Module 3
Rearrangements involving the neurotrophic-tropomyosin receptor kinase (NTRK) gene family (NTRK1, NTRK2, and NTRK3) are well-known drivers in a wide diversity of human cancers. NTRK gene fusions occur at low frequency (<5%) in common cancers such as colorectal, lung and breast carcinoma, head and neck squamous cell carcinoma, and melanoma [1,2,3]. Overall, they have been estimated to occur in up to 1% of all solid tumours (frequency of 0.31% in adult tumours and 0.34% of paediatric tumours) [3]. NTRK gene fusions have also been identified at lower frequencies across various other paediatric cancers, including undifferentiated sarcomas, gliomas, papillary thyroid cancers, spitzoid neoplasms, inflammatory myofibroblastic tumours, and acute leukaemia [4]. See also Module 1.
NTRK gene fusions occur however at high frequency (>90%) in certain rare tumours such as mammary analogue secretory carcinoma, secretory breast carcinoma, infantile fibrosarcoma, and cellular congenital mesoblastic nephroma, where they are considered molecular genetic hallmarks of those entities. For example, ETV6-NTRK3 fusions and NTRK1 gene rearrangements appear to define the vast majority of infantile fibrosarcoma and lipofibromatosis-like neural tumours, respectively [3,4].
NTRK fusions can be detected with immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), reverse transcriptase–polymerase chain reaction, or next-generation sequencing (NGS). To further enrich for NTRK fusions, both histology-based and genomic-based triaging approaches are used. See also Module 2.
This module (Module 3) focuses on specific tumour types including, lung, gastrointestinal (GI) and thyroid tumours and sarcomas, where NTRK gene fusions are relatively prevalent, and more awareness is warranted regarding the use of NTRK targeting agents.
Note: in each tumour-specific section information on brain metastasis and paediatric tumour types is also indicated, where available.
Case studies describing key aspects of the diagnostic procedure and treatment approach for patients with NTRK gene fusions can be found in Module 2.
References
- Chiang S, Cotzia P, Hyman DM et al. NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma. Am J Surg Pathol. 2018;42(6):791-798.
- Hechtman JF. NTRK insights: best practices for pathologists. Mod Pathol. 2022; 35(3):298-305.
- Okamura R, Boichard A, Kato S et al. Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis Oncol. 2018; 2018:PO.18.00183.
- Albert CM, Davis JL, Federman N et al. TRK fusion cancers in children: a clinical review and recommendations for screening. J Clin Oncol. 2019;37(6):513-524.
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Targeting NTRK Gene Fusions