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

Abstract

<div>AbstractPurpose:<p>Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous tumors. Despite recent large-scale genomic studies, current LMS risk stratification is not informed by molecular alterations. We propose a clinically applicable genomic risk stratification model.</p>Experimental Design:<p>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 1-year follow-up.</p>Results:<p>In STLMS, French Federation of Cancer Centers (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 <i>RB1</i> mutation and chr12q deletion (del12q)/<i>ATRX</i> mutation; intermediate risk: presence of <i>RB1</i> mutation, <i>ATRX</i> mutation, or del12q; low risk: lack of any of these three alterations. The ability of <i>RB1</i> and <i>ATRX</i> 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 <i>TP53</i> mutation and chr20q amplification/<i>ATRX</i> mutations; intermediate risk: presence of <i>TP53</i> mutation, <i>ATRX</i> 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.</p>Conclusions:<p>Compared with traditional clinicopathologic models, genomic risk stratification demonstrates superior prediction of clinical outcome in STLMS and is comparable in ULMS.</p></div>