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Genetics and Genomics

NTRK1 Fusions identified by non-invasive plasma next-generation sequencing (NGS) across 9 cancer types

Abstract

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.

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Fig. 1: Overview of the study and major findings.
Fig. 2: NTRK1 gene fusions by tumor type and histology.
Fig. 3: The patient was a male former 30-pack-year smoker diagnosed with stage IV lung adenocarcinoma at age 45 after presenting with chest wall pain, found to have a left lung mass, left pleural nodules and effusion.
Fig. 4: An illustrative case of the clonal evolution of an EGFR-mutated NSCLC under the selective pressure of treatments.
Fig. 5: An illustrative case of the utility of plasma NGS for NTRK gene fusion detection and identification of secondary mutations after acquired resistance to 1st generation TRK inhibitors.
Fig. 6: Clinical Utility of liquid biopsy in NTRK fusion-positive patients.

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Authors and Affiliations

Authors

Contributions

CR, LK, KP and DRG conceived the work; LK and KP acquired data; AD, JJL, AMS, LK and KP provided detailed cases information and materials; CR, AR, LK, KP and DRG drafted the manuscript and analysed the data; all the co-authors revised the manuscript. All the co-authors approved the final version.

Corresponding author

Correspondence to Christian Rolfo.

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Ethics approval and consent to participate

This research was conducted in accordance with the Declaration of Helsinki. Institutional Review Board approval (Advarra IRB Pro00034566/CR00218935) waived the need for individual informed consent for use of deidentified aggregate data for research purposes.

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Competing interests

Dr. Rolfo reports grants for Lung Cancer Research Foundation-Pfizer Grant 2019 NHI U54 grant (Project co-leader); He has received personal fees for attending advisory board with Inivata, ArcherDx, EMD Serono, BMS, Novartis, Boston Pharmaceuticals, Pfizer, Mirati, and Eisai; fee for speaking bureau: MSD, Astra Zeneca, Roche, and GuardantHealth; Participation in Safety Monitoring Board for EMD Serono Non-financial conflict included research collaboration: GuardantHealth. Dr. Drilon reports Honoraria/Advisory Boards from Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, Abbvie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX; Associated Research to Institution from Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar; Royalties from Wolters Kluwer; Other from Merck, Puma, Merus, Boehringer Ingelheim. Dr. Russo reports consultancy for Astra Zeneca, MSD, and Novartis outside the submitted work. Dr. Stinchcombe reports personal fees from Takeda, AstraZeneca, Genentech/Roche, Foundation Medicine, Pfizer, EMD Serono, Novartis, Daiichi Sankyo, Lilly, Medtronic, Puma Biotechnology, Janssen Oncology, Regeneron, non-financial support from Genentech/Roche, Blueprint Medicines, AstraZeneca, Takeda, Advaxis, Regeneron, outside the submitted work. Dr. Vidula reports institutional research funding from Radius, Merck, Daehwa, Pfizer (and travel), and Novartis; advisory board from AbbVie; Dr. Price is an employee and stock holder of Guardant Health.

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Rolfo, C., Drilon, A., Hong, D. et al. NTRK1 Fusions identified by non-invasive plasma next-generation sequencing (NGS) across 9 cancer types. Br J Cancer 126, 514–520 (2022). https://doi.org/10.1038/s41416-021-01536-1

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