Abstract 1555: TP53 oncomorphic mutations are associated with resistance to platinum- and taxol-based standard chemotherapy in advanced serous ovarian cancer patients

Abstract

Abstract Mutations in the tumor suppressor gene TP53 abrogate the tumor suppressive functions of the p53 protein, and some mutations endow the mutant protein with oncogenic activity. These specific mutations we term oncomorphic. Many studies have attempted to correlate p53 mutation status with patient outcomes; however the results have been controversial due to indiscriminate categorization of all TP53 mutations into one group. Using advanced ovarian cancer as a model, our objective was to determine the relationship of oncomorphic TP53 mutations with the development of chemoresistance in advanced serous ovarian cancer patients uniformly treated with platinum and taxol primary chemotherapy. Clinical, genetic, and protein expression data from 264 high-grade serous ovarian cancer patients were downloaded from The Cancer Genome Atlas (TCGA) data portal. Associations between mutation types, chemoresistance, and progression-free survival (PFS) were calculated for patients harboring oncomorphic TP53 mutations, loss of function mutations, or unclassified mutations. Using a large and uniform patient population, we demonstrate the phenomenon of oncomorphic mutations in ovarian cancer. Specifically, patients with oncomorphic TP53 mutations showed significantly worse PFS when compared with patients with unclassified TP53 mutations (Log-rank, p < 0.05). Patients with oncomorphic TP53 mutations displayed higher rates of platinum resistance (X2, p = 0.0024) and an almost 60% higher chance of recurrence (HR=1.59, 95% confidence intervals 1.09, 2.33, p = 0.016). Furthermore, tumors containing oncomorphic TP53 mutations displayed a unique protein expression profile distinct from tumors with LOF or unclassified mutations. Taken together, these data reveal that particular oncomorphic TP53 mutations are highly associated with worse patient outcomes. Importantly, not all TP53 mutations are equal, and future studies should segregate mutations based on functional consequence. These data may have important implications for the future treatment of patients based on which TP53 mutation is present. Citation Format: Pavla Brachova, Donghai Dai, Mathew Carlson, Michael Goodheart, Kristina Thiel, Eric Devor, Kimberly Leslie. TP53 oncomorphic mutations are associated with resistance to platinum- and taxol-based standard chemotherapy in advanced serous ovarian cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1555. doi:10.1158/1538-7445.AM2014-1555