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.
An Exosome-Based Liquid Biopsy for the Detection of Early-Onset Colorectal Cancer: The ENCODER Multicenter Study / Mannucci, Alessandro; Balaguer, Francesc; Yamada, Yasuhide; Nagasaka, Takeshi; Toiyama, Yuji; Okugawa, Yoshinaga; Martí-Gallostra, Marc; Jiménez-Toscano, Marta; Vidal-Tocino, Rosario; Jiménez, Fernando; Perea, Jose; Quintero, Enrique; Boland, C Richard; Cavestro, Giulia Martina; Goel, Ajay. - In: GASTROENTEROLOGY. - ISSN 0016-5085. - (2025). [10.1053/j.gastro.2025.08.013]
An Exosome-Based Liquid Biopsy for the Detection of Early-Onset Colorectal Cancer: The ENCODER Multicenter Study
Mannucci, Alessandro
;Cavestro, Giulia Martina;
2025-01-01
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
