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Circulating Tumour DNA After Neoadjuvant Therapy in Non-Metastatic Colon Cancer: A Systematic Review and Implications
Mahmoud M Salama1,2,3, Charles Eddershaw3, Hugo C Temperley2,4
1School of Medicine, Trinity College Dublin, D02 PN40 Dublin, Ireland.
Introduction:
Neoadjuvant systemic and immunotherapy strategies in non-metastatic colon cancer have demonstrated high pathological response rates, raising interest in surgery-sparing approaches. Circulating tumour DNA (ctDNA) is an emerging biomarker for treatment response and minimal residual disease, but its role in guiding surgical omission in colon cancer remains unclear. This systematic review evaluates the diagnostic and prognostic accuracy of ctDNA in predicting pathological response following neoadjuvant therapy in non-metastatic colon cancer.
Methods:
A systematic review was conducted in accordance with PRISMA guidelines. PubMed, Embase/MEDLINE, Scopus, and the Cochrane Register were searched from inception to 21 October 2025. Eligible studies included adults with non-metastatic colon cancer treated with neoadjuvant therapy who had serial ctDNA assessment prior to surgery.
Results:
Three cohort studies comprising 100 patients met inclusion criteria. Baseline ctDNA detection ranged from 42% to 84%. Across studies, ctDNA clearance following neoadjuvant therapy was consistently associated with major pathological response or pathological complete response, whereas persistent ctDNA strongly predicted residual viable tumour at resection. In the largest prospective cohort, 5 of 26 patients (19%) achieved ctDNA clearance prior to surgery; all were pathological responders, while 19 of 26 patients (73%) with persistent ctDNA demonstrated no pathological response. No study reported pathological complete response in the presence of persistently positive ctDNA. No prospective trial formally evaluated ctDNA-guided surgical omission.
Conclusions:
Current evidence does not support the use of ctDNA alone to guide omission of surgery after neoadjuvant therapy in non-metastatic colon cancer-even in patients who show complete pathological response. While persistent ctDNA reliably identifies patients with residual disease, ctDNA clearance lacks sufficient positive predictive value to safely forego surgery. Prospective trials with standardised ctDNA platforms and predefined non-operative management protocols are required before ctDNA-guided organ preservation can be recommended.
Insights
Circulating tumor DNA (ctDNA) shows promise in predicting colon cancer response to neoadjuvant therapy. However, current evidence suggests ctDNA alone is insufficient to guide surgical omission, necessitating further research.
Area of Science:
- Oncology
- Molecular Diagnostics
- Surgical Oncology
Background:
- Neoadjuvant therapies for non-metastatic colon cancer yield high pathological response rates, prompting interest in surgery-sparing strategies.
- Circulating tumor DNA (ctDNA) is an emerging biomarker for treatment response and minimal residual disease.
- The utility of ctDNA in guiding surgical omission for colon cancer requires further investigation.
Purpose of the Study:
- To systematically review the diagnostic and prognostic accuracy of ctDNA in predicting pathological response after neoadjuvant therapy in non-metastatic colon cancer.
- To evaluate the potential role of ctDNA in guiding surgical omission decisions.
Main Methods:
- A systematic review adhering to PRISMA guidelines was performed.
- Searches were conducted across PubMed, Embase/MEDLINE, Scopus, and the Cochrane Register up to October 21, 2025.
- Included studies involved adults with non-metastatic colon cancer receiving neoadjuvant therapy with serial ctDNA assessments before surgery.
Main Results:
- Three cohort studies with 100 patients met the criteria.
- ctDNA clearance post-neoadjuvant therapy correlated with major pathological response or complete pathological response.
- Persistent ctDNA strongly predicted residual tumor, while ctDNA clearance lacked sufficient positive predictive value to omit surgery.
Conclusions:
- Current data do not support using ctDNA alone to guide surgical omission in non-metastatic colon cancer, even with a complete pathological response.
- Persistent ctDNA reliably identifies patients with residual disease, but ctDNA clearance is not adequate to safely avoid surgery.
- Prospective trials with standardized ctDNA platforms and non-operative management protocols are essential before recommending ctDNA-guided organ preservation.
