Editor's Note:Traditionally, decisions regarding adjuvant chemotherapy after colorectal cancer surgery have been based on a patient's risk of recurrence, determined by TNM staging and histopathological features. However, emerging evidence suggests that these guidelines, in place since 2004, may not be the most effective approach and could be inadequate. In fact, surgery alone has already achieved high cure rates, preventing recurrence in 80% of stage II and 50% of stage III patients. Although adjuvant chemotherapy moderately improves disease-free survival (5–10% in stage II and 15–20% in stage III patients), many patients are exposed to unnecessary toxicity. Notably, even with adjuvant therapy, 15% of stage II and 30% of stage III patients still experience recurrence. This growing evidence highlights the relatively limited absolute benefit of adjuvant chemotherapy. Precisely predicting which patients will benefit from adjuvant therapy remains a significant challenge, underscoring the importance of developing more accurate biomarkers to guide treatment decisions.

Minimal residual disease (MRD) refers to any detectable tumor-derived molecular abnormalities after treatment, indicating the ongoing presence of cancer. In colorectal cancer, MRD assessment typically occurs after surgery or adjuvant chemotherapy. Recently, Dr. Alessandro Mannucci from San Raffaele Hospital and Dr. Ajay Goel from City of Hope Medical Center explored whether adjuvant chemotherapy is necessary after colorectal cancer surgery and which patients would benefit. Their discussion focused on the current and future applications of circulating tumor DNA (ctDNA) in predicting recurrence risk in the MRD era, aiming to provide more effective post-surgical treatment strategies for colorectal cancer.

ctDNA in Clinical Decision-Making

The shift from traditional pathological methods to MRD-based strategies has profoundly impacted colorectal cancer management, transforming treatment approaches, monitoring practices, and redefining concepts of cancer response, remission, and cure. Since the early stages of MRD research, ctDNA has demonstrated a more precise ability to predict recurrence compared to conventional pathological risk assessments.

A groundbreaking study revealed that 8% of stage II colorectal cancer patients, classified as “low-risk,” had detectable ctDNA after surgery, and 80% of these patients relapsed within two years. Among “high-risk” patients, 9% remained ctDNA-positive after completing adjuvant chemotherapy, and every one of these patients relapsed within a year. Subsequent studies have consistently shown that ctDNA can detect tumor recurrence 9–12 months earlier than traditional imaging and is strongly associated with a two-year disease-free survival rate of less than 5%. Notably, adjuvant chemotherapy successfully cleared ctDNA in approximately 25% of cases, suggesting a positive link between ctDNA clearance and improved prognosis, disease remission, and even potential cure.

This growing body of evidence raises a critical question: should ctDNA results, rather than traditional pathology, determine whether adjuvant chemotherapy is necessary? Currently, several clinical trials are actively exploring how ctDNA testing can optimize treatment strategies and advance colorectal cancer management.

Advances in Personalized Treatment for Colorectal Cancer

While most trials are still ongoing or in patient recruitment phases, 2024 has seen the release of several significant observational, prospective, large-scale, national, and multicenter studies assessing ctDNA’s clinical application. These include the CIRCULATE-Japan GALAXY, TRACC Part B, BESPOKE CRC, and Henriksen studies.

Two years ago, the DYNAMIC study demonstrated that ctDNA-guided treatment for stage II colorectal cancer was both practical—resulting in lower adjuvant chemotherapy use (relative risk of 1.82)—and safe, with similar two-year disease-free survival rates (93.5% vs. 92.4%) compared to standard care. Recently reported findings from the CIRCULATE-Japan GALAXY study confirmed that ctDNA-positive patients had significantly higher risks of recurrence (HR 11.99) and death (HR 9.68), reinforcing ctDNA’s prognostic value during MRD assessment.

The BESPOKE CRC and TRACC Part B trials have reported similar results. Interestingly, both the CIRCULATE-Japan GALAXY and BESPOKE CRC studies found that adjuvant chemotherapy did not improve survival rates in ctDNA-negative patients. Additionally, nearly all patients with radiographic recurrence had previously shown elevated ctDNA levels. Another key finding was that adjuvant chemotherapy could convert ctDNA-positive to ctDNA-negative status, and achieving ctDNA clearance within six months—rather than brief clearance—significantly improved disease-free survival outcomes (HR 11.12).

Moreover, patients who remained ctDNA-positive had a far higher risk of recurrence compared to those who consistently tested ctDNA-negative (HR 124.3). Early in 2024, Henriksen and colleagues also reported that patients with ctDNA positivity after surgery experienced a significantly shorter median time to recurrence than patients who initially tested ctDNA-negative but later became positive. Interestingly, patients with emerging clinical signs of recurrence also showed rising ctDNA levels.

Collectively, the 2024 findings from the CIRCULATE-Japan GALAXY, TRACC Part B, BESPOKE CRC, and Henriksen studies provide strong evidence that MRD-guided adjuvant therapy, rather than risk-based treatment, is feasible, practical, and, most importantly, safe.

The Next Steps

There is no doubt that traditional pathology-based approaches to adjuvant chemotherapy have limitations that must be addressed. The data from 2024 offers the most compelling evidence yet to support transitioning to ctDNA-guided methods. However, many unanswered questions remain. For ctDNA-positive patients, what is the optimal chemotherapy duration—three months or six months? Should treatment involve dual or triple-agent chemotherapy? What is the best chemotherapy combination?

For ctDNA-negative patients, could adjuvant chemotherapy be reduced in dosage or even omitted altogether? How should ctDNA testing be used for follow-up and monitoring? Could MRD clearance be adopted as a treatment endpoint to define remission and cure? Furthermore, how applicable is ctDNA analysis to rectal cancer?

Addressing these knowledge gaps is crucial for refining ctDNA-guided treatment strategies. It is hoped that ongoing clinical trials will provide the answers needed to move forward.