Abstract 1075: Piloting NTRK fusion-specific oncogenicity guidelines - lessons learned

Abstract Gene fusions involving neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, & NTRK3) are well-established oncogenic drivers and serve as critical diagnostic and therapeutic markers in cancer. Interpreting their clinical significance is a high priority given FDA approval of TRK inhibitors; however, this remains challenging due to the rapid pace of fusion discovery, the diversity of fusion partners and tumor types, inconsistent and incomplete reporting of fusion data elements, and the lack of standardized fusion-specific classification guidelines. The Clinical Genome Resource (ClinGen) NTRK Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) is addressing these challenges and creating a publicly available resource of high-quality clinically significant NTRK fusion classifications in the Clinical Interpretation of Variants in Cancer (CIViC; civicdb.org) knowledgebase to support patient care. Our NTRK fusion-specific oncogenicity guidelines (approved April 2022) classify NTRK fusions as Oncogenic, Likely Oncogenic, Fusion of Unknown Significance (FUS), or Benign based on four categories: Fusion Gene Structure (orientation/breakpoints/reading frame), Cancer Association (number of unique cases), Clinical Validity (response to targeted inhibitors), and Functional Status (pathway activation or expression). Piloting our guidelines on a range of common to rare NTRK fusions found in cancers resulted in 12 Oncogenic Assertions (6 Oncogenic, 1 Likely Oncogenic, 2 FUS, 3 Benign), 5 Diagnostic Assertions covering 3 cancers, and 10 Predictive Assertions supporting sensitivity to FDA approved TRK inhibitors, larotrectinib or entrectinib. This pilot introduced several modifications to our oncogenicity guidance including: 1) reducing case numbers required to reach cancer association or clinical validity due to the rarity of reported NTRK-positive tumors; 2) further clarifying NTRK fusion structure, e.g., both gene partners must contribute to the fusion protein sequence; 3) requiring fusions to be reported in the published literature as databases may lack vetting; 4) expanding our NTRK-associated tumor list as more tumors are screened for the presence of NTRK fusions; 5) strengthening Benign support by requiring the confirmed lack of both RNA and protein fusion expression. This process was a valuable step in enhancing the consistency and clarity of the ClinGen NTRK SC-VCEP fusion-specific oncogenicity guidelines to aid their widespread adoption. Future efforts will focus on the Oncogenic classification of the over 80 known NTRK fusions found in cancers and their distribution to the public through the CIViC knowledgebase. Citation Format: Jason Saliba, Shivani Golem, Arpad Danos, Laura B. Corson, Elan Hahn, Morteza Seifi, Emma G. Sullivan, Jan Clement A. Santiago, Valentina Nardi, Theodore W. Laetsch, Marilyn M. Li, Obi L. Griffith, Malachi Griffith, Gordana Raca, Larissa V. Furtado, Alanna J. Church, Angshumoy Roy. Piloting NTRK fusion-specific oncogenicity guidelines - lessons learned [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1075.