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. 2025 Jun;24(2):310-319.e1.
doi: 10.1016/j.clcc.2025.03.001. Epub 2025 Mar 19.

Circulating Tumor DNA in Addition to Fecal Immunochemical Test in a Dual-Test Colorectal Cancer Screening Approach

Caroline L Kahn  1 , Mathias M Petersen  2 , Jakob Kleif  3 , Mees S E Mansvelders  4 , Morten Rasmussen  5 , Lars N Jørgensen  5 , Jesper Vilandt  6 , Jakob B Seidelin  7 , Claudia Jaensch  8 , Peter Bondeven  9 , Kåre A Gotschalck  10 , Uffe S Løve  11 , Berit Andersen  12 , Ib J Christensen  4 , Lawrence C LaPoint  13 , Christina Therkildsen  4
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Free article

Circulating Tumor DNA in Addition to Fecal Immunochemical Test in a Dual-Test Colorectal Cancer Screening Approach

Caroline L Kahn et al. Clin Colorectal Cancer. 2025 Jun.
Free article

Abstract

Background: Early detection is paramount when reducing incidence and mortality of colorectal cancer (CRC). Current population-based screening programs primarily use fecal immunochemical test (FIT) to allocate individuals for colonoscopy although low specificity challenges colonoscopy capacities. We aimed to assess the potential of circulating tumor (ct)DNA markers for early CRC detection in a dual-test CRC screening approach among FIT positive individuals.

Methods: Plasma samples from 774 FIT positive (≥100 ng Hemoglobin/mL) individuals from the Danish CRC screening program were analyzed for hypermethylated DNA in the genes Branched Chain Amino-acid Transaminase 1 (BCAT1), Ikaros-Family Zinc Finger transcription 1 (IKZF1), and Interferon Regulator Factor 4 (IRF4). Multivariate logistic regression models were generated adding the ctDNA markers and age to the FIT value. The dual-test approach was benchmarked to FIT at specific thresholds.

Results: The dual-test approach improved CRC detection compared to the FIT alone (AUC of 87.2 [95% CI, 82.9-91.4] vs AUC of 72.5 [95% CI, 67.0-77.9]). This was also seen when adding advanced adenomas to the outcome resulting in AUCs of 71.8 [95% CI, 67.8-75.8] for the dual-test approach compared to 65.5 [95% CI, 61.3-69.7] for the FIT model alone. Benchmarking the dual-test approach at FIT cut-offs between 100 and 600 ng Hb/mL showed a potential for either reducing the colonoscopy requirement by up to 56% or increasing CRC detection by up to 28%.

Conclusions: As increasing FIT cutoff will decrease CRC detection rate, application of the ctDNA panel can increase the sensitivity and specificity in a dual-test approach among asymptomatic individuals.

Keywords: Colonic cancer; Early detection; Population-based screening; Predictive biomarkers; Rectal cancer.

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Conflict of interest statement

Disclosure LCL was during the study the CEO of Clinical Genomics Pty Ltd, North Ryde, NSW, Australia. All analyses were made blinded by this collaborator whereafter molecular data were merged to clinical data by the academic team at Copenhagen University Hospital, Hvidovre, which also performed statistical analyses. All other authors state that they have no conflicts of interest. LCL was involved in the conceptualization; development, validation, and investigation of the molecular methods; and data curation. Though statistical analyses were discussed with the industrial partners, the academic research team at Hvidovre Hospital decided and performed the formal analyses independently. LCL supervised and administrated the project, and all co-authors were involved in the review and editing part of the writing process.

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