Impact of race and ethnicity on outcomes in patients with hormone receptor-positive breast cancer treated with CDK4/6 inhibitors

乳腺癌（BC）是世界范围内女性最常见的癌症，也是第二大癌症病因 女人的死亡然而，BC患者结局的进展仅限于受影响的亚组， 人群，即欧洲裔美国人（EA）女性与非裔美国人（AA）女性相比 同行尽管有各种激素疗法，但激素受体（ER/PR）阳性（HR+）、人类激素受体（HR+）、人类激素 表皮生长因子受体2（HER 2）阴性（HR+/Her 2-）亚型的BC仍然难以治疗。 依赖性激酶4和6抑制剂（CDK 4/6 i）最近作为一种新的治疗策略出现。 有趣的 一项2022年的基于人群的研究证实，虽然HR+/Her 2-转移性BC的结局有所改善， 自2015年引入CDK 4/6 i以来，这一效应主要是由总生存期（OS）的改善驱动的， 非西班牙裔EA 患者，AA或西班牙裔患者无显著改善。 的相对贡献 遗传因素与药物依从性或健康的社会决定因素（SDOH）对这些结果的影响较小 明白最近为解决这一差距所做的努力包括“我们所有人”等数据库，旨在更好地 了解遗传因素和社会决定因素之间的相互作用。从功能上讲，我们 初步分析 癌症基因组图谱（TCGA）数据显示FAT 1的mRNA表达降低， 与EA HR+/Her 2- BC相比，AA中涉及对CDK 4/6 i的抗性的主要基因FAT 4和RB 1。 因此，在本发明中， 本课题将从两个方面对AA BC患者BC治疗抵抗进行初步分析。Aim-1 该项目将评估药物依从性和各种社会决定因素对临床结果的影响， 用CDK 4/6 i治疗的女性BC患者。Aim-2将分析遗传变异和低表达的影响 FAT 1、FAT 4和RB 1基因对患有BC的AA女性中CDK 4/6 i耐药性的发展的影响。我们将使用 调查，口头药物审查和电子健康记录的药物拥有收集信息 与药物依从性和可能影响依从性的社会决定因素有关。我们还将分析 BC中FAT 1、FAT 4和RB 1基因的生殖系和体细胞变异的患病率以及表观遗传状态 EA和非EA祖先的患者。使用计算建模，我们将预测的功能网络， FAT 1、FAT 4和RB 1在AA BC患者中低表达。使用已建立的数据库，临床信息 从电子健康记录（EHR）和探索SDOH和药物依从性的调查中获得 模式，该试点旨在生成初步数据，探索这些因素对治疗结果的影响 在接受口服靶向治疗的AA与EA患者中，包括CDK 4/6 i。AA-中心基因的发现 低表达的FAT 1、FAT 4和RB 1基因在功能网络中的变异和影响将被 这对于预先选择可能受益于CDK 4/6 i治疗的AA BC患者至关重要。

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.