| Sumario: | Simple Summary: Here, we evaluated whether circulating tumor DNA (ctDNA) measured after neoadjuvant therapy (NAT) or surgery can help to assess tumor response and predict recurrence risk in patients with locally advanced rectal cancer, including those managed non-operatively (NOM). In this large real-world study of 220 patients, ctDNA positivity after NAT or surgery was strongly correlated with recurrence risk. Among the NOM patients, post-NAT ctDNA positivity identified individuals at nearly universal risk of local regrowth, while ctDNA negativity predicted durable responses. In the surgical patients, ctDNA clearance after resection was associated with favorable outcomes. ctDNA provides a molecular measure of treatment response that complements radiographic and endoscopic assessment. These findings suggest that ctDNA may help to tailor local therapy and surveillance strategies in rectal cancer and warrant validation in prospective ctDNA-guided trials. Background: Circulating tumor (ct)DNA is a prognostic biomarker in gastrointestinal malignancies. In rectal cancer, its utility to inform perioperative management and predict recurrence, particularly in patients undergoing non-operative management (NOM), remains unclear. Studies are needed to clarify how post-neoadjuvant therapy (NAT) and post-surgical ctDNA status correlate with clinical outcomes in localized rectal cancer. Methods: We retrospectively analyzed ctDNA data from 220 patients with rectal cancer using a personalized tumor-informed assay (Signatera™, Natera, Inc., Austin, TX, USA). Of these, 148 (67.3%) underwent NAT followed by surgery, and 72 (32.7%) underwent NAT followed by NOM. We assessed associations between post-NAT ctDNA status and survival outcomes. In the surgical cohort, we examined associations between post-operative ctDNA status and clinical response, pathological response, survival outcomes, and NAR scores. Results: In the surgical cohort, ctDNA positivity at the post-operative MRD timepoint was a strong predictor of recurrence, with an 88.3% relapse rate compared to 11.5% in ctDNA-negative patients (p < 0.001). Among the 64 NOM patients with post-NAT ctDNA, 21.9% (14/64) were ctDNA-positive, of whom 100% (14/14) relapsed (92.9% local-only), 13 relapsed by the time of data cut-off, and one relapsed 8 months after the cut-off. Only 10% (5/50) of the ctDNA-negative NOM patients experienced local recurrence (p < 0.0001). ctDNA positivity post-NAT was associated with inferior DFS (p = 0.003). Conclusion: ctDNA was a strong predictor of recurrence in rectal cancer, including in NOM settings. In NOM patients, ctDNA detected local recurrences, highlighting its potential to guide post-NAT surveillance and treatment.
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