ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research.

Abstract

NTRK1, NTRK2 and NTRK3 fusions have been reported in a plethora of malignancies across different histologies and represent the most common mechanism of oncogenic activation of these receptor tyrosine kinases. These fusions result in chimaeric genes, where the 3 region of NTRK is joined with a 5 sequence of a fusion partner, resulting in a constitutively activated TRK with oncogenic properties. NTRK fusions have emerged as new targets for cancer therapy as they can be successfully inhibited by small molecule kinase inhibitors leading to durable responses across disease sites. Given the multitude of partners involved in NTRK1/2/3 fusions, crucial to the administration of NTRK inhibitors is the development of optimal approaches for the detection of human cancers harbouring activating NTRK1/2/3 fusion genes. The main techniques employed for NTRK fusion gene detection include immunohistochemistry, fluorescence in situ hybridization, RT-PCR, and both RNA-based and DNA-based next-generation sequencing. Each technique has advantages and limitations, and the choice of assays for screening and final diagnosis should also take into account the resources and clinical context. The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to review the available methods for the detection of NTRK gene fusions, their potential applications, and strategies for the implementation of a rational approach for the detection of NTRK1/2/3 fusion genes in human malignancies. We present here recommendations for the routine clinical detection of targetable NTRK1/2/3 fusions.