The landscape of NTRK fusions in Chinese patients with solid tumor

Ling, Qi; Li, B.; Wu, Xinglong; Wang, H.; Shen, Yang; Xiao, Mang; Yang, Zhenjie; Ma, Ruobing; Chen, D.; Chen, H.; Dong, Xiaowei; Wang, W.; Yao, Ming

doi:10.1093/annonc/mdy269.073

Cited by 11 publications

(10 citation statements)

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“…There was significant variability in the frequencies of NTRK gene fusion reported across tumor histology in the included studies, ranging from 0% to 92.87%, in keeping with what has been reported in the literature about the variability of NTRK gene fusion frequency across tumor types. 4,10 A total of 30 tumor histologies had an NTRK frequency of zero taken from single studies. These single-study frequencies are reported without a CI and standard error.…”

Section: Resultsmentioning

confidence: 99%

“…secretory breast carcinoma, secretory salivary gland cancer, also known as mammary analogue secretory carcinoma of the salivary gland, and congenital mesoblastic nephroma) and in some pediatric cancers. 4,10 Primary brain tumors have been noted as an area of interest for studying NTRK gene fusions, given the lack of effective treatment options and the relative frequency of the fusion in some brain tumor subtypes. 11 This variation across multiple histologies means that it is difficult to quantify the patient population for drugs such as larotrectinib, which is approved in the United States (US) and Europe as a tumor-agnostic therapy for advanced cancers with an NTRK gene fusion.…”

Section: Introductionmentioning

confidence: 99%

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A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors

Forsythe¹,

Zhang

Strauss

et al. 2020

Ther Adv Med Oncol

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Introduction: The research objective was to systematically review evidence on neurotrophic tyrosine receptor kinase ( NTRK) gene fusion frequency in solid tumors. Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review (SLR) was conducted of studies published from January 1987 to 2 January 2020. Selected studies were appraised for use in meta-analysis, with frequency reported as a point estimate with confidence intervals, to estimate NTRK gene fusion tumor incidence and prevalence. Results: The SLR identified 222 studies from North America ( n = 122), Europe ( n = 33), Asia ( n = 41), Brazil ( n = 5), Australia ( n = 2), and multi-continental ( n = 19) reporting NTRK gene fusion frequencies across 101 histologies. Studies were prospective ( n = 43) and retrospective ( n = 179). Testing methods involved DNA ( n = 93), RNA ( n = 72), combined DNA/RNA ( n = 48), protein [immunohistochemistry (IHC), n = 5], and unreported ( n = 5). Sample sizes ranged from 1 to 66,871. Of the 222 studies, 107 were suitable for meta-analysis. Highest NTRK gene fusion frequencies were reported in rare cancers: infantile/congenital fibrosarcoma (90.56%, 95% CI 67.42–100.00), secretory breast cancer (92.87%, 95% CI 72.62–100.00), and congenital mesoblastic nephroma (21.52%, 95% CI 13.06–32.20). Lower frequencies were reported in non-small cell lung cancer (0.17%, 95% CI 0.09–0.25), colorectal adenocarcinoma (0.26%, 95% CI 0.15–0.36), cutaneous melanoma (0.31%, 95% CI 0.07–0.55), and non-secretory breast carcinoma (0.60%, 95% CI 0.00–1.50). Reported frequency was ~0% for some cancers: mesothelioma, renal cell carcinoma, prostate cancer, and bone sarcoma. Estimated global overall NTRK gene fusion tumour incidence and 5-year prevalence in 2018 was 0.52 and 1.52 per 100,000 persons, respectively. Conclusion: This research confirms the rarity and varying frequency of NTRK gene fusion across tumor types. Limitations included relatively low historic NTRK gene fusion testing and reporting, limited study samples for some cancers, and suboptimal molecular testing methods. In this rapidly developing area, gold-standard testing methods and companion diagnostics are needed to capture all NTRK gene fusions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors

Forsythe¹,

Zhang

Strauss

et al. 2020

Ther Adv Med Oncol

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“…60,61 However, more recently, LMNA-NTRK1 and EML4-NTRK3 fusions have also been described in infantile fibrosarcoma. 53,72,73 1q21.3 Breast cancer, 2,27 cervical cancer, 22 cholangiocarcinoma, 2 colorectal cancer, 2,19,22,32,45 glioma, 22,46 infantile fibrosarcoma, 2 lung cancer, 20,22,32 soft tissue sarcoma, 2,22,33 thyroid cancer, 33,47…”

Section: Infantile Fibrosarcomamentioning

confidence: 99%

“…64,75,76 A morphologically and immunohistochemically related entity in the salivary gland was described by Skálová et al, 65 and similarly harbors ETV6-NTRK3 fusions in >90% of cases. Indeed, NGS analysis suggested that secretory breast carcinomas are genetically 12p13.2 Acute lymphoblastic leukemia, 54 acute myeloid leukemia, 55 breast cancer, 27,33 colorectal cancer, 33 congenital mesoblastic nephroma, 56e58 gastrointestinal tract stromal tumor, 2,59 glioma, 22,46 infantile fibrosarcoma, 2,60,61 inflammatory myofibroblastic tumor, 62 lung cancer, 2,19,22 more similar to secretory carcinomas of the salivary gland than they are to other primary breast cancers. 75 Recently, it has been reported that a subset of salivary gland carcinomas harbor ETV6-RET gene fusions.…”

Section: Secretory Carcinomasmentioning

confidence: 99%

Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy

Hsiao

Zehir

Sireci

et al. 2019

The Journal of Molecular Diagnostics

187

173

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Chromosomal rearrangements involving the NTRK1, NTRK2, and NTRK3 genes (NTRK genes), which encode the high-affinity nerve growth factor receptor (TRKA), brain-derived neurotrophic factor/ neurotrophin-3 (BDNF/NT-3) growth factor receptor (TRKB), and neurotrophin-3 (NT-3) growth factor receptor (TRKC) tyrosine kinases (TRK proteins), act as oncogenic drivers in a broad range of pediatric and adult tumor types. NTRK gene fusions have been shown to be actionable genomic events that are predictive of response to TRK kinase inhibitors, making their routine detection an evolving clinical priority. In certain exceedingly rare tumor types, NTRK gene fusions may be seen in the overwhelming majority of cases, whereas in a range of common cancers, reported incidences are in the range of 0.1% to 2%. Herein, we review the structure of the three NTRK genes and the nature and incidence of NTRK gene fusions in different solid tumor types, and we summarize the clinical data showing the importance of identifying tumors harboring such genomic events. We also outline the laboratory techniques that can be used to diagnose NTRK gene fusions in clinical samples. Finally, we propose a diagnostic algorithm for solid tumors to facilitate the identification of patients with TRK fusion cancer. This algorithm accounts for the widely varying frequencies by tumor histology and the underlying prevalence of TRK expression in the absence of NTRK gene fusions and is based on a combination of fluorescence in situ hybridization, next-generation sequencing, and immunohistochemistry assays.

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“…In the current study, no NTRK fusions were detected in this cohort, although NTRK fusions have been reported in NSCLC from the Chinese population. 35 We suppose that several potential reasons may help to explain the result. First, NTRK fusion is a relatively rare molecular event in patients with lung adenocarcinomas from the East Asian population.…”

Section: Discussionmentioning

confidence: 98%

Detection of Novel NRG1, EGFR, and MET Fusions in Lung Adenocarcinomas in the Chinese Population

Pan

Zhang

et al. 2019

Journal of Thoracic Oncology

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Introduction: Multiple oncogene fusions beyond ALK receptor tyrosine kinase (ALK), RET, and ROS1 fusion has been described in lung cancer, especially in lung adenocarcinomas without common oncogenic mutations. Molecular inhibitors have been developed and proved effective for patients whose tumors harbor these novel alterations. Methods: A consecutive series of surgically resected lung adenocarcinomas were collected and profiled using an enrichment strategy to detect nine common oncogenic driver mutations and fusions concerning EGFR, KRAS, HER2, BRAF, MET, ALK, RET, ROS1, and FGFR. Driver-negative cases were further analyzed by a comprehensive RNA-based nextgeneration sequencing (NGS) fusion assay for novel fusions. Results: In total, we profiled 1681 lung adenocarcinomas, among which 255 cases were common driver-negative. One hundred seventy-seven cases had sufficient tissue for NGS fusions screening, which identified eight novel fusions. NRG1 fusions occurred in 0.36% of all lung adenocarcinoma cases (6 of 1681 cases), including 4 CD74-NRG1-positive cases, 1 RBPMS-NRG1-positive case, and 1 novel ITGB1-NRG1-positive case. Furthermore, another 2 novel fusions were also detected, including 1 EGFR-SHC1 fusion and 1 CD47-MET fusion, both of which were in-frame and retained the functional domain of the corresponding kinases. No fusion event was detected for NTRK, KRAS, BRAF or HER2 genes in this cohort. Detailed clinicopathologic data showed that invasive mucous adenocarcinoma (three of eight cases) and acinar-predominant adenocarcinoma (three of eight cases) were the most prevalent pathologic subtypes among novel fusions. Conclusions: Fusions affecting NRG1, EGFR, and MET were detected in 0.48% of unselected lung adenocarcinomas, and NRG1 fusions ranked the most prevalent fusions in common driver-negative lung adenocarcinomas from Chinese population. RNA-based NGS fusion assay was an optional method for screening actionable fusions in common driver-negative cases.

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The landscape of NTRK fusions in Chinese patients with solid tumor

Cited by 11 publications

References 0 publications

A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors

A systematic review and meta-analysis of neurotrophic tyrosine receptor kinase gene fusion frequencies in solid tumors

Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy

Detection of Novel NRG1, EGFR, and MET Fusions in Lung Adenocarcinomas in the Chinese Population

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