Applications in NTRK Gene Fusion Testing
NTRK gene fusions are rare but occur in diverse tumour types and cell lineages, posing a considerable challenge for detection, while also creating an opportunity for IHC to be used alongside molecular testing .
IHC can detect TRK protein overexpression as a surrogate for the possible presence of a NTRK gene fusion and may be considered as a screening tool when access to NGS is limited; where possible, molecular testing should be performed in those who test positive by IHC [2-6].
Application of IHC within NTRK gene fusion testing workflows has been reported in the literature. Rudzinski et al. proposed that moderate-to-strong diffuse cytoplasmic pan-TRK IHC staining can be considered diagnostic of NTRK1/NTRK2 gene fusions, while nuclear pan-TRK staining can be considered a diagnostic surrogate of ETV6-NTRK3 gene fusions . In addition, Murphy et al. outlined a two-step diagnostic test to identify NTRK1, NTRK2, NTRK3, ROS1, and ALK rearrangements in tumour specimens, using IHC to screen negative specimens, followed by NGS to analyse putatively positive specimens . IHC can also be used to validate the results of DNA-based targeted NGS screening by confirming that a novel DNA-level NTRK gene structural variant/rearrangement leads to overexpression of TRK, which would be consistent with a fusion [9, 10].
- Chen Y, Chi P. Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers. J Hematol Oncol 2018; 11: 78.
- Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15: 731-747.
- Marchio C, Scaltriti M, Ladanyi M et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol. 2019 Jul 3. pii: mdz204. doi: 10.1093/annonc/mdz204. [Epub ahead of print].
- 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: 513-524.
- Penault-Llorca F, Rudzinski ER, Sepulveda AR. Testing algorithm for identification of patients with TRK fusion cancer. J Clin Pathol 2019.
- Kummar S, Lassen UN. TRK Inhibition: A New Tumor-Agnostic Treatment Strategy. Target Oncol 2018; 13: 545-556.
- Rudzinski ER, Lockwood CM, Stohr BA et al. Pan-Trk Immunohistochemistry Identifies NTRK Rearrangements in Pediatric Mesenchymal Tumors. Am J Surg Pathol 2018; 42: 927-935.
- Murphy DA, Ely HA, Shoemaker R et al. Detecting Gene Rearrangements in Patient Populations Through a 2-Step Diagnostic Test Comprised of Rapid IHC Enrichment Followed by Sensitive Next-Generation Sequencing. Appl Immunohistochem Mol Morphol 2017; 25: 513-523.
- Hechtman JF, Benayed R, Hyman DM et al. Pan-Trk Immunohistochemistry Is an Efficient and Reliable Screen for the Detection of NTRK Fusions. Am J Surg Pathol 2017; 41: 1547-1551.
- Hung YP, Fletcher CDM, Hornick JL. Evaluation of pan-TRK immunohistochemistry in infantile fibrosarcoma, lipofibromatosis-like neural tumour and histological mimics. Histopathology 2018; 73: 634-644.