Article Impact Level: HIGH Data Quality: STRONG Summary of Nature Medicine https://doi.org/10.1038/s41591-025-04030-w Dr. Jeanne Tie et al.
Points
- Adjuvant chemotherapy in stage III colon cancer has uncertain individual benefits, necessitating refined risk-adjusted treatment selection.
- The DYNAMIC-III trial randomized 968 patients to ctDNA-guided or standard management, assessing recurrence-free survival.
- CtDNA-negative patients (72.5%) had significantly fewer recurrences (3-year RFS 87% vs. 49% for ctDNA-positive, P < 0.001).
- De-escalation reduced oxaliplatin use (34.8% vs. 88.6%) and hospitalizations in ctDNA-negative patients, though RFS was slightly lower.
- Escalated therapy offered no RFS benefit in ctDNA-positive patients, indicating a need for novel strategies for this high-risk group.
Summary
The DYNAMIC-III trial, a multicenter, randomized phase 2/3 study, investigated the efficacy of circulating tumor DNA (ctDNA)-guided adjuvant therapy in patients with stage III colon cancer, where individual benefit from standard adjuvant chemotherapy remains uncertain. Patients (n=968) underwent ctDNA testing 5–6 weeks post-surgery and were randomized (1:1) to either ctDNA-guided or standard management. In the ctDNA-guided arm, ctDNA-negative patients received de-escalated therapy, while ctDNA-positive patients received escalated therapy. The primary endpoints were 3-year recurrence-free survival (RFS) for ctDNA-negative patients and 2-year RFS for ctDNA-positive patients, with secondary endpoints including treatment-related hospitalization and ctDNA clearance.
With a median follow-up of 47 months, ctDNA-negative patients (702 out of 968, or 72.5% of evaluable patients) demonstrated significantly fewer recurrences compared to ctDNA-positive patients (3-year RFS 87% versus 49%; P < 0.001). For ctDNA-negative patients, de-escalation of therapy reduced oxaliplatin use (34.8% versus 88.6%) and hospitalizations (8.5% versus 13.2%). However, this de-escalation yielded a slightly lower RFS than standard management (85.3% versus 88.1%), failing to meet the non-inferiority margin. In ctDNA-positive patients, a higher ctDNA burden correlated significantly with an increased recurrence risk (3-year RFS ranged from 77% to 23% across quartiles; P < 0.001). Escalated therapy did not improve outcomes over standard management, showing a 2-year RFS of 51% versus 61%.
The study validated ctDNA as a robust prognostic classifier. No unexpected toxicities were reported. Notably, persistent ctDNA after treatment was a strong predictor of markedly worse prognosis (3-year RFS 14% versus 79%). While ctDNA-guided de-escalation reduced oxaliplatin exposure and adverse events with RFS outcomes approaching standard of care, the exploratory chemotherapy intensification in ctDNA-positive disease conferred no RFS benefit. This suggests an urgent need for novel and more effective strategies tailored for ctDNA-positive stage III colon cancer patients.
Link to the article: https://www.nature.com/articles/s41591-025-04030-w
References
Tie, J., Wang, Y., Loree, J. M., Cohen, J. D., Wong, R., Price, T., Tebbutt, N. C., Gebski, V., Espinoza, D., Burge, M., Harris, S., Lynam, J., Lee, B., Lee, M. M., Breadner, D., Debrincat, M., Foroughi, S., Chantrill, L., Lim, S. H., … Gibbs, P. (2025). Circulating tumor DNA-guided adjuvant therapy in locally advanced colon cancer: The randomized phase 2/3 DYNAMIC-III trial. Nature Medicine, 1–10. https://doi.org/10.1038/s41591-025-04030-w
