MON-491 TRK-Fusion Thyroid Cancer: A Clinical Overview in a Large Population at a Single Cancer Center
Authors: Fazeli Sasan , Dadu Ramona , Waguespack Steven G , Sherman Steven I , Busaidy Naifa Lamki , Hu Mimi I , Jimenez Camilo , Habra Mouhammed A , Williams Michelle , Altameemi Lina , Poropatich Kate , Routbort Mark J , Luthra Raja , Patel Keyur P , Cabanillas Maria 
Published: May 2020

Abstract
Introduction: Most thyroid cancers (TC) are due to mutually exclusive somatic driver mutations. NTRK fusions are rare oncogenic drivers in papillary TC (PTC), poorly differentiated TC (PDTC) and anaplastic TC (ATC), estimated to be in 2.3% of all TC. However, the clinical presentation and behavior of TRK-fusion TC remains largely unknown. Methods / Case Presentation: Using institutional databases, we identified all TC patients (pts) with an NTRK fusion reported on somatic testing performed by a CLIA-certified laboratory. Data from the medical records were collected. The objective of this study was to investigate the clinical and pathological features of TC pts whose tumors harbored an NTRK fusion. Results / Discussion: We identified 36 TC pts with somatic NTRK fusions. Fusion testing was generally done in pts with advanced or radioactive iodine refractory (RAI-R) disease. Median age at diagnosis was 27.4 years (range 4–75 years), 21 (58%) were female and 16 (44%) were pediatric. 28/36 (78%) pts had PTC, 2/36 (5%) PDTC and 6/36 (17%) ATC. There were a total of 12 (33%) NTRK1, 24 (67%) NTRK3, and no NTRK2 fusions. In ATC and PDTC pts NTRK3 was the most common NTRK fusion 7/8 (87%). In PTC pts, 11 (39%) had NTRK1 and 17 (61%) had NTRK3. In the adult pts NTRK3 was more common 17/20 (85%) (Odds Ratio 7.2, P=0.013), however, in pediatric pts rate of NTRK1 and NTRK3 were similar. One pt had additional mutations along with the NTRK fusion, an ATC pt with multiple mutations including BRAF V600E. Of the 30 PTC/PDTC pts, 23 (77%) had distant metastases (mets). 14 (38%) pts had distant mets at diagnosis and 11 (69%) pediatric pts had distant mets. Lung 21 (70%) and bone 9 (30%) were the most common distant mets sites. In the PTC pts with distant mets, 9 (41%) had RAI-avid and 11 (50%) had RAI-R disease. In the entire cohort of 36 pts, 17 (53%) were on a systemic therapy of whom 11 pts were PTC. NTRK directed was the most common systemic therapy 16 (94%). All PTC pts were alive with a median time from diagnosis of 46 months (Interquartile 1–3: 25–118 months). Four ATC and one PDTC pts had died at the time of the analysis. Conclusions: In this study we confirmed that NTRK fusions occur primarily in PTC but also in less differentiated tumors. Most were young pts but NTRK fusions were identified in tumors from adults as old as 75 years. NTRK1 and NTRK3 were the most common NTRK fusions with NTRK3 being more common in adults. In thyrocyte-derived TC pts, NTRK fusions are mutually exclusive genetic events that occur in pts of all ages and varying histologies. Given the availability of NTRK targeted therapy, consideration should be given to testing for NTRK fusions in advanced thyroid cancer pts, especially those in whom prior genetic testing did not identify an oncogenic driver.