Postoperative ctDNA positivity signals poor prognosis in stage 3 colon cancer, despite chemotherapy escalation

New results from the DYNAMIC-III trial found that participants with detectable circulating tumour DNA (ctDNA) following curative resection face a high risk of recurrence, even after adjuvant chemotherapy, and that a ctDNA-informed escalation strategy does not appear to improve outcomes.

The phase 2/3 DYNAMIC-III trial (ACTRN12617001566325), as an intergroup study of the Australasian Gastro-Intestinal Trials Group and the Canadian Cancer Trials Group, randomised 1,002 participants with resected stage 3 colon cancer 1:1 to receive either standard-of-care adjuvant therapy (n=500) or a ctDNA-guided strategy (n=502). ctDNA analysis was tumour-informed and performed 5–6 weeks postoperatively. In the ctDNA-guided group, a ctDNA-positive result, observed in 129 participants (27%), informed a treatment escalation based on predefined intensification strategies, such as escalation from single agent fluoropyrimidine to oxaliplatin-based doublet, from 3 months doublet to 6 months doublet or FOLFOXIRI [clinician choice], or from 6 months doublet to FOLFOXIRI [1].

An earlier analysis of the ctDNA-positive stage 2 colon subgroup revealed sobering outcomes and was published in Nature Medicine [2]. Also for the ASCO2025-presented stage 3 colon cancers, the2-year recurrence-free survival (RFS) was 52% among those assigned to ctDNA-guided escalation therapy, compared with 61% in the ctDNA-positive participants who received standard therapy (HR 1.11; 90% CI 0.83–1.48; P=0.57), indicating no statistically significant benefit to the escalation approach.

Participants who achieved ctDNA clearance after chemotherapy had a 3-year RFS of 84%, compared with just 12% in those with persistent ctDNA positivity. However, a post-hoc analysis comparing specific regimens (doublet chemotherapy versus FOLFOXIRI) found no significant difference in RFS: 51% vs 47% at 3 years, respectively. It is important to note that treatment assignments for escalation were not randomised, and those receiving FOLFOXIRI likely had more aggressive disease at baseline, limiting the interpretability of direct comparisons.

“These results highlight the need for improved therapies beyond conventional chemotherapy in participants with ctDNA-positive results,” said presenter Prof. Jeanne Tie (Peter MacCallum Cancer Centre, Melbourne, Australia). “We found that participants with stage 3 colon cancer with detectable ctDNA had a high rate of cancer recurrence even after standard chemotherapy, and that more intensive chemotherapy did not improve their outcome.”

1. Tie J, et al. Post surgery ctDNA Positivity Indicates High Colon Cancer Recurrence Risk Despite Adjuvant Chemotherapy. Abstract #3503, ASCO Annual Meeting 2025, 30 May–3 June, Chicago, IL, USA.
2. Tie J, et al. Nat Med. 2025;31(5):1509–1518.

 

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Posted on 30 July 2025