Determinants of secondary alterations in WWTR1-CAMTA1 fusion epithelioid hemangioendothelioma.

Abstract

11045 Background: Epithelioid hemangioendothelioma (EHE) is a rare vascular sarcoma characterized by the WWTR1- CAMTA1 fusion ( WC-F) in a majority of cases. EHE demonstrates a biphasic clinical course; remaining indolent for many years before suddenly demonstrating aggressive progression. Cell cycle mutations have been previously noted to account for some secondary alterations; however, little is known regarding the chronicity of these secondary alterations or their clinical implications. Here we present the largest assessment of secondary genomic variants and their clinical import. Methods: Comprehensive genomic profiling from 45 WC-F positive EHE patients (pts) were provided by Foundation Medicine (FMI). 8 of these 45 pts were treated at The Ohio State University (OSU) and were evaluated retrospectively through chart review. Known deleterious alterations, variants of unknown significance (VUS), and genomic copy quantification for the WC-F was included in our analysis. Targetable gene variants were defined by OncoKB. Chi-square and student’s t-tests were used as appropriate. Results: Genomic copy number of the WC-F best fit a log-normal distribution (range: 13-2,131 copies). 20 pts (44%) did not exhibit any secondary genomic variants. The most commonly altered genes included: CDKN2A/B (7 variants), RB1 (3 variants), and ATRX (3 variants). Commonly identified pathways included: cell cycle (9 pts, 20.0%), epigenetic modulators (7 pts, 15.6%), and DNA damage repair (7 pts, 15.6%). Eight pts exhibited targetable gene variants (18%) as defined by OncoKB. Subjects ≥50 years of age exhibited a greater proportion of clinically targetable variants (27.6% vs 0%; p = 0.02). Pts with a secondary genomic variant exhibited elevated WC-F copy numbers (p < 0.001). OSU pts with aggressive EHE were more likely to have a second genomic variant (80% vs 0%; p = 0.03) when compared to indolent EHE, with trends toward higher WC-F copy numbers (809±315 vs 207±147; p = 0.2) and older age at diagnosis (59.5±5.5 vs 36.7±8.8; p = 0.1). Conclusions: In this study, secondary genomic variants in WC-F driven EHE are more common in older patients ( > 50 yo). Further, the presence of secondary genomic variants is associated with an aggressive phenotype and may drive poor prognosis. Prospective research is needed to confirm these findings.