Performance of a multi-cancer early detection test (MCED) for detecting small hepatocellular carcinoma (HCC) in a screening population.

Abstract

4168 Background: Early diagnosis of small HCC (defined as single nodule ≤ 3 cm) is crucial, as it represents the optimal window for curative treatments. Abdominal ultrasound with alpha-fetoprotein (AFP) is recommended for HCC surveillance in high-risk population. However, traditional modality detects only ~63% of small HCC, resulting in most HCC being diagnosed at advanced stages. Genie-Seq, a cfDNA-based MCED assay, covers 5 high-mortality cancers including HCC. Here, we report preliminary results evaluating the performance of Genie-Seq for small HCC in an asymptomatic screening population. Methods: Participants aged 40-74 years with no clinical suspicion of cancer were enrolled in a prospective, interventional study. All participants underwent Genie-Seq testing and standard-of-care (SOC) screenings according to the China Guidelines for Cancer Screening, including abdominal ultrasound and AFP. Genie-Seq detects cancer signals and localizes tissue-of-origin (TOO) simultaneously. Further HCC-focused diagnostic workup was performed per physician's discretion if: 1) suspicious findings on HCC screening, or 2) positive MCED results with liver as the top-predicted TOO. Diagnostic outcomes were reviewed for cancer status, TOO prediction accuracy, and stage. Results: As of December 2025, 1210 participants completed MCED testing and HCC screening. Nine participants were suspected of HCC and underwent further evaluation, with definitive diagnosis achieved in 7. Of these, 4 were confirmed as HCC (3 small HCCs, 1 stage II), 1 had synchronous gastric and colorectal cancers, and 2 had benign hepatic lesions. Genie-Seq identified all HCC cases with 100% TOO prediction accuracy, including 2 that were missed or initially misdiagnosed by traditional imaging. Patient 885 was exclusively identified by MCED, as no nodule was detected by ultrasound. Patient 888 had atypical features on contrast-enhanced CT/Gd-EOB-DTPA MRI (initial suspicion of inflammatory pseudotumor), and Genie-Seq positivity prompted contrast-enhanced ultrasound, leading to definitive diagnosis of small HCC. Conclusions: Genie-Seq exhibits excellent performance for small HCC detection in screening population, supporting it as a complementary tool to conventional preventive care and potentially improving curable HCC detection. Diagnostic outcomes of participants achieved diagnostic resolution. Participants Suspicious Lesions Detected by Ultrasound AFP (ng/ml) [1] MCED Results Diagnosis Tumor Stage (AJCC) 0108 Yes 2.96 Negative Hepatic cysts 0572 Yes 4.25 Negative Hepatic cavernous hemangioma 0640 No 2.6 Positive Multiple primary cancers Gastric cancer: IIB Colorectal cancer: I 0723 Yes 58.55 Positive HCC II 0885 No 8.16 Positive HCC IA 0888 Yes 42.53 Positive HCC IB 0971 Yes 9.11 Positive HCC IA [1] AFP levels of < 7 ng/mL were defined as normal.