China special issue on gastrointestinal tumors— NTRK fusion in a large real‐world population and clinical utility of circulating tumor DNA genotyping to guide TRK inhibitor treatment

China special issue on gastrointestinal tumors— NTRK fusion in a large real‐world population and clinical utility of circulating tumor DNA genotyping to guide TRK inhibitor treatment

Abstract Neurotrophic tropomyosin receptor kinase ( NTRK ) gene fusions are rare oncogenic drivers and targets of TRK inhibitors in solid tumors. Little is known about NTRK fusion in Chinese patients with pan‐cancer. Our study investigated the prevalence and genomic features of NTRK1/2/3 gene fusion...

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Bibliographic Details
Published in:International journal of cancer 2023-12, Vol.153 (11), p.1916-1927
Main Authors: Qi, Changsong, Zhou, Ting, Bai, Yuezong, Chen, Hui, Yuan, Jiajia, Zhao, Feilong, Liu, Chang, Ma, Mingyang, Bei, Ting, Chen, Shiqing, Zhao, Xiaochen, Chen, Chunzhu, Shen, Lin
Format: Article
Language:eng
Subjects:
Biomarkers
Cancer
Cancer therapies
Colorectal cancer
Drug resistance
Genotyping
Kinases
Medical research
Microsatellite instability
Next-generation sequencing
Oncology
Patients
Solid tumors
Tropomyosin
Tumors
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Summary:Abstract Neurotrophic tropomyosin receptor kinase ( NTRK ) gene fusions are rare oncogenic drivers and targets of TRK inhibitors in solid tumors. Little is known about NTRK fusion in Chinese patients with pan‐cancer. Our study investigated the prevalence and genomic features of NTRK1/2/3 gene fusions in 67 883 Chinese patients with pan‐cancer using next‐generation sequencing (NGS) data and circulating tumor DNA (ctDNA) NGS to guide TRK inhibitor treatment and resistance monitoring. The prevalence of NTRK fusion (tissue NGS) in the pan‐cancer population was 0.18%, with 46 unique NTRK ‐fusion partner pairs, of which 33 were not previously reported. NTRK2 breakpoint occurred more frequently in intron 15 than intron 12. In colorectal cancers (CRCs), compared to NTRK ‐negative tumors, NTRK‐ positive tumors displayed higher tumor mutational burden (TMB) levels (54.6 vs 17.7 mut/Mb, P < .0001). In microsatellite instability‐high (MSI‐H) CRC, patients with NTRK fusion had a significantly lower TMB than NTRK ‐negative cases (69.3 vs 79.9 mut/Mb, P = .012). The frequency of NTRK fusion in a ctDNA NGS cohort of 20 954 patients with cancer was similar to that of the tissue NGS cohort. In eight NTRK fusion ctDNA‐positive patients, larotrectinib induced objective response in 75% of patients and median progression‐free survival was 16.3 months. Blood samples collected from a patient with disease progression after larotrectinib treatment revealed NTRK3 G623R as the potential resistance mechanism. Our study revealed previously unreported NTRK fusion partners, associations of NTRK fusion with MSI and TMB, and the potential utility of ctDNA to screen candidates for TRK inhibitors and monitor drug resistance.
ISSN:0020-7136
1097-0215