Prognostic and Predictive Role of Circulating Tumor DNA in Locally Advanced Rectal Cancer Managed With Total Neoadjuvant Therapy: A Systematic Review

Background and Aims Circulating tumor DNA (ctDNA) has emerged as a promising biomarker of tumor burden and minimal residual disease. As total neoadjuvant therapy (TNT) increasingly supports organ‐preserving strategies in locally advanced rectal cancer (LARC), reliable markers of treatment response are needed. This review evaluates the prognostic and predictive value of ctDNA in this setting. Methods Following PRISMA guidelines, we systematically reviewed studies across PubMed/MEDLINE, Web of Science, Cochrane and Google Scholar evaluating ctDNA during or after TNT in LARC reporting treatment‐response or survival outcomes. Results Seven studies met inclusion criteria. Baseline ctDNA detection was near‐universal (83–100%) but lacked discriminatory value. ctDNA declined progressively during TNT, with post‐TNT negativity correlating with clinical or pathological complete response ( p = 0.007–0.038). Persistent positivity predicted residual disease and inferior survival (DFS HR 4.03; OS HR 23.0), with presurgical ctDNA in GEMCAD showing preferential association with hepatic recurrence suggesting a marker of systemic rather than locoregional disease. Post‐TNT ctDNA demonstrated high specificity but low sensitivity (23%–45%) for residual disease, and preceded clinical recurrence detection by weeks to months. Conclusions ctDNA clearance at the end of TNT may represent a biologically meaningful marker of treatment response and recurrence risk. However, current data derive from small, heterogeneous cohorts with variable assay platforms and sampling schedules, and ctDNA's limited sensitivity precludes its use as a standalone tool for non‐operative management selection.