Clinical Utility of ctDNA-Guided Adjuvant Therapy in Stage II Colon Cancer
Clinical Summary:
- Design/Population: The phase 3 CIRCULATE trial evaluated tumor-informed ctDNA testing to guide adjuvant chemotherapy in patients with proficient mismatch repair, microsatellite-stable stage II colon cancer who lacked conventional indications for postoperative chemotherapy.
- Key Outcomes: ctDNA positivity identified a subgroup at substantially higher risk of recurrence, and adjuvant chemotherapy markedly improved disease-free survival compared with observation among treated ctDNA-positive patients. These findings support the prognostic and predictive value of postoperative ctDNA testing.
- Clinical Relevance: The results suggest that ctDNA can identify patients with molecularly high-risk stage II colon cancer who may benefit from treatment escalation despite otherwise low-risk clinicopathologic features.
Gunnar Folprecht, MD, PhD, University Hospital Dresden, Dresden, Germany, discusses results from the CIRCULATE trial evaluating whether circulating tumor DNA (ctDNA) can identify patients with stage II colon cancer who benefit from adjuvant chemotherapy.
The study demonstrated that ctDNA-positive patients had a substantially higher risk of recurrence than ctDNA-negative patients and that adjuvant chemotherapy significantly improved outcomes among patients with molecularly detectable residual disease. Together with findings from DYNAMIC, CIRCULATE-Japan, and BESPOKE, these results support ctDNA-guided treatment decisions in patients with pMMR, microsatellite-stable stage II colon cancer.
Transcript:
Hello, my name is Gunnar Folprecht. I'm working at Dresden University Hospital, and I'm a medical oncologist specializing in colorectal cancer. We performed the CIRCULATE trial, which investigated circulating tumor DNA in patients with stage II colon cancer.
As you know, decision-making regarding adjuvant therapy in stage II colon cancer is difficult. There are several clinical risk factors, such as T4 disease or emergency resection, that are generally regarded as indications to consider adjuvant therapy. However, the predictive value of these factors is limited. The current mainstay of adjuvant treatment in colon cancer is fluoropyrimidine-based chemotherapy, and the incremental benefit of adding oxaliplatin is relatively limited.
What we already knew is that circulating tumor DNA has a prognostic value when we determine the mutations present in the tumor and then analyze a blood sample obtained after surgical resection. What we wanted to know was whether patients actually benefit from adjuvant chemotherapy.
For this purpose, we enrolled patients with stage II colon cancer who did not have a definite indication for adjuvant chemotherapy. We determined ctDNA status using an academic tumor-informed test, we knew which mutations were present in each patient's tumor. Approximately 3% of patients were found to be ctDNA positive. Overall, we screened about 2,100 patients, analyzed approximately 1,700, and identified 55 ctDNA-positive patients. Not all analyzed patients could be randomized. In total, nearly 1,400 ctDNA positive patients entered the randomization.
Among the ctDNA-positive patients, 41 were randomized. These patients were randomized in a 2:1 fashion to receive chemotherapy or observation. Patients who were ctDNA negative were randomized to observation or followed off study. Among the 26 patients assigned to receive chemotherapy, not all ultimately received treatment. In 2 patients, once we unblinded the ctDNA result and informed the investigators that the patients were ctDNA positive and should receive chemotherapy, additional imaging was performed immediately. That imaging detected metastatic disease that otherwise would not have been identified at that time. Three additional patients withdrew consent. Because of this, in addition to the intention-to-treat analysis, we also performed a per-protocol analysis comparing the patients who actually received chemotherapy with the ctDNA-positive patients who did not receive chemotherapy.
The differences we observed were quite dramatic. First, there was a very strong prognostic effect of ctDNA positivity. Patients who were ctDNA positive had a disease-free survival of only 38%, compared with 87% among ctDNA-negative patients. The hazard ratio was 6.3. Among the ctDNA-positive patients who were simply observed, 62% experienced recurrence. In contrast, only 19% of the ctDNA-positive patients who actually received chemotherapy experienced recurrence. For comparison, recurrence occurred in only 12% of the ctDNA-negative patients. The hazard ratio comparing treated versus untreated ctDNA-positive patients was 0.23, with a P value of 0.009. So there was a very substantial reduction in recurrence among the ctDNA-positive patients who actually received chemotherapy.
Looking at disease-free survival, it improved from 38% in untreated ctDNA-positive patients to 77% in those who actually received chemotherapy. The intention-to-treat analysis also showed a substantial difference, with a hazard ratio of 0.55. However, because of the relatively small number of ctDNA-positive patients, this difference did not reach statistical significance. That does not mean there was no treatment effect. Rather, it means that the study was underpowered to formally demonstrate significance in the intention-to-treat population.
Our conclusion is that, together with previously published evidence—including the DYNAMIC trial and observational studies such as CIRCULATE-Japan and the BESPOKE study in the United States—these data support treatment escalation for patients with proficient mismatch repair, microsatellite-stable stage II colon cancer who are ctDNA positive and who otherwise would not routinely receive adjuvant chemotherapy. Thank you.
Source:
Folprecht G, Stasik S, Reinacher-Schick A, et al. Chemotherapy for patients with circulating tumour DNA-positive, stage II colon cancer (CIRCULATE)—An AIO/ABCSG trial. Ann Oncol. Published online: May 31, 2026. doi: 10.1016/j.annonc.2026.05.001
