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

乳腺癌是全世界女性最常见的癌症，也是第二大致癌原因。 女性的死亡。然而，BC患者预后的进步仅限于一部分受影响的患者 人口，即欧洲裔美国人(EA)女性与其非洲裔美国人(AA)女性的比较 对口单位。尽管有各种激素治疗，但激素受体(ER/PR)阳性(HR)，人类 表皮生长因子受体2(HER2)阴性(HR/Her2-)亚型BC仍难以治疗。周期蛋白- 依赖性激酶4和6抑制剂(CDK4/6I)是最近出现的一种新的治疗策略。 有趣的是 2022年的一项基于人群的研究证实，虽然HR/Her2-转移性BC的结果有所改善 自2015年引入CDK4/6i以来，这种效果主要是由于 非西班牙裔EA 在再生障碍性贫血或拉美裔患者中没有明显改善。 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)对此类结果的影响较小 明白了。最近为解决这一差距所做的努力包括诸如“我们所有人”这样的数据库，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。从功能的角度来看，我们的 初步分析了几个方面的问题 癌症基因组图谱(TCGA)数据显示FAT1的mRNA表达减少， 与EA HR/Her2-BC相比，AA中与CDK4/6I抗性相关的主要基因FAT4和RB1。 因此， 本课题将对再障BC患者耐药的两个方面进行初步分析。此目标-1 该项目将评估服药依从性和各种社会决定因素对 女性BC患者接受CDK4/6i治疗。AIM-2将分析遗传变异和低表达的影响 FAT1、FAT4和RB1基因在再生障碍性贫血患者CDK4/6I耐药中的作用我们将使用 调查、口头用药回顾和药物拥有情况的电子病历记录，以收集信息 与服药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的种系和体细胞变异及FAT1、FAT4和RB1基因的表观遗传状态 EA患者和非EA血统患者。使用计算建模，我们将预测 再生障碍性贫血患者FAT1、FAT4和RB1低表达。使用已建立的数据库、临床信息 从电子健康记录(EHR)获得，以及探索SDOH和用药依从性的调查 模式，这项试点旨在产生初步数据，探索这些因素对治疗结果的影响 AA和EA患者接受口服靶向治疗，包括CDK4/6i。发现以AA为中心的基因 低表达的FAT1、FAT4和RB1基因在功能网络中的变异和影响 在预先选择可能受益于CDK4/6i治疗的AA BC患者时至关重要。

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.