81. The journey to the first full approval of a ClinGen somatic cancer variant curation expert panel - NTRK fusions

ABSTRACT

Introduction 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. The accurate and consistent interpretation of 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. Methods ClinGen SC-VCEPs follow a rigorous 4-step process to reach approval status. Throughout this process, SC-VCEPs liaise with the ClinGen Oversight and Cancer Variant Interpretation Committees. Following the definition of scope and membership recruitment (Step 1), standardized guidance was created to determine the oncogenicity of NTRK fusions (Step 2). This guidance was piloted on 12 NTRK fusions ranging from rare to common (Step 3). After incorporating modifications to the classification guidelines directly influenced by the pilot, we established protocols for collecting NTRK fusions and their evaluation (Step 4). Results The NTRK SC-VCEP created the first-ever standardized guidance to classify the oncogenicity of NTRK fusions through the systematic compilation, review, and discussion of fundamental fusion element annotations. The NTRK fusion-specific oncogenicity guidelines (approved April 2022) classify NTRK fusions as Oncogenic, Likely Oncogenic, Fusion of Unknown Significance (FUS), 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). For the pilot phase, over 70 evidence items from over 50 publications were entered into CIViC. These curations resulted in the creation of 12 Oncogenic classifications (6 Oncogenic, 1 Likely Oncogenic, 2 FUS, 3 Benign). This pilot prompted essential clarifications in our oncogenicity guidance related to case number and reporting requirements, fusion structure, and strengthening Benign support. We established sustained curation protocols to direct our ongoing coordinated team effort to evaluate the 80 plus NTRK fusions identified from public databases and private member laboratory lists and maintain their up-to-date record in CIViC with broader distribution in ClinVar. Conclusions Completing the ClinGen 4-step approval process assures access, accuracy, and transparency of the variant-level evidence, assessment process, and classifications of the NTRK SC-VCEP. As the first SC-VCEP to navigate this process, the work of the NTRK SC-VCEP provides the blueprint for other SC-VCEPs and, most importantly, aids clinicians in their pursuit of precision medicine.