Association between circulating tumor DNA and local tumor regrowth and distant metastasis during nonoperative management in stage I–III rectal cancer.

3615 Background: During nonoperative management (NOM) for rectal cancer after a clinical complete response (cCR) or near-CR (nCR), 25–30% develop local regrowth and 5–10% develop distant metastasis, highlighting the need for improved risk stratification and surveillance. Circulating tumor DNA (ctDNA) has emerged as a prognostic biomarker, but its utility in NOM decision making remains undefined. Methods: We retrospectively studied 110 patients with stages I-III, microsatellite stable rectal adenocarcinoma achieving cCR/nCR after neoadjuvant therapy (2020-2024) managed with NOM and tumor-informed ctDNA testing in the INTERCEPT program (Signatera Exome). We assessed longitudinal ctDNA status during NOM and the first post-treatment ctDNA in relation to local regrowth and/or distant metastasis (Kaplan–Meier/log-rank; Fisher’s exact). We also evaluated per-sample accuracy for events occurring within ±90 days of each blood draw. Results: Over a median follow-up of 25 months, 23 (20.9%) patients developed local regrowth and 12 (10.9%) developed distant metastases (Table 1). Patients with ever positive longitudinal ctDNA had an associated worse 2-year regrowth-free survival (41.7% vs 83.9%, P=0.0002) and metastasis-free survival (41.7% vs 94.9%, P<0.0001) than those with persistently negative ctDNA. Among patients with an evaluable first post-treatment ctDNA result (within 180 days post treatment; n=72), those with a positive result had an associated lower regrowth-free survival (P = 0.0006) and metastasis-free survival (P < 0.0001). In per-sample analysis (n=669), ctDNA showed low sensitivity and high specificity for local regrowth (41.4% and 94.3%) and higher sensitivity and specificity for distant metastasis (73.8% and 97.4%). Twenty-two of 23 patients with local regrowth underwent salvage surgery; ctDNA positivity at local regrowth was associated with more advanced pathological T stage (66.7% of ypT3–4 vs 15.4% of ypT0–2, P=0.01). Conclusions: During NOM for rectal cancer, ctDNA may be used to identify a small subgroup at high risk of local regrowth and/or distant metastasis. However, many local regrowth occurs despite persistently negative ctDNA, consistent with limited sensitivity. Negative ctDNA results should therefore not prompt de-escalation of endoscopic and radiologic surveillance when a NOM strategy is used. Overall rates of local regrowth and distant metastasis. Local regrowth (n=23) a P Distant metastasis (n=12) P Longitudinal ctDNA <.0001 <.0001 Persistently negative (n=95) 14/95 (14.7%) 3/95 (3.2%) Ever positive (n=15) 9/15 (60.0%) 9/15 (60.0%) First post-treatment ctDNA b 0.005 <.0001 Negative (n=67) 15/67 (22.4%) 5/67 (7.5%) Positive (n=5) 4/5 (80.0%) 4/5 (80.0%) a Two had synchronous and 5 had metachronous distant metastasis. b Within 6 months post treatment, n = 72.