Breast cancer (BC) is the most common cancer in women worldwide and is the second leading cause of cancer death in women. However, the advances in outcomes of BC patients have been limited to a subset of the affected population, namely European American (EA) women compared to their African American (AA) women counterparts. Despite various hormone therapies, the hormone receptor (ER/PR) positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/Her2-) subtype of BC remains difficult to treat. Cyclin- dependent kinase 4 and 6 inhibitors (CDK4/6i) have recently emerged as a new treatment strategy. Interestingly a 2022 population-based study confirmed that while the outcomes for HR+/Her2- metastatic BC have improved since CDK4/6i were introduced in 2015, this effect is primarily driven by the improved overall survival (OS) in non-Hispanic EA patients, without significant improvement in AA or Hispanics patients. The relative contribution of genetic factors vs. medication adherence or social determinants of health (SDOH) on such outcomes is less understood. Recent efforts to address this gap include databases such as ‘All of Us’, designed to better understand the interplay between genetic factors and social determinants. From a functional point, our preliminary analysis of The Cancer Genomic Atlas (TCGA) data shows decreased mRNA expression of FAT1, FAT4 and RB1, the major genes involved in resistance to CDK4/6i, in AA compared to EA HR+/Her2- BC. Thus, this project will do preliminary analysis of two aspects of BC therapy resistance in AA BC patients. Aim-1 of this project will assess the impact of medication adherence and various social determinants on clinical outcomes of female BC patients treated with CDK4/6i. Aim-2 will analyze the impact of genetic variations and low expression of FAT1, FAT4 and RB1 genes on the development of resistance to CDK4/6i in AA women with BC. We will use surveys, verbal medication review and EHR documentation of medication possession to gather information related to medication adherence and social determinants that may impact compliance. We will also analyze the prevalence of germline and somatic variations and epigenetic status of FAT1, FAT4 and RB1 genes in BC patients of EA and non-EA ancestry. Using computational modeling, we will predict the functional networking of FAT1, FAT4 and RB1 low expression in AA BC patients. Using established databases, clinical information obtained from the electronic health record (EHR), and surveys exploring SDOH and medication adherence patterns, this pilot aims to generate preliminary data exploring the impact of these factors on treatment outcomes in AA vs. EA patients receiving oral targeted therapy, including CDK4/6i. Discovery of AA-centric genetic variations and the impact of low expressed FAT1, FAT4 and RB1 genes in the functional networking will be critical in pre-selecting AA BC patients that may benefit from CDK4/6i therapy.