Background

Activating fusions of the NTRK1, NTRK2 and NTRK3 genes are drivers of carcinogenesis and proliferation across a broad range of tumour types in both adult and paediatric patients. Recently, the FDA granted tumour-agnostic approvals of TRK inhibitors, larotrectinib and entrectinib, based on significant and durable responses in multiple primary tumour types. Unfortunately, testing rates in clinical practice remain quite low. Adding plasma next-generation sequencing of circulating tumour DNA (ctDNA) to tissue-based testing increases the detection rate of oncogenic drivers and demonstrates high concordance with tissue genotyping. However, the clinical potential of ctDNA analysis to identify NTRK fusion-positive tumours has been largely unexplored.

Methods

We retrospectively reviewed a ctDNA database in advanced stage solid tumours for NTRK1 fusions.

Results

NTRK1 fusion events, with nine unique fusion partners, were identified in 37 patients. Of the cases for which clinical data were available, 44% had tissue testing for NTRK1 fusions; the NTRK1 fusion detected by ctDNA was confirmed in tissue in 88% of cases. Here, we report for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value.

Conclusion

Plasma ctDNA represents a rapid, non-invasive screening method for this rare genomic target that may improve identification of patients who can benefit from TRK-targeted therapy and potentially identify subsequent on- and off-target resistance mechanisms.

中文翻译：

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通过非侵入性血浆下一代测序 (NGS) 鉴定出 9 种癌症类型的 NTRK1 融合体

 背景

NTRK1 、 NTRK2和NTRK3基因的激活融合是成人和儿童患者中多种肿瘤类型的致癌和增殖的驱动因素。最近，基于对多种原发肿瘤类型的显着且持久的反应，FDA 批准了 TRK 抑制剂 larotrectinib 和 entrectinib 与肿瘤无关的批准。不幸的是，临床实践中的检测率仍然很低。将循环肿瘤 DNA (ctDNA) 的血浆新一代测序添加到基于组织的检测中，可以提高致癌驱动因素的检出率，并证明与组织基因分型的高度一致性。然而，ctDNA 分析识别NTRK融合阳性肿瘤的临床潜力尚未得到充分探索。

 方法

我们回顾性审查了晚期实体瘤中NTRK1融合的 ctDNA 数据库。

 结果

在 37 名患者中发现了NTRK1融合事件，其中有 9 个独特的融合伙伴。在可获得临床数据的病例中，44% 进行了NTRK1融合组织检测； 88% 的病例在组织中证实了 ctDNA 检测到的NTRK1融合。在这里，我们首次报道微创血浆NGS可以检测具有高阳性预测值的NTRK融合。

 结论

血浆 ctDNA 代表了一种针对这种罕见基因组靶点的快速、非侵入性筛查方法，可以改善对可受益于 TRK 靶向治疗的患者的识别，并有可能识别随后的靶向和脱靶耐药机制。