Abstract 3425: Mutations in DNA repair and microtubule assembly genes found in triple negative breast tumors treated with neoadjuvant chemotherapy

Abstract

Abstract Up to 20% of breast cancer is clinically defined as triple-negative breast cancer (TNBC) lacking estrogen, progesterone, and HER2 receptors. Because no targeted therapy is available, cytotoxic chemotherapy is the primary mode of adjuvant TNBC therapy, but is effective in ~30% patients. In order to determine molecular underpinnings of chemotherapy resistance in TNBC, we analyzed 12 TNBC patient tumor samples collected post neoadjuvant chemotherapy using DNA/RNA sequencing. DNA analysis showed two tumors contained TP53 inactivating mutations and two tumors PIK3CA activating mutations. In addition, a number of mutations in the DNA repair pathway genes were identified including XRCC1, XRCC3, and ATXR, suggesting that DNA damaging nature of chemotherapy agents may have enriched these mutations. In addition, we found mutations in the genes involved in microtubule assembly including BUB3 and APC2, suggesting that these gene mutations may confer resistance to taxol, an anti-microtubule chemotherapy agent. RNA sequencing revealed a true heterogeneous nature of TNBE in that unsupervised clustering did not identify any distinct gene signature correlative of chemotherapy resistance. We are currently evaluating phenotypes related to chemotherapy resistance using cells genetically engineered with the BUB3 or APC2 mutations. Citation Format: Michael Grant, George Snipes, Rebecca Halperin, Paul Heaton, Suwon Kim. Mutations in DNA repair and microtubule assembly genes found in triple negative breast tumors treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3425.