A Systematic Review with a Demonstrative Case of KIT and DOG-1 Expressing Gastrointestinal Stromal Tumors Harboring ETV6-NTRK3 Fusions

Abstract Introduction: Previous reports have described ETV6-NTRK3 fusion-positive gastrointestinal stromal tumors (GISTs) in cases lacking KIT, PDGFRA, RAS-pathway, or SDHx alterations. However, some investigators have questioned the rigor of these reports and the true existence of NTRK rearrangements in GIST. This study aims to: 1) resolve whether NTRK gene rearrangements exist in GIST; 2) review the relevant literature; and 3) demonstrate a case of NTRK fusion GIST. Methods: A comprehensive literature review using PubMed identified additional NTRK fusion-reported cases. Under an IRB-approved protocol, we describe a patient with biopsy-proven GIST who underwent genomic and transcriptomic CLIA-certified testing, precision-matched therapy, surgical resection, and pathological analysis. Results: We identified 17 reported cases of GIST with NTRK fusions. Five studies reported GIST with KIT/DOG-1 expression by IHC, wild-type KIT/PDGFRA, and an ETV6-NTRK3 fusion, consistent with GIST. We demonstrate a case of a 72-year-old female status post resection of a high-risk gastric GIST followed by 45 months of adjuvant imatinib. She developed recurrent disease and biopsy revealed mixed epithelioid and spindleoid GIST with IHC expression of KIT (CD117) and DOG-1. Imatinib was re-initiated, but her disease progressed, prompting molecular testing for the first time. RNA sequencing identified an in-frame fusion of ETV6 with NTRK3. Larotrectinib, a pan-NTRK inhibitor, was initiated for 7 months, resulting in shrinkage in five tumors (range: 4.2–77%). Surgical cytoreduction demonstrated a pathological near complete response (1% viable tumor cells). Conclusion: Our findings confirm the existence of ETV6-NTRK3 fusion GIST and demonstrate that these imatinib-resistant GISTs may be exquisitely sensitive to TRK