Chemotherapy for patients with circulating tumour DNA positive, stage II colon cancer (CIRCULATE) – an AIO / ABCSG trial

AbstractBackground Adjuvant chemotherapy provides limited benefit in unselected stage II colon cancer. Postoperative ctDNA has higher prognostic value than classical clinical markers, with ctDNA positivity indicating an unfavourable outcome. Patients and methods Patients with UICC II, pMMR/MSS colon cancer were tested for ctDNA using an academic, tumour-informed, NGS-based test. ctDNA-positive patients were randomised 2:1 to CHEMO (capecitabine ± oxaliplatin) versus observation (OBS). ctDNA-negative patients were randomised 1:4 to OBS versus OFF-STUDY. ctDNA results were not disclosed in the OBS group. The primary endpoint was DFS in ctDNA-positive patients. All differences were tested using one-sided log-rank tests. The trial ended early due to funding expiry. Results From 06/2020 to 07/2025, 2,126 patients were screened in Germany and Austria. Overall, 1,396 patients (2.9% ctDNA-positive) were randomised: 1,083 to OFF-STUDY, 287 to OBS, and 26 to CHEMO, of whom 81% started therapy. DFS and OS were significantly lower in ctDNA-positive versus ctDNA-negative patients (3-year DFS 52% versus 87%, HR 4.28 95% CI: 2.32–7.93, P ; 3-year OS 88% versus 98%, HR 5.48 1.64–18.28, P = 0.001). In the intention-to-treat cohort, the between-arm differences were not significant (3-year recurrence 36% versus 62%, HR 0.48 95% CI: 0.17–1.33, P = 0.075; 3-year DFS 61% versus 38%, HR 0.55 95% CI: 0.21–1.48, P = 0.12). In the per-protocol analysis (excluding untreated CHEMO patients), time-to-recurrence (TTR) and DFS were improved with CHEMO compared to OBS (3-year recurrence 19% versus 62%, HR 0.23 0.06–0.87, P = 0.009; 3-year DFS 77% versus 38%, HR 0.31 95% CI: 0.09–1.03, P = 0.021). Conclusion The primary ITT endpoint was not met, potentially related to the lower power due to premature trial closure. The per-protocol analysis suggests a benefit from adjuvant therapy in ctDNA-positive patients, supporting ctDNA testing for adjuvant decision making in the future.