Developing Novel Genomic Risk Stratification Models in Soft Tissue and Uterine Leiomyosarcoma

Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous tumors. Despite genomic studies, current LMS risk stratification is not informed by molecular alterations. We propose a clinically applicable genomic risk stratification model.We performed comprehensive genomic profiling in a cohort of 195 soft tissue LMS (STLMS), 151 primary at presentation, and a control group of 238 uterine LMS (ULMS), 177 primary at presentation, with at least one-year follow up.In STLMS, FNCLCC grade but not tumor size predicted progression-free survival (PFS) or disease-specific survival (DSS). In contrast, in ULMS, tumor size, mitotic rate and necrosis were associated with inferior PFS and DSS. In STLMS, a 3-tier genomic risk stratification performed well for DSS: high risk - co-occurrence of RB1 mutation and chr12q deletion (del12q)/ATRX mutation; intermediate risk - presence of RB1 mutation, ATRX mutation or del12q; low risk - lack of any of these three alterations. The ability of RB1 and ATRX alterations to stratify STLMS was validated in an external AACR GENIE cohort. In ULMS, a 3-tier genomic risk stratification was significant for both PFS and DSS: high risk - concurrent TP53 mutation and chr20q amplification/ATRX mutations; intermediate risk - presence of TP53 mutation, ATRX mutation or amp20q; low risk - lack of any of these three alterations. Longitudinal sequencing showed that most molecular alterations were early clonal events that persisted during disease progression.Compared to traditional clinicopathologic models, genomic risk stratification demonstrates superior prediction of clinical outcome in STLMS and is comparable in ULMS.