Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany.
German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany.
J Neurooncol. 2022 Sep;159(2):243-259. doi: 10.1007/s11060-022-04049-w. Epub 2022 Jul 21.
Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy.
Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected.
413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI.
A broad range of actionable alterations was targeted with available molecular therapeutics. However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary.
分子诊断学，包括下一代基因测序，越来越多地用于确定脑肿瘤患者个体化治疗的选择。我们旨在评估分子靶向治疗的决策过程，并分析耐受性数据以及疗效信号。
通过回顾性分析，我们确定了在法兰克福大学附属医院、歌德大学接受靶向治疗的脑肿瘤患者。我们分析了哪些类型的分子改变被用于指导分子的标签外治疗，并评估了在 2008 年至 2021 年期间的评估诊断程序。收集了耐受性和结局的数据。
共发现 413 例标签外治疗，2016 年后的时间段内每年的数量都在增加。37 项干预措施（9%）是基于分子标志物的靶向治疗。胶质细胞瘤和脑膜瘤是最常接受分子匹配靶向治疗的实体瘤。罕见的实体瘤包括髓母细胞瘤和颅咽管瘤。分子靶向方法包括检查点抑制剂、mTOR、FGFR、ALK、MET、ROS1、PIK3CA、CDK4/6、BRAF/MEK 和 PARP 抑制剂。首次随访 MRI 的反应包括部分缓解（13.5%）、稳定疾病（29.7%）和进展性疾病（46.0%）。没有新的安全信号。未观察到致命结局（CTCAE 分级 5）的不良事件。仅有两名患者因副作用而停止治疗。在至少稳定疾病的患者中，中位无进展生存期和总生存期分别为 9.1/18 个月，而在首次随访 MRI 中进展性疾病的患者中分别为 1.8/3.6 个月。
广泛的可靶向治疗的改变是针对现有的分子治疗方法。然而，疗效主要在具有典范致癌驱动因子的实体瘤中观察到，特别是在 BRAF 突变中。迫切需要进一步研究基于生物标志物的分子匹配治疗。
