Targeted Prevention of Postpartum-Related Breast Cancer (PRBC)

产后相关乳腺癌 (PRBC) 的针对性预防

基本信息

批准号：
10553696
负责人：
Derek C Radisky
金额：
$ 65.39万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553696
关键词：
Address Affect Aftercare Age Algorithms Anti-Inflammatory Agents Arachidonic Acids Area Under Curve Aspirin BCL1 Oncogene BCL2L1 gene BCL2L11 gene Benign Biological Assay Biopsy Birth Blood Breast Breast Cancer Prevention Breast Cancer Risk Factor Breast Diseases Breast biopsy C-reactive protein Characteristics Chemoprevention Childbirth Clinic Clinical Clinical Trials Contralateral DNA Damage Development Dinoprostone Discrimination Eicosanoids Enrollment Epidemiologic Factors Epidemiology Epithelial Cells Estrogen Receptors Estrogens Family history of First Births Freezing Frequencies Gamma-H2AX Immune Immune Targeting Immune response Immunohistochemistry Immunologic Markers Immunooncology Immunosuppression In Situ Inflammation Inflammatory Insulin Knowledge Label Lesion Link Lobule MS4A1 gene Malignant Neoplasms Mammary Gland Parenchyma Mammography Measures Modeling Multiparity Non-Steroidal Anti-Inflammatory Agents North Carolina Nulliparity Operative Surgical Procedures Participant Pathogenesis Pathology Pathway interactions Patients Persons Postpartum Period Pre-Clinical Model Pregnancy Prevention Prevention strategy Prevention trial Preventive Process Prognosis Prostaglandin Production Prostaglandins Proteins Questionnaires RNA Receiver Operating Characteristics Reporting Research Risk Risk Factors Risk Marker Sampling Schedule Serum Severity of illness Site Specimen Stains Testing Time Tissue Banks Tissue Microarray Tissues Universities Urine Weaning Woman adipokines aged biomarker panel breast cancer diagnosis breast cancer progression candidate identification carcinogenicity cyclooxygenase 2 digital early onset efficacy evaluation follow-up improved individualized prevention inflammatory marker innovation malignant breast neoplasm molecular subtypes mouse model nano-string parity parous predictive signature preventive intervention primary endpoint risk prediction secondary endpoint senescence wound healing young woman

项目摘要

Postpartum-related breast cancers (PRBCs), herein defined as breast cancers (BCs) diagnosed within five years after a birth, augur a poor prognosis. Although early age at first birth and multiparity lower risk of late onset BCs, childbirth transiently increases risks of both estrogen receptor (ER)+ and ER- BCs for over two decades, with peak risks at 5 years postpartum (parous vs. nulliparous: HR=1.80, 95%CI=1.63-1.99). Peak risks are even higher among women with a family history of BC (parous vs. nulliparous: HR=3.53, 95%CI=2.91-4.29), and for women whose first birth is at later ages (pinteraction=0.03). In preclinical models, post-partum involution (PPI), a pro-inflammatory process which restores the breast to a non-lactating state after weaning, is linked to activation of cyclooxygenase-2 (COX-2), which increases production of prostaglandins and results in an immune suppressed, pro-carcinogenic “wound healing” microenvironment that drives BC progression; in these models, treatment with non-steroidal anti-inflammatory agents (NSAIDs) inhibits PRBC development. Among women, both postpartum normal breast tissues and BBD biopsies are characterized by significant inflammation. We and others have reported significantly reduced risk of BC among NSAID users with benign breast disease (BBD), suggesting a potential preventive benefit for women at risk of PRBC. We propose 3 aims to test the hypothesis that dysregulated PPI increases risk of BBD and PRBC, and that inhibition of deleterious inflammation following PPI can lower BC risk. In Aim 1, we will define and validate a PPI-specific immune signature score to distinguish normal breast tissues of young nulliparous from parous women (obtained within 5 years of a birth, matched by age) using 240 samples donated to the Komen Tissue Bank (KTB). We will also measure eicosanoids, including prostaglandin E2, in frozen tissues from a subset (n=100) of these women. We will define factors related to PPI immune signature score, hypothesizing that higher scores may indicate increased PRBC risk. In Aim 2, we will refine and independently test whether a PRBC immune signature score based on 8 previously defined markers with a combined AUC=0.76 predicts risk in previously untested BBD biopsies (75 cases and 75 matched controls). We will compare PRBC immune signature scores in 707 BCs from women aged 40 years or less by parity status, molecular subtype, and adjusted for potential confounders. In Aim 3, we will conduct a window of opportunity clinical trial to test if a 6-week course of aspirin 81 mg per day can reduce the deleterious inflammation associated with PRBC risk (i.e., PRBC immune score) and favorably alter other BC risk markers in breast tissues, blood and urine. This significant and innovative proposal seeks to define a unifying mechanism of pathogenesis for PRBC, which will provide the basis for developing a short-term, well-tolerated prevention strategy using immune-targeting and/or anti-inflammatory agents to prevent BC.

与产后相关的乳腺癌（PRBC），在此定义为五年内诊断为乳腺癌（BC）生日后，预后不佳。尽管在第一个生日和多个生日时期很小分娩会暂时增加雌激素受体（ER）+和er-bcs的风险，二十年来产后5年的峰值风险（释放量与无效：HR = 1.80，95％CI = 1.63-1.99）。峰风险甚至是具有卑诗省家族史的女性中的较高（释放与无效：HR = 3.53，95％CI = 2.91-4.29），用于第一个生日的妇女是后来的（Pinteraction = 0.03）。在临床前模型中，产后相关（PPI），A 断奶后将乳房恢复到非泌乳状态的促炎性过程与激活有关环氧合酶-2（COX-2）的生产，增加了前列腺素的产生并导致免疫抑制了促进卑诗省进展的促促促癌“伤口愈合”微环境；在这些模型中，用非甾体类抗炎剂（NSAIDS）治疗可抑制PRBC的发展。在女性中，产后正常乳腺组织和BBD活检的特征是明显的炎症。我们和其他人报告说，患有良性乳房疾病（BBD）的NSAID使用者的风险大大降低了，暗示对有PRBC风险的妇女有潜在的预防益处。我们提出了3个旨在检验假设的目标这种失调的PPI增加了BBD和PRBC的风险，并抑制有害炎症遵循PPI可以降低BC风险。在AIM 1中，我们将定义和验证PPI特异性免疫特征分数以区分年轻无杀菌妇女的正常乳房组织（在5年内获得的5年一个生日，按年龄匹配），使用240个捐赠给Komen Tissue Bank（KTB）的样本。我们还将衡量来自这些女性子集（n = 100）的冷冻组织中的类花生酸（包括前列腺素E2）。我们将定义与PPI免疫签名评分有关的因素，假设较高的分数可能表明PRBC增加风险。在AIM 2中，我们将完善并独立测试PRBC免疫签名得分是否基于8 以前定义的标记物合并为AUC = 0.76预测先前未经测试的BBD活检的风险（75 案例和75个匹配的控件）。我们将比较女性707 BC中PRBC免疫签名分数以平等状态，分子亚型为40岁或更少的年龄，并针对潜在的混杂因素进行了调整。在AIM 3中，我们将进行机会临床试验窗口，以测试每天6周的阿司匹林81毫克减少与PRBC风险相关的已删除影响力（即PRBC免疫评分），并有利地改变乳腺组织，血液和尿液中的其他BC风险标记。这个重要而创新的提议试图定义PRBC发病机理的统一机制，这将为开发一个使用免疫靶向和/或抗炎剂的短期，耐受性良好的预防策略防止卑诗省。