TP53 Mutation as a Prognostic and Predictive Marker in Sarcoma: Pooled Analysis of MOSCATO and ProfiLER Precision Medicine Trials

Abstract

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