Circulating tumor DNA (ctDNA) analysis has emerged as a powerful tool for predicting survival outcomes and treatment response in patients with colorectal cancer (CRC). A recent study, which included 2,240 patients with surgically resectable CRC, demonstrated that ctDNA positivity after surgery is a significant predictor of both disease-free survival (DFS) and overall survival (OS). The study highlights the potential of ctDNA monitoring to guide adjuvant chemotherapy (ACT) decisions and improve patient outcomes.
ctDNA as a Prognostic Marker
The study found that patients with ctDNA positivity during the molecular residual disease (MRD) window had significantly worse DFS and OS compared to ctDNA-negative patients. Specifically, 15.93% of patients were MRD positive, and 78.27% of these experienced recurrence, compared to only 13.14% of MRD-negative patients (HR: 11.99, 95% CI: 10.02–14.35, P < 0.0001). The 24-month DFS was 20.57% for MRD-positive patients versus 85.10% for MRD-negative patients.
Furthermore, ctDNA positivity was associated with a significantly increased risk of mortality (HR: 9.68, 95% CI: 6.33–14.82, P < 0.0001), with 24-month OS rates of 83.65% and 98.50% for MRD-positive and MRD-negative patients, respectively. Multivariate analysis confirmed that ctDNA positivity was the most significant prognostic factor for both DFS (HR: 12.08, 95% CI: 9.56–15.27, P < 0.001) and OS (HR: 9.87, 95% CI: 5.60–17.40, P < 0.001), outperforming other clinicopathological risk factors.
During the surveillance window, patients with ctDNA positivity at any time point were approximately 34 times more likely to recur (HR: 33.56, 95% CI: 26.07–43.20, P < 0.0001) and had a significantly shorter OS (HR: 19.51, 95% CI: 10.44–36.44, P < 0.0001).
Impact on Post-Recurrence Survival
The study also investigated the impact of ctDNA status on post-recurrence survival (PRS). Patients with ctDNA positivity during the MRD and surveillance windows had significantly inferior OS compared to their ctDNA-negative counterparts, even after experiencing radiological recurrence. This suggests that ctDNA positivity not only predicts recurrence but also has an independent impact on overall prognosis.
ctDNA and Actionable Biomarkers
The researchers analyzed the association between ctDNA status and various actionable biomarkers. They found that MRD positivity was consistently associated with worse DFS across all biomarkers, except for TP53 Y220C. Notably, patients with BRAF V600E mutations who were MRD negative had a very low recurrence rate (7.89%) compared to those who were MRD positive (100%).
Guiding Adjuvant Chemotherapy Decisions
The study provides compelling evidence that ctDNA monitoring can help identify patients who are most likely to benefit from ACT. MRD-positive patients derived significant benefit from ACT (adjusted HR: 0.23, 95% CI: 0.15–0.35, P < 0.0001), while no statistically significant benefit was observed for MRD-negative patients (adjusted HR: 0.70, 95% CI: 0.46–1.06, P = 0.091).
Furthermore, the study assessed ctDNA clearance during ACT and found that patients with ctDNA clearance had superior DFS and OS compared to those who remained ctDNA positive. Specifically, clearance at 3 months was associated with a DFS HR of 5.38 (95% CI: 3.59–8.04, P < 0.0001) and an OS HR of 3.76 (95% CI: 1.53–9.24, P = 0.004).
Molecular Recurrence
The study also examined ctDNA clearance patterns and molecular recurrence. Patients with sustained ctDNA clearance had significantly longer DFS and OS compared to those with transient or no clearance. Among patients with transient clearance, most converted back to ctDNA positivity within 18 months after surgery.
Importantly, the study found that molecular recurrence, as detected by ctDNA, often preceded radiological recurrence. MRD-negative patients who experienced molecular recurrence had significantly worse OS, similar to MRD-positive patients. This highlights the potential of ctDNA monitoring for early detection of recurrence and timely intervention.
Clinical Implications
These findings underscore the importance of ctDNA analysis in the management of CRC. ctDNA monitoring can provide valuable prognostic information, guide adjuvant therapy decisions, and enable early detection of recurrence. By incorporating ctDNA analysis into clinical practice, healthcare professionals can personalize treatment strategies and improve outcomes for patients with CRC.
