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Serial analysis of circulating tumor DNA (ctDNA) fared no better than standard surveillance strategies for patients with resected colorectal cancer (CRC) in a small, single-center study.

In the retrospective analysis of nearly 50 patients, ctDNA's sensitivity for detecting recurrence was numerically lower than imaging alone, at 53.3% (95% CI 27.4-77.7) versus 60.0% (95% CI 32.9-82.5), respectively (P>0.99), according to researchers led by Marwan Fakih, MD, of City of Hope Comprehensive Cancer Center in Duarte, California.

Meanwhile, imaging and carcinoembryonic antigen (CEA) measurement combined held a sensitivity of 73.3% (95% CI 44.8-91.1), which was numerically higher than ctDNA (P=0.55), the group reported in .

Median time to detection of recurrence was similar for the three strategies:

• ctDNA: 14.3 months
• Imaging: 15 months
• Imaging with CEA: 15 months

"Imaging remains the most important surveillance assay in the follow-up of resected colorectal cancers," Fakih said in a press release. "Clinicians should continue to abide by [National Comprehensive Cancer Network] guidelines. For those who decide to implement ctDNA into their surveillance algorithm, they should be aware of the limitations associated with this assay."

In their study, Fakih and colleagues compared the sensitivity of Signatera (developed by Natera) -- a Clinical Laboratory Improvement Amendments (CLIA)–certified ctDNA assay for detecting minimal residual disease (MRD) -- with standard radiographic imaging and measurement of CEA levels in identifying early disease recurrence for patients with curatively resected stage I-IV CRC.

Of the 48 patients who met inclusion criteria, 15 had disease recurrence during surveillance. Imaging alone detected recurrence in nine of the patients, ctDNA detected recurrence in eight, and imaging and CEA detected recurrence in 11 of the patients.

Seven patients had a confirmed recurrence on imaging despite a negative ctDNA finding performed within 2 weeks of imaging -- five had low-volume lung disease, one had low-volume liver disease, and one had a brain lesion.

The results "bring into question the reliability of the ctDNA assay," according to Fakih and colleagues. "Although a positive ctDNA finding without doubt indicates an almost definitive risk of relapse, we show that a negative ctDNA finding is common in the setting of low-volume metastatic disease, especially in metastatic disease of the lung."

The ctDNA assay did identify recurrence before imaging in five patients, though the investigators suggested that the finding would not have altered treatment for these patients. One was subsequently identified as having multiple inoperable lung metastases. And while two of the patients underwent curative intent surgery after ctDNA, the researchers suggested a similar intervention would have followed detection via standard surveillance.

In a , Alan P. Venook, MD, of the University of California San Francisco, noted that in theory, surveillance with ctDNA can signal cancer recurrence at the stage of MRD, opening a "window of opportunity" for earlier and possibly more effective interventions.

However, Venook noted, the results of this study suggest "that finding MRD in a subset of patients with colorectal cancer may be both unachievable and -- worse -- not helpful."

Because the curative intervention in recurrent CRC is the elimination of oligometastatic disease, "ctDNA positivity is an intermediate finding that likely results in further imaging, because the site of recurrence must be identified before it can be surgically addressed," Venook said.

"Discovering MRD via ctDNA in a patient with colorectal cancer before the site of recurrence can be localized does not open the window of opportunity," he added. "Instead, it gives advanced notice that a patient has cancer recurrence when the only practical intervention is repeated imaging. In other words, patients receive bad news that is not actionable."

"Mature data from rigorous clinical trials, such as the BESPOKE study currently under the sponsorship of Natera, are needed to settle the issue of the role of ctDNA in colorectal cancer surveillance," Venook concluded. "If ctDNA can indeed detect MRD sooner than imaging, then interventional trials with molecular response as an end point are warranted to determine whether ctDNA detection is an actionable finding."

Fakih's group agreed that the findings call for "additional studies before the universal adoption of ctDNA in clinical practice," but also confirm the relevance of CT imaging in following patients with resected CRC.

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