NTRK-fused central nervous system tumours: clinicopathological and genetic insights and response to TRK inhibitors

Abstract

Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood-brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1-15 years) and six adults (aged 27-72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.

Keywords: NTRK fusion; Brain tumours; Next-generation sequencing; TRK inhibitors.

Fig. 1

A, B Patient #2 (15 y/F) presented with an intraventricular diffuse low-grade glioma located at the lateral ventricle, exhibiting heterogeneous high signal intensity on contrast-enhanced T1-weighted and T1-fluid-attenuated inversion recovery (FLAIR) images. B The tissue in the H&E section resembled a myxoid glioneuronal tumour, characterized by monotonous round cells within a myxoid background. D, F Immunohistochemical analysis revealed positivity for GFAP, TRK, and Olig2 in this tumour. G An Arriba plot generated from next-generation sequencing (NGS) data using RNA identified the KIF5A::NTRK2 in-frame fusion in the tumour (C, D: H&E, E: GFAP, F: Olig2; scale bar, C-E: 200 μm, F: 100 μm)

Fig. 2

Patient #5, a 27-year-old female, presented with an uncommon glioma harbouring the LHFPL3::NTRK2 fusion. A, B T1 and T2 FLAIR MR images revealed a 5.3 × 4.5 × 1.6 cm solid and cystic mass in the right lateral ventricle with multifocal enhancement in the right intra- and periventricular white matter. C, D H&E sections of the tumour exhibited a distinctive pathology characterized by multiple whorls formed by glial cells and neuropil-like islands. E The spindle-shaped glial cells forming the whorls were positive for GFAP and negative for synaptophysin, but F the neuropil-like islands were positive for synaptophysin and negative for GFAP. G An Arriba plot generated from next-generation sequencing (NGS) data for tumour RNA identified the LHFPL3::NTRK2 in-frame fusion (scale bar, C–E: 200 μm, F: 100 μm)

Fig. 3

Patient #12 had the BCR::NTRK2 fusion. A, B T2-weighted turbo spin‒echo (TSE) and T2 FLAIR images showing a hyperintense mass in the thalamus and bifrontal area with peritumoral oedema. C The tumour was composed of oligodendroglioma-like clear cells with microvascular proliferation and pseudopalisading necrosis. D and E Diffuse positivity for TRK and Olig2 was observed in the cytoplasm and nuclei, respectively, of tumour cells. F The Ki-67 labelling index was high (88.4%). G The Arriba plot revealed the in-frame fusion between the BCR gene and NTRK2 gene (scale bar, F: 50 μm)

Fig. 4

Illustration of the clinicopathological and genetic abnormalities in NTRK-fused gliomas in paediatric and adult patients, Abbreviations LG, low-grade; HG, high-grade; P, parietal lobe; LV, lateral ventricle; Thal, thalamus, TO, temporo-occipital lobe; T, temporal lobe; FT, fronto-temporal lobe; SP, spinal cord; CBLL, cerebellum; F/Thal, frontal lobe and thalamus; Hemi D, hemizygous deletion; HoD, homozygous deletion

Fig. 5

Summary of the radiological characteristics and treatment timelines for patients receiving TRK inhibitor therapy (IHG: Infant-type hemispheric glioma, DLGG: Diffuse low-grade glioma, DHGG: Diffuse high-grade glioma, GBM: Glioblastoma, IDH-Wild-type, OP: Operation, SD: Stable disease, PD: Progressive disease, NET: No evidence of tumour, aPBSCT: autologous peripheral blood stem cell transplantation; Carbo, carboplatin, Thio, thioflavin #3)