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

Caroline L. Kahn; Mathias M. Petersen; Jakob Kleif; Mees S.E. Mansvelders; Morten Rasmussen; Lars N. Jørgensen; Jesper Vilandt; Jakob B. Seidelin; Claudia Jaensch; Peter Bondeven; Kåre A. Gotschalck; Uffe S. Løve; Berit Andersen; Ib J. Christensen; Lawrence C. LaPoint; Christina Therkildsen

doi:10.1016/j.clcc.2025.03.001

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

Caroline L. Kahn^*, Mathias M. Petersen, Jakob Kleif, Mees S.E. Mansvelders, Morten Rasmussen, Lars N. Jørgensen, Jesper Vilandt, Jakob B. Seidelin, Claudia Jaensch, Peter Bondeven, Kåre A. Gotschalck, Uffe S. Løve, Berit Andersen, Ib J. Christensen, Lawrence C. LaPoint, Christina Therkildsen

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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.

Original language	English
Journal	Clinical Colorectal Cancer
Volume	24
Issue	2
Pages (from-to)	310-319.e1
Number of pages	11
ISSN	1533-0028
DOIs	https://doi.org/10.1016/j.clcc.2025.03.001
Publication status	Published - Jun 2025

Keywords

Colonic cancer
Early detection
Population-based screening
Predictive biomarkers
Rectal cancer

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10.1016/j.clcc.2025.03.001

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Kahn, C. L., Petersen, M. M., Kleif, J., Mansvelders, M. S. E., Rasmussen, M., Jørgensen, L. N., Vilandt, J., Seidelin, J. B., Jaensch, C., Bondeven, P., Gotschalck, K. A., Løve, U. S., Andersen, B., Christensen, I. J., LaPoint, L. C., & Therkildsen, C. (2025). Circulating Tumor DNA in Addition to Fecal Immunochemical Test in a Dual-Test Colorectal Cancer Screening Approach. Clinical Colorectal Cancer, 24(2), 310-319.e1. https://doi.org/10.1016/j.clcc.2025.03.001

@article{9ba4ec7a489f45b4a866bf7c65819dc0,

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

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",

author = "Kahn, {Caroline L.} and Petersen, {Mathias M.} and Jakob Kleif and Mansvelders, {Mees S.E.} and Morten Rasmussen and J{\o}rgensen, {Lars N.} and Jesper Vilandt and Seidelin, {Jakob B.} and Claudia Jaensch and Peter Bondeven and Gotschalck, {K{\aa}re A.} and L{\o}ve, {Uffe S.} and Berit Andersen and Christensen, {Ib J.} and LaPoint, {Lawrence C.} and Christina Therkildsen",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = jun,

doi = "10.1016/j.clcc.2025.03.001",

language = "English",

volume = "24",

pages = "310--319.e1",

journal = "Clinical Colorectal Cancer",

issn = "1533-0028",

publisher = "Elsevier Inc.",

number = "2",

}

Kahn, CL, Petersen, MM, Kleif, J, Mansvelders, MSE, Rasmussen, M, Jørgensen, LN, Vilandt, J, Seidelin, JB, Jaensch, C, Bondeven, P, Gotschalck, KA, Løve, US, Andersen, B, Christensen, IJ, LaPoint, LC & Therkildsen, C 2025, 'Circulating Tumor DNA in Addition to Fecal Immunochemical Test in a Dual-Test Colorectal Cancer Screening Approach', Clinical Colorectal Cancer, vol. 24, no. 2, pp. 310-319.e1. https://doi.org/10.1016/j.clcc.2025.03.001

Circulating Tumor DNA in Addition to Fecal Immunochemical Test in a Dual-Test Colorectal Cancer Screening Approach. / Kahn, Caroline L.; Petersen, Mathias M.; Kleif, Jakob et al.
In: Clinical Colorectal Cancer, Vol. 24, No. 2, 06.2025, p. 310-319.e1.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Circulating Tumor DNA in Addition to Fecal Immunochemical Test in a Dual-Test Colorectal Cancer Screening Approach

AU - Kahn, Caroline L.

AU - Petersen, Mathias M.

AU - Kleif, Jakob

AU - Mansvelders, Mees S.E.

AU - Rasmussen, Morten

AU - Jørgensen, Lars N.

AU - Vilandt, Jesper

AU - Seidelin, Jakob B.

AU - Jaensch, Claudia

AU - Bondeven, Peter

AU - Gotschalck, Kåre A.

AU - Løve, Uffe S.

AU - Andersen, Berit

AU - Christensen, Ib J.

AU - LaPoint, Lawrence C.

AU - Therkildsen, Christina

PY - 2025/6

Y1 - 2025/6

N2 - 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.

AB - 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.

KW - Colonic cancer

KW - Early detection

KW - Population-based screening

KW - Predictive biomarkers

KW - Rectal cancer

UR - http://www.scopus.com/inward/record.url?scp=105002258174&partnerID=8YFLogxK

U2 - 10.1016/j.clcc.2025.03.001

DO - 10.1016/j.clcc.2025.03.001

M3 - Journal article

C2 - 40204621

AN - SCOPUS:105002258174

SN - 1533-0028

VL - 24

SP - 310-319.e1

JO - Clinical Colorectal Cancer

JF - Clinical Colorectal Cancer

IS - 2

ER -

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

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