A landmark multicentre diagnostic study published in JAMA has evaluated an investigational circulating tumour DNA (ctDNA) blood test for colorectal cancer (CRC) screening. The study offers promising data supporting its role as a non-invasive alternative for average-risk individuals reluctant or unable to undergo colonoscopy.
Between May 2020 and April 2022, researchers recruited 48,995 asymptomatic adults aged 45–85 years across 201 clinical sites in the United States and the United Arab Emirates. Of the total cohort, 27,010 participants completed standard-of-care colonoscopy and were included in the primary analysis, with both participants and investigators blinded to ctDNA results.
The ctDNA assay demonstrated 79.2% sensitivity (57 of 72 cases) for detecting colorectal cancer, with a 95% confidence interval (CI) of 68.4–86.9%. It also achieved 91.5% specificity for advanced colorectal neoplasia—encompassing both CRC and advanced precancerous lesions—based on 22,306 true negatives out of 24,371 participants (95% CI: 91.2–91.9%).
Negative predictive value (NPV) stood at 90.8% (95% CI: 90.7–90.9%), while positive predictive value (PPV) was 15.5% (95% CI: 14.2–16.8%). These outcomes met the study’s prespecified performance thresholds.
However, the ctDNA test had only 12.5% sensitivity for advanced precancerous lesions (321 of 2,567 cases; 95% CI: 11.3–13.8%), falling short of expectations. The median participant age was 57, and women represented 55.8% of the cohort.
Clinical Implications
These findings suggest the ctDNA test is highly accurate for detecting established colorectal cancer and may serve as a valuable complementary screening tool—especially for those unwilling to undergo colonoscopy or stool-based testing. The robust NPV supports its potential as a rule-out test, whereas the modest PPV indicates a positive result would still necessitate colonoscopic confirmation.
Importantly, the test currently underperforms in identifying advanced precancerous lesions, meaning it cannot yet replace established screening methods in a comprehensive CRC prevention strategy.
Future Directions
To fully validate the ctDNA blood test, further studies are necessary to:
- Compare performance with fecal immunochemical testing (FIT) and colonoscopy,
- Assess cost-effectiveness, accessibility, and patient acceptance,
- Determine the impact on cancer incidence, mortality, and follow-up testing adherence.
Overall, this ctDNA assay represents a potential shift towards more acceptable, non-invasive CRC screening strategies, with promise in early cancer detection but limitations in polyp detection.
Paper: Shaukat A, Burke CA, Chan AT, et al. Clinical Validation of a Circulating Tumor DNA-–Based Blood Test to Screen for Colorectal Cancer. JAMA. 2025;334(1):56–63. doi:10.1001/jama.2025.7515 Access online here.
