Abstract GMM-037: CARBONIC ANHYDRASE 9 AND TUMOR HYPOXIA ARE ASSOCIATED WITH RECURRENCE AND RESISTANCE IN BRCA1-EXPRESSING HGSOC

Abstract

Abstract Tumor hypoxia contributes to poor outcome in multiple cancer types, in part by influencing the expression of DNA repair enzymes. The objective of this study was to examine the possible relationship between Carbonic Anhydrase 9 (CA-IX, an indicator of tumor hypoxia), BRCA1 expression (a potential indicator of competent DNA repair), and patient outcome in epithelial ovarian cancer. BRCA1 and CA-IX were evaluated by immunohistochemistry in a tissue microarray of 167 epithelial ovarian cancer (EOC) patient samples, and their respective expression correlated to other biological parameters in all patients. The correlations between BRCA1 and CA-IX expression, and clinical outcome were determined in the High Grade Serous Ovarian Carcinoma (HGSOC) samples (N = 101) on the array using Spearman's correlation and log-rank (Mantel-Cox) tests. Elevated expression of BRCA1 strongly correlated with shorter intervals for disease recurrence and mortality (median time to recurrence = 1.05 yrs vs 1.94 yrs, P <0.001; median time to mortality: 2.01 yrs vs 4.72 yrs, P <0.001). There was a significant positive correlation between CA-IX and BRCA1 expression (Spearman's r = 0.486, P < 0.001). CA-IX expression was significantly associated with recurrence-free survival (restricted to first 1500 days, P <0.01). When patients were stratified by BRCA1 expression, co-expression of CA-IX and BRCA1 correlated with the shortest recurrence-free interval (P <0.05). In complementary in vitro studies, exposure of multiple BRCA1-wild-type cell lines to hypoxia (1% O2, mimicking general tumor hypoxia) had only a minimal effect on BRCA1 expression. Additionally, in MTT viability assays, application of the hypoxia-activated pro-drug TH-302 preferentially killed cells in 1% O2 compared to standard conditions (21% O2). In contrast, the PARP inhibitor olaparib was 2-5 times less effective in hypoxic conditions than in standard growth conditions, suggesting that tumor hypoxia promotes a more resistant phenotype. CONCLUSION: The co-expression of CA-IX and BRCA1 may be a useful prognostic indicator for rapid recurrence in high grade serous ovarian cancer. Dissecting the mechanisms regulating therapeutic resistance in hypoxic ovarian cancer cells could lead to more effective treatment options for HGSOC patients. Citation Format: Adam J. Krieg, Shawn Campbell, Paulette Mhawech-Fauceglia, Jeong Youn Lim, Tanja Pejovic. CARBONIC ANHYDRASE 9 AND TUMOR HYPOXIA ARE ASSOCIATED WITH RECURRENCE AND RESISTANCE IN BRCA1-EXPRESSING HGSOC [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-037.