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.

产后相关乳腺癌（PRBC），本文定义为五年内诊断出的乳腺癌（BC）出生后，预示着预后不良，尽管初产年龄早和多产降低了晚发 BC 的风险，二十多年来，分娩会短暂增加雌激素受体 (ER)+ 和 ER- BC 的风险，产后 5 年出现峰值风险（经产与未产：HR=1.80，95%CI=1.63-1.99）。有 BC 家族史的女性中较高（已生育与未生育：HR=3.53，95%CI=2.91-4.29），第一次生育的女性年龄较晚（pinteraction=0.03）。断奶后将乳房恢复到非哺乳状态的促炎症过程与激活有关环氧合酶-2 (COX-2)，可增加前列腺素的产生并导致免疫在这些模型中，促进 BC 进展的受抑制的促癌“伤口愈合”微环境；非甾体类抗炎药 (NSAID) 治疗可抑制女性 PRBC 的发展。产后正常乳腺组织和 BBD 活检均具有明显的炎症特征。其他人报告称，患有良性乳腺疾病 (BBD) 的 NSAID 使用者患 BC 的风险显着降低，表明对有 PRBC 风险的女性具有潜在的预防益处，我们提出 3 旨在检验这一假设。 PPI 失调会增加 BBD 和 PRBC 的风险，并且抑制有害炎症遵循 PPI 可以降低 BC 风险在目标 1 中，我们将定义并验证 PPI 特异性免疫特征。用于区分年轻未产妇和已产妇女正常乳腺组织的评分（在产后 5 年内获得）我们还将使用捐赠给 Komen 组织银行 (KTB) 的 240 个样本进行测量。我们将定义这些女性的一部分（n=100）的冷冻组织中的类二十烷酸，包括前列腺素 E2。与 PPI 免疫特征评分相关的因素，假设较高的评分可能表明 PRBC 增加在目标 2 中，我们将完善并独立测试 PRBC 免疫特征评分是否基于 8。先前定义的组合 AUC=0.76 的标记物可预测先前未经测试的 BBD 活检的风险 (75 我们将比较 707 名女性 BC 中的 PRBC 免疫特征评分在目标 3 中，我们根据胎次状况、分子亚型对年龄在 40 岁或以下的人群进行了分析，并针对潜在的混杂因素进行了调整。将进行机会之窗临床试验，以测试每天服用 81 毫克阿司匹林，为期 6 周的疗程是否可以减少与 PRBC 风险相关的有害炎症（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 风险标志物这一重要且创新的提案旨在定义PRBC发病机制的统一机制，这将为开发PRBC的发病机制提供基础使用免疫靶向和/或抗炎药物的短期、耐受性良好的预防策略以防止 BC