Abstract Background: Surgery and ablation can be curative for early-stage HCC, but up to 70% recur or develop new primary HCC. ctDNA-based MRD assessment may improve risk assessment and identify recurrence earlier than current tools. Because HCC is often diagnosed radiologically and ablation yields no tissue, tumor-informed assays may be infeasible and unable to detect new primaries. Methods: Patients with completely resected or ablated stage I-III HCC were prospectively enrolled across 13 Japanese sites (Mar 2021-May 2022). Plasma was collected pre- and 4 weeks post-procedure and every 3-6 months with standard imaging and biomarker assessment. ctDNA was analyzed retrospectively using a tissue-free epigenomic assay (Guardant Reveal) evaluating ∼20,000 differentially methylated/control regions. Samples are classified as ctDNA detected/not detected based on a pre-defined threshold. Associations between ctDNA status and recurrence were analyzed. Results: Among 95 patients eligible for this interim analysis, (87% resected, 57% stage I, median age 74), 610/611 samples were successfully analyzed. At 36.9 months median follow-up, 42 recurred. Pre-procedure ctDNA was detected in 75% (70/94) and correlated with shorter time to recurrence (HR 4.4; 95% CI 1.7-14.6; p 0.001). Post-surgery ctDNA detection at 4 weeks also correlated (HR 3.8; 95% CI 1.7-7.8; p = 0.002) and was the only variable that remained statistically associated with recurrence on multivariate analysis at this timepoint. Surveillance ctDNA sensitivity was 60% (25/42), specificity was 98% (52/53), and median lead time was 63 days. ctDNA outperformed other biomarkers evaluated in this cohort (Table 1). Conclusions: Epigenomic ctDNA analysis enabled tissue-free MRD detection with high accuracy and superior performance vs conventional biomarkers, supporting its use for individualized recurrence risk assessment and surveillance. Citation Format: Masashi Kudo, Mitsuhito Sasaki, Shinji Itoh, Teiichi Sugiura, Tsuyoshi Kobayashi, Keishi Sugimachi, Shinichi Nakanuma, Yuta Abe, Hisashi Kosaka, Nobuhiro Nakamoto, Naoto Yamamoto, Makoto Ueno, Takuji Okusaka, Atsushi Takebe, Minoru Esaki, Kazuyoshi Ohkawa, Hisateru Komatsu, Yu Takahashi, Masatake Tanaka, Takeshi Aramaki, Tomokazu Kawaoka, Rie Sugimoto, Taro Yamashita, Takashi Yamaguchi, Masatoshi Kudo, Masato Ozaka, Chiemi Notake, Hiroshi Uchigata, Masafumi Ikeda, Naoto Gotohda, Yoshiaki Nakamura. Circulating tumor DNA (ctDNA) for molecular residual disease (MRD) detection and recurrence monitoring in hepatocellular carcinoma (HCC); COSMOS-HCC01 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1094.
Kudo et al. (Fri,) studied this question.