ctDNA Aids in Elucidating the Role of Select Therapies for CRC

Tanios S. Bekaii-Saab, MD

Guided approaches with circulating tumor DNA (ctDNA) have just begun to scratch the surface of showing prognostic and predictive abilities in colorectal cancer (CRC), and new data have further shed light on ctDNA’s role. Clinical trials demonstrated that ctDNA-guided approaches can reduce the use of chemotherapy without compromising outcomes in those with minimal residual disease (MRD)–positive disease, and that celecoxib (Celebrex) benefited these patients.1,2

“The results continue to be consistent across [the board] whether it’s the CIRCULATE-Japan GALAXY trial [UMIN000039205], [the observational] BESPOKE study [NCT04264702] from the US, or other smaller studies—they all suggest that patients who have MRD assessment may benefit at least from a discussion about whether to [move forward with] or forgo treatment,” Tanios S. Bekaii-Saab, MD, said in an interview with OncologyLive. “Assessment of MRD has made its way into CRC, specifically in the earlier stages of the disease, but also more into oligometastatic disease. Now, the role continues to be explored further. Most of the data we’ve had so far, except [for from] a couple of studies, were from large observational studies.”

The final analysis of the BESPOKE CRC study subcohort was published in 2025 as the largest multicenter ctDNA study reported in the US to date. It revealed that ctDNA testing following surgery led to a change in adjuvant treatment for 1 out of 6 patients with stage II/III CRC.3 Additionally, the adjuvant plan was validated for most patients, and a benefit with adjuvant chemotherapy was solely observed in those with MRD-positive disease.

Furthermore, the phase 2/3, prospective NRG-G1008 (CIRCULATE-North America) study (NCT05174169) is currently ongoing to evaluate the role of ctDNA in risk stratification for escalation or de-escalation of adjuvant therapy in patients with resected colon cancer.4 Aggregate data are planned to be combined with those from CIRCULATE-JAPAN.

Examining New Readouts of Data that Further Explore ctDNA's Role

According to an updated analysis of the phase 3 CALGB/SWOG 80702 study (NCT01150045), ctDNA was highly prognostic for disease-free survival (DFS) and overall survival (OS) in patients with stage III colon cancer, and ctDNA positivity appeared to be predictive of the benefit of adjuvant therapy with celecoxib for DFS and OS.5 Primary findings showed that patients in the study who received the anti-inflammatory drug plus FOLFOX (fluorouracil, leucovorin, and oxaliplatin) vs FOLFOX and placebo did not experience a statistically significant difference in DFS (HR, 0.89; 95% CI, 0.76-1.03; stratified log-rank P = .12).

“[Although] this study was negative for celecoxib’s effect vs placebo following adjuvant therapy, there were hints that there was a small subgroup of patients who may benefit,” Bekaii-Saab explained. “In the follow-up [data], approximately less than half of the patients had enough material that they could assess their MRD [with], and those who had MRD-positive disease appeared to benefit from the addition of celecoxib vs those who did not.”

Patients in the ctDNA-positive group experienced an estimated 5-year OS rate of 61.6% (95% CI, 52.4%-72.4%) when given celecoxib (n = 99) compared with 39.9% (95% CI, 29.6%-53.8%) when given placebo (n = 74; HR, 0.58; 95% CI, 0.38-0.90; P = .0135). Additionally, those who were ctDNA negative and received celecoxib (n = 375) achieved an estimated 5-year OS rate of 91.8% (95% CI, 88.9%-94.7%) vs 91.3% (95% CI, 88.4%-94.3%) in the placebo arm (n = 392; HR, 0.86; 95% CI, 0.55-1.35; P = .5098).

“The question is [whether that] would change our standard today,” Bekaii-Saab said. “Does it mean that patients who are MRD positive should be put on celecoxib? Celecoxib does come with its own toxicities. This study was a post hoc analysis, it was also a retrospective look, and less than half of the patients had materials [available to examine for MRD]. All these limitations have to be taken into account before making a decision, but I believe it’s worth discussing with patients. I’m finding myself at least having some level of discussion with patients about this [therapy], given the pros and the cons, and the fact that the data are still [developing] and further study [is needed].”

Another study that was reported as negative has posed important questions about the role of ctDNA in guiding decisions. The phase 3 ALTAIR study (NCT04457297) revealed that there was not a statistically significant DFS benefit when patients who were ctDNA positive following curative resection in the CIRCULATE-Japan study were given trifluridine/ tipiracil vs placebo.2 A numerical benefit was seen, as the median DFS was 9.30 months (95% CI, 7.92- 10.84) vs 5.55 months (95% CI, 4.17-7.33), respectively (HR, 0.79; 95% CI, 0.60-1.05; P = .107). Additionally, investigators found that the DFS benefit was clinically meaningful in patients who had resected stage IV disease.

“That [study] was a bit disappointing,” BekaiiSaab noted. “However, on the other side, one would ask the question: Is trifluridine/tipiracil the right agent? It is a fluoropyrimidine, and patients were already exposed to capecitabine. Does that make sense? Should we go more toward targeted approaches? [For example], if a patient has a BRAF V600E mutation, do we go to BRAF-targeted strategies, rather than just switch to another chemotherapy? That study, unfortunately, tells us that another chemotherapy may not cut it.”

Trying to Determine the Necessity of Adjuvant Chemotherapy

The phase 2 DYNAMIC study (ACTRN12615000381583) randomly assigned patients with resected stage II colon cancer to either standard management, which included adjuvant treatment decisions based on conventional clinicopathologic criteria, or ctDNA-guided management, which encompassed observation for those who were ctDNA negative and adjuvant chemotherapy for those who were ctDNA positive.1 The 5-year relapse-free survival rate was 88.3% in the ctDNA arm (n = 294) vs 87.2% in the standard of care (SOC) arm (n = 147), confirming initial findings from the study that these patients could benefit from a ctDNA-guided approach, as the use of chemotherapy was reduced and survival outcomes were maintained.

Additional data from DYNAMIC showed the 5-year OS rates were 93.8% in the ctDNA arm vs 93.3% in the SOC arm (HR, 1.05; 95% CI, 0.47- 2.37; P = .887). Patients in the ctDNA arm who had ctDNA-negative disease (n = 246) experienced a 5-year OS rate of 95.3% compared with 85.6% in the ctDNA-positive group (n = 45; HR, 3.30; 95% CI, 1.20-9.05; P = .014). Investigators noted that most patients who are ctDNA positive following surgery can achieve ctDNA clearance with adjuvant chemotherapy and this is associated with positive outcomes. They added that although validation of these findings is needed, there could be potential to improve the precision of the ctDNA-informed approach by increasing variant number and incorporating ctDNA molecular burden.

Bekaii-Saab will discuss the use of ctDNA in the clinic and more at the 2025 International Symposium of Gastrointestinal Oncology conference, which he is cochairing.6 Slated for September 12 to 13, 2025, in Austin, Texas, the multidisciplinary meeting will comprehensively review the gastrointestinal cancer landscape and focus on examining the complex array of recent studies that are informing clinical practice. As the role of ctDNA continues to be examined, the conference will cover that aspect of care and more.

“Attendees [of] the conference will come out of it with what I hope is a clear understanding of the shifting landscape on a yearly basis. What they want to take home with them is one, what do I do for my patients after this conference? How can I change my practice in a way that’s positively affecting outcomes?” Bekaii-Saab noted. “The second is a clear understanding of what’s coming. What should I need? What should I continue to pay attention to and what may be a practice-changing element next year or the year after?”

References

1. Tie J, Wang Y, Lo SN, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: overall survival and updated 5-year results from the randomized DYNAMIC trial. J Clin Oncol. 2024;42(suppl 16):108. doi:10.1200/ JCO.2024.42.16_suppl.108
2. Bando H, Watanabe J, Kotaka M, et al. A randomized, doubleblind, phase III study comparing trifluridine/tipiracil (FTD/ TPI) versus placebo in patients with molecular residual disease following curative resection of colorectal cancer (CRC): the ALTAIR study. J Clin Oncol. 2025;43(suppl 4):LBA22. doi:10.1200/JCO.2025.43.4_suppl.LBA22
3. Shah PK, Aushev VN, Ensor J, et al. Circulating tumor DNA for detection of molecular residual disease (MRD) in patients (pts) with stage II/III colorectal cancer (CRC): final analysis of the BESPOKE CRC sub-cohort. J Clin Oncol. 2025;43(suppl 4):15. doi:10.1200/JCO.2025.43.4_suppl.15
4. Lieu CH, Yu G, Kopetz S, et al. NRG-GI008: colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-North America). J Clin Oncol. 2025;43(suppl 4):TPS310. doi:10.1200/JCO.2025.43.4_suppl.TPS310
5. Nowak JA, Shi Q, Twombly T, et al. Prognostic and predictive role of circulating tumor DNA (ctDNA) in stage III colon cancer treated with celecoxib: findings from CALGB (Alliance)/SWOG 80702. J Clin Oncol. 2025;43(suppl 4):LBA14. doi:10.1200/ JCO.2025.43.4_suppl.LBA14