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

PURPOSE: Previous reports have described ETV6-NTRK3 fusion-positive gastrointestinal stromal tumors (GIST) 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 (i) resolve whether NTRK gene rearrangements exist in GIST; (ii) review the relevant literature; and (iii) demonstrate a case of GIST with NTRK fusion. EXPERIMENTAL DESIGN: A comprehensive literature review using PubMed identified additional NTRK fusion-reported cases. Under an institutional review board-approved protocol, we describe a patient with biopsy-proven GIST who underwent genomic and transcriptomic Clinical Laboratory Improvement Amendments-certified testing, precision-matched therapy, surgical resection, and pathologic 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 after 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 reinitiated, 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 at a dose of 100 mg twice daily for 7 months, resulting in shrinkage in five tumors (range, 4.2%-77%). Surgical cytoreduction demonstrated a pathologic near-complete response (1% viable tumor cells). CONCLUSIONS: Our findings confirm the existence of GIST with ETV6-NTRK3 fusion and demonstrate that these imatinib-resistant GIST may be exquisitely sensitive to tropomyosin receptor kinase inhibitors, although radiologic partial response may not be commensurate with pathologic responses.