Stage-specific circulating tumor DNA (ctDNA) positivity and minimal residual disease (MRD) decision making in colorectal cancer (CRC) in the prospective INTERCEPT program.

3623 Background: ctDNA positivity is a strong prognostic biomarker for recurrence after curative-intent procedures for CRC and defines MRD in the absence of radiographic disease. Our aim was to assess stage-specific positivity rates across follow-up intervals and the clinical actions associated with ctDNA+. Methods: The INTERCEPT program enrolled patients undergoing curatively intended procedures for stage I-IV CRC at MD Anderson Cancer Center. Tumor informed MRD assays (Signatera) were drawn postoperatively and every 3 months according to reimbursement guidelines. ctDNA draws were grouped into 6-month intervals from completion of definitive therapy. Clinical decisions after the first ctDNA+ result in the MRD window were classified as: MRD-trial, systemic therapy, diagnostic escalation, early follow-up, ctDNA confirmation, or no change. Results: The final cohort included 1,603 patients (40% stage IV, 32% stage III, 20% stage II, 8% stage I). Median follow-up was 18.4 months. Patients that were ctDNA- on first post-definitive draw had longer recurrence-free survival (RFS) than ctDNA+ patients (median RFS 62.6 vs 4.8 months, HR 11.6 [95% CI 9.6-14.1]), remaining significant in stage subgroups. Among all patients 28% were ctDNA+ at any post-definitive timepoint, the rates were highest for stage IV, followed by stage III, II, and I (Table). ctDNA+ rates were highest in early follow-up and got lower at later intervals (21% to 5%), with similar patterns for all stages. Among 271 patients that were ctDNA+ in the MRD window the initial therapeutic approach was MRD trial screening for 59 (22%), diagnostic escalation in 73 (18%), early follow-up in 57 (21%), confirmation of ctDNA+ by repeat testing in 23 (8%), no change in management for 38 (14%), and 21 (8%) patients started other systemic therapy. MRD trials were discussed prior to recurrence with 144 (53%) of the patients. Conclusions: ctDNA positivity is more common in higher stage tumors and becomes less frequent during follow-up. ctDNA positivity confirms its established prognostic value and meaningfully impacts clinical management, including diagnostic workup and MRD trial enrollment. Even within a single center, heterogeneity in initial management of ctDNA+ patients and timing for MRD trial enrollment is evident. Stage-specific ctDNA+ rates during follow-up after definitive therapy. All Stage IV Stage III Stage II Stage I p Any time 444 / 1,603 (28%) 313 / 646 (48%) 87 / 513 (17%) 40 / 322 (12%) 4 / 122 (3%) <0.001 <6 months 329 / 1603 (21%) 249 / 646 (39%) 57 / 513 (11%) 21 / 322 (7%) 2 / 122 (2%) <0.001 6 to <12 months 151 / 1,018 (15%) 97 / 349 (28%) 36 / 351 (10%) 17 / 230 (7%) 1 / 88 (1%) <0.001 12 to <18 months 75 / 672 (11%) 50 / 197 (25%) 15 / 250 (6%) 10 / 161 (6%) 0 / 64 (0%) <0.001 18 to <24 months 16 / 264 (6%) 10 / 71 (14%) 3 / 94 (3%) 3 / 71 (4%) 0 / 28 (0%) 0.019 ≥24 months 9 / 147 (6%) 5 / 41 (12%) 2 / 58 (3%) 1 / 33 (3%) 1 / 15 (7%) 0.259