ctDNA Positivity in CRC Links to Chemotherapy Response

Medscape

06-05-2025

SAN DIEGO — Molecular residual disease (MRD) positivity, as detected via circulating tumor (ct) DNA following curative resection, was significantly associated with improved disease-free survival after chemotherapy in patients with stage II or III colorectal cancer (CRC), the results of the BESPOKE study showed.
'These findings highlight the value of utilizing ctDNA to select which patients should receive management chemotherapy and which patients can be potentially spared chemotherapy's physical, emotional, and financial toxicities without compromising their long-term outcomes,' said first author Kim Magee, of Natera, Inc., in Austin, Texas.
'ctDNA is emerging as the most powerful and prognostic biomarker in colorectal cancer,' said Magee, who presented the findings at Digestive Disease Week (DDW) 2025.
In stage II CRC, as many as 80% of patients are cured by surgery alone, while only about 5% benefit from chemotherapy. In stage III CRC, about half of patients are cured by surgery alone, while only 20% benefit from chemotherapy, and 30% recur despite chemotherapy, Magee explained.
The inability to pinpoint which patients will most benefit from chemotherapy means 'we know we are needlessly treating [many] of these patients,' she said.
ctDNA Offers Insights Into Tumor's Real-Time Status
Just as cells release fragments (cell-free DNA) into the blood as they regenerate, tumor cells also release fragments — ctDNA — which can represent a biomarker of a cancer's current state, Magee explained.
Because the DNA fragments have a half-life of only about 2 hours, they represent a key snapshot in real time, 'as opposed to imaging, which can take several weeks or months to show changes,' she said.
To determine the effects of ctDNA testing on treatment decisions and asymptomatic recurrence rates, Magee and colleagues analyzed data from the multicenter, prospective study, which used the Signatera (Natera, Inc.) residual disease test.
The study included 1794 patients with resected stage II-III CRC who were treated with the standard of care between May 2020 and March 2023 who had complete clinical and laboratory data available.
ctDNA was collected 2-6 weeks post-surgery and at surveillance months 2, 4, 6, and every 3 months through month 24.
Among the 1166 patients included in a final analysis, 694 (59.5%) patients received adjunctive chemotherapy, and 472 (40.5%) received no chemotherapy.
Among those with stage II CRC, a postoperative MRD positivity rate was 7.54%, while the rate in those with stage III disease was 28.35%.
Overall, 16.1% of patients had a recurrence by the trial end at 24 months.
The results showed that among patients who tested negative for ctDNA, the disease-free survival estimates were highly favorable, at 91.8% for stage II and 87.4% for stage III CRC.
Comparatively, for those who were ctDNA-positive, disease-free survival rates were just 45.9% and 35.5%, respectively, regardless of whether those patients received adjunctive chemotherapy.
At the study's first ctDNA surveillance timepoint, patients who were ctDNA-positive with stage II and III CRC combined had substantially worse disease-free survival than patients who were ctDNA-negative (HR, 26.4; P < .0001).
Impact of Chemotherapy
Patients who were found to be MRD-positive on ctDNA testing and treated with chemotherapy had a 40.3% 2-year disease-free survival rate compared with just 24.7% among patients with MRD-positive who did not receive chemotherapy.
Meanwhile, those who were MRD-negative and treated with chemotherapy had a substantially higher 2-year disease-free survival rate of 89.7% — nearly identical to the 89.5% observed in the no-chemotherapy group.
The findings underscored that 'the adjuvant chemotherapy benefits were only observed among those who were ctDNA-positive,' Magee said.
'ctDNA can guide postsurgical treatment decisions by identifying which patients are most likely to benefit from chemotherapy, and in the surveillance setting, ctDNA can predict recurrence — usually ahead of scans,' she added.
'This opens the opportunity to intervene and give those patients a second chance at cure.'
On the heels of major recent advances including CT, MRI, and PET-CT, 'we believe that ctDNA represents the next major pivotal advancement in monitoring and eventually better understanding cancer diagnostics,' Magee said.
Commenting on the study, William M. Grady, MD, medical director of the Fred Hutchinson Cancer Center Gastrointestinal Cancer Prevention Clinic in Seattle, said the BESPOKE trial represents a 'well-done' study, adding to research underscoring that 'MRD testing is a more accurate prognostic assay than the current standards of CT scan and CEA (carcinoembryonic antigen, a tumor marker) testing.'
However, 'a limitation is that this is 2 years of follow-up, [while] 5-year follow-up data would be ideal,' he told Medscape Medical News , noting, importantly, that 'a small number of patients who have no evidence of disease (NED) at 2 years develop recurrence by 5 years.'
Furthermore, more research demonstrating the outcomes of MRD detection is needed, Grady added.
'A caveat is that studies are still needed showing that if you change your care of patients based on the MRD result, that you improve outcomes,' he said. 'These studies are being planned and initiated at this time, from my understanding.'
Oncologists treating patients with CRC are commonly performing MRD assessment with ctDNA assays; however, Grady noted that the practice is still not the standard of care.
Regarding the suggestion of ctDNA representing the next major, pivotal step in cancer monitoring, Grady responded that 'I think this is aspirational, and further studies are needed to make this claim.'
However, 'it does look like it has the promise to turn out to be true.'