Abstract P3-14-03: The DNA damage repair landscape in Black women with breast cancer

Abstract Black women have 42% higher mortality rate from estrogen receptor positive (ER+) breast cancer than white women. Molecular mechanisms underlying worse outcome in black women are understudied. Recently, downregulation of specific DNA damage repair (DDR) genes was shown to causally induce resistance to standard care endocrine therapy by dysregulating cell cycle regulation, and to associate with poor outcome in white women with ER+ breast cancer. However, frequency and patterns of DDR dysregulation in Black women with ER+ breast cancer and impact on survival outcomes remains untested. By assessing RNA expression of 104 DDR genes across three tumor, and two normal breast, datasets, here, we map for the first time, global patterns of DDR gene expression regulation specific to Black women, both in tumors and in the normal breast. We identify a specific subset of 8 candidate DDR genes that are dysregulated at the RNA level in tumors from Black women. Of note, a novel DDR regulation signature where genes from the homologous recombination pathway are upregulated and genes from SSBR pathways (mainly base excision repair) are coincidently downregulated is almost uniquely detectable in tumors from Black women (8% incidence relative to 1% in tumors from white women, p=0.01). Moreover, this coincident DDR signature associates with dysregulated cell cycle gene expression (p<0.001). In accordance, patients whose tumors demonstrate this coincident DDR signature also have significantly worse survival outcomes across datasets (hazard ratio of 9.5, p<0.001). Overall, these results constitute the first systematic analysis of differences in DDR gene expression regulation between Black and white women and identify a specific DDR signature associated with poor outcome in tumors from Black women. These results provide new grounds for refining biomarker profiles and improving precision medicine for underserved populations. Citation Format: Aloran Mazumder, Athena Jimenez, Rachel E Ellsworth, Sophia George, Stephen J Freedland, Matthew N Bainbridge, Svasti Haricharan. The DNA damage repair landscape in Black women with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-03.