10543 Background: Radiographic findings concerning for malignancy frequently prompt extensive diagnostic evaluations that fail to yield a definitive diagnosis, resulting in delayed treatment, persistent uncertainty, and unnecessary interventions. Multi-cancer early detection (MCED) tests based on circulating cell-free DNA (cfDNA) methylation have demonstrated high specificity in asymptomatic screening populations; however, performance in individuals with clinical suspicion of malignancy remains unclear. We compared the performance of a cfDNA methylation–based MCED test in asymptomatic participants and in participants with imaging-based suspicion of malignancy. Methods: Adults aged 45–79 years enrolled in CORE-HH (NCT05435066) were evaluated in (1) a case–control cohort (n = 4,137) comprising asymptomatic participants who reported no history of cancer (n = 2,523) and newly diagnosed cancer participants (n = 1,614); and (2) a prospective cohort (n = 209) of individuals with imaging-based suspicion of malignancy undergoing clinical evaluation (cancer confirmed, n = 155; no cancer, n = 54). Cancer types included lung, breast, colorectal, prostate, pancreatic/hepatobiliary, head and neck, gynecologic, and hematologic malignancies. Samples were analyzed using a cfDNA methylation–based MCED test incorporating an AI/ML model, at a pre-specified specificity of 98.5%. Test performance was compared between cohorts among non-cancer participants and among early-stage (stage I–II) and late-stage (stage III–IV) cancer cases using Fisher’s exact test (two-sided). Results: Among non-cancer participants (n = 2,577), empirical specificity was 98.1% (53/54) in the clinical suspicion cohort and 98.5% (2,485/2,523) in the asymptomatic case–control cohort (OR, 1.23; 95% CI, 0.03–7.6; p = 0.56). Overall sensitivity was 54.8% (85/155) in the clinical suspicion cohort and 53.9% (870/1,614) in newly diagnosed cancer cases from the case–control cohort (OR, 1.04; 95% CI, 0.74–1.47; p = 0.87). Stage I–II sensitivity was 27.7% (18/65) vs 28.7% (204/711) (p = 1.00), and stage III–IV sensitivity was 82.9% (58/70) vs 81.5% (573/703) (p = 0.87), for the clinical suspicion and case–control cohorts, respectively. Overall cancer stage distribution was similar between cohorts (p = 0.89). Conclusions: At the prespecified 98.5% specificity threshold, the cfDNA methylation–based MCED test demonstrated comparable specificity and sensitivity in prospectively enrolled participants undergoing evaluation for imaging-based suspicion of malignancy and in a case–control cohort of newly diagnosed cancer cases versus asymptomatic controls. Recognizing the tendency of case–control designs to overestimate test performance, these results describe MCED test performance in a cohort with clinical suspicion of malignancy, extending characterization beyond asymptomatic screening populations. Clinical trial information: NCT05435066 .
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