Circulating Tumour DNA After Neoadjuvant Therapy in Non-Metastatic Colon Cancer: A Systematic Review and Implications for Surgical Decision-Making

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Abstract
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.

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