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Observational Study
. 2025 Jul 1;334(1):56-63.
doi: 10.1001/jama.2025.7515.

Clinical Validation of a Circulating Tumor DNA-Based Blood Test to Screen for Colorectal Cancer

Aasma Shaukat  1   2 , Carol A Burke  3 , Andrew T Chan  4 , William M Grady  5   6 , Samir Gupta  7 , Bryson W Katona  8 , Uri Ladabaum  9 , Peter S Liang  1 , Julia J Liu  10 , Girish Putcha  11   12 , Douglas J Robertson  13 , Robert E Schoen  14 , Zhen Meng  11 , Andrew Piscitello  11 , Chung-Kai Sun  11 , Chuanbo Xu  11   15 , C Jimmy Lin  11 , Lilian C Lee  11 , Lance Baldo  11   16 , Theodore R Levin  17 ; PREEMPT CRC Investigators
Affiliations
Observational Study

Clinical Validation of a Circulating Tumor DNA-Based Blood Test to Screen for Colorectal Cancer

Aasma Shaukat et al. JAMA. .

Abstract

Importance: Colorectal cancer screening is widely recommended but underused. Blood-based screening offers the potential for higher adherence compared with endoscopy or stool-based testing but must first be clinically validated in a screening population.

Objective: To evaluate the clinical performance of an investigational blood-based circulating tumor DNA test for colorectal cancer detection in an average-risk population using colonoscopy with histopathology as the reference method.

Design, setting, and participants: Prospective, multicenter, cross-sectional observational study enrolling participants between May 2020 and April 2022 who were asymptomatic adults aged 45 to 85 years, at average risk of colorectal cancer, and willing to undergo a standard-of-care screening colonoscopy. Participants, staff, and pathologists were blinded to blood test results, and laboratory testing was performed blinded to colonoscopy findings. The study was conducted at 201 centers across 49 US states and the United Arab Emirates. Site-based and mobile phlebotomy were used for blood collection.

Exposures: Participants were required to complete a screening colonoscopy after blood collection.

Main outcomes and measures: The primary end points were sensitivity for colorectal cancer, specificity for advanced colorectal neoplasia (colorectal cancer or advanced precancerous lesions), negative predictive value for advanced colorectal neoplasia, and positive predictive value for advanced colorectal neoplasia. The secondary end point was sensitivity for advanced precancerous lesions.

Results: The median age of participants in the evaluable cohort (n = 27 010) was 57.0 years, and 55.8% were women. Sensitivity for colorectal cancer was 79.2% (57/72; 95% CI, 68.4%-86.9%) and specificity for advanced colorectal neoplasia was 91.5% (22 306/24 371; 95% CI, 91.2%-91.9%). The negative predictive value for advanced colorectal neoplasia was 90.8% (22 306/24 567; 95% CI, 90.7%-90.9%) and the positive predictive value for advanced colorectal neoplasia was 15.5% (378/2443; 95% CI, 14.2%-16.8%). All primary end points met prespecified acceptance criteria. The sensitivity for advanced precancerous lesions was 12.5% (321/2567; 95% CI, 11.3%-13.8%), which did not meet the prespecified acceptance criterion.

Conclusions and relevance: In an average-risk colorectal cancer screening population, a blood-based test demonstrated acceptable accuracy for colorectal cancer detection, but detection of advanced precancerous lesions remains a challenge, and ongoing efforts are needed to improve test sensitivity.

Trial registration: ClinicalTrials.gov Identifier: NCT04369053.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Shaukat reported receipt of personal fees from Freenome Holdings Inc, Geneoscopy, Iterative Health, and UniversalDx. Dr Burke reported receipt of research funding from Emtora; receipt of consulting fees from Sebela, Guardant, Almirall, Lumabridge, Freenome Holdings Inc, and Janssen; speaker fees from Ambry; receipt of other fees from AbbVie, Medtronic, Myriad, Genzyme, Ferring, Salix, and Merck; and serving as a member of the US Multi-Society Task Force on Colorectal Cancer and National Comprehensive Cancer Network Guideline on Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric. Dr Chan reported receipt of grants from Pfizer Inc, consulting fees from Pfizer Inc and Boehringer Ingelheim, and honoraria from UpToDate. Dr Grady reported receipt of consulting fees from Karius, Diacarta, Guardant Health, Natera, and Freenome Holdings Inc; honoraria from UpToDate; and research support from Lucid Diagnostics. Dr Gupta reported receipt of consulting fees from Guardant Health, Geneoscopy, Universal Diagnostics, CellMax, and InterVenn. Dr Katona reported receipt of research funding from Janssen, Immunovia, Epigenomics, Guardant Health, Freenome Holdings Inc, Universal Diagnostics, and Recursion (paid to his institution) and membership on an advisory board for Immunovia. Dr Ladabaum reported receipt of consulting fees from ChekCap, Guardant Health, Freenome Holdings Inc, Neptune Medical, Medacorp, Mosaic, William Blair, Guidepoint, Medial EarlySign, Geneoscopy, and Medtronic; membership on advisory boards for UniversalDx, Lean Medical, Cylinder, Lumiinus, and Kohler Ventures; stock options in UniversalDx, Cylinder, and Lumiinus; and equity in Lean Medical. Dr Liang reported receipt of consulting fees from Guardant Health and Natera. Dr Putcha reported equity in Freenome Holdings Inc and being an employee of Freenome Holdings Inc at the time the study and analyses were conducted. Dr Robertson reported receipt of consulting fees from and serving on a publication steering committee for Freenome Holdings Inc and receipt of personal fees from Topography. Dr Schoen reported receipt of research support from Exact Sciences, Freenome Holdings Inc, and Immunovia and advisory support from Guardant Health. Dr Meng reported being an employee of Freenome Holdings Inc. Mr Piscitello reported receipt of consulting fees from Bluestar Genomics, Elephas, Nucleix, Caris, Karius, Thermo Fisher Scientific, Viome, Iterative Scopes, Innovenn, and Medtronic prior to employment with Freenome Holdings Inc. Mr Sun reported being an employee of Freenome Holdings Inc. Dr Xu reported being an employee of Freenome Holdings Inc at the time the study and analyses were conducted. Dr Lin reported being an employee of Freenome Holdings Inc. Dr Lee reported being an employee of Freenome Holdings Inc. Dr Baldo reported being an employee of Freenome Holdings Inc at the time the study and analyses were conducted. Dr Levin reported receipt of research funding from the Patient-Centered Outcomes Research Institute and Freenome Holdings Inc; employment with Permanente Medical Group; participation on a data safety monitoring board/advisory board for the CONFIRM trial (NCT01239082); and having an unpaid leadership/fiduciary role with the California Colorectal Cancer Coalition. No other disclosures were reported.

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