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

SIMPLE SUMMARY: Sarcomas have a high recurrence rate and no validated genomic marker to guide decisions of peri-operative systemic treatments. We pooled two precision oncology trials in order to identify genomic markers prognostic and/or predictive of response to treatment with anthracyclines in sarcoma patients. Molecular analysis consisted of targeted next generation sequencing and comparative genomic hybridization array. TP53 mutations were the most frequent alteration, found in 20% of sarcomas. Disease-free survival of localized sarcomas was shorter in TP53 mutated sarcomas, both in our cohort and in The Cancer Genome Atlas database. Objective response rate to anthracycline-based chemotherapy was increased in TP53 mutated sarcomas, in localized and advanced settings in this pooled analysis. Post-validation, TP53 mutations may serve as a biomarker to assist decision of peri-operative anthracycline prescription. 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 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.