海报库PosterKeep
PO.CL09.01 · 临床研究

KRAS突变和CDKN2A缺失在IDH1突变型肝内胆管癌中的预后影响和临床特征

Prognostic impact and clinical characteristics of KRAS mutations and CDKN2A loss in IDH1 -mutant intrahepatic cholangiocarcinoma

海报缩略图：KRAS突变和CDKN2A缺失在IDH1突变型肝内胆管癌中的预后影响和临床特征
编号 5346 展板 14 时间 4/21 09:00–12:00 区域 Section 46 主讲 Eiichiro So, MD
分会场 Precision Oncology and Real World Data
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作者与单位 Authors & Affiliations

Eiichiro So1, Chigusa Morizane1, Kouya Shiraishi2, Nobuyoshi Hiraoka3, Miyuki Sone4, Takafumi Koyama5, Rui Kitadai6, Yusuke Okuma7, Takashi Kohno2, Tetsuro Shiraishi2, Yuno Goto1, Shiho Hakui1, Kiyoaki Ochi1, Keita Fujisaki1, Kazunori Onuma1, Yasuhiro Komori1, Daiki Yamashige1, Mao Okada1, Shota Harai1, Yuta Maruki1, Yasuyuki Kawamoto1, Yoshikuni Nagashio1, Susumu Hijioka1, Hideki Ueno1, Kenro Hirata8, Takanori Kanai8, Takuji Okusaka1

1Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan,2Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan,3Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan,4Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan,5Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan,6Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan,7Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan,8Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

摘要 Abstract

中文摘要
背景：在ClarIDHy试验中，与安慰剂相比，ivosidenib显著改善了既往接受治疗的IDH1突变型胆管癌（CCA）患者的无进展生存期（PFS），目前正在日本等待医保批准。然而，两组中约40%的患者在2个月内出现疾病进展，提示IDH1突变型CCA内部存在潜在的生物学异质性。我们假设基因组共改变可能作为这种异质性的潜在决定因素。 方法：我们分析了2019年6月至2025年6月间癌症基因组学与先进治疗中心（C-CAT）数据库中的肝内胆管癌（iCCA）患者。使用OncoKB对点突变进行注释，使用C-CAT评估拷贝数变异和重排（批准号CDU2021-001N）。此外，我们回顾了2001年10月至2025年10月间诊断的IDH1突变型iCCA机构患者，进行了详细的病理和影像学评估（批准号2018-149）。 结果：在2484例iCCA患者中，353例（14.2%）具有IDH1突变。IDH1突变型iCCA在一线治疗中往往表现出比IDH1野生型更长的总生存期（OS）和治疗失败时间（TTF）（中位OS，22.4 vs. 20.1个月；HR，0.83；P=0.054；中位TTF，7.8 vs. 6.4个月；HR，0.87；P=0.068）。在IDH1突变型iCCA中，KRAS突变和CDKN2A缺失的频率低于IDH1野生型（KRAS突变，11.6% vs. 27.6%，P<0.001；CDKN2A缺失，17.8% vs. 27.5%，P<0.001）。在IDH1突变型iCCA中，KRAS突变显示出OS缩短的趋势（中位，17.0 vs. 23.2；HR，1.60；P=0.069），并与TTF缩短相关（中位，5.7 vs. 8.5个月；HR，1.86；P=0.0039）。CDKN2A缺失与OS缩短相关（中位，17.6 vs. 23.7个月；HR，1.58；P=0.037）。无KRAS突变或CDKN2A缺失的IDH1突变型iCCA表现出显著更长的OS（中位，24.9 vs. 17.6个月；HR，0.61，P=0.010）和TTF（中位，8.4 vs. 6.1个月；HR，0.70，P=0.020），优于其他亚组。在多变量分析中，KRAS突变预测更短的OS（HR，1.75；P=0.046）和TTF（HR，1.77；P=0.012）。在37例患者的机构队列中，仅有一例在病理上被分类为大导管型并携带KRAS突变，所有其他病例均被分类为小导管型。在影像学上，无KRAS突变和CDKN2A缺失的IDH1突变型iCCA往往表现为外周位置（60.0% vs. 33.3%）和瘤内穿行血管（84.0% vs. 55.6%）。 结论：IDH1突变与KRAS突变和CDKN2A缺失共同发生的频率较低。无这些共改变的IDH1突变型iCCA表现出良好的临床结局和独特的影像病理特征，凸显了IDH1突变型iCCA中与基因组共改变相关的生物学异质性。
查看英文原文 English abstract
Background: In the ClarIDHy trial, ivosidenib significantly improved progression-free survival (PFS) compared with placebo in patients with previously treated IDH1 -mutant cholangiocarcinoma (CCA) and is currently awaiting insurance approval in Japan. However, approximately 40% of patients in both arms experience disease progression within 2 months, suggesting underlying biological heterogeneity within IDH1 -mutant CCA. We hypothesized that genomic co-alterations may serve as potential determinants of this heterogeneity. Methods: We analyzed patients with intrahepatic cholangiocarcinoma (iCCA) in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database between June 2019 and June 2025. Point mutations were annotated using OncoKB, and copy number variants and rearrangements were evaluated using C-CAT (approval number CDU2021-001N). Additionally, we reviewed institutional patients with IDH1 -mutant iCCA diagnosed between October 2001 and October 2025, with detailed pathological and radiological assessments (approval number 2018-149). Results: Among 2484 patients with iCCA, 353 had IDH1 mutations (14.2%). IDH1 -mutant iCCA tended to show longer overall survival (OS) and time to treatment failure (TTF) for first-line therapy than IDH1 -wild type (median OS, 22.4 vs. 20.1 months; HR, 0.83; P =0.054; median TTF, 7.8 vs. 6.4 months; HR, 0.87; P =0.068). In IDH1 -mutant iCCA, KRAS mutations and CDKN2A loss were less frequent than IDH1 -wild type ( KRAS mutations, 11.6% vs. 27.6%, P <0.001; CDKN2A loss, 17.8% vs. 27.5%, P <0.001). Among IDH1 -mutant iCCA, KRAS mutations showed a trend toward shorter OS (median, 17.0 vs. 23.2; HR, 1.60; P =0.069) and were associated with shorter TTF (median, 5.7 vs. 8.5 months; HR, 1.86; P =0.0039). CDKN2A loss was correlated with shorter OS (median, 17.6 vs. 23.7 months; HR, 1.58; P =0.037). IDH1 -mutant iCCA without KRAS mutations or CDKN2A loss demonstrated significantly longer OS (median, 24.9 vs. 17.6 months; HR, 0.61, P =0.010) and TTF (median, 8.4 vs. 6.1 months; HR, 0.70, P =0.020) than the other subsets. In multivariate analysis, KRAS mutations predicted shorter OS (HR, 1.75; P =0.046) and TTF (HR, 1.77; P =0.012). In an institutional cohort of 37 patients, only one case was pathologically classified as large-duct type and harbored KRAS mutation, with all other cases classified as small-duct type. Radiologically, IDH1 -mutant iCCA without KRAS mutations and CDKN2A loss tended to present in a peripheral location (60.0% vs. 33.3%) and intratumoral transversing vessels (84.0% vs. 55.6%). Conclusions: IDH1 mutations less frequently co-occur with KRAS mutations and CDKN2A loss. IDH1 -mutant iCCA without these co-alterations exhibited favorable clinical outcomes and distinct radiopathological characteristics, highlighting the biological heterogeneity associated with genomic co-alterations in IDH1 -mutant iCCA.
利益披露 Disclosure
E. So, None.. C. Morizane, None.. K. Shiraishi, None.. N. Hiraoka, None.. M. Sone, None.. T. Koyama, None.. R. Kitadai, None.. Y. Okuma, None.. T. Kohno, None.. T. Shiraishi, None.. Y. Goto, None.. S. Hakui, None.. K. Ochi, None.. K. Fujisaki, None.. K. Onuma, None.. Y. Komori, None.. D. Yamashige, None.. M. Okada, None.. S. Harai, None.. Y. Maruki, None.. Y. Kawamoto, None.. Y. Nagashio, None.. S. Hijioka, None.. H. Ueno, None.. K. Hirata, None.. T. Kanai, None.. T. Okusaka, None.

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