TY - JOUR
T1 - NTRK1 Fusions identified by non-invasive plasma next-generation sequencing (NGS) across 9 cancer types
AU - Rolfo, Christian
AU - Drilon, Alexander
AU - Hong, David
AU - McCoach, Caroline
AU - Dowlati, Afshin
AU - Lin, Jessica J.
AU - Russo, Alessandro
AU - Schram, Alison M.
AU - Liu, Stephen V.
AU - Nieva, Jorge J.
AU - Nguyen, Timmy
AU - Eshaghian, Shahrooz
AU - Morse, Michael
AU - Gettinger, Scott
AU - Mobayed, Mohammad
AU - Goldberg, Sarah
AU - Araujo-Mino, Emilio
AU - Vidula, Neelima
AU - Bardia, Aditya
AU - Subramanian, Janakiraman
AU - Sashital, Deepa
AU - Stinchcombe, Thomas
AU - Kiedrowski, Lesli
AU - Price, Kristin
AU - Gandara, David R.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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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U2 - 10.1038/s41416-021-01536-1
DO - 10.1038/s41416-021-01536-1
M3 - Article
C2 - 34480094
AN - SCOPUS:85114603631
SN - 0007-0920
JO - British journal of cancer
JF - British journal of cancer
ER -