ctDNA and RNA-based tests are expanding colorectal cancer screening options

Screening is an effective prevention strategy for colorectal cancer (CRC), but rates of uptake among eligible individuals remain suboptimal with approximately 40% of average-risk subjects not being screened in the United States (Cancer Epidemiol Biomarkers Prev. 2021;30:1554–1565). Colonoscopy can detect both cancerous and precancerous lesions, but it is an invasive procedure that requires a bowel prep, sedation and time away from work, which may discourage its acceptance. The advent of blood-based cancer screening that relies on circulating tumour (ct)DNA has provided an additional screening option. The DNA Shield blood test interrogates cell-free DNA genomic alterations, aberrant methylation and fragmentomic patterns. Its sensitivity and specificity for the detection of CRC and advanced adenomas in patients undergoing screening colonoscopy was shown in the ECLIPSE trial (N Engl J Med. 2024;390:973–983), which led to U.S. Food and Drug Administration approval. A different ctDNA-based multiomics assay demonstrated acceptable accuracy for CRC detection in the PREEMPT CRC study (JAMA. 2025:e257515), although it has not yet received regulatory approval.

The main drawback of these new ctDNA tests is that even though their performance characteristics are as good as the standard faecal immunochemical test (FIT) for the detection of CRC, they are less effective in detecting stage I disease and, perhaps more importantly, precancerous colorectal lesions. In fact, the ECLIPSE and the PREEMPT CRC trials reported detection of only around 13% of advanced precancerous lesions, which is less than the approximate 45% that could be expected with a next-generation multitarget stool-based DNA test (N Engl J Med. 2024;390:984–993). The relatively poorer capacity of blood-based testing to identify precancer and early-stage disease is probably due to the invasive nature of more advanced cancers and their greater access to, and therefore shedding of tumour DNA into, the bloodstream. However, being able to identify precancerous lesions is key to preventing CRC and to reducing the overall CRC burden. Efforts to improve sensitivity of ctDNA assays are a high priority, and one such strategy is the analysis of cell-free DNA fragment patterns in blood termed ‘fragmentomics’. This technology has been shown to detect early-stage CRC with high sensitivity and specificity and holds promise for the detection of precancerous lesions (Cancer Res. 2024;84:3286–3295).

Alternative avenues are also being explored and one promising area of investigation is the use of RNA-based markers. The multitarget stool-RNA ColoSense test has shown promise in the detection of CRC and advanced adenomas and has been shown to be more sensitive than FIT alone (JAMA. 2023;330:1760–1768). Excitement is also growing for the use of exosomal microRNAs. These have shown diagnostic potential in pancreatic cancer and it is hoped that their application can be expanded to other solid tumour types, including CRC. Advances in technology are also being leveraged to enhance existing screening methods, such as the use of artificial intelligence (AI) to further improve the polyp detection rate of colonoscopy.

The introduction of new methodologies means that we will be able to offer individuals an expanding menu of screening options – stool-based, blood-based and invasive testing with the potential to increase adherence to screening recommendations. As clinicians, we know that the best test is the one that an individual agrees to undergo. However, the impact of both test efficacy and cost on availability and choice of screening assays are unavoidable factors (Clin Gastroenterol Hepatol. 2025:S1542-3565(25)00320-9). Going forward, the main goal is to find affordable non-invasive testing that can provide both cancer prevention and detection so that the incidence and mortality of this disease can be substantially reduced.