The use of circulating tumor DNA (ctDNA) is emerging as a powerful tool in colorectal cancer management, but its potential to address disparities in care remains an ongoing challenge. Although ctDNA offers a promising approach for early detection, monitoring minimal residual disease (MRD), and predicting recurrence, its implementation is not without barriers—especially in under-resourced settings.
“New technologies often debut in academic centers, so the challenge is how we disseminate and implement them effectively in diverse care environments,” said Stacey Cohen, MD, a gastrointestinal oncologist at Fred Hutchinson Cancer Center and associate professor of oncology and medicine at the Division of Hematology/Oncology at University of Washington.
What Is ctDNA, and Why Does It Matter?
Dr Cohen explained that ctDNA refers to tumor-derived fragments of cell-free DNA circulating in the bloodstream. “Because ctDNA has a short half-life—just a few hours—it gives us a near real-time snapshot of disease activity,” she said at the Summit on Cancer Health Disparities 2025 in Seattle.1 That makes it particularly valuable as a dynamic biomarker for monitoring MRD, assessing treatment response, or detecting recurrence.
In colorectal cancer, where tumors tend to shed higher levels of ctDNA compared with other malignancies, this approach is especially feasible. However, Dr Cohen cautioned that not all tumors or metastatic sites shed ctDNA uniformly. “What works in colorectal cancer doesn’t necessarily translate to other cancers,” she noted.
Tumor-Informed Versus Tumor-Uninformed Testing
Two main approaches to ctDNA testing exist: tumor-informed and tumor-uninformed. Tumor-informed testing involves sequencing the original tumor to identify patient-specific mutations, which are then tracked in the blood. Tumor-uninformed testing uses a broader panel without prior tumor sequencing.
“Tumor-informed tests may be more sensitive for detecting MRD,” Dr Cohen said, “but they take longer—up to 4 to 6 weeks—to generate results because of the extra tumor-matching step.” In contrast, blood-only testing typically has a turnaround time of 7 to 14 days, but may sacrifice some specificity.
The Prognostic Power of ctDNA
Multiple retrospective studies have shown that ctDNA is a strong prognostic factor after surgery. “Broadly speaking, patients who are ctDNA negative after surgery seem to do way better than patients who are ctDNA positive,” Dr Cohen said. “We see very big differences between patients who are negative and positive.”
Yet, despite its prognostic value, ctDNA is not yet widely used to guide treatment decisions. Most supporting data are observational or retrospective, and limited prospective evidence has slowed integration into routine care.
Clinical Trials: Can ctDNA Guide Chemotherapy Decisions?
Dr Cohen highlighted the DYNAMIC trial, a prospective study in stage II colon cancer that compared ctDNA-guided management with standard management. In the ctDNA-guided arm, only patients who were ctDNA positive postsurgery received chemotherapy. This approach led to a reduction in chemotherapy use—15% versus 28% in the standard group—without compromising recurrence-free survival at 2 years.
However, differences in chemotherapy intensity between the groups (more oxaliplatin-based regimens in the ctDNA-guided arm) complicated interpretation. “When they did give chemotherapy in the ctDNA-guided group, they more often got a more intense regimen,” Dr Cohen noted. “It muddies the water as we think about this study.”
She added, “This is why it’s not practice-changing at this time, despite being a prospective study. But it really tested our idea that we know best who needs chemotherapy—or maybe we know best who does not need chemotherapy.”
Looking at Stage III: CIRCULATE and Ongoing Questions
Dr Cohen also discussed the CIRCULATE-NORTH AMERICA trial, which focuses on stage III disease and includes high-risk stage II patients. The study is testing whether ctDNA-negative patients can safely forgo chemotherapy and whether ctDNA-positive patients might benefit from more intensive regimens. “This is testing a big de-escalation question in ctDNA-negative patients,” she said, “and an escalation question in those who are positive.”
Longitudinal Testing: Beyond a Single Time Point
In addition to single time-point testing, Dr Cohen highlighted data from observational studies such as GALAXY, BESPOKE, and INTERCEPT, suggesting the value of tracking ctDNA over time. “Patients who are negative and stay negative do the best. Patients who are positive and stay positive do the worst,” she said. “But unfortunately, being positive—ever—is still a negative prognostic sign.”
The INTERCEPT study showed that when ctDNA was positive but imaging was negative, the median lead time to radiographic recurrence was about 5 and a half months. “That helps us understand how to frame this to patients,” Dr Cohen said.
Looking Ahead: A Tool for the Future?
Dr Cohen emphasized that ctDNA is unlikely to be a one-size-fits-all tool, but it may play an increasingly valuable role in combination with clinical judgment, imaging, and pathology.
“At this time, ctDNA doesn’t replace standard of care, but it is part of many ongoing clinical trials,” she said. The hope is that ctDNA can eventually help guide adjuvant therapy decisions, identify high-risk patients for early intervention, and avoid overtreatment in those unlikely to benefit.
In her closing remarks, Dr Cohen summarized the field’s trajectory: “ctDNA is a good prognostic marker, and it’s emerging as a predictive one. Positive patients are at high risk of relapse (and may benefit most from chemotherapy), and longitudinal testing may help further stratify who needs what level of treatment.”
Reference
- Cohen S. Summit on Cancer Health Disparities 2025. ctDNA in the management and surveillance of colorectal cancers. April 25-27, 2025. Seattle, WA.