Amayiri Nisreen, Al-Hussaini Maysa, Maraqa Bayan, Alyazjeen Shaza, Alzoubi Qasem, Musharbash Awni, Ibrahimi Ahmad Kh, Sarhan Nasim, Obeidat Mouness, Hawkins Cynthia, Bouffet Eric
Department of Pediatrics, King Hussein Cancer Center, Amman, Jordan.
Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan.
Front Oncol. 2024 Feb 19;14:1329024. doi: 10.3389/fonc.2024.1329024. eCollection 2024.
Advances in molecular diagnostics led to improved targeted interventions in the treatment of pediatric CNS tumors. However, the capacity to test for these is limited in LMICs, and thus their value needs exploration.
We reviewed our experience with NGS testing (TruSight RNA Pan-Cancer-seq panel) for pediatric CNS tumors at KHCC/Jordan (March/2022-April/2023). Paraffin blocks' scrolls were shipped to the SickKids laboratory based on the multidisciplinary clinic (MDC) recommendations. We reviewed the patients' characteristics, the tumor types, and the NGS results' impact on treatment.
Of 237 patients discussed during the MDC meetings, 32 patients (14%) were included. They were 16 boys and 16 girls; the median age at time of testing was 9.5 years (range, 0.9-21.9 years). There were 21 samples sent at diagnosis and 11 upon tumor progression. The main diagnoses were low-grade-glioma (15), high-grade-glioma (10), and other histologies (7). Reasons to request NGS included searching for a targetable alteration (20) and to better characterize the tumor behavior (12). The median turnaround time from samples' shipment to receiving the results was 23.5 days (range, 15-49 days) with a median laboratory processing time of 16 days (range, 8-39 days) at a cost of US$1,000/sample. There were 19 (59%) tumors that had targetable alterations (FGFR/MAPK pathway inhibitors (14), checkpoint inhibitors (2), NTRK inhibitors (2), and one with PI3K inhibitor or IDH1 inhibitor). Two rare BRAF mutations were identified (BRAFp.G469A, BRAFp.K601E). One tumor diagnosed initially as undifferentiated round cell sarcoma harbored NAB2::STAT6 fusion and was reclassified as an aggressive metastatic solitary fibrous tumor. Another tumor initially diagnosed as grade 2 astroblastoma grade 2 was reclassified as low-grade-glioma in the absence of MN1 alteration. NGS failed to help characterize a tumor that was diagnosed histologically as small round blue cell tumor. Nine patients received targeted therapy; dabrafenib/trametinib (6), pembrolizumab (2), and entrectinib (1), mostly upon tumor progression (7).
In this highly selective cohort, a high percentage of targetable mutations was identified facilitating targeted therapies. Outsourcing of NGS testing was feasible; however, criteria for case selection are needed. In addition, local capacity-building in conducting the test, interpretation of the results, and access to "new drugs" continue to be a challenge in LMICs.
分子诊断技术的进步使儿科中枢神经系统肿瘤的靶向治疗得到了改进。然而，在低收入和中等收入国家（LMICs），进行这些检测的能力有限，因此其价值有待探索。
我们回顾了在KHCC/约旦（2022年3月至2023年4月）对儿科中枢神经系统肿瘤进行二代测序（NGS）检测（TruSight RNA泛癌测序面板）的经验。根据多学科诊所（MDC）的建议，将石蜡块切片运往病童医院实验室。我们回顾了患者的特征、肿瘤类型以及NGS结果对治疗的影响。
在MDC会议讨论的237例患者中，32例（14%）被纳入。其中16名男孩和16名女孩；检测时的中位年龄为9.5岁（范围0.9 - 21.9岁）。诊断时送检21份样本，肿瘤进展时送检11份样本。主要诊断包括低级别胶质瘤（15例）、高级别胶质瘤（10例）和其他组织学类型（7例）。要求进行NGS检测的原因包括寻找可靶向改变（20例）以及更好地描述肿瘤行为（12例）。从样本运送至收到结果的中位周转时间为23.5天（范围15 - 49天），实验室中位处理时间为16天（范围8 - 39天），每份样本成本为1000美元。有19例（59%）肿瘤存在可靶向改变（FGFR/MAPK通路抑制剂相关改变14例、检查点抑制剂相关改变2例、NTRK抑制剂相关改变2例，1例有PI3K抑制剂或IDH1抑制剂相关改变）。鉴定出两种罕见的BRAF突变（BRAFp.G469A、BRAFp.K601E）。一例最初诊断为未分化圆形细胞肉瘤的肿瘤存在NAB2::STAT6融合，被重新分类为侵袭性转移性孤立性纤维瘤。另一例最初诊断为2级成星形细胞瘤的肿瘤在不存在MN1改变的情况下被重新分类为低级别胶质瘤。NGS未能帮助明确一例组织学诊断为小圆蓝细胞肿瘤的肿瘤特征。9例患者接受了靶向治疗；达拉非尼/曲美替尼（6例）、帕博利珠单抗（2例）和恩曲替尼（1例），大多在肿瘤进展时接受治疗（7例）。
在这个高度选择性的队列中，发现了高比例的可靶向突变，有助于进行靶向治疗。NGS检测外包是可行的；然而，需要病例选择标准。此外，在低收入和中等收入国家，开展检测、解读结果以及获取“新药”方面的当地能力建设仍然是一项挑战。
