NTRK fusion-positive cancer is a tumor-agnostic molecular diagnosis defined by chromosomal rearrangements involving NTRK1, NTRK2, or NTRK3 genes encoding neurotrophic tyrosine receptor kinases (TRK). These fusions create constitutively active chimeric proteins that drive oncogenesis across diverse tumor types. NTRK fusions occur at varying frequencies: very common in secretory breast carcinoma and infantile fibrosarcoma (>90%), but rare (<1%) in common solid tumors. The development of TRK inhibitors larotrectinib and entrectinib represents a paradigm shift in oncology, providing highly effective tumor-agnostic targeted therapy based solely on the presence of NTRK fusions regardless of tumor histology or site of origin.
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name: NTRK Fusion-Positive Cancer
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-04-22T20:53:03Z'
description: >-
NTRK fusion-positive cancer is a tumor-agnostic molecular diagnosis defined by
chromosomal rearrangements involving NTRK1, NTRK2, or NTRK3 genes encoding neurotrophic
tyrosine receptor kinases (TRK). These fusions create constitutively active chimeric
proteins that drive oncogenesis across diverse tumor types. NTRK fusions occur at
varying frequencies: very common in secretory breast carcinoma and infantile fibrosarcoma
(>90%), but rare (<1%) in common solid tumors. The development of TRK inhibitors
larotrectinib and entrectinib represents a paradigm shift in oncology, providing
highly effective tumor-agnostic targeted therapy based solely on the presence of
NTRK fusions regardless of tumor histology or site of origin.
categories:
- Molecularly-Defined Cancer
- Tumor-Agnostic Indication
parents:
- neoplasm
has_subtypes:
- name: NTRK1 Fusion-Positive Cancer
description: >-
Fusions involving NTRK1 (encoding TRKA) are common in papillary thyroid cancer,
lung adenocarcinoma, and colorectal cancer. Common fusion partners include TPM3,
TPR, and LMNA.
- name: NTRK2 Fusion-Positive Cancer
description: >-
Fusions involving NTRK2 (encoding TRKB) are less common than NTRK1 or NTRK3
fusions. Found in various tumor types including gliomas.
- name: NTRK3 Fusion-Positive Cancer
description: >-
Fusions involving NTRK3 (encoding TRKC) are characteristic of secretory breast
carcinoma and infantile fibrosarcoma. ETV6-NTRK3 is the classic fusion in these
tumors.
pathophysiology:
- name: NTRK Gene Fusion and Constitutive TRK Activation
description: >-
Chromosomal rearrangements fuse the kinase domain of NTRK genes with various
upstream partners that provide dimerization domains. This creates constitutively
active chimeric TRK proteins that signal independently of neurotrophin ligands.
evidence:
- reference: PMID:39988443
reference_title: "[A Case Report of Lung Adenocarcinoma with EGFR G719A Mutation and LMNA-NTRK1 Fusion]."
supports: PARTIAL
snippet: "Fusion variations of neurotrophic receptor tyrosine kinase (NTRK) are oncogenic drivers in various solid tumors such as breast cancer, salivary gland carcinoma, infant fibrosarcoma, etc."
explanation: "Supports NTRK fusions as oncogenic drivers across solid tumors."
biological_processes:
- preferred_term: protein tyrosine kinase activity
modifier: INCREASED
term:
id: GO:0006468
label: protein phosphorylation
downstream:
- target: RAS-MAPK Pathway Activation
description: TRK activation drives RAS-RAF-MEK-ERK signaling
- target: PI3K-AKT Pathway Activation
description: TRK activation stimulates PI3K-AKT-mTOR survival signaling
- target: PLCgamma Pathway Activation
description: TRK activation engages phospholipase C gamma signaling
- name: RAS-MAPK Pathway Activation
description: >-
Constitutive TRK activation drives the RAS-RAF-MEK-ERK signaling cascade,
promoting uncontrolled cell proliferation. This is a major effector pathway
of TRK-mediated oncogenesis.
biological_processes:
- preferred_term: MAPK cascade
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
- name: PI3K-AKT Pathway Activation
description: >-
TRK activation recruits PI3K and stimulates AKT-mTOR signaling, promoting
cell survival and resistance to apoptosis. Combined with MAPK activation,
this drives aggressive tumor growth.
biological_processes:
- preferred_term: phosphatidylinositol 3-kinase signaling
modifier: INCREASED
term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
histopathology:
- name: Histology-Agnostic Solid Tumors
finding_term:
preferred_term: Malignant Solid Neoplasm
term:
id: NCIT:C132146
label: Malignant Solid Neoplasm
frequency: COMMON
description: NTRK gene fusions are found across cancer types.
evidence:
- reference: PMID:36914665
reference_title: "Systematic review of NTRK 1/2/3 fusion prevalence pan-cancer and across solid tumours."
supports: SUPPORT
snippet: "NTRK gene fusions are rare somatic mutations found across cancer types with"
explanation: Abstract notes NTRK fusions occur across cancer types.
phenotypes:
- category: General
name: Tumor Growth
frequency: VERY_FREQUENT
description: >-
Clinical presentation depends on tumor type and location. NTRK fusions
can occur in virtually any solid tumor type.
phenotype_term:
preferred_term: Neoplasm
term:
id: HP:0002664
label: Neoplasm
- category: Constitutional
name: Fatigue
frequency: FREQUENT
description: >-
Constitutional symptoms are common in advanced disease regardless of
tumor histology.
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
biochemical:
- name: NTRK Fusion Detection
notes: >-
Multiple testing methods detect NTRK fusions including RNA-based NGS (preferred),
DNA-based NGS, FISH, and immunohistochemistry for pan-TRK expression. RNA-based
testing captures the full spectrum of fusion partners.
genetic:
- name: NTRK1
association: Somatic Gene Fusions
notes: >-
NTRK1 encodes TRKA receptor. Common fusion partners include TPM3, TPR, LMNA,
and SQSTM1. Fusions are found in papillary thyroid cancer, NSCLC, colorectal
cancer, and other tumor types.
evidence:
- reference: PMID:33258061
reference_title: "[Diagnosis and therapy of tumors with NTRK gene fusion]."
supports: PARTIAL
snippet: "NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities."
explanation: "Abstract notes NTRK gene fusions occur across tumor entities, supporting NTRK1 fusion involvement."
- name: NTRK2
association: Somatic Gene Fusions
notes: >-
NTRK2 encodes TRKB receptor. Less commonly involved in oncogenic fusions
than NTRK1 or NTRK3. Found in various tumor types including gliomas.
evidence:
- reference: PMID:33258061
reference_title: "[Diagnosis and therapy of tumors with NTRK gene fusion]."
supports: PARTIAL
snippet: "NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities."
explanation: "Abstract notes NTRK gene fusions occur across tumor entities, supporting NTRK2 fusion involvement."
- name: NTRK3
association: Somatic Gene Fusions
notes: >-
NTRK3 encodes TRKC receptor. ETV6-NTRK3 fusion is characteristic of secretory
breast carcinoma (>90%) and infantile fibrosarcoma (>90%). Also found in other
pediatric and adult tumors.
evidence:
- reference: PMID:33258061
reference_title: "[Diagnosis and therapy of tumors with NTRK gene fusion]."
supports: PARTIAL
snippet: "NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities."
explanation: "Abstract notes NTRK gene fusions occur across tumor entities, supporting NTRK3 fusion involvement."
treatments:
- name: Larotrectinib
description: >-
Highly selective TRK inhibitor approved for adult and pediatric solid tumors
with NTRK gene fusions. Demonstrates remarkable efficacy across tumor types
with overall response rate of approximately 75% and durable responses. First
tumor-agnostic TRK inhibitor approval.
evidence:
- reference: PMID:33258061
reference_title: "[Diagnosis and therapy of tumors with NTRK gene fusion]."
supports: SUPPORT
snippet: "If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity."
explanation: "Abstract states larotrectinib can be used when NTRK fusions are detected."
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: larotrectinib
term:
id: NCIT:C115977
label: Larotrectinib
- name: Entrectinib
description: >-
TRK inhibitor with additional activity against ROS1 and ALK. Approved for
NTRK fusion-positive solid tumors in adults and children. Penetrates CNS,
providing activity against brain metastases.
evidence:
- reference: PMID:33258061
reference_title: "[Diagnosis and therapy of tumors with NTRK gene fusion]."
supports: SUPPORT
snippet: "If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity."
explanation: "Abstract states entrectinib can be used when NTRK fusions are detected."
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: entrectinib
term:
id: CHEBI:195558
label: entrectinib
- name: Repotrectinib
description: >-
Next-generation TRK inhibitor designed to overcome resistance mutations
including solvent front mutations (G595R, G623R). Option for patients who
progress on first-generation TRK inhibitors.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: repotrectinib
term:
id: CHEBI:229220
label: repotrectinib
disease_term:
preferred_term: NTRK fusion positive cancer
term:
id: MONDO:0700215
label: NTRK fusion positive cancer
classifications:
icdo_morphology:
classification_value: Carcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: DOI:10.1002/cam4.7351
title: Prevalence of neurotrophic tropomyosin receptor kinase (<scp>NTRK</scp>) fusion gene positivity in patients with solid tumors in Japan
found_in:
- NTRK_Fusion_Positive_Cancer-deep-research-falcon.md
findings:
- statement: Members of the neurotrophic tropomyosin receptor kinase (NTRK) gene family, NTRK1, NTRK2, and NTRK3 encode TRK receptor tyrosine kinases.
supporting_text: Members of the neurotrophic tropomyosin receptor kinase (NTRK) gene family, NTRK1, NTRK2, and NTRK3 encode TRK receptor tyrosine kinases.
evidence:
- reference: DOI:10.1002/cam4.7351
reference_title: Prevalence of neurotrophic tropomyosin receptor kinase (<scp>NTRK</scp>) fusion gene positivity in patients with solid tumors in Japan
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Members of the neurotrophic tropomyosin receptor kinase (NTRK) gene family, NTRK1, NTRK2, and NTRK3 encode TRK receptor tyrosine kinases.
explanation: Deep research cited this publication as relevant literature for NTRK Fusion Positive Cancer.
- reference: DOI:10.1038/s41591-025-04079-7
title: 'Repotrectinib in NTRK fusion–positive advanced solid tumors: a phase 1/2 trial'
found_in:
- NTRK_Fusion_Positive_Cancer-deep-research-falcon.md
findings:
- statement: Early-generation TRK tyrosine kinase inhibitors (TKIs) approved for treating NTRK fusion–positive ( NTRK + ) solid tumors provide clinical benefit; however, resistance emerges.
supporting_text: Early-generation TRK tyrosine kinase inhibitors (TKIs) approved for treating NTRK fusion–positive ( NTRK + ) solid tumors provide clinical benefit; however, resistance emerges.
evidence:
- reference: DOI:10.1038/s41591-025-04079-7
reference_title: 'Repotrectinib in NTRK fusion–positive advanced solid tumors: a phase 1/2 trial'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Early-generation TRK tyrosine kinase inhibitors (TKIs) approved for treating NTRK fusion–positive ( NTRK + ) solid tumors provide clinical benefit; however, resistance emerges.
explanation: Deep research cited this publication as relevant literature for NTRK Fusion Positive Cancer.
- reference: DOI:10.1080/14740338.2023.2274426
title: Safety of current treatment options for NTRK fusion-positive cancers
found_in:
- NTRK_Fusion_Positive_Cancer-deep-research-falcon.md
findings:
- statement: Safety of current treatment options for NTRK fusion-positive cancers
supporting_text: Safety of current treatment options for NTRK fusion-positive cancers
- reference: DOI:10.1093/jjco/hyaf015
title: 'Current management of neurotrophic receptor tyrosine kinase fusion-positive sarcoma: an updated review'
found_in:
- NTRK_Fusion_Positive_Cancer-deep-research-falcon.md
findings:
- statement: In recent years, pembrolizumab has demonstrated significant efficacy in treating tumors characterized by a high tumor mutational burden and high microsatellite instability.
supporting_text: In recent years, pembrolizumab has demonstrated significant efficacy in treating tumors characterized by a high tumor mutational burden and high microsatellite instability.
evidence:
- reference: DOI:10.1093/jjco/hyaf015
reference_title: 'Current management of neurotrophic receptor tyrosine kinase fusion-positive sarcoma: an updated review'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In recent years, pembrolizumab has demonstrated significant efficacy in treating tumors characterized by a high tumor mutational burden and high microsatellite instability.
explanation: Deep research cited this publication as relevant literature for NTRK Fusion Positive Cancer.
- reference: DOI:10.1093/oncolo/oyad075
title: A Two-Step Diagnostic Approach for <i>NTRK</i> Gene Fusion Detection in Biliary Tract and Pancreatic Adenocarcinomas
found_in:
- NTRK_Fusion_Positive_Cancer-deep-research-falcon.md
findings:
- statement: It is of interest to determine the incidence and molecular characteristics of NTRK gene fusions in patients with bilio-pancreatic cancers, because of possible treatment with TRK inhibitors for advanced tumors.
supporting_text: It is of interest to determine the incidence and molecular characteristics of NTRK gene fusions in patients with bilio-pancreatic cancers, because of possible treatment with TRK inhibitors for advanced tumors.
evidence:
- reference: DOI:10.1093/oncolo/oyad075
reference_title: A Two-Step Diagnostic Approach for <i>NTRK</i> Gene Fusion Detection in Biliary Tract and Pancreatic Adenocarcinomas
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: It is of interest to determine the incidence and molecular characteristics of NTRK gene fusions in patients with bilio-pancreatic cancers, because of possible treatment with TRK inhibitors for advanced tumors.
explanation: Deep research cited this publication as relevant literature for NTRK Fusion Positive Cancer.
- reference: DOI:10.1200/po.24.00321
title: '<i>NTRK</i> Fusion–Positive Thyroid Carcinoma: From Diagnosis to Targeted Therapy'
found_in:
- NTRK_Fusion_Positive_Cancer-deep-research-falcon.md
findings:
- statement: Neurotrophic tropomyosin receptor kinase ( NTRK ) fusions may act as an oncogenic driver in thyroid carcinomas.
supporting_text: Neurotrophic tropomyosin receptor kinase ( NTRK ) fusions may act as an oncogenic driver in thyroid carcinomas.
evidence:
- reference: DOI:10.1200/po.24.00321
reference_title: '<i>NTRK</i> Fusion–Positive Thyroid Carcinoma: From Diagnosis to Targeted Therapy'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Neurotrophic tropomyosin receptor kinase ( NTRK ) fusions may act as an oncogenic driver in thyroid carcinomas.
explanation: Deep research cited this publication as relevant literature for NTRK Fusion Positive Cancer.
- reference: DOI:10.1210/jendso/bvae158
title: Single-Institution Experience of Larotrectinib Therapy for Patients With <i>NTRK</i> Fusion-Positive Thyroid Carcinoma
found_in:
- NTRK_Fusion_Positive_Cancer-deep-research-falcon.md
findings:
- statement: Context The real world efficacy and tolerability of NTRK inhibitor larotrectinib has not yet been reported in the literature although trial data has shown promising results.
supporting_text: Context The real world efficacy and tolerability of NTRK inhibitor larotrectinib has not yet been reported in the literature although trial data has shown promising results.
evidence:
- reference: DOI:10.1210/jendso/bvae158
reference_title: Single-Institution Experience of Larotrectinib Therapy for Patients With <i>NTRK</i> Fusion-Positive Thyroid Carcinoma
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Context The real world efficacy and tolerability of NTRK inhibitor larotrectinib has not yet been reported in the literature although trial data has shown promising results.
explanation: Deep research cited this publication as relevant literature for NTRK Fusion Positive Cancer.
- reference: DOI:10.21037/pcm-23-19
title: 'NTRK1/2/3: biology, detection and therapy'
found_in:
- NTRK_Fusion_Positive_Cancer-deep-research-falcon.md
findings:
- statement: 'NTRK1/2/3: biology, detection and therapy'
supporting_text: 'NTRK1/2/3: biology, detection and therapy'
- reference: DOI:10.3233/cbm-220357
title: 'Pan-TRK immunohistochemistry as screening tool for NTRK fusions: A diagnostic workflow for the identification of positive patients in clinical practice'
found_in:
- NTRK_Fusion_Positive_Cancer-deep-research-falcon.md
findings:
- statement: 'Pan-TRK immunohistochemistry as screening tool for NTRK fusions: A diagnostic workflow for the identification of positive patients in clinical practice'
supporting_text: Pan-TRK inhibitors Entrectinib and Larotrectinib have been recently approved as tumor-agnostic therapies in NTRK1-2-3 rearranged patients and there is therefore an urgent need to identify reliable and accessible biomarkers for capturing NTRK fusions in the real-world practice.
evidence:
- reference: DOI:10.3233/cbm-220357
reference_title: 'Pan-TRK immunohistochemistry as screening tool for NTRK fusions: A diagnostic workflow for the identification of positive patients in clinical practice'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Pan-TRK inhibitors Entrectinib and Larotrectinib have been recently approved as tumor-agnostic therapies in NTRK1-2-3 rearranged patients and there is therefore an urgent need to identify reliable and accessible biomarkers for capturing NTRK fusions in the real-world practice.
explanation: Deep research cited this publication as relevant literature for NTRK Fusion Positive Cancer.
- reference: DOI:10.3390/ijms25042366
title: NTRK Therapy among Different Types of Cancers, Review and Future Perspectives
found_in:
- NTRK_Fusion_Positive_Cancer-deep-research-falcon.md
findings:
- statement: Neurotrophic tyrosine receptor kinase (NTRK) has been a remarkable therapeutic target for treating different malignancies, playing an essential role in oncogenic signaling pathways.
supporting_text: Neurotrophic tyrosine receptor kinase (NTRK) has been a remarkable therapeutic target for treating different malignancies, playing an essential role in oncogenic signaling pathways.
evidence:
- reference: DOI:10.3390/ijms25042366
reference_title: NTRK Therapy among Different Types of Cancers, Review and Future Perspectives
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Neurotrophic tyrosine receptor kinase (NTRK) has been a remarkable therapeutic target for treating different malignancies, playing an essential role in oncogenic signaling pathways.
explanation: Deep research cited this publication as relevant literature for NTRK Fusion Positive Cancer.
NTRK fusion-positive cancer refers to solid tumors (adult or pediatric) that harbor oncogenic gene fusions involving NTRK1, NTRK2, or NTRK3, which encode the TRK receptor tyrosine kinases TRKA/TRKB/TRKC, respectively. These fusions create constitutively active TRK signaling and predict sensitivity to TRK inhibitors in a tumor-agnostic manner. (bungaro2024ntrk123biologydetection pages 5-6, vingiani2023pantrkimmunohistochemistryas pages 1-3)
Synonyms / alternative names (commonly used): - “TRK fusion cancer” (yang2023safetyofcurrent pages 4-6) - “NTRK-rearranged tumors” / “NTRK fusion–positive solid tumors” (nakata2024prevalenceofneurotrophic pages 2-4, besse2026repotrectinibinntrk pages 1-2)
Most information is derived from aggregated disease-level resources (pan-cancer cohorts, multi-site clinicogenomic datasets, pooled trial analyses) rather than individual EHR-only sources. (nakata2024prevalenceofneurotrophic pages 2-4, bungaro2024ntrk123biologydetection pages 2-4)
Primary causal factor: somatic gene fusions involving NTRK1/2/3, produced by intra- or inter-chromosomal rearrangements, that encode oncogenic fusion proteins. Nakata et al. describe that “Intra‐ or inter‐chromosomal gene rearrangements produce NTRK gene fusions encoding fusion proteins which are oncogenic drivers in various solid tumors.” (Cancer Medicine; 2024-06; https://doi.org/10.1002/cam4.7351) (nakata2024prevalenceofneurotrophic pages 1-2)
Because NTRK fusion-positive cancer is a genomic alteration rather than a specific histology, “risk factors” are best framed as tumor-type and age-group enrichment patterns rather than traditional exposures: - Strong enrichment in some rare/pediatric histologies (e.g., infantile fibrosarcoma, secretory breast carcinoma, congenital mesoblastic nephroma), versus very low prevalence in unselected adult solid tumors. (bungaro2024ntrk123biologydetection pages 2-4) - Pediatric patients show consistently higher NTRK fusion prevalence than adults in large datasets (see Epidemiology). (nakata2024prevalenceofneurotrophic pages 2-4, kubota2025currentmanagementof pages 1-2)
No protective factors or gene–environment interaction evidence was identified in the retrieved sources.
Clinical features are largely those of the underlying tumor histology and site, rather than a single shared syndrome. However, two cross-cutting clinical patterns emerge: 1) Age enrichment: pediatric cancers show higher NTRK fusion prevalence than adults. (nakata2024prevalenceofneurotrophic pages 2-4, kubota2025currentmanagementof pages 1-2) 2) Testing context: in large clinicogenomic cohorts, testing tends to occur in advanced/metastatic disease; in the Japanese C-CAT cohort, most profiled patients had metastatic disease at the time of comprehensive genomic profiling (CGP). (nakata2024prevalenceofneurotrophic pages 2-4)
Thyroid carcinoma (NTRK1/NTRK3 fusions): NTRK fusion-positive thyroid cancers include papillary thyroid carcinoma (PTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC). (marczyk2025ntrkfusion–positivethyroid pages 1-2)
Sarcoma: NTRK fusions are present in soft tissue sarcomas (STS), with pediatric enrichment and variable histologic distribution by age. (kubota2025currentmanagementof pages 2-2, nakata2024prevalenceofneurotrophic pages 2-4)
Because phenotypes are histology-driven, ontology annotation should generally be layered: - Primary disease layer (histology/site): e.g., “papillary thyroid carcinoma”, “soft tissue sarcoma”, “salivary gland carcinoma” (not all codes retrievable here). - Molecular feature layer: “NTRK gene fusion” (molecular abnormality).
Example HPO (symptom/sign) terms (tumor-generic, for downstream curation): - Neoplasm (HP:0002664) - Metastatic neoplasm (HP:0030800)
Example UBERON (anatomy) terms: - Thyroid gland (UBERON:0002046) (thyroid cases) (marczyk2025ntrkfusion–positivethyroid pages 1-2) - Salivary gland (UBERON:0001830) (head & neck enrichment) (nakata2024prevalenceofneurotrophic pages 2-4)
(These ontology suggestions are provided as standard mappings; specific ontology IDs were not provided in the retrieved primary sources.)
NTRK fusions typically involve a 5’ fusion partner joined to the 3’ region of NTRK containing the kinase domain, leading to kinase activation; Vingiani et al. describe fusions as “3’ regions of NTRK genes… fused with 5’ fusion partners.” (Cancer Biomarkers; 2023-11; https://doi.org/10.3233/cbm-220357) (vingiani2023pantrkimmunohistochemistryas pages 1-3)
Examples of recurrent fusions in large cohorts include: - ETV6::NTRK3 (prominent in head & neck cancers in the Japanese cohort). (nakata2024prevalenceofneurotrophic pages 4-7, nakata2024prevalenceofneurotrophic pages 1-2) - LMNA::NTRK1 (noted among STS in Japan). (nakata2024prevalenceofneurotrophic pages 1-2) - TPM3::NTRK1 (seen as a rare IHC-negative/NGS-positive case in NSCLC in Vingiani). (vingiani2023pantrkimmunohistochemistryas pages 1-3)
The retrieved evidence frames NTRK fusions as tumor genomic drivers detected by tumor profiling; germline NTRK fusion predisposition was not described in the retrieved sources. (nakata2024prevalenceofneurotrophic pages 2-4, bungaro2024ntrk123biologydetection pages 2-4)
Under selective pressure from TRK inhibitors, tumors can acquire on-target kinase domain mutations, including: - Solvent-front mutations: examples NTRK1 G595R and NTRK3 G623R, observed as emergent resistance in aggressive thyroid cancers treated with larotrectinib. (marczyk2025ntrkfusion–positivethyroid pages 1-2) - Resistance “via solvent-front, gatekeeper, and xDFG mutations” is described in a 2023 safety-focused review of TRK inhibitors. (yang2023safetyofcurrent pages 4-6)
No specific environmental toxins, lifestyle factors, or infectious etiologies were identified in the retrieved sources for NTRK fusion-positive cancers as a class.
1) Chromosomal rearrangement generates an NTRK fusion gene. (nakata2024prevalenceofneurotrophic pages 1-2) 2) The fusion encodes an oncogenic TRK fusion protein, functioning as an activating driver alteration. (nakata2024prevalenceofneurotrophic pages 1-2) 3) Targeted therapy with TRK inhibitors can induce tumor regression, but prolonged therapy can select for on-target resistance mutations (solvent-front, gatekeeper, xDFG). (yang2023safetyofcurrent pages 4-6, marczyk2025ntrkfusion–positivethyroid pages 1-2)
(These are suggested scaffolds; explicit GO/CL IDs were not provided in the retrieved sources.)
NTRK fusions occur across many anatomic sites; in the Japanese national clinicogenomic cohort (C-CAT), NTRK fusions were observed across 21 tumor types. (nakata2024prevalenceofneurotrophic pages 2-4)
Commonly represented sites in that cohort (adult): head and neck (including salivary), soft tissue, thyroid. (nakata2024prevalenceofneurotrophic pages 4-7, nakata2024prevalenceofneurotrophic pages 2-4)
NTRK fusions are found in both pediatric and adult cancers, with higher prevalence in pediatric populations. (nakata2024prevalenceofneurotrophic pages 2-4, kubota2025currentmanagementof pages 1-2)
Testing is commonly performed in advanced disease. In the C-CAT cohort, most NTRK fusion-positive patients were profiled in the metastatic setting. (nakata2024prevalenceofneurotrophic pages 2-4)
Large series consistently show that NTRK fusions are rare overall, but have strong tumor-type and age-group enrichment.
| Study (first author, year) | Cohort/source | Country | N (denominator) | Overall prevalence of NTRK fusions | Tumor-type-specific prevalences (with denominators) | Adult vs pediatric prevalence | Notes |
|---|---|---|---|---|---|---|---|
| Nakata, 2024 | C-CAT clinicogenomic cohort of solid tumors profiled by CGP | Japan | 46,621 patients | 91/46,621 = 0.20% (nakata2024prevalenceofneurotrophic pages 2-4, nakata2024prevalenceofneurotrophic pages 1-2) | Head & neck: 22/1,678 = 1.31%; thyroid: 7/534 = 1.31%; soft tissue sarcoma: 19/2,077 = 0.91%; lung cancers: 0.08%; bowel cancers MSI-stable: 3/6,661 = 0.05%; bowel cancers MSI-high: 2/742 = 0.27%; rare types included testis cancer 1/84 and peripheral nervous system cancer 1/78 (nakata2024prevalenceofneurotrophic pages 4-7, nakata2024prevalenceofneurotrophic pages 7-9, nakata2024prevalenceofneurotrophic pages 2-4, nakata2024prevalenceofneurotrophic pages 1-2) | Adults: 74/45,613 = 0.16%; pediatrics: 17/1,008 = 1.69% (nakata2024prevalenceofneurotrophic pages 7-9, nakata2024prevalenceofneurotrophic pages 2-4, nakata2024prevalenceofneurotrophic pages 1-2) | Fusions found across 21 tumor types and 38 partner genes; NTRK1 47/97 (49.5%), NTRK3 42/97 (44.2%), NTRK2 6/97 (6.3%); ETV6::NTRK3 dominated head/neck cancers (22 cases); in STS, recurrent fusions included ETV6::NTRK3 (n=7) and LMNA::NTRK1 (n=5) (nakata2024prevalenceofneurotrophic pages 4-7, nakata2024prevalenceofneurotrophic pages 1-2) |
| Bungaro, 2024 | Review summarizing large pan-cancer sequencing series (Solomon et al., Rosen et al., Westphalen et al.; cited in review) | Multinational / pan-cancer | 33,997; 26,312; 295,676 patients across cited series | 0.26% (33,997-case series); ~0.28% (26,312-case series); 0.30% (295,676-case real-world series) (bungaro2024ntrk123biologydetection pages 2-4, kubota2025currentmanagementof pages 1-2) | Rare enriched tumors: infantile/congenital fibrosarcoma 90.56%; secretory breast carcinoma 92.87%; congenital mesoblastic nephroma 21.52%; common tumors: NSCLC ~0.17%, colorectal adenocarcinoma ~0.26%, cutaneous melanoma ~0.31%, non-secretory breast carcinoma ~0.60% (bungaro2024ntrk123biologydetection pages 2-4) | In the 295,676-patient real-world series cited by the review: adults 0.28% vs children 1.34% (kubota2025currentmanagementof pages 1-2) | Highlights strong enrichment in pediatric/rare histologies versus very low rates in unselected adult solid tumors; ETV6::NTRK3 strongly associated with secretory breast carcinoma (reported in 92% of cases in cited data) (bungaro2024ntrk123biologydetection pages 2-4) |
| Kubota, 2025 | Sarcoma-focused review citing Japanese and meta-analytic datasets | Japan / multinational literature | 46,621-patient Japanese cohort; sarcoma meta-analysis denominators not fully shown in excerpt | In Japanese cohort, 91/46,621 = 0.20% overall NTRK positivity (kubota2025currentmanagementof pages 2-2) | Adult STS: 0.57%; childhood STS: 5.06%; meta-analysis estimates: soft tissue sarcoma 0.69%, bone sarcoma 0.16%; most frequent adult NTRK-positive sarcoma histologies included MPNST 2.97%, fibrosarcoma 2.75%, IMT 2.27%, STS NOS 1.70%, myxofibrosarcoma ~1.31% (kubota2025currentmanagementof pages 2-2) | Adult STS 0.57% vs childhood STS 5.06% in Japanese analysis (kubota2025currentmanagementof pages 2-2) | Pediatric NTRK-positive sarcomas were dominated by fibrosarcoma (~52%), followed by solitary fibrous tumor/hemangiopericytoma (20%), chondrosarcoma (8.3%), undifferentiated STS (5.0%), and MPNST (4.65%); review emphasizes higher prevalence in younger patients (kubota2025currentmanagementof pages 2-2) |
Table: This table compiles key prevalence estimates for NTRK fusion-positive cancers across large pan-cancer cohorts and sarcoma-focused analyses. It highlights the consistently low overall prevalence in adult solid tumors, contrasted with marked enrichment in pediatric and rare histologic subtypes.
Key recent datapoints: - Japan (C-CAT, 2019–2023; published 2024-06): 91/46,621 = 0.20% overall; pediatric 1.69% vs adult 0.16%; highest among large adult tumor categories were head & neck and thyroid (~1.31% each) and STS (~0.91%). (nakata2024prevalenceofneurotrophic pages 2-4, nakata2024prevalenceofneurotrophic pages 1-2) - Pan-cancer sequencing estimates summarized in 2024 review: prevalence ~0.26–0.30% in large unselected cohorts, but >90% in certain rare histologies (infantile fibrosarcoma; secretory breast carcinoma). (bungaro2024ntrk123biologydetection pages 2-4)
Sex ratios and detailed geographic distributions were not reported in the retrieved excerpts.
A common real-world approach is: 1) Screen with pan-TRK immunohistochemistry (IHC), especially in tumor types where NTRK fusions are rare, to enrich candidates. 2) Confirm with nucleic-acid assays—preferably RNA-based NGS; DNA-based NGS may miss fusions due to intronic complexity.
Bungaro & Garbo note that DNA-based NGS can miss NTRK fusions “due to large intronic regions,” motivating panels “capable of detecting all NTRK rearrangements.” (Precision Cancer Medicine; 2024-09; https://doi.org/10.21037/pcm-23-19) (bungaro2024ntrk123biologydetection pages 5-6)
Vingiani et al. (2023) evaluated VENTANA pan-TRK IHC vs an RNA fusion panel in 117 evaluable cases and found: - sensitivity 91.7%, specificity 81.9%, NPV 98.8%, PPV 36.7%. (vingiani2023pantrkimmunohistochemistryas pages 1-3, vingiani2023pantrkimmunohistochemistryas media 404d7635) - among 30 IHC-positive cases, only 11 (37%) were NGS-confirmed, emphasizing the need for confirmatory testing. (vingiani2023pantrkimmunohistochemistryas pages 1-3)
| Modality | Typical role | Strengths | Limitations / pitfalls | Key performance metrics / notes |
|---|---|---|---|---|
| pan-TRK IHC | Screening (especially low-prevalence tumors); reflex to molecular confirmation | Widely available, relatively fast and inexpensive; high negative predictive value makes it useful to enrich cases for downstream testing; aligns with ESMO-style two-step workflows in low-prevalence settings | False positives from physiologic/non-specific TRK expression; performance is tumor-type dependent; lower specificity in breast and salivary carcinomas; in sarcomas both sensitivity and specificity can be poor; some false negatives occur, including occasional NTRK1-rearranged NSCLC | In Vingiani 2023, sensitivity 91.7%, specificity 81.9%, NPV 98.8%, PPV 36.7%; among 30 IHC-positive cases, only 11 (37%) were NGS-confirmed; 1 of 87 IHC-negative cases (1.1%) was NGS-positive for TPM3::NTRK1 (vingiani2023pantrkimmunohistochemistryas pages 1-3, vingiani2023pantrkimmunohistochemistryas media 404d7635, bungaro2024ntrk123biologydetection pages 5-6) |
| RNA-NGS | Confirmatory / preferred comprehensive fusion detection | Preferred assay for expressed fusion transcripts; can detect diverse/novel fusion partners; strong sensitivity and specificity after IHC enrichment; directly confirms transcribed fusions | More expensive and slower than IHC; requires adequate RNA quality from FFPE, which can be challenging | In MSI-high mCRC after IHC enrichment, sensitivity 90% and specificity 100%; guideline-preferred confirmatory approach in many settings (vingiani2023pantrkimmunohistochemistryas pages 1-3, demols2023atwostepdiagnostic pages 6-6) |
| DNA-NGS | Confirmatory / broad genomic profiling, often paired with RNA | Enables simultaneous assessment of multiple biomarkers and broad tumor profiling; useful when integrated into comprehensive genomic profiling workflows; FDA-approved companion diagnostics exist for some platforms | May miss actionable NTRK fusions because large intronic regions and complex breakpoints are hard to cover; less reliable than RNA alone for some rearrangements, so RNA add-on is often needed | Bungaro 2024 notes DNA-based NGS can miss fusions due to large intronic regions; panels capable of detecting all NTRK rearrangements and/or RNA confirmation are advised (bungaro2024ntrk123biologydetection pages 5-6) |
| FISH | Confirmatory in selected contexts; useful when a specific recurrent fusion is strongly suspected or for discordant cases | Can be effective for highly recurrent canonical rearrangements (for example, tumor types enriched for specific fusions); useful orthogonal method when IHC/NGS disagree | Limited breadth for novel partners; lower sensitivity/robustness in some tumor types; not recommended as a universal stand-alone method; labor-intensive and may require multiple probes | In MSI-high mCRC, sensitivity 78%, specificity 100%, robustness 70%; Schraa 2023 concluded FISH was not recommended for routine NTRK fusion detection in mCRC because of limited sensitivity and robustness (demols2023atwostepdiagnostic pages 6-6) |
| RT-PCR / qRT-PCR (including 5'/3' imbalance assays) | Confirmatory in restricted settings with known recurrent fusions; niche use after screening | Fast and potentially highly sensitive when the target fusion/rearrangement pattern is known; practical for tumors with stereotyped fusions | Limited to known fusions or known imbalance patterns; poor fit for pan-cancer discovery because many NTRK fusion partners are diverse/novel | Bungaro 2024 states RT-PCR is mainly suitable for tumors with high prevalence of a specific known fusion (e.g., ETV6::NTRK3 in secretory tumors); in MSI-high mCRC, qRT-PCR sensitivity 100% and specificity 100%, but robustness was 70% (bungaro2024ntrk123biologydetection pages 5-6, demols2023atwostepdiagnostic pages 6-6) |
Table: This table compares the main laboratory approaches used to detect NTRK fusions, summarizing their clinical role, advantages, and known pitfalls. It is useful for selecting testing strategies and understanding why screening with pan-TRK IHC is often paired with confirmatory RNA-based sequencing.
Visual evidence (diagnostic performance): tables containing the IHC vs NGS correlation and derived sensitivity/specificity/NPV/PPV were extracted from Vingiani et al. (2023). (vingiani2023pantrkimmunohistochemistryas media 404d7635)
False-positive pan-TRK staining can occur due to physiologic/non-specific expression; in some tumor classes, IHC sensitivity/specificity are poor, particularly in sarcomas. (bungaro2024ntrk123biologydetection pages 5-6)
In a single-institution thyroid cancer cohort (n=8; published 2024-08), larotrectinib was associated with a median PFS of 24.7 months and median OS of 43.8 months. (Journal of the Endocrine Society; 2024-08; https://doi.org/10.1210/jendso/bvae158) (elghawy2024singleinstitutionexperienceof pages 1-2)
Because NTRK fusion-positive cancer spans many histologies, prognosis is highly tumor-type and stage dependent; broad, tumor-agnostic OS benchmarks were not extractable from the retrieved excerpts.
Two first-generation TRK inhibitors are widely used as tissue-agnostic therapies: - Larotrectinib (highly selective TRK inhibitor) - Entrectinib (TRK/ROS1/ALK inhibitor with CNS penetration)
A 2023 safety review summarized pooled larotrectinib outcomes and reported: ORR 69% (95% CI 63–75) and median DOR 32.9 months (95% CI 27.3–41.7). (Expert Opinion on Drug Safety; 2023-10; https://doi.org/10.1080/14740338.2023.2274426) (yang2023safetyofcurrent pages 4-6)
Entrectinib integrated adult outcomes summarized in the same review include ORR 61% and median DOR 13.8 months (with intracranial ORR 63.6% noted). (yang2023safetyofcurrent pages 4-6)
| Agent | Approval / tissue-agnostic indication | Key trial(s) / setting | N | ORR (95% CI) | CR / PR | Median DOR | Median PFS | OS notes | Intracranial activity | Common adverse events | Citation |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Larotrectinib | FDA tissue-agnostic approval in 2018 for adult and pediatric patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion and no satisfactory alternative treatments; EMA tissue-agnostic approval also noted in reviews | Pooled phase I/II studies: LOXO-TRK-14001, SCOUT, NAVIGATE; additional single-institution thyroid cohort | 244 pooled; thyroid cohort n=8 | 69% (63–75) in pooled analysis; earlier pooled estimates 75% (61–85) and 79% reported in reviews; thyroid cohort responses 87.5% overall (1 CR, 6 PR, 1 SD) | Pooled: 26% CR, 43% PR; thyroid cohort: 12% CR, 75% PR | 32.9 months (27.3–41.7); review also cites ~34 months in pooled dataset | Thyroid cohort: 24.7 months (11.3–38.1); earlier thyroid pooled analysis cited 44.0 months | Pooled mOS not reached at 39.8 months in thyroid-focused review; thyroid cohort mOS 43.8 months (29.8–56.8) | CNS cohort ORR 30%; 24-week disease control rate 73% | Generally grade 1–2; anemia, neutrophil decrease, transaminase elevation, weight gain; dizziness and fatigue also reported; grade 3–4 AEs uncommon, ~2% discontinued for toxicity in one review | (yang2023safetyofcurrent pages 4-6, theik2024ntrktherapyamong pages 4-6, elghawy2024singleinstitutionexperienceof pages 1-2, vingiani2023pantrkimmunohistochemistryas pages 1-3) |
| Entrectinib | FDA tissue-agnostic approval in 2019/2020 for NTRK fusion-positive solid tumors; EMA approval also noted | Integrated adult analyses from STARTRK-1, STARTRK-2, ALKA-372-001; thyroid subgroup discussed in reviews | 54 adults in integrated analysis | 57% (43.2–70.8) in one review; 61% in another integrated adult summary; 63.5% reported in diagnostic review summary | 7% CR, 50% PR in one review; 7% CR noted in integrated analysis | 13.8 months in integrated summary; 12.9 months in review summary | Not consistently reported in available excerpts | Thyroid-focused review notes approval and activity; detailed OS not reported in available excerpts | Intracranial ORR 63.6% in one review; BBB penetration emphasized | Dizziness, cognitive changes, weight gain; broader pharmacovigilance signals include nervous system disorders, cardiac disorders, metabolism/nutrition disorders | (yang2023safetyofcurrent pages 4-6, theik2024ntrktherapyamong pages 4-6, vingiani2023pantrkimmunohistochemistryas pages 1-3) |
| Repotrectinib | FDA-approved next-generation ROS1/TRK inhibitor; 2024 review describes tissue-agnostic use in NTRK fusion-positive cancers, with later phase 1/2 trial providing fuller efficacy dataset | TRIDENT-1 phase 1/2 in advanced NTRK fusion-positive solid tumors; includes TKI-naive and TRK TKI-pretreated cohorts | 51 TKI-naive; 69 TKI-pretreated; safety population 565 | TKI-naive: 59% (44–72); TKI-pretreated: 48% (36–60); solvent-front mutation subgroup: 53% (34–72) | Not fully reported in available excerpts | TKI-naive: not estimable; TKI-pretreated: 9.8 months (7.4–13.0) | TKI-naive: 30.3 months (9.0–NE); TKI-pretreated: 7.4 months (3.9–9.7) | Mature OS not summarized in available excerpts | Intracranial responses in 2/3 TKI-naive and 4/6 TKI-pretreated patients with measurable brain disease; no intracranial progression reported in some NSCLC subsets | Dizziness most common (57% treatment-related; 63% overall), dysgeusia, anemia, paresthesia, dyspnea, fatigue; mostly low-grade; 4% treatment-related discontinuation | (besse2026repotrectinibinntrk pages 1-2, besse2026repotrectinibinntrk pages 5-7, bungaro2024ntrk123biologydetection pages 8-9, theik2024ntrktherapyamong pages 4-6) |
| Selitrectinib (LOXO-195/BAY2731954) | Investigational / expanded-access next-generation TRK inhibitor designed to overcome acquired on-target resistance; not described as broadly approved in available excerpts | Phase I/expanded-access studies; case-based and small-series use after resistance to first-generation TRK inhibitors; thyroid resistance cases | Phase I trial enrollment 81 in registry context; efficacy details limited in provided evidence; thyroid rescue cases n=3 | Numeric pooled ORR not available in provided excerpts | Thyroid resistance series: 3/3 partial responses after emergent solvent-front mutations | Not available in provided excerpts | Not available in provided excerpts | In thyroid ATC/PDTC resistance cases, responses occurred but ATC progressed within a year | No pooled intracranial dataset available in provided excerpts | Safety not quantified in provided excerpts; review states second-generation TRK inhibitors generally manageable | (marczyk2025ntrkfusion–positivethyroid pages 1-2, yang2023safetyofcurrent pages 4-6, theik2024ntrktherapyamong pages 4-6) |
Table: This table summarizes currently available efficacy, safety, and regulatory information for first- and next-generation TRK inhibitors used in NTRK fusion-positive cancers. It is useful for comparing approved therapies with emerging resistance-directed agents across pooled trials and thyroid-specific real-world data.
Acquired on-target mutations—especially solvent-front mutations—are recurrent resistance mechanisms: - NTRK3 G623R and NTRK1 G595R were observed after larotrectinib in PDTC/ATC and were associated with progression. (marczyk2025ntrkfusion–positivethyroid pages 1-2)
(MAXO term IDs were not available in the retrieved sources.)
No established primary prevention exists for NTRK fusion formation in cancers as a class (not addressed in retrieved sources).
The principal prevention-like strategy is secondary prevention through systematic molecular testing, enabling earlier deployment of effective targeted therapy. International practice patterns support screening (often IHC) and confirmatory sequencing workflows, particularly in low-prevalence tumors. (vingiani2023pantrkimmunohistochemistryas pages 1-3, bungaro2024ntrk123biologydetection pages 5-6)
No veterinary or cross-species naturally occurring NTRK fusion-positive cancer evidence was identified in the retrieved sources.
No specific animal model organisms or engineered in vivo models were described in the retrieved excerpts. This is a gap in the currently retrieved evidence set; additional targeted searches in model-organism databases (MGI/IMPC) and translational NTRK fusion modeling literature would be required.
1) National-scale prevalence estimates with pediatric enrichment: Nakata et al. (2024-06) quantified low overall prevalence (0.20%) but substantially higher pediatric prevalence (1.69%) in a national clinicogenomic cohort. (nakata2024prevalenceofneurotrophic pages 2-4, nakata2024prevalenceofneurotrophic pages 1-2) 2) Operational diagnostic workflows and performance metrics: Vingiani et al. (2023-11) provided real-world screening performance for pan-TRK IHC with high NPV but low PPV, reinforcing reflex NGS confirmation. (vingiani2023pantrkimmunohistochemistryas pages 1-3, vingiani2023pantrkimmunohistochemistryas media 404d7635) 3) Growing emphasis on resistance-aware sequencing and next-generation inhibitors: 2023–2024 expert reviews emphasize acquired resistance mechanisms (solvent-front/gatekeeper/xDFG) and newer agents designed to overcome them. (yang2023safetyofcurrent pages 4-6, bungaro2024ntrk123biologydetection pages 5-6)
Several of the retrieved sources are indexed by DOI and journal metadata, but PMIDs were not available in the retrieved excerpts for most of the key 2023–2024 papers. Where PMIDs are required for knowledge-base ingestion, an additional PubMed-specific retrieval step would be needed.
References
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