Mutation As a Prognostic and Predictive Marker in Sarcoma: Pooled Analysis of MOSCATO and ProfiLER Precision Medicine Trials

(1) Background: locally resected high-grade sarcomas relapse in 40% of cases. There is no prognostic or predictive genomic marker for response to peri-operative chemotherapy. (2) Methods: MOSCATO and ProfiLER are pan-tumor prospective precision medicine trials for advanced tumors. Molecular analysis in both trials comprised targeted next-generation sequencing and comparative genomic hybridization array. We investigated if molecular alterations identified in these trials in sarcomas were associated with disease-free survival (DFS) and response to anthracyclines. (3) Results: this analysis included 215 sarcomas, amongst which 53 leiomyosarcomas, 27 rhabdomyosarcomas, 20 undifferentiated pleomorphic sarcomas, and 17 liposarcomas. The most frequently altered gene was (46 mutations and eight deletions). There were 149 surgically resected localized sarcomas. Median DFS in wild type (WT), deleted, and mutated sarcomas was 16, 10, and 10 months, respectively ( = 0.028; deletions: HR = 1.55; 95% CI = 0.75-3.19; mutations: HR = 1.70; 95%CI = 1.13-2.64). In multivariate analysis, mutations remained associated with shorter DFS ( = 0.027; HR = 2.30; 95%CI = 1.10-4.82). There were 161 localized and advanced sarcomas evaluable for response to anthracyclines. Objective response rates were 35% and 55% in WT and mutated sarcomas, respectively (OR = 2.24; 95%CI = 1.01-5.03; = 0.05). In multivariate analysis, mutations remained associated with increased response (OR = 3.24; 95%CI = 1.30-8.45; = 0.01). (4) Conclusions: mutations are associated with shorter DFS and increased response to anthracyclines. Post-validation, these findings could assist in decision-making for peri-operative treatments.