New Data Support ctDNA-Guided Treatment in CRC

New data from two large studies presented at the 2025 ASCO Gastrointestinal Cancers Symposium (GICS) 2025 provide evidence of the clinical utility of circulating tumor DNA (ctDNA) testing in early-stage colorectal cancer (CRC).

The BESPOKE CRC study, presented by Purvi Shah, MD, of the Virginia Cancer Institute, Richmond, Virginia, and the CALGB/SWOG 80702 analysis, presented by Jonathan Nowak, MD, PhD, of Brigham and Women’s Hospital, Boston, both used tumor-informed ctDNA testing to evaluate molecular residual disease (MRD) and its implications for patient outcomes.

In an interview, Richard D. Kim, MD, of H. Lee Moffitt Cancer Center, who was not involved in the two studies, said, “ctDNA-MRD testing is prognostic for recurrence both during MRD and in surveillance windows. ctDNA can potentially be predicted for adjuvant therapy in stages II and III colon cancer.”

He also emphasized the relevance of these findings for patients with stage II disease, noting that “stage II CRC has always been tricky because standard guidelines do not clearly identify which patients need chemotherapy and which patients could do fine without it.”

“With ctDNA testing, we can pinpoint those stage II patients who have a real chance of recurrence and would benefit from additional treatment,” he said.

BESPOKE CRC: Real-World Evidence of the Prognostic Value of ctDNA Testing

The BESPOKE CRC study evaluated 1166 patients with stage II/III CRC using Signatera, a tumor-informed assay.

In her presentation, Shah emphasized that this is the largest US-based prospective observational study of its kind and that it revealed differences in ctDNA positivity rates between stage II (7.5%) and stage III (28.5%) patients.

During her presentation, Shah commented on the study’s findings regarding the role of ctDNA testing in guiding adjuvant treatment decisions.

“When asked whether postoperative ctDNA results influenced their adjuvant treatment plan, 16% of treating oncologists said yes,” she explained. “Of those, 60% de-escalated adjuvant chemotherapy, and 35% escalated adjuvant chemotherapy based on postoperative MRD test.”

In her presentation, Shah discussed survival data that demonstrate the prognostic value of ctDNA.

“Being ctDNA-positive at the MRD timepoint leads to a statistically significant inferior outcome with 2-year disease-free survival of 45% and 35% in stages II and III disease, respectively,” Shah said.

In contrast, patients who were ctDNA-negative at the MRD timepoint had a favorable prognosis, with 2-year disease-free survival at 91% for stage II and 87% for stage III.

In her presentation, Shah noted that 13% of patients were diagnosed with metastatic disease due to a positive postoperative ctDNA test, which “allowed appropriate initiation of stage IV therapy.”

In an interview, Kim said the “clear, high correlation between ctDNA positivity and worse disease-free survival underlines the strong prognostic value of ctDNA in identifying patients at high risk of recurrence.”

The BESPOKE study also evaluated the role of ctDNA testing in surveillance and guiding metastasis-directed therapy (MDT). It was found among 188 patients who experienced recurrence that 86% (162 patients) had their recurrence preceded by a positive ctDNA result. Of these ctDNA-detected recurrences, 30% of patients were able to undergo potentially curative MDT.

Commenting on these findings, Kim said in an interview: “By integrating ctDNA testing into routine follow-up, we can potentially detect recurrences earlier and intervene sooner.”

He added, “Over time, this may enable risk-based surveillance, where ctDNA-positive patients receive more intensive monitoring, while ctDNA-negative patients can safely avoid unnecessary procedures.”

CALGB/SWOG 80702: ctDNA as Predictive Biomarker for Celecoxib Benefit

The CALGB/SWOG 80702 analysis examined ctDNA status in 1011 patients with stage III colon cancer from the original trial, which showed no significant benefit from adding celecoxib to standard FOLFOX chemotherapy in the overall population. However, Nowak presented findings from a new analysis that suggested that ctDNA status might identify patients who could benefit from celecoxib.

Nowak presented data showing that among ctDNA-positive patients, celecoxib significantly improved disease-free survival compared with placebo (hazard ratio [HR], 0.59, 95% CI, 0.42-0.85, P = .004), with 3-year disease-free survival rates of 44.1% vs 26.6%. In contrast, this benefit was not observed in ctDNA-negative patients.

These data suggest that patients who are ctDNA-positive may derive a significant benefit from the addition of celecoxib to standard FOLFOX chemotherapy, Nowak noted in his talk.

In his discussion session, Kim said that the celecoxib findings from the CALGB/SWOG 80702 study are “very intriguing, with a meaningful improvement in regard to overall survival and disease-free survival with hazard ratio being around 0.6.”

However, he cautioned that the interaction P value was not significant, “suggesting a difference between the ctDNA-positive and negative group could be due to chance.”

During a press briefing, Laura Vater, MD, MPH, of IU Simon Comprehensive Cancer Center, Indianapolis, commented on the practical implications of these new findings from the CALGB/SWOG 80702 analysis.

“Testing patients with stage III colon cancer for ctDNA following surgery is a low-risk procedure. It is blood-based and fairly simple to complete,” she said.

Challenges and Future Directions

According to Kim, several challenges remain in the implementation of ctDNA testing to guide treatment decisions. In an interview, he said that while tumor-informed assays offer highly personalized and precise testing, the high cost of ctDNA testing and its limited availability in certain regions can be significant barriers, particularly when healthcare budgets are constrained.

“ctDNA is a powerful tool poised to revolutionize oncology practice, but the science has outpaced clinical data, creating some uncertainty for oncologists,” Kim added.

During the discussion session, Kim pointed to several ongoing trials that are investigating the role of ctDNA in treatment decision-making, including CIRCULATE-NORTH AMERICA NRG-GI008, CIRCULATE-JAPAN VEGA & ALTAIR, SU2C ACT3, and DYNAMIC-III.

“These studies will help determine whether treatment can be de-escalated in ctDNA-negative patients or intensified in ctDNA-positive patients,” he said.

Kim also noted that current guidelines do not yet recommend routine ctDNA testing in this setting. He added, however, that “most of us are checking that in our current practice.”

He also emphasized that “while it’s premature to recommend systemic treatment based on ctDNA positivity alone, multiple ongoing clinical trials are exploring novel therapeutics, such as bispecific antibodies, in this setting.”

Regarding feature research priorities, Kim stated that robust, randomized trials are needed to confirm the advantages of ctDNA testing, establish cost-effectiveness, and inform official guidelines.

“Details of stratification, adjuvant regiment, and duration should be determined by randomized studies,” he added.

“In the long run, ctDNA testing has the potential to become a cornerstone of postsurgical care, but its widespread adoption will depend on findings from larger studies and real-world experience,” Kim concluded in his interview.

The BESPOKE CRC subcohort study was independently supported. The CALGB (Alliance)/SWOG 80702 study was funded by the National Cancer Institute (U10 CA180821), National Cancer Institute (U10 CA180882), Alliance Foundation, and Natera.

Kim reported receiving consulting or advisory fees from Abb AbbVie, AstraZeneca, Bayer, Eisai, Exelixis, Jazz Pharmaceuticals, Pfizer, Roche/Genentech, Servier, and Taiho Oncology; honoraria from Natera; and speakers’ bureau from AstraZeneca and Incyte. Nowak reported receiving consulting or advisory fees from Leica B and research funding from Natera.Shah reported no relevant financial relationships. Vater reported financial relationships with Indiana University Health (employment), GoodRx (other relationships), and MDLinx (other relationships).

Christos Evangelou, PhD, is a freelance medical writer and science communications consultant.