated with poorer RFS/DFS (pooled unadjusted HR 5.15, 95% CI 3.65–7.27; I2 = 0%). Five studies provided adjusted estimates (pooled HR 4.95, 95% CI 2.45–10.01; I2 = 60.5%). Serial monitoring provided additional prognostic information: persistent ctDNA positivity or conversion from negative to positive during follow-up was associated with poor outcomes, whereas ctDNA clearance was generally associated with a lower risk of recurrence. ctDNA could precede radiological recurrence by approximately 2.5 to >20 months, although detection was less reliable in patients with small-volume pulmonary recurrence. In contrast, the prognostic value of preoperative ctDNA was less consistent and appeared to depend on assay methodology, quantitative ctDNA burden, and previous systemic treatment. Observational studies reported associations between postoperative MRD status and outcomes following adjuvant chemotherapy, but non-randomized treatment allocation and potential time-related bias limit conclusions about treatment benefit. Considerable variation in assay platforms and postoperative sampling schedules remained across studies. Conclusions: Postoperative ctDNA positivity is associated with poorer recurrence-related outcomes after CRLM resection. However, the moderate-to-high risk of bias and differences between studies limit confidence in the evidence. The predictive value of ctDNA for adjuvant chemotherapy benefit remains unproven. Prospective randomized trials are needed to determine whether ctDNA-guided management improves patient outcomes.
SN  - 2072-6694
ER  -