P-212 Wild-type gastrointestinal stromal tumors with NTRK gene fusions

The NTRK gene fusion can define a special subgroup of wild-type GIST and its clinical manifestations and treatment may be significantly different from other GIST. Therefore, it is of great clinical significance to explore the prevalence of NTRK fusion in wild-type GIST, analyze the clinicopathological characteristics of NTRK fusion GIST and standardize the testing algorithm. In this study, we retrospectively collected the primary KIT/PDGFRA wild-type GIST who underwent surgical resection in our center from 2011 to 2018 and did not receive other therapy before operation. By Pan-TRK IHC staining and FISH break-apart probe, the incidence of NTRK fusion in wild-type was preliminarily obtained and the efficacy of Pan-TRK IHC in screening NTRK fusion was analyzed. By comparing different detection methods, a testing algorithm for NTRK fusion in wild-type GIST was proposed. Furthermore, an extensive literature search was conducted in PubMed, Web of Science and Embase. A NTRK fusion GIST cohort was integrated and the clinicopathological features of this subgroup were analyzed. Finally, a total of 50 patients with wild-type GIST were enrolled, including 27 males (54%) and 23 females (46%) with mean age±SD: 49.9±14.4. There were 34 cases of gastric GIST (68%) and 16 cases of small intestinal GIST (32%). Pan-TRK IHC staining was positive in 23 cases and highly expressed in 21 cases, which were significantly higher than those in the non-wild type GIST cohort (P < 0.0005). Three cases of NTRK fusion GIST with strong Pan-TRK expression were detected by FISH in the wild-type GIST cohort (3/50) and all were NTRK3 fusion. Two NTRK3 fusions displayed nuclear staining. A total of 12 GISTs with NTRK fusion were retrieved (from 6 literatures) and 3 cases in this study were integrated to obtain a cohort of 15 cases. In this cohort, there were 10 males and 5 females with mean age±SD: 50±12. The most common primary site was colorectum (5/15), especially rectum (4/15), followed by small intestine and stomach (4/15 and 4/15, respectively). According to modified NIH, there were 11 patients at high risk. Finally, five patients progressed or relapsed and four patients died. NTRK3 fusion was the most common alteration (11/15), followed by NTRK1 fusion (4/15). NTRK2 fusion has not been found in GIST. FISH and NGS had a good consistency for detecting NTRK fusion, while Pan-TRK staining had a lower efficacy (sensitivity and specificity were 45.5% and 67.9%, respectively). The incidence of NTRK fusion in GIST is extremely low (＜1%), but an increased incidence has been reported in wild-type GIST (6% in this study and 5% to 25% in other studies), which established the necessity of detecting NTRK fusion in wild-type GIST. NGS or FISH may be preferred to Pan-TRK IHC to diagnose NTRK fusion GIST. Compared with classic GIST, NTRK fusion GIST showed significant difference in clinicopathological features: more common in men, younger at diagnosis, more common in colorectum and higher recurrence risk, which may indicate a higher malignant tendency. However, there conclusions warrant further investigation in larger cohort.