Performance of a blood-based screening test for the early detection of advanced precancerous lesions

Current colorectal cancer (CRC) screening methodologies, such as colonoscopy and stool-based tests, have shown substantial efficacy but are often constrained by low patient compliance. A minimally-invasive blood-based test can enhance screening adherence. Previous studies evaluating the performance of our blood-based CRC screening test demonstrated high sensitivity and specificity; however these studies did not include precursor or early cancer lesions, the identification of which is critical for cancer prevention. Here, we evaluate the performance of a blood-based early cancer detection (ECD) screening test for advanced colorectal neoplasia (ACN) with a focus on advanced precancerous lesion (APL) performance in an average-risk population. A targeted panel for CRC screening composed of differentially methylated genomic regions was developed, and a machine-learning model was trained to classify patient samples into cancer-free and ACN based on observed differential methylation patterns in circulating cell-free DNA. This ECD screening blood test was applied to plasma samples from 92 sequentially collected subjects with APL and a representative cohort of 366 healthy individuals. These participants were drawn from the first 1400 cases of the ongoing, prospective, PROCEED-CRC clinical study (NCT06620627), designed for the collection of clinically annotated biospecimens from participants ≥40 years old who underwent asymptomatic colonoscopy screening. Performance of the blood-based ECD test was assessed based on its sensitivity to detect APL and specificity across different APL types and age groups. Based on colonoscopy findings from the 458 PROCEED-CRC study participants included in the study (median age: 57 years, range: 43-75 years), 79.9% (n=366) were cancer-free and 20.1% (n=92) had APL. Among those with APL, 6.5% (n=6) had polyps with high-grade dysplasia. Mean sensitivity across all subtypes of APL was 22.5% (CI: 15.4%-32.4%). Median size of APL lesions was 12 mm and 99% of APL were <30mm in size. Sensitivity of APL at 5-9 mm was 20% and sensitivity increased with increasing size. Overall specificity was 91.5% (CI: 88.2%-94%). We did not observe deterioration of specificity with increasing age (p-value n.s., p > 0.05). APL detection is critical for intercepting CRC before it develops. The performance reported here highlights the strong potential of minimally invasive, blood-based early detection assays in identifying ACNs, including APLs, with robust performance across the screening participant ages. Notably, most APLs included in this study were <30 mm, representing a challenging set of lesion sizes to detect. Detection of CRC and APL will be further evaluated in the ongoing FIND clinical study (NCT07046585).