(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 TP53 (46 mutations and eight deletions). There were 149 surgically resected localized
sarcomas. Median DFS in TP53 wild type (WT), deleted, and mutated
sarcomas was 16, 10, and 10 months, respectively (p = 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, TP53 mutations remained associated with shorter DFS (p = 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 TP53 WT and mutated
sarcomas, respectively (OR = 2.24; 95%CI = 1.01-5.03; p = 0.05). In multivariate analysis, TP53 mutations remained associated with increased response (OR = 3.24; 95%CI = 1.30-8.45; p = 0.01). (4) Conclusions: TP53 mutations are associated with shorter DFS and increased response to
anthracyclines. Post-validation, these findings could assist in decision-making for peri-operative treatments.