ctDNA Blood Test Guides Chemotherapy Decisions for Tailored Colon Cancer Treatment

Findings from the DYNAMIC-III trial, show that ctDNA testing can transform post-surgical care in Stage III colon cancer. Among more than 1,000 patients, ctDNA-negative individuals achieved 87% three-year recurrence-free survival with reduced chemotherapy, while ctDNA-positive patients faced a 50% recurrence risk despite intensified therapy, as escalated treatment did not improve outcomes and higher ctDNA burden correlated with poorer recurrence-free survival.

A simple blood test may redefine how oncologists decide who truly needs chemotherapy after colon cancer surgery, and who can safely avoid it. In a landmark international trial presented at the ESMO 2025 Congress and simultaneously published in Nature Medicine, researchers demonstrated that circulating tumor DNA (ctDNA) can serve as a powerful guide for tailoring postoperative therapy in stage III colon cancer.

From One-Size-Fits-All to Individualized Risk

For decades, adjuvant chemotherapy in colon cancer has followed a blunt rule: most patients receive similar regimens, even though many are already cured by surgery alone.

“Right now, we give most stage III patients the same chemotherapy,” said Professor Jeanne Tie, WEHI’s medical oncologist and lead investigator of the DYNAMIC-III trial. “But ctDNA testing can help tailor treatment based on individual risk. For some patients, this means a less intensive approach may be just as effective while reducing unnecessary toxicity from chemotherapy.”

The DYNAMIC-III trial enrolled over 1,000 patients with stage III colon cancer across Australia, New Zealand, and Canada. Each patient underwent a ctDNA blood test roughly six weeks after surgery. Those without detectable ctDNA fragments—signifying no molecular evidence of residual disease—were classified as low-risk. Patients with detectable ctDNA were labeled high-risk.

Participants were then randomized to receive either standard chemotherapy or treatment directed by their ctDNA results. The outcomes marked a pivotal moment for precision oncology.

DNA Fragments That Foretell Recurrence

The study’s results were striking. Among ctDNA-negative patients, 87% remained cancer-free three years after surgery. In this group, chemotherapy could be safely de-escalated—reducing oxaliplatin exposure from nearly 90% to just 35% with outcomes approaching those of standard care, although non-inferiority for recurrence-free survival was not met. The de-escalated approach also led to fewer hospitalizations (8.5% versus 13.2%) and less nerve damage, a common side effect of oxaliplatin.

By contrast, patients whose ctDNA remained detectable after surgery had a much higher risk of recurrence – only about half remained cancer-free at three years, and the risk worsened as ctDNA levels rose. 

“For this group, receiving more intensive chemotherapy did not improve results, suggesting new treatment approaches are needed,”  explained Professor Tie.

These findings confirm ctDNA as one of the strongest prognostic biomarkers ever identified in colorectal cancer. Its ability to detect molecular traces of disease long before visible relapse could fundamentally reshape postoperative care.

Precision Without Overtreatment

In the ctDNA-guided arm, the researchers achieved a key goal: maintaining excellent survival for low-risk patients while reducing unnecessary chemotherapy.  

“ctDNA is a powerful tool that can help guide treatment choices and identify which patients might safely receive less intensive treatment and those who might need to seek alternative options,” said Professor Tie. “Right now, we give most stage 3 patients the same chemotherapy, but ctDNA testing can help tailor treatment based on individual risk.”

However, the study also underscored the limits of current treatments. For patients with persistent ctDNA, intensifying chemotherapy brought no added benefit—highlighting an urgent need for novel strategies, possibly immunotherapy or targeted combinations, to clear microscopic residual disease.

A Path to Routine Clinical Use

“This study provides the best available prospective evidence of the prognostic value of ctDNA in selecting adjuvant chemotherapy for patients with resected stage 3 colon cancer,” said Dr Jonathan Loree, DYNAMIC-III Canadian Study Chair and CCTG Senior Investigator. “Its results are crucial as we build the evidence needed to move ctDNA into the clinic.”