TP53 gain-of-function mutations in circulating tumor DNA in men with metastatic castration-resistant prostate cancer mCRPC

Abstract Background Circulating tumor DNA (ctDNA) from liquid biopsy can provide valuable genomic information that may impact treatment response in prostate cancer. The aim of this study was to characterize TP53 mutations and treatment history in prostate cancer. Methods This study included 143 patients with metastatic castration-resistant prostate cancer (mCRPC) who had ctDNA sequencing via Guardant360 testing (Guardant Health, Redwood City, CA). Presence or absence of TP53 mutations was analyzed with treatment history for this group. TP53 mutations were further classified as gain-of-function (GOF), or not gain-of-function, and analyzed with prior therapies. Results A chi square statistic was performed for treatment history and TP53 status (further specified as all TP53 mutations, or only TP53 GOF mutations). There were no associations between prior abiraterone/enzalutamide and all TP53 mutations, nor docetaxel and all TP53 mutations. However, TP53 GOF mutations had a positive association with prior abiraterone/enzalutamide (p = 0.047). There was no association of TP53 GOF mutations with prior docetaxel. The most frequent alterations co-occurring with all TP53 mutations were in AR, BRAF, EGFR, MYC, and PIK3CA. Common co-alterations with TP53 GOF mutations included AR, BRAF, EGFR, RB1, NF1, and PIK3CA alterations. There was an association of RB1 mutations with TP53 GOF mutations, versus RB1 mutations and no TP53 GOF mutations (p = 0.0036). Conclusions TP53 GOF mutations may provide a valuable pathway to delineate mCRPC TP53 mutations into therapeutic categories. Association with abiraterone/enzalutamide progression was apparent in this study; however, further studies are needed to elaborate on therapeutic and prognostic implications.