PO.CL01.18 · 临床研究

循环肿瘤DNA(ctDNA)用于肝细胞癌(HCC)分子残留病灶(MRD)检测与复发监测；COSMOS-HCC01

Circulating tumor DNA (ctDNA) for molecular residual disease (MRD) detection and recurrence monitoring in hepatocellular carcinoma (HCC); COSMOS-HCC01

编号 1094 展板 4 时间 4/19 02:00–05:00 区域 Section 43 主讲 Masashi Kudo

分会场 Early Detection Biomarkers 1

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作者与单位 Authors & Affiliations

Masashi Kudo¹, Mitsuhito Sasaki², Shinji Itoh³, Teiichi Sugiura⁴, Tsuyoshi Kobayashi⁵, Keishi Sugimachi⁶, Shinichi Nakanuma⁷, Yuta Abe⁸, Hisashi Kosaka⁹, Nobuhiro Nakamoto¹⁰, Naoto Yamamoto¹¹, Makoto Ueno¹², Takuji Okusaka¹³, Atsushi Takebe¹⁴, Minoru Esaki¹⁵, Kazuyoshi Ohkawa¹⁶, Hisateru Komatsu¹⁷, Yu Takahashi¹⁸, Masatake Tanaka¹⁹, Takeshi Aramaki²⁰, Tomokazu Kawaoka²¹, Rie Sugimoto²², Taro Yamashita²³, Takashi Yamaguchi²⁴, Masatoshi Kudo²⁵, Masato Ozaka²⁶, Chiemi Notake²⁷, Hiroshi Uchigata²⁷, Masafumi Ikeda², Naoto Gotohda¹, Yoshiaki Nakamura²⁷

¹Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Chiba, Japan,²Department of Hepatobiliary & Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan,³Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan,⁴Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan,⁵Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan,⁶Department of Hepatobiliary and Pancreatic Surgery, NHO Kyushu Cancer Center, Fukuoka, Japan,⁷Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Ishikawa, Japan,⁸Department of Surgery, Keio University School of Medicine, Tokyo, Japan,⁹Department of Hepatobiliary Surgery, Kansai Medical University, Osaka, Japan,¹⁰Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan,¹¹Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Kanagawa, Japan,¹²Department of Gastroenterology and Hepatology, Kanagawa Cancer Center, Kanagawa, Japan,¹³Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan,¹⁴Department of Surgery, Kindai University Faculty of Medicine, Osaka, Japan,¹⁵Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan,¹⁶Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka, Japan,¹⁷Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan,¹⁸Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan,¹⁹Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan,²⁰Division of Interventional Radiology, Shizuoka Cancer Center, Shizuoka, Japan,²¹Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan,²²Department of Hepato-Biliary-Pancreatology, NHO Kyushu Cancer Center, Fukuoka, Japan,²³Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan,²⁴Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan,²⁵Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan,²⁶Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan,²⁷Translational Research Support Office, National Cancer Center Hospital East, Chiba, Japan

摘要 Abstract

中文摘要

背景：手术和消融对早期HCC可能具有治愈性，但高达70%的患者会复发或发生新的原发性HCC。基于ctDNA的MRD评估或可改善风险评估，并较现有工具更早识别复发。由于HCC常通过影像学诊断且消融不产生组织，基于肿瘤组织的检测方法可能不可行，且无法检出新发原发灶。方法：在日本13个中心前瞻性纳入完全切除或消融的I-III期HCC患者(2021年3月至2022年5月)。在术前及术后4周采集血浆，并每3-6个月采集一次，同时进行标准影像学和生物标志物评估。ctDNA采用一种无需肿瘤组织的表观基因组检测方法(Guardant Reveal)进行回顾性分析，评估约20,000个差异甲基化/对照区域。样本根据预先设定的阈值分类为ctDNA检出/未检出。分析了ctDNA状态与复发之间的关联。结果：在95例符合本次中期分析条件的患者中(87%为切除,57%为I期,中位年龄74岁)，610/611份样本成功完成分析。中位随访36.9个月时，42例复发。术前ctDNA检出率为75%(70/94)，且与更短的复发时间相关(HR 4.4;95% CI 1.7-14.6;p < 0.001)。术后4周ctDNA检出同样相关(HR 3.8;95% CI 1.7-7.8;p = 0.002)，且是该时间点多因素分析中唯一仍与复发保持统计学相关的变量。监测期ctDNA敏感性为60%(25/42)，特异性为98%(52/53)，中位提前时间为63天。ctDNA优于本队列中评估的其他生物标志物(表1)。结论：表观基因组ctDNA分析实现了无需组织的MRD检测，准确性高，性能优于传统生物标志物，支持其用于个体化复发风险评估与监测。表1. 各生物标志物(曾检出/从未检出)预测HCC治疗后复发的性能 ctDNA AFP(>10ng/mL) AFP-L3(>9.9%) PIVKA-II(>39mAU/mL) 敏感性(阳性/复发) 60%(25/42) 33%(14/42) 54%(13/24) 44%(18/41) 特异性(阴性/无复发) 98%(52/53) 87%(46/53) 68%(15/22) 87%(45/52) 中位提前时间 63天 55天 12天 32天 HR(95% CI) 10.1(5.3-20.3),P < 0.001 2.2(1.1-4.1),P = 0.024 1.7(0.7-3.9),P = 0.213 3.6(1.9-6.7),P < 0.001

查看英文原文 English 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. Table 1. Performance of biomarkers (ever/never detected) to predict HCC recurrence during post-treat ctDNA AFP (>10ng/mL) AFP-L3 (>9.9%) PIVKA-II (>39mAU/mL) Sensitivity (positive/recurrence) 60% (25/42) 33% (14/42) 54% (13/24) 44% (18/41) Specificity (negative/no recurrence) 98% (52/53) 87% (46/53) 68% (15/22) 87% (45/52) Median lead time 63 days 55 days 12 days 32 days HR (95% CI) 10.1 (5.3-20.3), P < 0.001 2.2 (1.1-4.1), P = 0.024 1.7 (0.7-3.9), P = 0.213 3.6 (1.9-6.7), P < 0.001

利益披露 Disclosure

M. Kudo, None.. M. Sasaki, None. S. Itoh, Chugai Pharma Other, Lecture fees. AstraZeneca Other, Lecture fees. Eisai Other, Lecture fees. T. Sugiura, None.. T. Kobayashi, None.. K. Sugimachi, None.. S. Nakanuma, None.. Y. Abe, None.. H. Kosaka, None.. N. Nakamoto, None.. N. Yamamoto, None. M. Ueno, Astellas Pharma ). AstraZeneca ), Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Chugai Pharmaceutical ), Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. DFP ). Eisai ), Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Incyte ), Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. MSD ), Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Ono Pharmaceutical ), Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Taiho Pharmaceutical, ), Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Novartis ), Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. J-pharma ), Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Novocure ). Chiome Bioscience ). Revolution Medicine ). Jazz Pharmaceuticals ). Nihon servier ), Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Boehringer Ingelheim ). Amgen ). Nippon Boehringer Ingelheim Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Daiichi Sankyo, Takeda Pharmaceutical, Yakult Honsha, Aska, Viatris, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. T. Okusaka, AstraZeneca ), Other, Consulting fees / Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Syneos ). Incyte ). CHIOME Bioscience Inc. ). Sysmex Corporation ). Amgen Inc. ), Other, Consulting fees. Linical ). Labcorp Genetics ). Eisai Other, Consulting fees / Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Nihon Medi-Physics Co.,Ltd Other, Consulting fees. Jazz Pharmaceuticals Other, Consulting fees. OHARA Pharmaceutical Co.,Ltd. Other, Consulting fees. MSD Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Taiho Pharmaceutical Co.,Ltd. Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Ono Pharmaceutical Co., Ltd. Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Daiichi Sankyo Co., Ltd. Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Nihon Servier Co., Ltd. Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Chugai Pharmaceutical Co., Ltd. Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Johnson & Johnson K.K. Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Kyowa Kirin ,Novartis Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. A. Takebe, None.. M. Esaki, None.. K. Ohkawa, None.. H. Komatsu, None.. Y. Takahashi, None.. M. Tanaka, None.. T. Aramaki, None. T. Kawaoka, Chugai Pharmaceutical Co., Ltd. Other, speakers’ bureau. Eisai Co., Ltd. Other, speakers’ bureau. AstraZeneca Other, speakers’ bureau. R. Sugimoto, Esai Co. Other, lecture fee. Chugai Pharma, Other, lecture fee. AstraZeneca Other, lecture fee. T. Yamashita, Chugai Pharmaceutical Co., Ltd. ), Other, Lecture fee. Esai Co. ), Other, Lecture fee. AstraZeneca ), Other, Lecture fee. T. Yamaguchi, None. M. Kudo, Chugai ), Other, Lecture/ Honoraria. Eisai Other, Lecture/ Honoraria, Advisory Consulting. AstraZeneca Other, Lecture/ Honoraria, Advisory Consulting. Otsuka ). M. Ozaka, Taiho Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Ono Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. MSD Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Novartis Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Servier Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. AstraZeneca Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. C. Notake, None.. H. Uchigata, None. M. Ikeda, AbbVie ), Other, Consulting fees. AstraZeneca ), Other, Consulting fees / Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Bristol Myers Squibb ), Other, Consulting fees. Chugai ), Other, Consulting fees / Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Eisai ), Other, Consulting fees / Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. MSD ), Other, Consulting fees / Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. GlaxoSmithKline Other, Consulting fees. Ono Other, Consulting fees / Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. EA Pharma Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. Takeda Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events. N. Gotohda, None. Y. Nakamura, Guardant Health Pte Ltd. Other, reports advisory role. Natera,Inc. Other, reports advisory role. Exact Sciences Corporation, Tempus AI, Inc. Other, reports advisory role. Pfizer Inc. Other, reports advisory role. Shionogi & Co., Ltd. Inc. Other, reports advisory role. MSD K.K. Other, speakers’ bureau. Merck Biopharma Co., Ltd. Other, speakers’ bureau. Daiichi Sankyo Co., Ltd. Other, speakers’ bureau. Chugai Pharmaceutical Co., Ltd. Other, speakers’ bureau. Guardant Health Japan Corp. Other, speakers’ bureau.

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