In a large study of paediatric cancer patients, researchers from Children's Hospital of Philadelphia (CHOP) have analysed the frequency, fusion partners, and clinical outcome of neurotrophic tyrosine receptor kinase (NTRK) fusions, which are clinical biomarkers that identify patients suitable for treatment with FDA-approved TRK inhibitors.
The researchers found that NTRK fusions are more common in paediatric tumours and also involve a wider range of tumours than adult cancers, information that could help prioritise screening for NTRK fusions in paediatric cancer patients who might benefit from treatment with TRK inhibitors.
The findings were published in JCO Precision Oncology.
"Our findings demonstrate that NTRK fusions are far more frequently seen in paediatric tumours than in adult tumours and involve a broader panel of fusion partners and wider range of paediatric tumours than previously recognised," said senior author Marilyn M. Li, MD, Vice Chief of the Division of Genomic Diagnostics and Director of Cancer Genomic Diagnostics at CHOP.
"With the recent FDA approval of larotrectinib and entrectinib for the treatment of adult and pediatric NTRK-positive, unresectable solid tumors, identification of these fusions directly impacts patient care."
Previous studies have shown that rearrangements of NTRK genes drive tumour growth in a diverse range of cancers.
This led to the development of the first generation oral NTRK inhibitors, larotrectinib and entrectinib, and have spurred the development of other NTRK inhibitors, which are currently in clinical development. Ongoing clinical trials hope to identify optimal use of these drugs in children.
Given that in children, certain cancers like infantile fibrosarcoma (IF) and secretory carcinoma have very high incidence of NTRK fusions (>90%), whereas other cancers like melanoma and acute leukaemia rarely involve NTRK fusions, the researchers sought to better understand the frequency of these gene fusions across all paediatric cancers.
To do so, they analysed 1,347 consecutive paediatric tumours from 1,217 patients who underwent tumour genomic profiling using custom-designed DNA and RNA next generation sequencing panels.
The researchers identified NTRK fusions in 29 tumours from 27 patients, with a positive yield of 2.22% for all tumours and 3.08% for solid tumours. NTRK fusions were detected in 13% of papillary thyroid carcinomas (PTCs), 1.9% of central nervous system (CNS) tumours, 1.8% of non-CNS, non-PTC solid tumours, and 0.4% of haematologic malignancies.
Patients in the study were followed for up to 46 months, and in almost all cases, the detection of an NTRK fusion confirmed the diagnosis of the lesion type, including five cases where the final tumour diagnosis was largely based on the discovery of an NTRK fusion.
In one patient, the diagnosis was changed due to the identification of an NTRK fusion. In a separate case, a 6-month-old infant with a mass in his upper left extremity due to IF, which would have required extremely complex surgery to remove, was treated with larotrectinib and achieved complete pathologic remission.
"The identification of these NTRK fusions has facilitated precision cancer diagnosis and TRK inhibitor targeted therapy," Li said. "Our experience highlights the clinical utility of screening NTRK fusions for all paediatric tumours."