ctDNA test in question for detecting colorectal cancer recurrence

While the circulating tumor DNA (ctDNA) biomarker holds promise for the surveillance and management of various cancers, it may be of limited help when it comes to colorectal cancer (CRC). A study in JAMA Network Open found that while the ctDNA assay provided good results when it came to detecting recurrent cancer in CRC patients, it didn’t perform better than surveillance by imaging. The study was done because “I was concerned over the over-reliance on ctDNA, specifically Signatera, on the surveillance of resected colorectal cancer,” said lead author Dr. Marwan Fakih, a professor of medical oncology at the City of Hope cancer center in California. While it did detect some early recurrences, it is costly and didn’t change outcome, he said. ctDNA is a type of liquid biopsy, and liquid biopsies encompass three approaches. One is tumor-specific cfDNA—essentially tumor DNA dissolved in solution. When a cancer cell dies, DNA is released from the dying cell into the bloodstream. The second type of liquid biopsy detects circulating tumor cells—whole tumor cells that break off and enter the bloodstream. The third relies on detection of exosomal DNA which contains both DNA and RNA from the tumor. Often any of the three types are referred to as ctDNA. They can reduce the need for tissue biopsy and have quick results. “Our study highlights the limitations of ctDNA in the surveillance of resected colorectal cancer and calls for additional studies before the universal adoption of ctDNA in clinical practice…our findings confirm the ongoing relevance of CT imaging in the follow-up of patients with resected colorectal cancer,” the researchers said. The National Comprehensive Cancer Network (NCCN) and other international groups recommend defined periodic surveillance of colorectal cancer with measurements of carcinoembryonic antigen (CEA) levels and CT studies depending on the stage of disease. But there is considerable disagreement regarding the impact of these assays on CRC outcome. Two ctDNA assays are marketed in the US for CRC surveillance, and many clinicians use them for the surveillance of resected colorectal cancer, despite limited supportive clinical data. Read: Lung cancer detected earlier in breast cancer patients A retrospective, single-center cohort study was conducted to compare ctDNA assay with standard radiographic imaging and measurement of CEA levels in the surveillance of stage I to IV patients who had undergone colorectal cancer resection. All CRC patients undergoing surveillance with the Signatera ctDNA assay from September 1, 2019, to November 30, 2021 were identified, then divided into groups depending on their stage of cancer. All patients were undergoing minimal residual disease surveillance, had undergone surgical treatment and, where needed, had completed adjuvant therapy. Of the CRC patients identified, 48 patients had curative resections. There were 28 men (58.3%) and 20 women (41.7%) with a median age of 60 years. Of these, 31 (64.6%) had stage II-III cancer, and 17 (35.4%) had stage IV cancer. All underwent surveillance by ctDNA assay, imaging, and measurement of CEA levels throughout the study period. The researchers categorized recurrences as ctDNA, imaging, and CEA-detected recurrences. A total of 15 patients had confirmed recurrences. Of these, ctDNA and imaging studies identified the recurrence concurrently in three patients (20%), only one of whom had elevated CEA levels. Seven of 15 patients (46.7%) had their confirmed recurrence identified by imaging, despite a negative ctDNA finding. CEA levels had a low sensitivity for identifying disease recurrence, with only three patients (20.0%) having elevated CEA levels at the first sign of confirmed relapse. The results showed no statistical difference between the three modalities in how long they too to identifying a recurrence. This was a median of 14.3 months for ctDNA, compared to 15.0 months for imaging, and 15.0 months for imaging plus CEA measurement. “Although ctDNA assay identified five patients before imaging, it is unlikely that this intervention would have changed the treatment of these patients,” the study said. Dr. Fakih added that while it “identified recurrences ahead of imaging in several patients with liver and retroperitoneal metastatic disease, it is possible that Signatera and imaging can be complementary for optimal sensitivity.” While the study was small, it prompted a commentary in the same issue of JAMA which stated “ctDNA did not detect recurrence sooner than imaging in the surveillance setting. Even when it did so, as in 2 of the 3 patients in this series who underwent a curative operation and remain disease-free with long-term follow-up, it could not be argued that it triggered the curative intervention.” It also stated that using the technology to detect minimal residual disease (MRD) “has different implications in different cancers and circumstances,” and more clinical trials are needed. “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 or merely advanced notice that the cancer is destined to recur,” it said. Read: Few newly approved cancer drugs change first-line treatments According to Dr. Lillian Siu who was not involved in the study, “The JAMA paper is interesting but it is a small group of patients and also retrospective in nature. One would need larger prospective evaluations to understand (accept or refute) the utility of ctDNA in MRD study. Also, it is likely also disease specific.” She is an oncologist and professor of medicine at the University of Toronto. Dr. Siu coauthored a review on the topic Science Advances, which stated that “ctDNA concentration varies by tumor type and is broadly correlated with tumor volume; however, this correlation is confounded by tumor heterogeneity and ctDNA release mechanisms. Baselines have to be established for different tumor types and situations.” Also, “The promise of ctDNA analysis is to make cancer biomolecular testing noninvasive. Treatment monitoring is one of the most exciting potential clinical applications of this advancing technology.”

ctDNA test in question for detecting colorectal cancer recurrence

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