Abstract 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). Citation Format: Prashanthi Natarajan, Preethi Srinivasan, Hsiao-Yun Huang, Alan Selewa, Rebecca Panitch, Caitlin Guccione, Fatemeh Almodaresi, Jayashree Joshi, Su Maw, Misagh Kordi, Yunshu Song, Yu Lin, Osama Khan, Breeana L. Mitchell, Adham Jurdi, Minetta C. Liu, Johannes G. Reiter, Trupti Kawli, Matthew Rabinowitz, Alexey Aleshin. Performance of a blood-based screening test for the early detection of advanced precancerous lesions abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1097.
Natarajan et al. (Fri,) studied this question.