In an average-risk screening population, cell-free DNA (cfDNA) blood-based test showed 83% sensitivity for the detection of colorectal cancer (CRC), 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. The findings from the ECLIPSE study are reported by Dr. William M. Grady of the Fred Hutchinson Cancer Center in Seattle, WA, US, and colleagues on 14 March 2024 in The New England Journal of Medicine.
In BLUE-C prospective study, the study team evaluated a next generation multitarget stool DNA test and found that the sensitivity of the test for CRC was 93.9% and that the specificity for advanced neoplasia was 90.6%. Comparisons with foecal immunochemical test (FIT) showed that the stool DNA test had higher sensitivity, but lower specificity. The findings are reported by Dr. Thomas F. Imperiale of the Regenstrief Institute in Indianapolis, IN, US and colleagues on 14 March 2024 in The New England Journal of Medicine.
Early detection could prevent more than 90% of CRC–related deaths. However, more than one third of the screening-eligible population is not up to date with screening despite multiple available tests. Factors contributing to low screening adherence include the time required to perform screening, scheduling challenges, concern over test invasiveness and pain, fear of the test, discomfort or embarrassment associated with endoscopic examinations, lack of insurance coverage, distance from the test provider, and lack of physician recommendation for screening. Alternative screening tests have the potential to improve screening adherence, detect CRC earlier, and reduce CRC–related mortality.
Performance of cfDNA blood-based test
The ECLIPSE (Evaluation of the ctDNA LUNAR Test in an Average Patient Screening Episode) study was designed to evaluate the performance of the cfDNA blood-based test (Shield, Guardant Health) to detect asymptomatic and early-stage CRC in a screening-relevant population. Eligible persons were enroled in this prospective, observational, multicentre study at 265 sites in the US, including primary care and endoscopy centres in academic and community-based institutions.
The study team assessed the performance characteristics of a cfDNA blood-based test in a population eligible for CRC screening. The co-primary outcomes were sensitivity for CRC and specificity for advanced neoplasia (CRC or advanced precancerous lesions) relative to screening colonoscopy. The secondary outcome was sensitivity to detect advanced precancerous lesions.
The clinical validation cohort included 10258 persons, 7861 of whom met eligibility criteria and were evaluable. A total of 83.1% of the participants with CRC detected by colonoscopy had a positive cfDNA test and 16.9% had a negative test, which indicates a sensitivity of the cfDNA test for detection of CRC of 83.1% (95% confidence interval [CI] 72.2 to 90.3). Sensitivity for stage I, II, or III CRC was 87.5% (95% CI 75.3 to 94.1), and sensitivity for advanced precancerous lesions was 13.2% (95% CI 11.3 to 15.3).
A total of 89.6% of the participants without any advanced colorectal neoplasia (CRC or advanced precancerous lesions) identified on colonoscopy had a negative cfDNA blood-based test, whereas 10.4% had a positive cfDNA blood-based test, which indicates a specificity for any advanced neoplasia of 89.6% (95% CI 88.8 to 90.3). Specificity for negative colonoscopy (no CRC, advanced precancerous lesions, or non-advanced precancerous lesions) was 89.9% (95% CI 89.0 to 90.7).
ECLIPSE was a large-scale study of colonoscopy screening alternatives that evaluated persons 45 to 49 years of age alongside those 50 years of age or older. The authors wrote that given the increasing incidence of CRC among persons younger than 45 years of age, understanding the potential clinical and health economic effect of a blood-based testing strategy to expand the screening age will be of interest.
In an accompanied editorial article on science behind the study, Y.M. Dennis Lo of the State Key Laboratory of Translational Oncology, Department of Chemical Pathology, and the Li Ka Shing Institute of Health Sciences, the Chinese University of Hong Kong, and the Center for Novostics, Hong Kong Science Park, Pak Shek Kok, all in Hong Kong, wrote that Shield, a commercially available assay to analyze the plasma cfDNA, characterises and then integrates 3 types of information about the person’s cfDNA: methylation status, aberrant fragmentation patterns, and the presence or absence of somatic pathogenic variants in the genes APC and KRAS.
Although the study team demonstrated the feasibility of using plasma cfDNA to screen for CRC, the relatively low sensitivity for the detection of advanced precancerous lesions is a limitation. Moreover, colonoscopy not only detects such lesions with high sensitivity, but also permits their immediate removal. The non-invasiveness of the plasma cfDNA assay, though, is a feature that seems likely to result in greater uptake than colonoscopy, but further work is warranted to determine whether this is true and whether the cost–benefit ratio would justify its implementation. Also, of note are foecal tests which are truly non-invasive, such as the one reported in same issue of the journal.
Guardant Health funded the ECLIPSE study which was designed by the authors.
Performance of a next generation multitarget stool DNA test
A non-invasive multitarget stool DNA test that includes assessment of DNA molecular markers and haemoglobin level was approved by the US Food and Drug Administration in 2014 and is included in the CRC screening guidelines for persons at average risk. In the initial trial of the multitarget stool DNA test, the detection of CRC and advanced precancerous lesions was significantly higher than with a comparator FIT, but specificity was lower.
A next generation multitarget stool DNA test was developed to improve specificity and reduce the occurrence of false positive results while maintaining or improving sensitivity. In the BLUE-C study, the investigators evaluated the performance characteristics of the next generation multitarget stool DNA test in asymptomatic adults 40 years of age or older who were undergoing screening colonoscopy.
The primary objective was to determine the sensitivity of the test for CRC and the specificity for advanced neoplasia (CRC or advanced precancerous lesions). Advanced precancerous lesions included one or more adenomas or sessile serrated lesions measuring at least 1 cm in the longest dimension, lesions with villous histologic features, and high-grade dysplasia. Secondary objectives included the quantification of sensitivity for advanced precancerous lesions and specificity for non-neoplastic findings or negative colonoscopy and a comparison of the test results with those of a commercially available FIT. The study was conducted at 186 sites across the US.
Of 20176 participants, 98 had CRC, 2144 had advanced precancerous lesions, 6973 had non-advanced adenomas, and 10961 had non-neoplastic findings or negative colonoscopy. With the next generation test, sensitivity for CRC was 93.9% (95% CI 87.1 to 97.7), and specificity for advanced neoplasia was 90.6% (95% CI 90.1 to 91.0). Sensitivity for advanced precancerous lesions was 43.4% (95% CI 41.3 to 45.6), and specificity for non-neoplastic findings or negative colonoscopy was 92.7% (95% CI 92.2 to 93.1).
With the FIT, sensitivity was 67.3% (95% CI 57.1 to 76.5) for CRC and 23.3% (95% CI 21.5 to 25.2) for advanced precancerous lesions; specificity was 94.8% (95% CI 94.4 to 95.1) for advanced neoplasia and 95.7% (95% CI 95.3 to 96.1) for non-neoplastic findings or negative colonoscopy. As compared with FIT, the next generation test had superior sensitivity for CRC (p < 0.001) and for advanced precancerous lesions (p < 0.001), but had lower specificity for advanced neoplasia (p < 0.001). No adverse events occurred.
BLUE-C study was funded by Exact Sciences and was designed by the sponsor and authors.
In an accompanied editorial article, Dr. John M. Carethers of the Division of Gastroenterology and Hepatology, Department of Medicine, Moores Cancer Center, and the Herbert Wertheim School of Public Health and Human Longevity Science, University of California in San Diego, CA, US wrote that screening tests have evolved to include stool-based, endoscopic and image-based, and blood-based methods, with minimal thresholds for sensitivity and specificity for CRC set by the baseline characteristics of FIT. Although multiple tests have been developed over time and vary in cost-effectiveness for CRC, the best screening test is the one that gets completed by the patient.
Most of the recommended tests, including the two newer tests assessed in the studies now published in The New England Journal of Medicine, improve on the sensitivity and approach the specificity of FIT, such that these tests appear to be at least as effective as FIT. Adherence to screening is a key factor, and ease of test use may contribute to increased adherence. Cost-effectiveness and the selection of the testing interval may play roles in adherence, particularly in populations that already have lower rates of adherence to CRC screening than the general population. Adherence to screening varies according to age group, including persons in the 45-to-49-year age group who are now eligible for average-risk screening. It is hoped that these newer tests will increase use and adherence to screening in order to reduce deaths from CRC.
References
- Chung DC, Gray II DM, Singh H, et al. A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening. N Engl J Med 2024; 390:973-983.
- Dennis Lo YM. Cell-free DNA for Colorectal Cancer Screening. N Engl J Med 2024;390:1047-1050.
- Imperiale TF, Porter K, Zella J, et al. for the BLUE-C Study Investigators. Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening. N Engl J Med 2024;390:984-993.
- Carethers JM. Improving Noninvasive Colorectal Cancer Screening. N Engl J Med 2024;390:1045-1046.