A large-scale prospective multicenter clinical trial initiated by Chinese scholars has successfully demonstrated that circulating tumor DNA (ctDNA) methylation can achieve risk stratification, chemotherapy monitoring, and early recurrence monitoring in stage I-III colorectal cancer (CRC) patients after radical surgery, thereby changing postoperative management of CRC patients.
This groundbreaking achievement was recently published online in JAMA Oncology, a top international oncology journal. Professor Guoxiang Cai from Fudan University Shanghai Cancer Center stated that "the latest research results on ctDNA methylation monitoring molecular residual disease (MRD) after surgery for CRC provide a new 'weapon' for predicting and managing the risk of recurrence in stage I-III CRC patients, thus laying another cornerstone for improving the overall survival rate of CRC patients."
Over four years, the study searched for six CRC ctDNA markers based on DNA methylation in more than 1,200 blood samples from 299 stage I to III CRC patients, including samples collected before and after surgery and after treatment. Based on samples collected every three months for up to two years, the team found that methylation-based ctDNA detection can identify CRC cases with MRD after surgery or adjuvant chemotherapy, indicating the potential of using methylation markers for cost-effective disease monitoring.

Figure 1. Patient Enrollment and Definition of the Patient Subgroups

Prof. Cai explained that "the longitudinal changes of ctDNA methylation can effectively monitor disease progression from MRD to recurrence," and pointed out that the team's clinical pathology risk assessment analysis indicated that ctDNA methylation is "the most important prognostic factor for recurrence-free survival."
Specifically, researchers found that the risk of recurrence in ctDNA methylation-positive patients one month after surgery was significantly higher than that in ctDNA-negative patients. The sensitivity of ctDNA prediction for tumor recurrence reached 78%, significantly better than that of carcinoembryonic antigen (CEA) prediction. Moreover, for CEA-negative patients before surgery (66%), who previously lacked effective monitoring indicators, postoperative ctDNA has a higher value in predicting and monitoring positive patients, with a recurrence risk 35.2 times that of negative patients.

Figure 2. Circulating Tumor DNA (ctDNA) Analysis of Plasma at Postoperative Month 1 for Detecting Colorectal Cancer Recurrence

"The study successfully verified the tremendous potential of ctDNA methylation status in postoperative management of CRC patients, whose sensitivity for predicting tumor recurrence is significantly better than that of CEA, currently used in regular clinical testing. It can identify tumor recurrence up to 20 months earlier than imaging tests, providing an important basis for the value of ctDNA methylation status in postoperative monitoring of CRC," said Professor Guoxiang Cai. "Compared with the expensive and labor-intensive ctDNA genetic mutation detection technology, the ctDNA multi-gene fluorescence PCR method developed by the researchers provides a more universally applicable and cost-effective tool to help guide CRC patient's risk stratification, adjuvant chemotherapy decision-making, and recurrence dynamic monitoring."

Figure 3. Longitudinal Circulating Tumor DNA (ctDNA) Analysis for Detecting Colorectal Cancer Recurrence

In a related editorial in JAMA Oncology, researchers Ajay Goel from City of Hope Comprehensive Cancer Center and Beckman Research Institute of City of Hope and Juan Ruiz-Ba?obre from the University of Santiago de Compostela in Spain pointed out that "there is substantial value in prospectively validating the clinical importance of ColonAiQ in randomized clinical trials."

"If successful," they explained, "this liquid biopsy assay could represent a simple and cost-effective means for a more accessible and facile decentralized implementation in routine clinical practice."
Prof. Cai also proposed potential clinically guided applications of ctDNA methylation in the future. He pointed out, "Future ctDNA-guided clinical research is expected to address relevant clinical problems, thus improving the survival rate and quality of life of CRC patients."