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Article

Quantitative ctDNA Profiling of RAS Mutations as a Prognostic Biomarker in Metastatic Colorectal Cancer

by
Benoist Chibaudel
1,*,
Elisabeth Carola
2,
Hamid Mekranter
3,
Perrine Goyer
4,
Arnaud Saget
4,
Olivier Oberlin
4,
Hélène Marijon
1,
Hubert Richa
5,
Ida Iurisci
1,
Honorine Gervais
1,
Nathalie Perez-Staub
1,
Linda Dainese
6,
Pascal Pujol
7,
Alain Toledano
8,
Jean-Baptiste Bachet
9 and
Aimery de Gramont
1
1
Department of Medical Oncology, Hôpital Franco-Britannique—Fondation Cognacq-Jay, Cancérologie Paris Ouest, 92300 Levallois-Perret, France
2
Department of Medical Oncology, Groupe Hospitalier du Sud de l’Oise, 60100 Creil, France
3
Department of Medical Oncology, Centre Hospitalier François Quesnay, 78200 Mantes La Jolie, France
4
Digestive Surgery, Cabinet ADN, 75017 Paris, France
5
Department of Digestive Surgery, Hôpital Franco-Britannique—Fondation Cognacq-Jay, 92300 Levallois-Perret, France
6
Department of Pathology and Molecular Biology, IHP Group—Paris, 92240 Malakoff, France
7
Department of Genetic, Centre Hospitalier Universitaire de Montpellier, 34090 Montpellier, France
8
Department of Radiotherapy, Hartmann Oncology Radiotherapy Group, Cancérologie Paris Ouest, 92300 Levallois-Perret, France
9
Department of Gastroenterology, Hôpital La Pitié-Salpétrière, 75013 Paris, France
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(1), 8; https://doi.org/10.3390/ijms27010008
Submission received: 10 October 2025 / Revised: 9 December 2025 / Accepted: 15 December 2025 / Published: 19 December 2025
(This article belongs to the Section Molecular Biology)
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Abstract

Circulating tumor DNA (ctDNA) analysis offers a non-invasive approach to molecular profiling. While RAS mutations are well-established predictive biomarkers in metastatic colorectal cancer (mCRC), the prognostic value of their variant allele frequency (VAF) remains unclear. We retrospectively analyzed individual patient data with mCRC who underwent ctDNA testing using the FoundationOne® Liquid CDx assay. The primary objective was to determine the optimal RAS VAF cutoff for overall survival (OS) prognostication. Between November 2020 and July 2024, 282 patients were enrolled. Among 265 eligible patients, 134 (50.6%) were ctRAS mutant, 25 (9.4%) ctBRAFV600E mutant, and 106 (40.0%) were ctRAS/BRAF wild-type. A RAS VAF threshold of 5% yielded the highest prognostic discrimination for OS (HR = 2.41; 95% CI 1.65–3.55; p < 0.0001; C-index = 0.601). ctRAS-high mutant tumors (VAF ≥ 5%) were associated with synchronous metastatic disease, multiple metastatic sites, higher blood tumor mutational burden, and elevated tumor fraction. ctRAS-low mutant tumors (VAF < 5%) were more frequently metachronous, presented with a single metastatic site, and showed liver involvement. High RAS VAF in ctDNA is a strong and independent prognostic marker for OS in mCRC. Quantitative ctDNA profiling may enhance risk stratification and guide personalized management strategies.
Keywords: colorectal cancer; circulating tumor DNA; variant allele frequency; RAS mutation; comprehensive genomic profiling; liquid biopsy; biomarkers; prognosis; precision medicine; survival analysis colorectal cancer; circulating tumor DNA; variant allele frequency; RAS mutation; comprehensive genomic profiling; liquid biopsy; biomarkers; prognosis; precision medicine; survival analysis
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MDPI and ACS Style

Chibaudel, B.; Carola, E.; Mekranter, H.; Goyer, P.; Saget, A.; Oberlin, O.; Marijon, H.; Richa, H.; Iurisci, I.; Gervais, H.; et al. Quantitative ctDNA Profiling of RAS Mutations as a Prognostic Biomarker in Metastatic Colorectal Cancer. Int. J. Mol. Sci. 2026, 27, 8. https://doi.org/10.3390/ijms27010008

AMA Style

Chibaudel B, Carola E, Mekranter H, Goyer P, Saget A, Oberlin O, Marijon H, Richa H, Iurisci I, Gervais H, et al. Quantitative ctDNA Profiling of RAS Mutations as a Prognostic Biomarker in Metastatic Colorectal Cancer. International Journal of Molecular Sciences. 2026; 27(1):8. https://doi.org/10.3390/ijms27010008

Chicago/Turabian Style

Chibaudel, Benoist, Elisabeth Carola, Hamid Mekranter, Perrine Goyer, Arnaud Saget, Olivier Oberlin, Hélène Marijon, Hubert Richa, Ida Iurisci, Honorine Gervais, and et al. 2026. "Quantitative ctDNA Profiling of RAS Mutations as a Prognostic Biomarker in Metastatic Colorectal Cancer" International Journal of Molecular Sciences 27, no. 1: 8. https://doi.org/10.3390/ijms27010008

APA Style

Chibaudel, B., Carola, E., Mekranter, H., Goyer, P., Saget, A., Oberlin, O., Marijon, H., Richa, H., Iurisci, I., Gervais, H., Perez-Staub, N., Dainese, L., Pujol, P., Toledano, A., Bachet, J.-B., & de Gramont, A. (2026). Quantitative ctDNA Profiling of RAS Mutations as a Prognostic Biomarker in Metastatic Colorectal Cancer. International Journal of Molecular Sciences, 27(1), 8. https://doi.org/10.3390/ijms27010008

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