Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Pediatric Patients.

Sébastien Perreault,Aru Narendran,Dina El Demellawy,Benjamin Ellezam,Rose Chami,Stephen Yip,Daniel A Morgenstern,Rebecca J Deyell,Poul H B Sorensen,Jonathan D Wasserman,Nada Jabado

doi:10.3390/curroncol28010038

Abstract

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.

Highlights

An oncogenic neurotrophic tyrosine receptor kinase 1 (NTRK1) gene fusion cloned from a colon cancer sample was first reported in 1982 based on murine fibroblast transformation assays [1,2]
To the best of our knowledge, no Neurotrophic tyrosine receptor kinase gene fusions (NTRK) gene fusions have been identified in RMS, so we focus instead on non-RMS soft tissue sarcomas (STSs) and unspecified spindle cell tumours
Up to 30% of patients with infantile fibrosarcoma (IFS) may be negative for the ETV6-NTRK3 gene fusion and other NTRK, BRAF, and MET gene fusions have been identified in IFS [48,63,70,71]

Summary

Introduction

An oncogenic neurotrophic tyrosine receptor kinase 1 (NTRK1) gene fusion cloned from a colon cancer sample was first reported in 1982 based on murine fibroblast transformation assays [1,2]. Encoded chimeric oncoproteins contain constitutively activated kinase domains, as the 5 partner of the fusion contributes a protein domain that promotes ligand independent oligomerization (i.e., without requiring ligand binding), driving kinase activation and uncontrolled signaling and oncogenesis [1] These fusions are typically mutually exclusive with other primary oncogenic drivers [12,13]. The prevalence of NTRK gene fusions in pediatric tumours varies among studies, it appears to exceed that in adults and may be as high as 26% [78]. IFS [36,61,105] and cellular and mixed congenital mesoblastic nephroma [36,46,47,48] harbour ETV6-NTRK3 gene fusions at a frequency of >80%. This illustrates that TRK fusion cancer can respond to standard of care, but not with a high ORR [13]

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