A study of the gaps and opportunities with fusion detection beyond NTRKs on 422 patients from the community.
Authors: Husain Hatim , Duong Chaugiang , Rivera Steven , Montgomery Nathan , Puentes Roisin , Lyle Derek , Lopez-Diaz Fernando J. 
Published: June 2024

e15186

Background: Gene fusions have important implications for therapeutic selection and patient quality of care and many fusions are targeted effectively in a tumor type agnostic manner. While most assays detect hundreds of fusions at once, typically the results are masked and analyzed according to medical requisition. Unfortunately, patients in the community setting most often are only tested for NTRK fusions, which have a prevalence of ~ 1%, and often following a positive IHC screen result. Here we compared side by side the clinical actionability gap in the community when using panTRK IHC testing and NGS fusion panels for NTRKs or for additional fusions, with both NGS panels selected presenting identical assay performance characteristics and medicare coverage. Methods: Clinical samples (n = 8307) from 33 tumor types were tested for RNA fusions using a hybridization capture RNA-seq based fusionome assay for solid tumors in our clinical laboratory, targeting RNA breakpoints at 1104 genes. Deidentified results were analyzed for either the 19 actionable fusion genes (ALK, BRAF, FGFR1-4, MET, NOTCH1/2, NRG1, NTRK1-3, PDGFB, PDGFRA/B, RAF1, RET and ROS1) reportable under Solid Tumor NGS fusion Panel, or only for NTRK fusions. Pan-TRK IHC results on fusion positive patients were analyzed. All the Deidentified patient data presented, was analyzed according to an IRB-approved protocol. Results: Targeted therapy -associated fusions were present in 422 (5.1%) patients, where 53% of patients were female with a median age of 68 years old, and 47% were male with a median age of 70 years old. However, when filtering only for NTRK fusions, just 104 (1.25%) patients had an actionable fusion (38 NTRK1, 10 NTRK2, 56 NTRK3). The additional 318 (3.8%) patients had other therapy candidate fusions: ALK (0.6%), BRAF 0.3%, FGFRs 0.9%, MET 0.4%, NOTCH2 0.2%, NRG1 0.2%, PDGFRA 0.1%, RAF1 0.2%, RET 0.5%, ROS1 0.2%, excluding NTRK positive cases. There were only 2 (0.02%) cases that were positive for both an NTRK fusion and an additional Targeted Panel fusion gene. Interestingly, we found that IHC testing was able to identify 75% of NTRK1 and 55% NTRK2 positive samples but only 20% of NTRK3 fusion positive patients. Moreover only 54% of the panTRK IHC positive patients expressed and NTRK fusion while 46% expressed one of the other 16 druggable fusions, with FGFRs on 20%, and ALK and ROS1 with 4% each. Conclusions: The data demonstrates that up to 4 -fold more patients can have a fusion matched therapy when testing for these 19 druggable fusions at once as compared to testing only for NTRK fusions or following IHC testing. Moreover, IHC testing as a screening method as very poor sensitivity for NTRK fusions, specially for NTRK3. Changes on the molecular testing paradigm in the community setting is needed to provide more patients with a therapeutic opportunity, when assay performance and financial considerations are equal to increase cancer care access.