Abstract 1264: A targeted methylation-based multi-cancer early detection blood test preferentially detects high-grade prostate cancer and minimizes overdiagnosis

Abstract Background: Indolent prostate cancer (PCa) is prevalent in men in the intended use population (adults aged 50-79 years) for blood-based multi-cancer early detection (MCED) tests. It is thus important to understand detectability of PCa by MCED tests across the spectrum of disease aggressiveness, including detection of indolent disease. Methods: PCa detectability by a targeted methylation-based MCED test that interrogates circulating cfDNA was assessed in 2 studies: 1) the Circulating Cell-free Genome Atlas (CCGA, NCT02889978), a case-control study (Substudy 3) that demonstrated detection of a shared cancer signal across 50 cancer types and accurate prediction of cancer signal origin (CSO) with an observed false positive rate of 0. 5%; and 2) PATHFINDER (PF, NCT04241796), a return of results cohort study in the intended use population without clinical suspicion of cancer. MCED test performance was assessed by Gleason grade group (GG) and clinical stage, and the association between tumor methylated fraction (TMeF) and cancer detectability was investigated. Results: The CCGA3 study included 420 recently diagnosed PCa cases with a median age of 65 years (IQR, 59-70). Test sensitivity for PCa was 11. 2% (47/420), and CSO accuracy was 91. 5% (43/47). Median PSA was higher in detected cases (14 ng/dL, IQR 7-38 vs 6 ng/dL, IQR 5-9, p 0. 05). The MCED test detected no low grade (GG1, 0/58), 1. 9% (3/157) of favorable intermediate grade (GG2), 5. 1% (4/78) of unfavorable intermediate grade (GG3), and 31. 9% (36/113) of high grade (GG4 0. 05), and detected cases had similar survival (HR 0. 672, CI 0. 323 - 1. 21, p=0. 2) compared to SEER estimates matched for age, stage and GG. Median TMeF was higher for detected cases (0. 002106, IQR 0. 000350 - 0. 024376 vs 0. 000024, IQR 0. 00001 - 0. 000038, p 0. 05). Performance was similar in PF (median age 66 years, IQR 58 -70) with overall sensitivity for PCa of 5. 9% (1/17), including no (0/12) detected GG1-2 cases and one of five GG3-5 cases. No Stage I or II (0/15) and 1/2 (50%) Stage III Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1264.