Impact Of Ews-Fli1 Fusion Type On Disease Progression In Ewing'S Sarcoma: Prospective Results From The Cooperative Euro-Ewing99 Trial

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO The EWS-FLI 1 fusion gene (EF) is the driving force in Ewing´s sarcoma pathogenesis. Due to variable breakpoint locations in the involved genes, there is heterogeneity in fusion RNA and protein architecture. The two most frequent rearrangements lead to fusions of EWS exon 7 to FLI1 exon 6 (EF 1) or 5 (EF 2) on the RNA level. Other fusion types include additional EWS and FLI1 exons (EFX). In about 10% of cases, FLI1 is replaced by ERG , and rarely by other members of the ETS transcription factor family. Since previous retrospective studies suggested a prognostic benefit for patients with EF1 localized disease, the impact of EF architecture on disease progression and relapse was studied prospectively within the EE99 clinical trial. Of 1843 patients registered by the German/Austrian/Dutch, the British, and the French study groups before 01/01/2007, tumors of 703 patients were accessible to the molecular biology study which was performed by 6 reference labs. Fusion type was assessed by PCR on frozen (82%) or paraffin embedded materials (18%).The main end-point was the time to disease progression or relapse. After exclusion of fusion negative patients (70), 2 patients with EWS-ETV1 fusion, patients with a follow-up shorter than 1 year, and of toxic deaths in the first year without disease progression, 567 patients were entered into the prognostic factor study. Median observation time was 4.5y. Clinical and tumor characteristics of the assessed study cohort were not different from the whole EE99 trial population except for an over-representation of patients with localized disease (71% vs. 66%) and a higher proportion of French patients in the cohort (56% vs. 32%). EF1 and EF2 were found in 53% and 23% of cases, EFX fusions in 16% and ERG fusions in 8% of tumors. No significant differences between fusion type distributions were observed comparing patients of different sexes, age groups, tumor volume or site, disease extension, histological response or risk group. With respect to risk of progression or relapse, we did not observe any increased risk with EF2 or ERG fusions compared to EF1; the only difference observed was a slight increase associated with EFX fusions compared to other fusion types, by 1.42 fold (95%CI, 0.99-2.03, p=.06) independently of disease extension and treatment. When comparing this group to all others, the risk of death was increased 1.59 fold (95%CI, 1.07-2.4, p=.03). Thus, in contrast to retrospective studies, the prospective evaluation did not confirm a prognostic benefit of EF1 but identified a slightly increased risk for patients with EFX fusions. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5680.