Subclonal heterogeneity and outcome disparities in Triple-Negative Breast Cancer among African Americans

非裔美国人三阴性乳腺癌的亚克隆异质性和结果差异

• 批准号: 10347682
• 负责人: LEIF W ELLISEN
• 金额: $ 75.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10347682
• 关键词: Accounting; Address; African American; African American population; Area; Biological; Biological Markers; Biology; Boston; Breast Cancer Patient; Cancer Biology; Caucasians; Cells; Characteristics; Chemoresistance; Clinical; Cohort Analysis; Collaborations; Complement; Consensus; Data; Disease; Disease Progression; Epigenetic Process; Excess Mortality; FBXW7 gene; Gene Expression Profiling; Genes; Genomics; Germ-Line Mutation; Hospitals; Inferior; Institution; Investigation; Measures; Medical center; Methodology; Methylation; Minor; Molecular Analysis; Mutation; Neoadjuvant Therapy; New England; Outcome; Pathway interactions; Patients; Pharmacology Study; Population; Prevalence; Publishing; Race; Relapse; Research; Research Personnel; Residual Tumors; Resistance; Socioeconomic Status; Somatic Mutation; Specimen; Survival Rate; Testing; Therapeutic; Tissue Microarray; Treatment outcome; Tumor Suppressor Proteins; Underserved Population; Woman; Work; aggressive breast cancer; cancer cell; cancer health disparity; chemotherapy; clinical care; clinical translation; cohort; driver mutation; drug sensitivity; epigenetic silencing; epigenomics; experience; experimental study; homologous recombination; innovation; insight; malignant breast neoplasm; molecular subtypes; mortality; neoplastic cell; novel; novel therapeutics; outcome prediction; patient derived xenograft model; personalized approach; personalized medicine; predictive marker; prognostic; ras GTPase-Activating Proteins; response; safety net; single cell analysis; single-cell RNA sequencing; sociodemographic factors; subclonal heterogeneity; treatment response; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity

Project Summary African American (AA) women experience higher rates of breast cancer mortality, even when accounting for confounding clinical and sociodemographic factors. This disparity reflects in part the fact that AA women in the US are approximately twice as likely as Caucasian (CA) women to develop Triple-Negative Breast Cancer (TNBC), a particularly aggressive breast cancer subset. However, even among those with TNBC, AA race is independently associated with inferior treatment responses and poorer survival rates. These and other data including our own work have led to an emerging consensus that that this excess mortality is due in part to biological differences between TNBCs in AA versus CA women. For example, recent genomic analyses have demonstrated distinct somatic mutation profiles in TNBCs among AA women. Our recent analysis of gene expression subtypes of TNBC by race showed that the increase in disease progression among AA women was selective for the intrinsic basal TNBC subset. In a separate study, we and collaborators demonstrated distinct mechanisms of homologous recombination (HR) deficiency in TNBCs from AA versus CA women. Finally, we also discovered that inferred subclonal heterogeneity, a measure reflecting malignant cell sub-populations within the tumor that is known to be associated with poor clinical outcomes in TNBC, in significantly higher in TNBCs of AA compared to CA women. This finding may explain why bulk tumor analysis has largely failed to provide mechanistic or actionable insights into the biological differences in TNBC between AA and CA women. Collectively, these findings support the hypothesis that distinct tumor characteristics including increased subclonal heterogeneity contribute to poorer clinical outcomes for AA women with TNBC. These results warrant a focused and detailed investigation of TNBC biology in AA women. Accordingly, we have initiated a coordinated, innovative and highly synergistic inter-institution collaboration, bringing together leading investigators with complementary expertise, employing state-of-the-art methodologies to address this unmet need. We propose genomic, epigenetic and gene expression profiling including single-cell analysis in TNBCs among AA and other women in order to reveal drivers that explain poorer outcomes in the AA population and discover new, therapeutically actionable means of intervening. We will Identify driver pathways and cell subpopulations that correlate with primary response to neoadjuvant chemotherapy among AA vs. CA women with TNBC. We will then examine clonal selection and discover resistant sub-populations through pre/post neoadjuvant chemotherapy analysis of TNBC in AA women. Next, we will determine the prevalence by race of genomic/epigenetic alterations and cell subpopulations and their ability to predict long-term outcomes through retrospective TNBC cohort analysis. Finally, we will establish ex vivo and PDX models of primary TNBC for specific mechanistic and therapeutic hypothesis testing. Together, these studies will provide the means for rapid clinical translation and will enable personalized therapy for AA women with TNBC.

项目摘要 非裔美国人（AA）女性乳腺癌死亡率较高，即使在考虑 混淆临床和社会人口学因素。这种差异部分反映了AA妇女在 美国女性患三阴性乳腺癌的可能性约为白人（CA）女性的两倍 （TNBC），一种特别侵袭性的乳腺癌亚群。然而，即使在TNBC患者中，AA种族也是 与较差的治疗反应和较差的生存率独立相关。这些和其他数据 包括我们自己的工作，已经导致了一个新兴的共识，即这种超额死亡率部分是由于 AA与CA女性中TNBC之间的生物学差异。例如，最近的基因组分析 在AA女性中的TNBC中显示出不同的体细胞突变谱。我们最近对基因的分析 按种族划分的TNBC表达亚型显示，AA女性中疾病进展的增加是 对固有的基础TNBC亚群具有选择性。在一项单独的研究中，我们和合作者证明了不同的 AA与CA女性TNBC中同源重组（HR）缺陷的机制。最后我们 还发现推断的亚克隆异质性，一种反映恶性细胞亚群的指标， 在已知与TNBC临床结局不良相关的肿瘤中， AA与CA女性的TNBC比较。这一发现可以解释为什么大块肿瘤分析在很大程度上未能 为AA和CA女性之间TNBC的生物学差异提供机制性或可操作的见解。 总的来说，这些发现支持了这样的假设，即不同的肿瘤特征，包括增加 亚克隆异质性导致患有TNBC AA女性的临床结果较差。这些结果 因此，需要对AA女性中的TNBC生物学进行重点和详细的调查。因此，我们已启动了一项 协调、创新和高度协同的机构间合作， 具有互补专长的调查员，采用最先进的方法解决这一未得到满足的问题 需要的我们提出了基因组，表观遗传和基因表达谱，包括单细胞分析在TNBC 在AA和其他女性中，以揭示解释AA人群中较差结果的驱动因素， 发现新的、治疗上可行的干预手段。我们将识别驱动途径和细胞 AA与CA女性中与新辅助化疗的主要应答相关的亚群 关于TNBC然后，我们将研究克隆选择，并通过前/后发现抗性亚群 AA妇女中TNBC的新辅助化疗分析。接下来，我们将按种族确定 基因组/表观遗传改变和细胞亚群及其通过以下方式预测长期结果的能力 回顾性TNBC队列分析。最后，我们将建立原代TNBC的离体和PDX模型， 具体机制和治疗假设检验。总之，这些研究将提供一种手段， 快速的临床转化，将使个性化治疗AA妇女与TNBC。