Neurotrophic tyrosine receptor kinase gene fusions (NTRK) are oncogenic drivers present at a low frequency in most tumour types (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., infantile fibrosarcoma [IFS]) and considered mutually exclusive with other common oncogenic drivers. Health Canada recently approved two tyrosine receptor kinase (TRK) inhibitors, larotrectinib (for adults and children) and entrectinib (for adults), for the treatment of solid tumours harbouring NTRK gene fusions. In Phase I/II trials, these TRK inhibitors have demonstrated promising overall response rates and tolerability in patients with TRK fusion cancer who have exhausted other treatment options. In these studies, children appear to have similar responses and tolerability to adults. In this report, we provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor for pediatric patients with solid tumours. We focus on three pediatric tumour types: non-rhabdomyosarcoma soft tissue sarcoma/unspecified spindle cell tumours including IFS, differentiated thyroid carcinoma, and glioma. We also propose a tumour-agnostic consensus based on the probability of the tumour harbouring an NTRK gene fusion. For children with locally advanced or metastatic TRK fusion cancer who have either failed upfront therapy or lack satisfactory treatment options, TRK inhibitor therapy should be considered.

中文翻译：

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加拿大关于儿科患者 TRK 融合癌生物标志物检测和治疗的共识

神经营养性酪氨酸受体激酶基因融合 (NTRK) 是致癌驱动因素，在大多数肿瘤类型中以低频率 (<5%) 存在，在少数罕见肿瘤 (例如婴儿纤维肉瘤) 中以更高频率 (>80%) 存在。 IFS]) 并被认为与其他常见的致癌驱动因素相互排斥。加拿大卫生部最近批准了两种酪氨酸受体激酶 (TRK) 抑制剂 larotrectinib（成人和儿童）和 entrectinib（成人），用于治疗携带 NTRK 基因融合的实体瘤。在 I/II 期试验中，这些 TRK 抑制剂在已经用尽其他治疗选择的 TRK 融合癌患者中显示出有希望的总体反应率和耐受性。在这些研究中，儿童似乎对成人有相似的反应和耐受性。在这份报告中，我们就何时以及如何测试 NTRK 基因融合以及何时考虑使用 TRK 抑制剂治疗患有实体瘤的儿科患者提供了加拿大共识。我们专注于三种儿科肿瘤类型：非横纹肌肉瘤软组织肉瘤/未指定的梭形细胞肿瘤，包括 IFS、分化型甲状腺癌和神经胶质瘤。我们还提出了基于肿瘤携带 NTRK 基因融合的可能性的肿瘤不可知共识。对于前期治疗失败或缺乏满意治疗方案的局部晚期或转移性TRK融合癌儿童，应考虑TRK抑制剂治疗。非横纹肌肉瘤软组织肉瘤/未特指的梭形细胞肿瘤，包括 IFS、分化型甲状腺癌和神经胶质瘤。我们还提出了基于肿瘤携带 NTRK 基因融合的可能性的肿瘤不可知共识。对于前期治疗失败或缺乏满意治疗方案的局部晚期或转移性TRK融合癌患儿，应考虑TRK抑制剂治疗。非横纹肌肉瘤软组织肉瘤/未特指的梭形细胞肿瘤，包括 IFS、分化型甲状腺癌和神经胶质瘤。我们还提出了基于肿瘤携带 NTRK 基因融合的可能性的肿瘤不可知共识。对于前期治疗失败或缺乏满意治疗方案的局部晚期或转移性TRK融合癌儿童，应考虑TRK抑制剂治疗。