Identification of resistant clone for the chemotherapy of hepatocellular carcinoma using cell free DNA

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07950
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kindai University
• Principal Investigator: Kudo Masatoshi 近畿大学, 医学部, 教授 (10298953)
• Co-Investigator(Kenkyū-buntansha): 西田 直生志 近畿大学, 医学部, 教授 (60281755)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 肝細胞癌 / 免疫チェックポイント阻害剤 / アジュバント療法 / 腫瘍免疫微小環境 / cell-free DNA / ドライバー変異

Outline of Final Research Achievements

We investigated the association between the circulating tumor DNA (ctDNA) in postoperative plasma and recurrence in 32 patients who received adjuvant immune checkpoint inhibitors (ICIs) after radical hepatocellular carcinoma (HCC) surgery. A valiant of 10 copies/ml or more was considered as ctDNA positive. Tumor immune microenvironment (TIME) was classified by examining immune-related molecules and β-catenin-associated molecules. Patients were classified into 2 groups (β-catenin pathway activated and inactivated), and TIME-hot/exhausted and cold/Treg types). Postoperative recurrence-free survival (RFS) on ICI was significantly longer in the β-catenin pathway inactivation group and in the hot/exhausted TIME group. The median RFS for ctDNA-positive cases was 26.2 months and NR for ctDNA-negative cases, with a trend toward shorter RFS in ctDNA-positive cases . The cases with copy number variation on the β-catenin-related loci showed significantly shorter RFS under ICI treatment.

Free Research Field

消化器内科

Academic Significance and Societal Importance of the Research Achievements

免疫チェックポイント阻害剤(ICI)は肝癌治療の重要な薬剤であるが、腫瘍免疫微小環境(TIME)が効果に影響する。TIMEの解析には腫瘍組織が必要であり、生検は侵襲的でリスクを伴う。一方、循環血液中の腫瘍由来DNA（ctDNA）は非侵襲的、かつ繰り返し採取可能である。近年、β-catenin 経路の活性化はnon-inflamed型のTIMEの誘因になることが報告されたが、本研究ではβ-catenin 経路異常をctDNAから検出でき、ICIの治療効果予測に応用できる可能性を示した。また、ICI治療中のctDNAは癌細胞残存の指標となることを示した。この成果は肝癌の治療戦略に意義がある。