细胞周期蛋白依赖性激酶4/6抑制剂作为一种治疗GNAS突变腹膜黏液性癌的新疗法

IF 42.1 1区 医学 Q1 ONCOLOGY
Journal of Clinical Oncology Pub Date : 2025-02-20 Epub Date: 2024-10-16 DOI:10.1200/JCO.24.00511
Jonathan Weitz, Daisuke Nishizaki, Joy Liau, Jay Patel, Isabella Ng, Siming Sun, Dana Ramms, Jingjing Zou, Brian Wishart, Jordan Rull, Joel Baumgartner, Kaitlyn Kelly, Rebekah White, Jula Veerapong, Mojgan Hosseini, Hitendra Patel, Gregory Botta, J Sylvio Gutkind, Herve Tiriac, Shumei Kato, Andrew M Lowy
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引用次数: 0

摘要

目的:胃肠道黏液性肿瘤的特点是容易转移到腹膜,导致腹膜黏液性癌(PMC)。这些肿瘤中有一部分最常见于阑尾,它们携带 GNAS 致癌基因突变。虽然GNAS突变型腹腔粘液癌的自然病史各不相同,但患者的预后和对细胞毒化疗的反应一般都很差。本研究旨在评估单药帕博西尼(一种细胞周期蛋白依赖性激酶(CDK)4/6抑制剂)对GNAS突变型PMC患者的临床疗效:我们在一项单臂个性化癌症治疗试验中招募了16名PMC患者。我们对所有患者的肿瘤组织和/或循环肿瘤DNA基因组进行了新一代测序,并在可能的情况下对PD-L1表达、肿瘤突变负荷和微卫星不稳定性状态进行了评估。16名患者中有12名曾在至少一种化疗方案中出现过疾病进展。13名患者的原发肿瘤为阑尾,2名患者的原发肿瘤未知,1名患者的原发肿瘤为胰腺。11例被归类为低级别,5例被归类为高级别:在16例患者中,我们观察到13例患者的癌胚抗原(CEA)下降,其中6例患者的CEA下降>50%。根据临床和改良腹膜RECIST标准,50%的可评估患者在服用帕博西尼12个月后病情稳定。中位随访时间为17.6个月,尚未达到中位生存期。利用体外临床前平台,CDK4/6抑制剂的临床反应反映在GNAS突变和粘液组织学肿瘤中:结论:使用帕博西尼(palbociclib)抑制CDK4/6对GNAS突变的PMC具有临床活性,优于之前报道的细胞毒性化疗。CDK4/6抑制是一种新型治疗策略,值得对这一胃肠道肿瘤亚群进行进一步评估。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cyclin-Dependent Kinase 4/6 Inhibition as a Novel Therapy for Peritoneal Mucinous Carcinomatosis With GNAS Mutations.

Purpose: Mucinous neoplasms of the gastrointestinal tract are characterized by a propensity for metastasis to the peritoneum, resulting in peritoneal mucinous carcinomatosis (PMC). A subset of these tumors, most often originating in the appendix, harbor mutations in the GNAS oncogene. While the natural history of GNAS-mutant PMC varies, patient outcomes are generally poor, as is response to cytotoxic chemotherapy. The purpose of this study was to evaluate the clinical efficacy of single-agent palbociclib, a cyclin-dependent kinase (CDK)4/6 inhibitor, in patients with GNAS-mutant PMC.

Patients and methods: We enrolled 16 patients with PMC in a single-arm personalized cancer therapy trial. For all patients, tumor tissue and/or circulating tumor DNA genomic profiling using next-generation sequencing and, when possible, PD-L1 expression, tumor mutational burden, and microsatellite instability status was assessed. Twelve of 16 patients had previous disease progression on at least one previous line of chemotherapy. The primary tumor was appendix in 13 patients, unknown in two patients, and pancreas in one patient. Eleven cases were classified as low grade, and five as high grade.

Results: In 13 of 16 patients, we observed a decrease in carcinoembryonic antigen (CEA), and in six patients, the CEA declined by >50%. As measured by clinical and modified peritoneal RECIST criteria, 50% of evaluable patients had stable disease after 12 months of palbociclib. At a median follow-up of 17.6 months, median survival has not been reached. Clinical response to CDK4/6 inhibition was mirrored in tumors with GNAS mutation and mucinous histology using an ex vivo preclinical platform.

Conclusion: CDK4/6 inhibition with palbociclib had clinical activity in PMC characterized by mutations in GNAS that was superior to that previously reported with cytotoxic chemotherapy. CDK4/6 inhibition is a novel therapeutic strategy worthy of further evaluation in this subgroup of gastrointestinal neoplasms.

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来源期刊
Journal of Clinical Oncology
Journal of Clinical Oncology 医学-肿瘤学
CiteScore
41.20
自引率
2.20%
发文量
8215
审稿时长
2 months
期刊介绍: The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.
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