Introduction
Colorectal cancer frequently spreads to the liver, and surgical removal of these liver metastases (colorectal liver metastases, CRLM) offers a chance for long-term survival. However, deciding which patients benefit from additional treatment after surgery, namely adjuvant chemotherapy (ACT), remains controversial. Although ACT can reduce recurrence risk, its impact on overall survival (OS) has been inconsistent in clinical studies, and there is no standard tool for identifying patients who truly benefit.
Circulating tumor DNA (ctDNA) analysis has emerged as a promising biomarker to detect minimal residual disease (MRD) — tiny amounts of cancer DNA remaining in the body after surgery, which might indicate a higher risk of relapse. Personalized, tumor-informed ctDNA testing can sensitively detect MRD and guide informed clinical decision-making. This study evaluates the relationship between ctDNA-defined MRD status, survival outcomes, and the benefit of ACT in patients who have undergone curative surgery for CRLM.
Study Design and Methods
This prospective analysis enrolled patients from the CIRCULATE-Japan GALAXY study between May 2020 and July 2024. Included were patients with resected CRLM who had ctDNA testing performed between 2 and 10 weeks post-surgery. Two patient cohorts were analyzed separately: those who underwent upfront surgery without prior chemotherapy and those who received neoadjuvant chemotherapy (NAC) prior to surgery.
Postoperative ctDNA was tested using a personalized, tumor-informed assay tailored to each patient’s tumor genetic profile to detect residual cancer DNA circulating in the bloodstream. Patients were then either observed or treated with ACT, and their disease-free survival (DFS) and overall survival (OS) outcomes were monitored. Landmark analysis was conducted 70 days after surgery to ensure comparability.
Patient Characteristics
The study included 298 patients; the median age was 67 years (range 33–85), and 64.4% were male. The median follow-up duration was 43.2 months. Of these, 191 patients underwent upfront surgery, and 107 were treated preoperatively with NAC.
Key Findings
1. Prognostic Value of Postoperative ctDNA (MRD) Status
In patients undergoing upfront surgery, postoperative ctDNA positivity indicated molecular residual disease and was strongly associated with worse DFS (Hazard Ratio [HR], 4.14) and OS (HR, 9.13) compared to ctDNA-negative patients. In the NAC cohort, ctDNA positivity also predicted poor outcomes: DFS HR of 4.82 and OS HR of 9.43.
2. Benefit of Adjuvant Chemotherapy Based on MRD Status
Among patients with postoperative ctDNA-positive status after upfront surgery, ACT was linked to significant improvements in DFS (HR, 0.07) and OS (HR, 0.27). At 48 months, DFS was 37.5% for ACT-treated patients versus not reached in untreated, and OS was 65.3% vs. 32.9%, respectively.
However, in patients with ctDNA-negative status post-surgery, ACT did not confer clear improvements in DFS or OS, suggesting that these patients may safely avoid chemotherapy without compromising long-term outcomes.
Conversely, in the NAC cohort, ACT did not demonstrate a survival benefit regardless of MRD status. Additionally, ctDNA positivity measured after NAC but before surgery was associated with poorer OS, highlighting persistent residual disease despite chemotherapy.
Clinical Implications
This study provides strong evidence that postoperative ctDNA testing effectively stratifies patients by risk after CRLM resection and predicts who benefits from ACT. It suggests a precision oncology approach where:
- Patients with detectable ctDNA after surgery — indicative of MRD — should be prioritized for ACT to improve survival.
- Patients with undetectable ctDNA may avoid unnecessary chemotherapy, sparing them toxicity and preserving quality of life.
These findings are particularly robust for patients undergoing upfront surgical resection without prior chemotherapy. For patients receiving neoadjuvant chemotherapy, the utility of postoperative ACT appears limited and requires further research.
Background on ctDNA and MRD
Circulating tumor DNA refers to fragments of DNA shed by cancer cells into the bloodstream. Sensitive assays targeting tumor-specific genetic mutations enable detection of MRD that is otherwise invisible on scans and pathology. Rising evidence supports ctDNA as a powerful prognostic tool across multiple cancer types, helping to identify residual disease after curative-intent surgery or systemic therapy.
Adjuvant chemotherapy aims to eradicate micrometastases and reduce recurrence risk. Tailoring its use based on MRD status optimizes treatment by focusing on patients most likely to benefit and avoiding overtreatment in low-risk groups.
Limitations and Future Directions
While this study is prospective and comprehensive, limitations include its observational design and that the NAC cohort did not derive differential benefit from ACT, possibly related to prior chemotherapy effects or tumor biology variations. Randomized controlled trials are necessary to validate ctDNA-guided ACT strategies definitively.
Future investigations should explore ctDNA monitoring dynamics over time, integration with other biomarkers, and application in diverse clinical settings. Expanding ctDNA testing accessibility and standardization will be key for broad clinical adoption.
Conclusion
Postoperative ctDNA-defined molecular residual disease is a robust prognostic marker in colorectal liver metastases and identifies patients who benefit from adjuvant chemotherapy following surgical resection. Patients without detectable ctDNA post-surgery exhibit excellent long-term survival and may safely forgo ACT. These findings advocate for introducing personalized ctDNA-guided treatment strategies into routine clinical practice to enhance outcomes and reduce treatment burden in patients with resected colorectal liver metastases.
