Circulating tumor DNA (ctDNA) testing is emerging as a valuable tool for guiding treatment decisions and predicting outcomes in patients with stage II/III colorectal cancer (CRC). Recent studies presented at the 2025 ASCO Gastrointestinal Cancers Symposium highlight the potential of ctDNA to personalize adjuvant therapy and improve recurrence detection.
Impact on Adjuvant Therapy Decisions
Final analysis data from the observational BESPOKE CRC subcohort (NCT04264702) revealed that ctDNA testing influenced adjuvant treatment decisions in 16.3% of cases. Purvi K. Shah, MD, a medical oncologist at Virginia Cancer Institute, noted that this testing led to a change in adjuvant management for 1 out of 6 patients and validated the adjuvant plan for most patients. Specifically, 59.9% of these changes resulted in chemotherapy de-escalation, while 35.7% led to chemotherapy intensification. Notably, 13.2% of patients were diagnosed with metastatic disease due to a positive postoperative ctDNA test.
Prognostic and Predictive Value of ctDNA
Several studies have demonstrated the prognostic value of ctDNA in predicting disease-free survival (DFS). Patients with ctDNA-positive stage II and III CRC experienced inferior DFS compared to those with ctDNA negativity. For stage II disease, the median DFS was 12.7 months (95% CI, 8.3-NE) in ctDNA-positive patients versus not estimable in ctDNA-negative patients, with respective 2-year DFS rates of 45.9% and 91.8%. Similarly, for stage III disease, the median DFS was 16.2 months (95% CI, 13.6-18.9) versus not estimable, with 2-year DFS rates of 35.5% and 87.4%. A time-dependent DFS analysis found that the hazard ratio was 26.4 (95% CI, 21.6-32.4) for patients with stage II/III disease and ctDNA positivity (P <.0001).
Furthermore, ctDNA clearance, defined as the conversion of a positive ctDNA test after surgery into a negative test without subsequent conversion, was associated with superior DFS. The hazard ratios for ctDNA clearance by month 3 and month 6 were 0.43 (95% CI, 0.29-0.64; P <.0001) and 0.31 (95% CI, 0.19-0.52; P <.0001), respectively.
ctDNA for Recurrence Detection
ctDNA testing has shown high sensitivity in detecting recurrence across various anatomical sites. Among 188 patients who recurred, 162 (86%) were ctDNA-positive within week 24. The sensitivity rates were 96% for liver, 89% for lymph nodes, 86% for abdomino-pelvic mass, 79% for peritoneum, and 76% for lung. Serial ctDNA testing was associated with a high rate of potentially curative metastasis-directed therapy (MDT).
Guiding Adjuvant Chemotherapy Decisions
ctDNA testing was also predictive of the benefit of adjuvant chemotherapy (ACT) in patients with stage II/III CRC. Among patients with MRD-positive status, ACT elicited a median DFS of 17.7 months (95% CI, 14.6-21.4) after surgery versus 7.1 months (95% CI, 4.6-21.4) with observation (HR, 0.48; 95% CI, 0.31-0.77; P = .0008). The DFS rates were 40.3% and 24.7% in the respective arms. This highlights the potential value of utilizing a positive ctDNA test to select patients for adjuvant chemotherapy.
ctDNA in Rectal Cancer
In patients with T1-3, N0 low or mid rectal cancer, detectable ctDNA following neoadjuvant chemotherapy was associated with persistent disease and recommendation for total mesorectal excision (TME). A retrospective analysis of the phase 2 NEO/CCTG CO.28 trial (NCT03259035) found that detection of ctDNA post-chemotherapy but prior to excision was associated with a recommendation for TME (P= .03).
Future Directions
While ctDNA testing shows great promise, ongoing phase III trials are needed to solidify its role in clinical practice. Studies are underway to determine the predictive value of ctDNA for 3 versus 6 months of adjuvant chemotherapy. Additionally, research is focusing on identifying therapies that could intervene in patients who are ctDNA positive after adjuvant therapy.
