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Background: Neurotrophic tyrosine receptor kinase ( NTRK ) fusion has been detected in rare types of CNS tumours, which can promote tumorigenesis. The efficacy of Trk inhibitor became a significant therapeutic interest. Our aim was to investigate whether Pan-Trk immunohistochemistry (IHC) is a reliable and efficient marker for detecting NTRK- fusion in different brain tumours. Methods: This study included 23 patients diagnosed with different types of CNS tumours. Testing for Pan-Trk IHC with monoclonal Ab (EPR17341) has been performed on all FFPE tissues. Parallelly, NTRK -rearrangements were tested using both DNA and RNA-based next-generation sequencing (NGS) assay using TruSight Onco500 platform. Results: The cohort included eight pilocytic astrocytomas, one oligodendroglioma, six IDH wildtype glioblastomas, four IDH mutant grade four astrocytomas, and one sample of each (astroblastoma, central neurocytoma, medulloblastoma, and liponeurocytoma). The mean age was 35 years; seven cases were in the paediatric age group, and 16 were adult. Pan-Trk expression was detected in 11 (47.8%) tumours, and 12 (52.1%) tumours showed no Pan-Trk expression. Nine Cases (82%) with different Pan-Trk expressions did not reveal NTRK -rearrangement. The other two positively expressed cases (liponeurocytoma and glioblastoma) were found to have NTRK2 -fusions ( SLC O 5A1-NTRK2, AGBL4-NTRK2, BEND5-NTRK2 ). All the 12 cases (100%) with no Pan-Trk expression have shown no NTRK -fusions. There was no statistically significant association between Pan-Trk expression and NTRK -fusion ( p = 0.217). The detection of NTRK- fusions using NGS had high specificity over NTRK -fusion detection by using Pan-Trk IHC. Conclusion: Pan-Trk IHC is not a suitable tissue-efficient biomarker to screen for NTRK -fusions in CNS tumours, however RNA-based NGS sequencing should be used as an alternative method., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mohamed, Kurdi, Baeesa, Sabbagh, Hakamy, Maghrabi, Alshedokhi, Dallol, Halawa, Najjar and Fdl-Elmula.)

[Display omitted] • Agnostic markers represent the novel frontier of precision medicine. • The first agnostic drugs have been approved regardless of tumor histology. • This model presents a great potential to change the oncological therapeutic scenario. • Despite the clinical opportunity, critical aspects are emerging. • A governance is mandatory to ensure genomic testing homogeneity and sustainability. The personalized medicine is in a rapidly evolving scenario. The identification of actionable mutations is revolutionizing the therapeutic landscape of tumors. The morphological and histological tumor features are enriched by the extensive genomic profiling, and the first tumor-agnostic drugs have been approved regardless of tumor histology, guided by predictive and druggable genetic alterations. This new paradigm of "mutational oncology", presents a great potential to change the oncologic therapeutic scenario, but also some critical aspects need to be underlined. A process governance is mandatory to ensure the genomic testing accuracy and homogeneity, the economic sustainability, and the regulatory issues, ultimately granting the possibility of translating this model in the "real world". In this position paper, based on experts' opinion, the AIOM–SIAPEC-IAP–SIBIOC–SIF Italian Scientific Societies revised the new agnostic biomarkers, the diagnostic technologies available, the current availability of agnostic drugs and their present indication. [ABSTRACT FROM AUTHOR]