Circulating tumor DNA (ctDNA) was found to be a strong prognostic classifier for patients with stage III colon cancer following surgery, according to findings from the phase II/III DYNAMIC-III trial. Findings from the study presented at the European Society for Medical Oncology (ESMO) Congress 2025 (Abstract LBA9) and published in Nature Medicine show that treatment de-escalation guided by postsurgical ctDNA levels led to reduced oxaliplatin exposure and fewer adverse events in patients with low recurrence risk.
On the other hand, in patients with ctDNA-positive disease following surgery, exploratory chemotherapy intensification did not lead to survival benefits.
“This study clearly shows the value of measuring tumor-specific genetic alterations in the blood of patients, informing their management and improving the lives of patients who don’t need aggressive therapy,” stated study co-author Bert Vogelstein, MD, Clayton Professor of Oncology at the Johns Hopkins University School of Medicine, Co-Director of the Ludwig Center at Johns Hopkins Kimmel Cancer Center, and an Investigator at the Howard Hughes Medical Institute.
Study Methods
The multicenter, randomized phase II/III DYNAMIC-III trial explored the de-escalation or escalation of adjuvant chemotherapy in patients with stage III colon cancer (n = 968) based on postsurgical ctDNA results. All patients underwent ctDNA testing 5 to 6 weeks after surgery, and were then randomly assigned to either a ctDNA-guided therapy arm or a standard management arm. If patients in the ctDNA-guided arm had ctDNA-negative disease, they were given one of three de-escalated treatment options: from 6 to 3 months of fluoropyrimidine or observation, from 3 months of doublet to single-agent fluoropyrimidine, or from 6 months of doublet to 3 months doublet or single-agent fluoropyrimidine.
The primary endpoint was 3-year recurrence-free survival.
Key Study Findings
After surgery, 702 patients (72.5%) were ctDNA-negative, and 353 of these patients were randomly assigned to the ctDNA-guided arm. Patients were followed for a median of 45 months.
In the ctDNA-guided arm, 90.4% of patients received de-escalated treatment as guided by their ctDNA results. This treatment de-escalation reduced the amount of oxaliplatin-based chemotherapy used compared with the standard management arm (34.8% vs 88.6%; P < .001). Rates of grade 3 or higher adverse events of special interest (6.2% vs 10.6%; P = .037) and treatment-related hospitalization rates (8.5% vs 13.2%; P = .048) were also lowered with de-escalated chemotherapy.
At 3 years, the recurrence-free survival rate in the ctDNA-guided arm was 85.3% as compared with 88.1% in the standard management arm, which failed to demonstrate noninferiority. However, a pre-planned subgroup analysis showed that de-escalation may be noninferior to standard therapy for patients with clinical low-risk tumors (T1-3 N1) with 3-year recurrence-free survival rates of 91% with ctDNA-guided therapy vs 93.2% with standard management.
“This study demonstrates that likely, in the near future, ctDNA can be used to help make clinical decisions for patients with colon cancers,” said study co-author Yuxuan Wang, MD, PhD, Assistant Professor of Oncology at Johns Hopkins University School of Medicine. “Conceivably, we can use ctDNA in other tumor types to inform patient management the same way.”
Disclosure: The study was supported by the Australian National Health and Medical Research Council, the Marcus Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the Lustgarten Foundation, The Sol Goldman Charitable Trust, the National Institutes of Health, the Epworth Medical Foundation, and the Eastern Health Research Foundation. In Canada, the study was supported by a project grant from the Canadian Institutes of Health Research and operational support to the Canadian Cancer Trials Groups provided by the Canadian Cancer Society. For full disclosures of the study authors, visit nature.com.