A large prospective diagnostic study, published in JAMA, evaluates an investigational blood-based circulating tumor DNA (ctDNA) test for colorectal cancer (CRC) in an asymptomatic, average-risk population. The findings may herald a shift in non-invasive screening options beyond colonoscopy and stool-based testing.
Study Design & Participants
Conducted across 201 centers in the USA and the United Arab Emirates, this cross-sectional observational trial recruited adults aged 45–85 years from May 2020 to April 2022. Among 48,995 enrolled participants, 27,010 were evaluable following standard-of-care colonoscopy, with both participants and assessors blinded to ctDNA test outcomes.
- Key Findings
Sensitivity for CRC detection: 79.2% (57/72 cases; 95% CI: 68.4–86.9%) - Specificity for advanced colorectal neoplasia (cancer or advanced precancerous lesions): 91.5% (22,306/24,371; 95% CI: 91.2–91.9%)
- Negative Predictive Value (NPV): 90.8% (22,306/24,567; 95% CI: 90.7–90.9%)
- Positive Predictive Value (PPV): 15.5% (378/2,443; 95% CI: 14.2–16.8%)
All primary endpoints met the prespecified performance criteria
However, sensitivity for detecting advanced precancerous lesions was only 12.5% (321/2,567; 95% CI: 11.3–13.8%), falling short of the trial’s threshold.
Clinical Context & Implications
The ctDNA blood test demonstrates high sensitivity and specificity for colorectal cancer, which suggests it could serve as a complementary screening tool, especially for patients reluctant to undergo colonoscopy or fecal testing. Its NPV indicates strong rule-out capability, while the modest PPV would still necessitate confirmatory colonoscopy for positive cases.
However, the limited detection of advanced precancerous lesions signals that stool-based assays or colonoscopy remain essential components of a comprehensive screening strategy.
What It Means for Practice
This trial provides evidence supporting ctDNA as a viable non-invasive screening modality for CRC in average-risk individuals, with a sensitivity comparable to current stool-based tests but with superior procedural adherence potential. Before adoption in guideline frameworks, further investigation is needed into:
- Comparative performance versus established screening methods.
- Cost-effectiveness and acceptability in diverse healthcare systems.
- Longer-term outcomes, including interval cancer rates and cancer prevention efficacy.
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.
