Abstract 7064: Minimally invasive detection of advanced adenomas in colorectal cancer screening through circulating epithelial cells and somatic DNA aberrations

Abstract Aim: Advanced adenomas (AAs), precursors to colorectal cancer (CRC), affect 5% of individuals under 50 and 8% of those 50 and older. Current blood-based tests have limited AA sensitivity (12-13%) compared to FIT (23.8%), highlighting the need for improved detection methods. The FirstSight assay combines circulating tumor DNA (ctDNA) and circulating epithelial cells (CECs) to enhance AA detection. Initial results show that FirstSight achieves higher sensitivity and specificity than existing blood-based tests. Here we analyze the contributions of ctDNA and CEC in the detection of AA. Methods: FirstSight was validated in a study of 1, 038 prospectively collected, diverse subjects from a majority screening cohort. CEC data were analyzed using a multi-dye machine learning algorithm. The FirstSight algorithm incorporated patient age, sex, and CRC incidence from SEER statistics to adjust baseline risk and refine probability distributions for improved predictive performance. We estimated the contribution of ctDNA and CEC in the detection of AA, and as an example, the cumulative effect of ctDNA and a single CEC-derived marker GM1. Results: CEC (p < 0.01) and ctDNA (p < 0.0001) biomarkers were significant predictors of AA. A CEC marker, GM1, improved specificity for AA. At a prespecified 90% specificity for the detection of advanced neoplasia (CRC+AA), the best single ctDNA marker and the CEC marker GM1 individually had a sensitivity of 20% and 16%, respectively, for AA. The combined use of all ctDNA markers had a sensitivity of 39% for AA and the further addition of GM1 raised the sensitivity to 49% for AA. Finally, the integration of ctDNA, CEC markers, their interaction, and demographics improved FirstSight sensitivity to 54.5% for AA.The contribution of GM1 was significant (ꭓ2 = 9.7272, p = 0.02103); removing GM1 reduced the AUC for AA from 0.8165 to 0.745. Consistent with the CRC dysplasia-malignancy continuum, FirstSight demonstrated higher sensitivity for stage I CRC compared to first-generation blood-based tests (92.3% vs. 54.5%). Conclusions: The multimodal FirstSight test, combining ctDNA and CEC biomarkers, achieved 54.5% sensitivity and 90.6% specificity for AA detection in a 1, 038-subject study. CEC signals are found to be most contributory to the detection of AA and the interaction of a single CEC marker, GM1, with ctDNA further improves AA sensitivity, making the performance not simply additive. FirstSight demonstrates the potential for superior AA detection and effective colorectal cancer prevention strategies. This minimally invasive test offers a patient-friendly alternative, with ongoing validation to confirm its clinical utility. Citation Format: Shai Friedland, Drew Watson, Zhen Zhang, Alexander Atkins, Huangpin Ben Hsieh, Jr-Ming Lai, Stephen Su, Hung-Jen Shao, Jen-chia Wu, John Sninsky, Rui Mei. Minimally invasive detection of advanced adenomas in colorectal cancer screening through circulating epithelial cells and somatic DNA aberrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7064.