Longitudinal ctDNA Methylation Status and Risk of Recurrence After Surgery in Patients With Stage I to III Colorectal Cancer

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In a Chinese study reported in JAMA Oncology, Mo et al found that longitudinal measurement of circulating tumor DNA (ctDNA) methylation permitted early detection of disease recurrence in patients undergoing surgery for stage I to III colorectal cancer. 

Study Details

In the prospective cohort study, 296 patients from two Chinese centers were enrolled between December 2019 and February 2022. Collection of patient blood samples took place before and after surgery, during and after adjuvant chemotherapy, and every 3 months for up to 2 years for detection of any of six methylation markers in ctDNA in plasma.

Key Findings

Among 296 patients with preoperative samples, 232 (78.4%) were positive for any of the six ctDNA methylation markers.

In testing at postoperative month 1, ctDNA methylation–positive patients were significantly more likely to have relapse vs ctDNA methylation–negative patients (hazard ratio [HR] = 17.5, 95% confidence interval [CI] = 8.9–34.4, P < .001). The combination of ctDNA methylation and positive carcinoembryonic antigen testing was associated with an elevated risk of disease recurrence (HR = 19.0, 95% CI = 8.9–40.7, P < .001).

ctDNA methylation status at postoperative month 1 was associated with prognosis in patients who received adjuvant chemotherapy (including different durations and intensities). After adjuvant chemotherapy, ctDNA methylation–positive patients had significantly reduced recurrence-free survival vs ctDNA methylation–negative patients (HR = 13.8, 95% CI = 5.9–32.1, P < .001).

Longitudinal ctDNA methylation analysis after definitive treatment showed poorer recurrence-free survival among ctDNA methylation–positive vs ctDNA methylation–negative patients (HR = 20.6, 95% CI = 9.5–44.9, P < .001). Risk of poor recurrence-free survival was elevated among patients with maintained ctDNA methylation over follow-up (HR = 68.8, 95% CI = 18.4–257.7, P < .001).

Post–definitive treatment analysis of ctDNA methylation status detected colorectal cancer recurrence earlier than radiological confirmation of recurrence, with a median lead time of 3.3 months (interquartile range = 0.5–6.5 months).

The investigators concluded, “The findings of this cohort study suggest that longitudinal assessment of ctDNA methylation may enable the early detection of recurrence, potentially optimizing risk stratification and postoperative treatment of patients with [colorectal cancer].”

Zheng Wang, MD, of the School of Medicine, Shanghai Jiao Tong University, and Guoxiang Cai, MD, of the Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, are the corresponding authors for the JAMA Oncology article.

Disclosure: The study was funded by the National Natural Science Foundation of China, Shanghai Science and Technology Committee, and others. For full disclosures of the study authors, visit

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