Real-world performance of a multimodal cell-free DNA multi-cancer early detection test in Asian populations.

Abstract

14 Background: Multi-cancer early detection (MCED) addresses a critical unmet need by enabling simultaneous screening for multiple malignancies, particularly those lacking standard-of-care (SOC) options. SPOT-MAS is a liquid biopsy assay integrating methylomic, fragmentomic, and genomic signatures of cell-free DNA to detect signals across 10 cancer types. Building on its validation in the K-DETEK trial (NCT05227261), this study evaluates the clinical performance and feasibility of SPOT-MAS in a large-scale, real-world cohort across six Asian countries. Methods: Plasma cfDNA samples were analyzed from 84,145 individuals undergoing SPOT-MAS testing. Of these, 22,597 asymptomatic participants who completed a mandatory 12-month follow-up were included in the analysis. Participants with positive ctDNA signals underwent standardized post-test consultation and diagnostic workup, including imaging and/or histopathology, according to a predefined protocol to establish clinical status. Results: SPOT-MAS identified 94 positive cases (0.42%). Diagnostic workup confirmed 64 malignancies or precancerous lesions, including 20 cases (31.2%) diagnosed with cancers lacking SOC screening options, yielding a PPV of 68.1%. The assay demonstrated a Sensitivity of 79.0%, Specificity of 99.9%, NPV of 99.9% and Tissue-of-Origin accuracy of 80.0%. These performance metrics are consistent with the results of the K-DETEK trial. Conclusions: To the best of our knowledge, this study provides the first large-scale real-world evidence from Asia supporting the robustness and clinical utility of SPOT-MAS as a complementary screening strategy, particularly in LMICs lacking accessible national screening programs. Diagnostic performance comparison of the SPOT-MAS multi-cancer early detection test between the prospective K-DETEK trial and the expanded real-world data cohort. Test performance K-DETEK Real-World Data N = 9,024 % (95%CI) N = 22,597 % (95%CI) ctDNA signal detected 43 0.48 94 0.42 True positive 25 0.28 64 0.28 - Precancerous lesions 8 0.09 32 0.14 - Cancerous lesions 17 0.19 32 0.14 False positive 18 0.20 30 0.13 ctDNA signal not detected 8,981 99.52 22,503 99.58 True negative 8,974 99.45 22,486 99.51 False negative 7 0.08 17 0.08 - Precancerous lesions 0 0.00 7 0.03 - Cancerous lesions 7 0.08 10 0.04 Sensitivity 78.12 (61.24–88.98) 79.01 (68.93–86.46) Specificity 99.80 (99.68–99.87) 99.87 (99.81–99.91) Positive predictive value 58.14 (43.33–71.62) 68.09 (58.11–76.64) Negative predictive value 99.92 (99.84–99.96) 99.92 (99.88–99.95) Prediction accuracy of TOO 84.00 (65.35–93.60) 79.69 (68.29–87.73) Abbreviations: CI, confidence interval; PPV, positive predictive value; NPV, negative predictive value; TOO, tissue-of-origin. All 95% CIs were calculated using the Wilson score method. RWD cohort includes participants who completed ≥12 months of clinical follow-up.