Association of NAB2–STAT6 distal fusion with risk level of metastatic disease and thoracic primary site.

11519 Background: Solitary fibrous tumors (SFTs) are defined by the NAB2–STAT6 gene fusion, but the clinical significance of these breakpoints remains incompletely understood. Although fusion breakpoint heterogeneity has been implicated in influencing biologic behavior, there are few studies linking variant location to outcomes. Recent genome analyses suggest that proximity based breakpoint clustering approaches can reveal driver loci, suggesting investigation of NAB2–STAT6 fusion breakpoints may be potential prognostic markers. Because individual variants are rare, we used a proximal vs distal breakpoint analysis to evaluate high-risk clinical features. In this study, we evaluated trends between the NAB2–STAT6 breakpoint and metastases, primary tumor location, and recurrence in a single-institution, retrospective cohort study. Methods: We performed an analysis of patients with SFTs treated at the Sylvester Comprehensive Cancer Center (n=48). Samples without pathology-confirmed NAB2–STAT6 fusions were excluded. Clinical variables included primary tumor site, size, stage, and recurrence. Molecular data was extracted from next-generation whole transcriptome and exome sequencing reports. Breakpoints were categorized by exon numbers. NAB2 breakpoints were considered proximal if they occurred before exon 6 and distal if they occurred at exon 6 or more distally. STAT6 breakpoints were considered proximal if they occurred at exon 6 or earlier and distal if they occurred at exon 16 or more distally. Associations were analyzed using Fisher exact tests. Results: Breakpoint patterns were significantly associated with metastatic presentation at diagnosis. Metastatic disease at the time of diagnosis was not observed in any patients with proximal STAT6 breakpoints (n= 29) but was present in 24% (n = 17) of those with distal STAT6 breakpoints (p=0.02). Additionally, metastatic disease occurred exclusively in tumors with distal NAB2 breakpoints (n=14, p=0.01). Breakpoint patterns were also associated with primary tumor sites. The majority of proximal STAT6 fusions were present mostly in thoracic cavity tumors (55%), while distal STAT6 fusions occurred mainly in tumors at non-thoracic sites (p=0.02). Among fusion subtypes, metastatic presentation was absent in ex4: ex2 tumors but observed in 31% of tumors with ex6: ex16/17 tumors (p=0.02). Distal STAT6 breakpoints also showed trends toward higher recurrence rates and grades as well as larger tumor sizes. Conclusions: Our study shows that NAB2–STAT6 distal fusion breakpoint patterns are associated with metastatic disease at diagnosis, non-thoracic primary tumor locations and more aggressive clinical features. These findings support the consideration of breakpoint patterns as part of molecular risk stratification and identifies a potential biomarker for SFT patients with a primary tumor who may benefit from chemotherapy.