Genomic Predictors of Survival Outcomes in Pediatric Sarcomas

Abstract

Increased availability of next generation sequencing has allowed for the genomic characterization of a variety of pediatric tumors, although genetic determinants of response to treatment remain largely unknown. We sought to evaluate the genomic landscape and genomic predictors of survival outcomes in rhabdomyosarcoma (RMS) and Ewing sarcoma (ES). Of 29,067 patients who underwent genomic profiling at our institution using a 468-gene oncopanel with complete records, 164 had either RMS (n=87, of whom 22 were fusion-positive) or ES (n=77) For the analysis, the 10 most common genetic alterations were associated with locoregional control (LC), progression-free survival (PFS), and overall survival (OS) for each individual tumor type. Tumor mutational burden (TMB), defined as the total number of somatic non-synonymous mutations normalized to the number of sequenced megabases, was also associated with disease outcomes. Median age at diagnosis was 15.7 years and 20.6 years for RMS and ES, respectively, and median follow up was 27.1 months. The median number of alterations found on genomic sequencing for RMS and ES were 4 (range, 0-25) and 2 (range, 0-21), respectively. Patients with fusion-positive RMS had less alterations on sequencing than patients with fusion-negative RMS (median 2 versus 5, p=0.007). The most common genetic alterations in RMS included TP53 (17%), NF1 (13%), CDKN2A (11%), NRAS (11%), MYOD1 (10%) MDM2 (9%), BCOR (9%) CDKN2B (9%), CDK4 (8%), and GLI1 (7%). The most common genetic alterations in ES included TP53 (12%), STAG2 (10%), ERG (9%), ERF (6%), CDKN2A (5%), CREBBP (5%), TERT (5%), BCOR (5%), FAT1 (4%), and CCND1 (4%). The 3-year LC, PFS, and OS for RMS were 52.4%, 27.5%, and 56.1%. The 3-year LC, PFS, and OS for ES were 84.7%, 61.6%, and 82.2%. Genetic alterations in TP53 were associated with significantly worse OS in RMS (p=0.03), while genetic alterations in CDKN2A were associated with worse OS in ES (p=0.002). Higher TMB (defined as >3) was significantly associated with worse LC (p=0.05), PFS (p=0.04), and OS (p=0.01) in RMS (with significance retained when separated by fusion status). Higher TMB was also associated with worse LC (p=0.02) and PFS (p=0.009) in ES, with a trend toward worse OS (p=0.16). Higher TMB predicted for worse local control and survival outcomes in both RMS and ES. Our preliminary results must be correlated with other well-known clinicopathologic risk factors with the ultimate goal of guiding risk stratification and treatment decisions.