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

BACKGROUND

Adjuvant chemotherapy provides limited benefit in unselected stage II colon cancer. Post-operative circulating tumour DNA (ctDNA) has higher prognostic value than classical clinical markers, with ctDNA positivity indicating an unfavourable outcome.

PATIENTS AND

METHODS

Patients with Union for International Cancer Control stage II, mismatch repair proficient/microsatellite stable colon cancer were tested for ctDNA using an academic, tumour-informed, next-generation sequencing-based test. ctDNA-positive patients were randomly assigned 2:1 to CHEMO (capecitabine ± oxaliplatin) or observation (OBS). ctDNA-negative patients were randomly assigned 1:4 to OBS or OFF-STUDY. ctDNA results were not disclosed in the OBS group. The primary endpoint was disease-free survival (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 June 2020 to July 2025, 2126 patients were screened in Germany and Austria. Overall, 1396 patients (2.9% ctDNA-positive) were randomly assigned: 1083 to OFF-STUDY, 287 to OBS, and 26 to CHEMO, of whom 81% started therapy. DFS and overall survival (OS) were significantly worse in ctDNA-positive versus ctDNA-negative patients [3-year DFS 52% versus 87%, hazard ratio (HR) 4.28, 95% confidence interval (CI) 2.32-7.93, P < 0.001; 3-year OS 88% versus 98%, HR 5.48, 95% CI 1.64-18.28, P = 0.001]. In the intention-to-treat (ITT) 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 and DFS were improved with CHEMO compared with OBS (3-year recurrence 19% versus 62%, HR 0.23, 95% CI 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 reduced 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.