3.3. Outcome and prognostic factors
The median follow-up of patients was 5.2 years in COG study and 5.4 years in EpSSG. At the time of the analysis, 45 patients in the COG cohort had relapsed, of whom, 38 died (37 by disease progression and 1 by an unrelated disease). Seventy-eight patients in the EpSSG cohort had relapsed, 69 of whom died (66 by disease progression, 2 by toxic deaths and 1 by a second neoplasm). Outcomes of patients (EFS and OS) included in the study are detailed in Table 3 . The 5-year EFS of the COG cohort was 44% (95% CI: 30.0-58.1) compared with 49% (95% CI 38.8-59.3) of the EpSSG. The 5-year OS was 53.6% in COG (95% CI 39.6-67.7) and 51% in EpSSG (95% CI 40.9-60.9) (Figure 1 ). There were no differences in EFS or OS between the analytic cohort of RMS2005 and ARST0531. These results held when EFS (p=0.2) and OS (p=0.28) were compared while adjusting for tumor size, nodal status and IRS Group (I/II vs III). In the combined analysis of both cohorts, outcomes by FOXO1 fusion status showed 5-year EFS of 63% for patients with fusion-negative tumors (95% CI 44.6-81.0)vs 47.6% for fusion-positive (95% CI 37.2-58.1). The 5-year OS for patients with fusion-negative tumors was 69% (95% CI 51.7-86.3) compared with 52.7% (95% CI 42.6-62.9), for fusion-positive.
However, results from each cohort showed striking differences on the impact of the presence of FOXO1 fusion on prognosis. In EpSSG, the 5-year EFS of patients with FOXO1 fusion-positive tumors (49.3%, 95% CI 35.8-62.8) was significantly inferior to those withFOXO1 fusion-negative ones (73%, 95% CI 53.0-92.8) (p=0.034). In contrast, COG patients showed no differences between these two groups: The EFS of COG patients with FOXO1 fusion-positive tumors was 45.1% (95% CI 28.8-61.5) compared with 43.8% (95% CI 6.6-80.9%) of FOXO1 fusion-negative (Figure 2 ).
Five-year OS of patients with FOXO1 fusion-positive tumors in the EpSSG cohort was 51.6%, compared with 76% of FOXO1fusion-negative and approached significance (p=0.069). In contrast, there were no differences in the outcomes between COG patients with fusion-positive or fusion-negative tumors (53.7% and 56.2%, respectively) (Figure 3 ).
The pooled COG and EpSSG 5-year EFS and OS did not show statistically significant differences by location of primary tumor.
The site of the first relapse was also similar in both cohorts (Supplementary Table S4 ). Metastatic relapses with or without local recurrence represented half of the relapses in both protocols. Loco-regional relapses represented 35% and 29% of all recurrences in COG and EpSSG cohorts, respectively. Tumor progression during treatment occurred in 13% of the patients in COG and 18% in EpSSG.