An Exosome-Based Liquid Biopsy for the Detection of Early-Onset Colorectal Cancer: The ENCODER Multicenter Study.

Journal: Gastroenterology
Published Date: Dec 9, 2025

Abstract

BACKGROUND & AIMS: The incidence of early-onset colorectal cancer (EOCRC; diagnosed before age 50 years) continues to increase, now standing as the leading cause of cancer-related deaths in young men. Screening participation in young adults remains low, but a noninvasive test may help. METHODS: Early Onset Colorectal Cancer Detection (ENCODER) was an international, multicentric cohort study involving 542 individuals from 4 countries (ie, United States, Italy, Spain, and Japan). A panel of 6 cell-free and exosome-based circulating biomarkers were identified through small RNA sequencing from a biomarker discovery cohort (n = 118). A machine learning model (Extreme Gradient Boosting) was then trained on reverse-transcription quantitative polymerase chain reaction results from a training cohort (n = 192) and tested in an external and independent cohort (n = 191). Finally, we investigated the temporal dynamics of biomarker levels before and after surgery (n = 41). RESULTS: Our liquid biopsy was highly accurate in detecting EOCRC in 2 independent cohorts (area under the receiver-operating characteristic curve, 97.5% in training vs 95.6% in testing). In the independent testing cohort, patients with EOCRC could be readily distinguished from nondisease controls, even in the age range from 20 to 35 years (area under the receiver-operating characteristic curve, 98.5%). This liquid biopsy had a specificity of 87.5% (95% CI, 79.4%-92.7%) and an overall sensitivity of 91.6% (95% CI, 84.2%-95.7%); the sensitivity for screening-relevant EOCRC stages I-III was 97.3% (95% CI, 90.6%-99.3%) and the sensitivity for premalignant lesions with high-grade dysplasia was 61.5% (95% CI, 35.5%-82.3%). Finally, we observed a reduction in the liquid biopsy values after surgery, reaching negativity after 4 days. CONCLUSIONS: ENCODER represents the largest EOCRC study to date to develop, train, and externally test a liquid biopsy for the growing population at risk of EOCRC, offering a complementary screening strategy. CLINICALTRIALS: gov, Number: NCT06342401.

Authors

  • Alessandro Mannucci
    Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, California; Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, I.R.C.C.S. San Raffaele Hospital, Milan, Italy.
  • Francesc Balaguer
    Hospital Clinic Barcelona, Gastroenterology Department, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomédiques August Pi i Sunyer, Barcelona, Spain; University of Barcelona, Barcelona, Spain.
  • Yasuhide Yamada
    Department of Medical Research, National Center for Global Health and Medicine, Tokyo, Japan.
  • Takeshi Nagasaka
    Department of Clinical Oncology, Kawasaki Medical School, Okayama, Japan.
  • Yuji Toiyama
    Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Japan.
  • Yoshinaga Okugawa
    Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Japan.
  • Marc Martí-Gallostra
    Spanish Early-Onset Colorectal Cancer Consortium; Colorectal Surgery, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain.
  • Marta Jiménez-Toscano
    Spanish Early-Onset Colorectal Cancer Consortium; Surgery Department, Hospital del Mar, Barcelona, Spain.
  • Rosario Vidal-Tocino
    Spanish Early-Onset Colorectal Cancer Consortium; Medical Oncology Department, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca, Salamanca, Spain.
  • Fernando Jiménez
    Artificial Intelligence and Knowledge Engineering Group, Faculty of Computer Science, University of Murcia, Spain.
  • Jose Perea
    Spanish Early-Onset Colorectal Cancer Consortium; Institute of Biomedical Research of Salamanca, University of Salamanca and Spanish National Research Council, Salamanca, Spain.
  • Enrique Quintero
    Spanish Early-Onset Colorectal Cancer Consortium; Gastroenterology Department, Hospital Universitario de Canarias, Instituto Universitario de Tecnologías Biomédicas, Centro de Investigación Biomédica de Canarias, Universidad de La Laguna, Tenerife, Spain.
  • C Richard Boland
    Division of Gastroenterology, School of Medicine, University of California, San Diego, La Jolla, California.
  • Giulia Martina Cavestro
    Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • Ajay Goel
    Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, California.

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