42. Piloting NTRK fusion-specific oncogenicity guidelines: Lessons learned

Gene fusions involving neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, & NTRK3) are well-established oncogenic drivers and important diagnostic and therapeutic markers in cancers. Interpreting their clinical significance is a high priority given FDA approval of TRK inhibitors (e.g, larotrectinib and entrectinib), but remains challenging due to rapid fusion discovery, diversity of fusion partners and tumor types, and lack of fusion-specific classification rules. The ClinGen NTRK Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) is addressing these challenges and creating publicly available high-quality clinically significant NTRK fusion assertions in the CIViC (civicdb.org) knowledgebase to support patient care.

Our NTRK fusion-specific oncogenicity guidelines (approved April 2022) classify NTRK fusions as Oncogenic, Likely Oncogenic, Unknown Significance (VUS), or Benign based on Fusion Structure (orientation/breakpoints/reading frame), Cancer Association (number of unique cases), Clinical Validity (targeted inhibitor response), and Functional Status (pathway activation or expression). Pilot guideline application to a range of common to rare NTRK fusions found in cancers resulted in 11 Oncogenic Assertions (6 Oncogenic, 1 Likely Oncogenic, 4 VUS), 5 Diagnostic Assertions, and 10 Predictive Assertions supporting sensitivity to larotrectinib or entrectinib. This pilot introduced several modifications including: 1) reducing case number required to reach cancer association or clinical validity due to the rarity of reported NTRK-positive tumors; 2) further clarifying NTRK fusion structure; 3) requiring fusions to be reported in the published literature, as databases sometimes lack vetting; 4) expanding the NTRK-associated tumor list. Future efforts will evaluate the clinical utility of these guidelines and improve our workflows and guidance.