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An Exosome-Based Liquid Biopsy for the Detection of Early-Onset Colorectal Cancer: The ENCODER Multicenter Study
Alessandro Mannucci1, Francesc Balaguer2, Yasuhide Yamada3
1Department 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.
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.
