Neurotrophic receptor tyrosine kinase (NTRK) fusions and their role in cancer

Abstract

Neurotrophic receptor tyrosine kinase (NTRK) fusions are rare, therapeutically actionable, and, in some cases, diagnostic oncogenic events that can occur in a variety of adult and pediatric cancers. Cytopathologists need to be a familiar with the types of tumors that can harbor NTRK fusions to triage specimens accordingly for testing.

Multiplexed single‐cell analysis of FNA allows accurate diagnosis of salivary gland tumors

“…To explore this possibility, we evaluated NTRK expression in SC of the salivary gland using the FAST‐FNA antibody probes. NTRK activation can result from various genomic NTRK alterations, including mutations, splice variants, copy number variations, and fusions, the latter being the most common mechanisms for TRK activation 21 . NTRK activation is most commonly diagnosed by IHC when ≥1% tumor cells show either membranous, cytoplasmic, or nuclear staining above background 13 .…”

“…NTRK activation can result from various genomic NTRK alterations, including mutations, splice variants, copy number variations, and fusions, the latter being the most common mechanisms for TRK activation. 21 NTRK activation is most commonly diagnosed by IHC when ≥1% tumor cells show either membranous, cytoplasmic, or nuclear staining above background. 13 Diagnosis of NTRK activation has emerged as clinically significant because of the recent FDA approval of NTRK inhibitors.…”

Circulating tumour DNA testing in metastatic breast cancer: Integration with tissue testing

“…Although rare, NTRK fusions are present in both secretory and non‐secretory breast cancer subtypes as suggested by recently published data 55 . Importantly, NTRK fusion‐positive tumours can be treated with TRK small molecule inhibitors (e.g., larotrectinib and entrectinib) based on the tumour‐agnostic approval that was granted by the FDA 56 . The main technologies for NTRK fusion testing encompass DNA‐ and RNA‐based NGS, qPCR, immunohistochemistry, and fluorescent in situ hybridisation, carried out on tissue samples.…”

“…55 Importantly, NTRK fusion-positive tumours can be treated with TRK small molecule inhibitors (e.g., larotrectinib and entrectinib) based on the tumour-agnostic approval that was granted by the FDA. 56 The main technologies for NTRK fusion testing encompass DNA-and RNA-based NGS, qPCR, immunohistochemistry, and fluorescent in situ hybridisation, carried out on tissue samples. In 2019, a strategy for the most appropriate implementation according to samples availability was proposed by the European Society for Medical Oncology's Translational Research and Precision Medicine Working Group.…”

Is genomic analysis possible in a tissue acquired via endoscopic ultrasound-guided fine-needle biopsy in cholangiocarcinoma?

“…This study describes the genomic analysis of tissue samples obtained via EUS-FNB to evaluate eight critical therapeutic molecular markers as follows: IDH1 variants (involved in metabolic pathways) 11 ; FGFR2 fusions (keys to cell growth and angiogenesis) 12 ; neurotrophic receptor tyrosine kinase (NTRK) fusions (important for neural development and function) 13 ; BRAF V600E variants (keys to the MAPK signaling pathway) 14 ; receptor tyrosine-protein kinase erbB-2 (ERBB2) amplifications (associated with cell proliferation and survival) 15 ; rearrangements during transfection (RET) fusions (impacting cell growth and differentiation) 16 ; microsatellite instability-high status (indicative of a defective DNA mismatch repair system) 17 ; and tumor mutational burden (TMB, reflecting the number of mutations carried by tumor cells). 18 FGFR2 fusions were detected in 12.9% of intrahepatic CCA, making it the most prevalent variant.…”