CtDNA-guided surveillance catches postoperative CRC recurrences early for curative treatment

For patients who have undergone curative resection for nonmetastatic colorectal cancer (CRC), performing circulating tumour DNA (ctDNA) methylation analysis during surveillance facilitates earlier detection of recurrences suitable for curative therapy, according to interim data from the phase III FIND trial.

Over a median follow-up of 12 months, recurrence was identified in 8.3 percent of patients who underwent ctDNA-guided surveillance and 10.5 percent of those who underwent standard surveillance (control). While recurrence rates were similar between the two groups, twice as many patients who experienced recurrence in the ctDNA arm vs the control arm received curative-intent treatment (50 percent vs 22.6 percent; relative risk [RR], 2.214, 95 percent confidence interval [CI], 1.060–4.780; p=0.034). [ESMO GI 2025, abstract LBA1]

CtDNA-guided surveillance allowed detection of tumour recurrence an average of 3.05 months (95 percent CI, 1.43-4.67) earlier than standard surveillance (median time to clinical recurrence [TTCR], 9 vs 12 months; p<0.001). In the ctDNA group, the lead time between a positive ctDNA test result and clinical recurrence was <8 months in 75 percent of patients, ≤4 months in 52 percent, and ≤2 months in 24 percent.

“These results show that detection of ctDNA positivity triggered immediate contrast-enhanced imaging test to expedite confirmation of recurrence following curative resection for nonmetastatic colorectal cancer,” said lead investigator Dr Junjie Peng of Fudan University Shanghai Cancer Center, Shanghai, China.

“They demonstrate the feasibility of a ctDNA methylation assay with a clinically actionable turnaround time for reporting results to guide surveillance decisions,” Peng added.

Intensified surveillance strategy

In FIND, ctDNA testing was conducted within 1 month prior to resection, within 1 month after the procedure, then every 3 months for 2 years. Peng pointed out that they used an intensified surveillance strategy for ctDNA-positive patients.

This intensified strategy involved immediately undergoing a CT scan or MRI after testing positive for ctDNA to investigate the potential recurrence. If the scan returned a positive result, a multidisciplinary team performed a comprehensive review to assess the patient and determine the best course of action, such as further treatment. In cases where the scan result was negative, the patient underwent repeated CT scan or MRI twice within the next 6 months. If both scans returned negative results, the patient returned to the protocol follow-up of ctDNA testing every 3 months.

CtDNA testing was conducted using an improved single-tube, methylation-specific quantitative PCR assay targeting 10 methylation markers, with the ability to detect tumour DNA down to a 0.01 percent allelic fraction, Peng said.

On the other hand, standard surveillance involved physical examination and carcinoembryonic antigen testing, chest/abdominal/pelvis CT scan, and colonoscopy.

Recurrent lesion characteristics

Most patients who had recurrent lesions had liver and/or lung lesions only, 15 of 24 in the ctDNA group and 16 of 31 in the control group (62.5 percent vs 51.6 percent; p=0.032), with 11 and five of them receiving curative-intent treatment, respectively.

Notably, the recurrent lesions detected in the ctDNA group were smaller, fewer, and more contained compared with those identified in the control group. The largest tumours were no bigger than 3 cm in 77.8 percent of patients in the ctDNA group vs 42.9 percent in the control group. The number of metastatic lesions was three or fewer in 88.9 percent vs 42.9 percent, and the lesions were confined to one lobe in 88.9 percent vs 42.9 percent.

These recurrent lesion data suggest that ctDNA-guided surveillance catches recurrence when it is still in a very early, localized, and more manageable stage, making it more treatable with a curative approach, according to Peng. He highlighted its significance, saying that standard postoperative surveillance may be ineffective at finding cancer recurrences early enough for a second surgery to be a viable curative treatment option, based on prior data.

A total of 728 patients who underwent curative resection for nonmetastatic CRC participated in FIND and were randomly assigned to ctDNA methylation-guided surveillance (n=363) or standard surveillance (n=365). A total of 74 and 70 patients in the respective groups did not undergo monitoring due to various reasons, leaving 289 and 295 patients in the intent-to-treat (ITT) population. Furthermore, 25 and 11 patients in the respective groups had protocol violations, resulting in 264 and 284 patients being included in the per-protocol population.

In the ITT population, most patients were aged 45–54 years (59.2 percent in the ctDNA group and 52.5 percent in the control group), had rectal tumours (45.7 percent and 45.4 percent), and did not receive neoadjuvant therapy (86.2 percent and 88.8 percent).

TNM stage was I in 20.4 percent of patients in the ctDNA group and 20 percent in the control group, II in 36 percent and 36.9 percent, III in 39.1 percent and 39.7 percent, and PCR in 4.5 percent and 3.4 percent, respectively. Genetic alterations identified included BRAF V600E mutations (2.7 percent and 2 percent), KRAS mutations (47.5 percent and 51.6 percent), and NRAS mutations (3.8 percent and 5.1 percent).

The primary endpoint was the proportion of patients with recurrent CRC receiving curative-intent therapy. Secondary end points included time to clinical recurrence, disease-free survival, overall survival, and health-related quality of life.