Abstract PO-090: Coordinate dysregulation of base excision repair and homologous recombination pathways predominates in ER+/HER2- breast tumors from African American patients, and associates with worse disease-specific outcomes

Abstract

Abstract African American (AA) women with breast cancer are 42 % more likely to die from the disease compared to their white counterparts. This is evident from population- based studies which show a disparity in breast cancer mortality rates within United States even when confounding factors related to socioeconomic status and lifestyle are considered. Most of these studies focus on triple negative breast cancer, however the majority of breast cancer patients are diagnosed with estrogen receptor positive (ER+) disease. This results in a gap in knowledge in understanding molecular factors that contribute to worse outcome in AA patients with ER+ breast cancer. Endocrine therapy in the form of tamoxifen or aromatase inhibitor is first line standard of care for ER+ breast cancer. Nevertheless, 1 in 4 patients develop resistance to this treatment modality resulting in disease recurrence, metastasis and eventually death from disease. Recently, dysregulation of mismatch, nucleotide and base excision repair pathways were identified as causal to endocrine resistance and poor survival in Caucasian American ER+ breast cancer patients. Whether these same pathways, or distinct ones, associate with poor outcome in AA patients remains as yet unstudied. Here, we use a discovery data set with 87 AA patients and two publicly available validation data sets (TCGA and GSE50939 which has 49 and 45 AA patients respectively) to address this gap in knowledge. We demonstrate that a distinct subset of single stand break repair genes belonging to base excision repair (BER) and nucleotide excision repair (NER) pathways are downregulated specifically in tumors from AA patients. In parallel, double stand break repair genes from homologous recombination (HR) and Fanconi anemia (FA) pathways are upregulated in tumors from AA patients. Uniquely, tumors from AA patients more frequently have coordinated dysregulation of both homologous recombination and base excision repair genes, and this coordinate dysregulation associate with poor outcomes in AA patients. Overall, the results of this study provide the first thorough interrogation of DNA damage repair dysregulation in ER+/HER2- breast tumors from AA women. This systematic analysis identifies a unique profile of DNA repair dysregulation in AA patients and associates them with survival outcome. Datasets with better representation of AA patients are required for a more nuanced understanding of how DNA repair, and other molecular pathways, contribute to the worse outcomes seen in this underserved population. These results have implications for refining biomarker profiles by race, and improving precision medicine approaches. Citation Format: Aloran Mazumder, Athena Jimenez, Svasti Haricharan. Coordinate dysregulation of base excision repair and homologous recombination pathways predominates in ER+/HER2- breast tumors from African American patients, and associates with worse disease-specific outcomes [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-090.