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Updated: Oct 21, 2025
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
NTRK1 Fusions identified by non-invasive plasma next-generation sequencing (NGS) across 9 cancer types
Christian Rolfo1, Alexander Drilon2, David Hong3
1Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai System & Icahn School of Medicine, Mount Sinai, New York, NY, USA. christian.rolfo@mssm.edu.
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.
Insights
Plasma next-generation sequencing (NGS) can detect NTRK1 fusions in circulating tumor DNA (ctDNA) with high accuracy. This minimally-invasive approach may improve identification of patients eligible for TRK-targeted therapies.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- Activating NTRK gene fusions drive carcinogenesis in diverse adult and pediatric tumors.
- FDA-approved TRK inhibitors (larotrectinib, entrectinib) show efficacy, but testing rates are low.
- Plasma ctDNA (circulating tumor DNA) analysis complements tissue testing for oncogenic drivers.
Purpose of the Study:
- To explore the clinical potential of ctDNA analysis for identifying NTRK fusion-positive tumors.
- To evaluate the utility of plasma next-generation sequencing (NGS) for detecting NTRK fusions.
Main Methods:
- Retrospective review of a ctDNA database in advanced solid tumors.
- Analysis focused on identifying NTRK1 fusions using plasma NGS.
Main Results:
- NTRK1 fusions with nine partners were identified in 37 patients via ctDNA.
- Plasma ctDNA detected NTRK1 fusions with a high positive predictive value.
- NTRK1 fusions detected by ctDNA were confirmed in tissue in 88% of evaluable cases.
Conclusions:
- Plasma ctDNA is a rapid, non-invasive method for screening rare genomic targets like NTRK fusions.
- This approach may enhance identification of patients benefiting from TRK-targeted therapy.
- Plasma ctDNA analysis could also help identify resistance mechanisms to TRK inhibitors.
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