Systematic review of NTRK 1/2/3 fusion prevalence pan-cancer and across solid tumours

O’Haire, Sophie; Franchini, Fanny; Kang, Yoon‐Jung; Steinberg, Julia; Canfell, Karen; Desai, Jayesh; Fox, Stephen B.; IJzerman, Maarten J.

doi:10.1038/s41598-023-31055-3

Cited by 16 publications

(9 citation statements)

References 26 publications

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“…Among the adult non-NSCLC malignancies, our study has confirmed a substantial frequency of NTRK fusions in microsatellite-unstable colorectal carcinomas (12.5%). Overall, our data on the occurrence and spectrum of NTRK translocations are in good agreement with previously published studies [ 34 , 35 , 36 , 37 , 38 ].…”

Section: Discussionsupporting

confidence: 93%

Cost-Efficient Detection of NTRK1/2/3 Gene Fusions: Single-Center Analysis of 8075 Tumor Samples

Romanko,

Mulkidjan,

Tiurin

et al. 2023

IJMS

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The majority of NTRK1, NTRK2, and NTRK3 rearrangements result in increased expression of the kinase portion of the involved gene due to its fusion to an actively transcribed gene partner. Consequently, the analysis of 5′/3′-end expression imbalances is potentially capable of detecting the entire spectrum of NTRK gene fusions. Archival tumor specimens obtained from 8075 patients were subjected to manual dissection of tumor cells, DNA/RNA isolation, and cDNA synthesis. The 5′/3′-end expression imbalances in NTRK genes were analyzed by real-time PCR. Further identification of gene rearrangements was performed by variant-specific PCR for 44 common NTRK fusions, and, whenever necessary, by RNA-based next-generation sequencing (NGS). cDNA of sufficient quality was obtained in 7424/8075 (91.9%) tumors. NTRK rearrangements were detected in 7/6436 (0.1%) lung carcinomas, 11/137 (8.0%) pediatric tumors, and 13/851 (1.5%) adult non-lung malignancies. The highest incidence of NTRK translocations was observed in pediatric sarcomas (7/39, 17.9%). Increased frequency of NTRK fusions was seen in microsatellite-unstable colorectal tumors (6/48, 12.5%), salivary gland carcinomas (5/93, 5.4%), and sarcomas (7/143, 4.9%). None of the 1293 lung carcinomas with driver alterations in EGFR/ALK/ROS1/RET/MET oncogenes had NTRK 5′/3′-end expression imbalances. Variant-specific PCR was performed for 744 tumors with a normal 5′/3′-end expression ratio: there were no rearrangements in 172 EGFR/ALK/ROS1/RET/MET-negative lung cancers and 125 pediatric tumors, while NTRK3 fusions were detected in 2/447 (0.5%) non-lung adult malignancies. In conclusion, this study describes a diagnostic pipeline that can be used as a cost-efficient alternative to conventional methods of NTRK1–3 analysis.

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Section: Discussionsupporting

confidence: 93%

Cost-Efficient Detection of NTRK1/2/3 Gene Fusions: Single-Center Analysis of 8075 Tumor Samples

Romanko,

Mulkidjan,

Tiurin

et al. 2023

IJMS

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“…NTRK fusions are typically present in a mutually exclusive manner with other oncogenic mutations and fusions ( 3 ). In this study, concurrent EGFR sensitising mutations were identified in almost a third of cases with high NTRK expression including one patient with a concurrent EGFR L858R mutation and MET amplification.…”

Section: Discussionmentioning

confidence: 99%

“…Chromosomal rearrangements of these genes cause activation and/or overexpression of TRK receptors resulting in activation of downstream oncogenic pathways, establishing NTRK as a major target for therapy ( 2 ). NTRK gene fusions have been reported across a wide range of solid tumour types as the primary oncogenic driver, however their frequency is low in more common cancers ( 3 ). Larotrectinib, a specific TRK inhibitor, and entrectinib, a multi-kinase TRK inhibitor, have been approved by the US Food and Drug Administration and European Medicines Agency as cancer agnostic drugs for patients with solid tumours harbouring a NTRK fusion.…”

Section: Introductionmentioning

confidence: 99%

Real-world challenges in undertaking NTRK fusion testing in non-small cell lung cancer

Poh¹,

Sammour²,

Mathai³

et al. 2023

J Thorac Dis

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Background We performed a retrospective analysis to determine the incidence of neurotrophic tropomyosin-receptor kinase ( NTRK) fusion in non-small cell lung cancer (NSCLC). Methods Archival NSCLC tissues between 2018–2020 were screened by immunohistochemistry (IHC) with IHC-positive cases undergoing confirmatory molecular analysis. Correlative clinicopathologic parameters were collected. Results Of 289 samples analyzed, 10 (3.5%) cases had NTRK expression on IHC. The median age of patients with NTRK-positivity on IHC was 74.9 (range, 44–88) years and 70% had a smoking history. The cohort included seven adenocarcinomas and one each squamous cell carcinoma, large-cell neuroendocrine and not otherwise specified histologies. PDL1 expression was ≤50% in five cases. Concurrent EGFR mutations were detected in three cases, with two cases also showing a PIK3CA E542K mutation and MET amplification, respectively. Due to insufficient tumor material, RNA-sequencing was undertaken in only one IHC-positive case, with the other nine cases analyzed by Fluorescent in-situ Hybridisation. A NTRK fusion, EML4-NTRK3 gene fusion was detected in one patient, a frequency of 0.35%. Conclusions NTRK fusions in NSCLC are rare. This study highlights real world diagnostic challenges regarding NTRK testing, such as requirements of adequate tumor tissue and appropriate testing methodologies.

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“…However, NTRK1-3 rearrangements are included in the majority of multigene diagnostic panels, so their detection is supported by the rapidly increasing utilization of NGS. While the incidence of NTRK activation in commonly occurring carcinomas affecting adults falls below 1:500-1:1000, NTRK1-3 translocations are detected at frequency of about 5% in pediatric tumors, sarcomas, and salivary gland carcinomas [53,54]. NTRK1-3 fusions are particularly common in microsatellite-unstable RAS/RAF mutation-negative colorectal carcinomas, while non-colorectal tumors with MSI rarely carry gene translocations [37].…”

Section: Ntrk1-3 Rearrangementsmentioning

confidence: 99%

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

Aleksakhina,

Ivantsov,

Imyanitov

2024

IJMS

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Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying ALK and ROS1 translocations, biallelic BRCA1/2 inactivation and/or homologous recombination deficiency (HRD), strong HER2 amplification/overexpression coupled with the absence of other MAPK pathway-activating mutations, etc. On the other hand, some well-known targets are not agnostic: for example, PD-L1 expression is predictive for the efficacy of PD-L1/PD1 inhibitors only in some but not all cancer types. Unfortunately, the individual probability of finding a druggable target in a given tumor is relatively low, even with the use of comprehensive next-generation sequencing (NGS) assays. Nevertheless, the rapidly growing utilization of NGS will significantly increase the number of patients with highly unusual or exceptionally rare tumor-target combinations. Clinical trials may provide only a framework for treatment attitudes, while the decisions for individual patients usually require case-by-case consideration of the probability of deriving benefit from agnostic versus standard therapy, drug availability, associated costs, and other circumstances. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.

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Systematic review of NTRK 1/2/3 fusion prevalence pan-cancer and across solid tumours

Cited by 16 publications

References 26 publications

Cost-Efficient Detection of NTRK1/2/3 Gene Fusions: Single-Center Analysis of 8075 Tumor Samples

Cost-Efficient Detection of NTRK1/2/3 Gene Fusions: Single-Center Analysis of 8075 Tumor Samples

Real-world challenges in undertaking NTRK fusion testing in non-small cell lung cancer

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

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