Analysis of TP53 gain of function mutations in metastatic castration-resistant prostate cancer.

246 Background: TP53, an oncogene implicated in the development of many malignancies, is commonly altered in mCRPC. Gain-of-function mutations in TP53 confer increased oncogenic properties of this gene and play a role in mCRPC. The goal of this study was to characterize somatic TP53 mutations, specifically gain-of-function mutations, in the ctDNA of mCRPC patients in the context of prior therapies. Methods: A retrospective analysis of mCRPC patients at Tulane Cancer Center between 2015-2022 was performed. All patients had ctDNA testing performed with the Guardant360 multigene panel assay. Clinical annotation including initial diagnosis, staging, treatment history, and family history were obtained. TP53 mutations were classified based on existing published functional studies and/or in silico evaluation. Statistical analyses were performed with Fisher's exact and Chi-squared tests where appropriate. Results: 338 mCRPC patients with ctDNA testing were included in this analysis. 76 patients had no prior treatment with either abiraterone or enzalutamide, while 262 patients had been treated with abiraterone and/or enzalutamide. Somatic TP53 mutations were similar in frequency between those with or without abiraterone/enzalutamide pretreatment; 46% (35/76) of patients in the abiraterone/enzalutamide naïve subset had a somatic TP53 mutation, compared to 41% (108/262) of patients previously treated with abiraterone and/or enzalutamide. Only 9% (7/76) of abiraterone/enzalutamide naïve patients had a TP53 gain-of-function mutation, compared to 19% (49/262) of patients previously treated with one or both drugs ( p = 0.05). The most common type of TP53 mutation was loss-of-function. There were no significant associations between TP 53 mutations and occurrence of other common mutations. Conclusions: mCRPC patients with prior treatment of abiraterone and/or enzalutamide were significantly more likely to have a gain-of-function TP53 mutation. Further studies are needed to investigate therapeutic implications of these findings.