Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States.
Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States.
Oncologist. 2024 Aug 5;29(8):725-730. doi: 10.1093/oncolo/oyae163.
Isocitrate dehydrogenase 1 (IDH1) missense mutations occur at a frequency of 10%-15% in intrahepatic cholangiocarcinoma (iCCA). IDH1 mutations result in accumulation of (R)-2-hydroxyglutarate, an oncometabolite that leads to DNA hypermethylation and impairment of homologous recombination (HR). Impairment of HR results in a "BRCAness" phenotype which may confer sensitivity to poly(ADP ribose) polymerase (PARP) inhibition.
We conducted a retrospective cohort review to identify patients with advanced, IDH1 mutated iCCA treated with a PARP inhibitor (PARPi) at the University of Michigan between 2018 and 2023. Patients are described with respect to prior lines of therapy, response to platinum-based chemotherapy, and progression-free survival (PFS) and overall survival (OS) from the time of PARPi initiation.
Between 2018 and 2023 we identified 40 patients with IDH1 mutated iCCA of which 6 patients were treated with a PARPi as monotherapy or in combination with an ATR inhibitor or anti-PD-1 immune checkpoint inhibitor. Majority of patients (n = 5) carried an IDH1 R132C mutation per tissue-based next generation sequencing. All patients had previously received at least one line of cisplatin-based systemic therapy for advanced disease prior to treatment with PARPi. PFS and OS from time of PARPi initiation ranged from 1.4 to 18.5 months and 2.8 to 42.4 months, respectively. Best response on PARPi therapy included 2 partial responses.
This is the first case series to describe PARPi treatment in IDH1 mutated iCCA. Results underscore the limitation of PARPi monotherapy, potentially support combined PARPi therapies, and highlight a need for effective treatment options for patients with IDH1 mutated iCCA.
异柠檬酸脱氢酶 1（IDH1）错义突变在肝内胆管癌（iCCA）中的发生率为 10%-15%。IDH1 突变导致（R）-2-羟基戊二酸的积累，这是一种致癌代谢物，导致 DNA 超甲基化和同源重组（HR）受损。HR 受损导致“BRCA 样”表型，这可能使患者对聚（ADP 核糖）聚合酶（PARP）抑制剂敏感。
我们对密歇根大学在 2018 年至 2023 年间接受 PARP 抑制剂（PARPi）治疗的晚期 IDH1 突变型 iCCA 患者进行了回顾性队列研究。根据先前的治疗线、对铂类化疗的反应以及从 PARPi 开始时的无进展生存期（PFS）和总生存期（OS），对患者进行描述。
在 2018 年至 2023 年间，我们确定了 40 名 IDH1 突变型 iCCA 患者，其中 6 名患者接受了 PARPi 单药治疗或与 ATR 抑制剂或抗 PD-1 免疫检查点抑制剂联合治疗。大多数患者（n=5）的组织下一代测序显示存在 IDH1 R132C 突变。所有患者在接受 PARPi 治疗之前，均已接受过至少一线基于顺铂的系统治疗。从 PARPi 开始时的 PFS 和 OS 分别为 1.4 至 18.5 个月和 2.8 至 42.4 个月。PARPi 治疗的最佳反应包括 2 例部分缓解。
这是首例描述 IDH1 突变型 iCCA 中 PARPi 治疗的病例系列。结果强调了 PARPi 单药治疗的局限性，可能支持联合 PARPi 治疗，并突出了需要为 IDH1 突变型 iCCA 患者提供有效的治疗选择。
