NSAIDs During Postpartum Involution for Breast Cancer Chemoprevention

产后复健期间使用非甾体抗炎药进行乳腺癌化学预防

• 批准号: 8640114
• 负责人: VIRGINIA F. BORGES
• 金额: $ 5.93万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8640114
• 关键词: Address; Age; Alveolus; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibody Formation; Apoptosis; Area; Autoantigens; Autoimmune Diseases; Biological Assay; Biopsy; Breast; Breast Cancer Model; Breast Cancer Prevention; Breast Cancer Prevention Trial; Breast Epithelial Cells; Breeding; Cathepsin L; Cathepsins B; Cell Death; Cell Nucleus; Cells; Chemopreventive Agent; Child; Childbirth; Cleaved cell; Clinical Research; Clinical Trials; Cohort Studies; Collagen; Computer Assisted; DNA; Data; Deposition; Development; Diagnosis; Disease; Dose; Epidemiology; Epithelial; Epithelial Cells; Estrogens; Evaluation; Face; Family; Fertility; Fish Oils; Frequencies; Gland; Goals; Grant; Growth; Harvest; Health; High Risk Woman; Histology; Human; Hyperplasia; Ibuprofen; Image; Immune; Incidence; Infiltration; Inflammatory; Intervention; Knowledge; Lactates; Lactation; Lead; Life; Liver; Lobular; Lobule; Lung; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary gland; Measures; Mediating; Molecular; Mothers; Mus; Neoplasm Metastasis; Non-Steroidal Anti-Inflammatory Agents; Nurses; Outcome; PTGS2 gene; PTPRC gene; Pharmaceutical Preparations; Phase; Physiology; Postpartum Period; Postpartum Programs; Postpartum Women; Pre-Clinical Model; Pregnancy; Pregnant Women; Prevention; Prevention strategy; Probability; Process; Protocols documentation; Recording of previous events; Recruitment Activity; Research; Resolution; Risk; Rodent; Rodent Model; Safety; Scanning; Schedule; Signal Transduction; Site; Slide; Specimen; Tenascin; Time; Tissues; Translating; Trichrome stain; Weaning; Woman; Wound Healing; Xenograft Model; base; breast cancer diagnosis; cancer chemoprevention; cancer diagnosis; cancer prevention; career; caspase-3; cell growth; cohort; design; driving force; efficacy testing; high risk; human data; insight; macrophage; malignant breast neoplasm; mortality; neoplastic cell; novel; outcome forecast; parity; pill; postnatal; preclinical study; pregnant; prevent; productivity loss; programs; prospective; public health relevance; pup; safety study; tumor; tumorigenesis; tumorigenic; young woman

DESCRIPTION (provided by applicant): Background: All women have an immediate period of increased risk for developing breast cancer after childbirth, regardless of their age. Among women who have children at a relatively young age, pregnancy does eventually provide long term protection against breast cancer. However, older first-time mothers have a lifelong elevated risk for breast cancer. Currently accepted definitions of pregnancy-associated breast cancer (PABC) include cases diagnosed during pregnancy and within 1 year postpartum. However, peak incidence of PABC occurs at 5-7 years postpartum. In addition, several studies identify diagnosis up to 5 years postpartum as an independent predictor of poor prognosis, whereas diagnosis during pregnancy is not. These data identify cancers diagnosed within 5 years of a completed pregnancy as a high risk subset of PABC and provide important rationale for expansion of the definition of PABC to include later postpartum cases. Breast cancer is the leading cancer in women age 20-50, more than the 5 other top cancers combined in this age range. Parity influences the outcome of breast cancer in young women, with 34% mortality at 5 years for women within 5 years of childbirth at diagnosis, fully justifying a research focus on thi subset of breast cancer. In animal models, we demonstrate that wound healing-like programs required to remodel the lactation-competent gland to its pre-pregnant state are tumor promotional. Further, we show that NSAIDs can inhibit these tumorigenic attributes of involution. Our overall goal is to determine whether postpartum breast involution in women represents a window of opportunity for the reduction of PABC. Given that important details of postpartum human breast involution are unknown; our rodent studies do not directly address the relevance of NSAID based intervention for women. Further, we lack applicable safety data for human trials. In this proposal, we identify the missing data required to translate our PABC prevention strategy to postpartum women and propose specific aims to address each of these needs. Aim 1a- Perform a Phase 0 study in unaffected post- partum/post-lactation women to demonstrate that normal human involution is a dominant, cell death program, which occurs rapidly and completely in the majority of women after the delivery of a child whether or not she lactates. We will obtain appropriate breast tissue specimens with detailed parity and lactation history. We will examine postpartum human breast involution using state-of-the-art quantitative IHC assays on breast biopsies utilizing markers identified in our preclinical models. Aim 1b-Will confirm the presence of a pro-tumor wound healing like stromal microenvironment and identify the presence, and preliminarily the mechanisms of, a pro- inflammatory signature in breast tissue from women undergoing normal postpartum involution. Aim 2A-Expand our preclinical studies to verify efficacy of ibuprofen in an immune competent PABC model and investigate chemopreventive strategies that can be targeted to lactating women by evaluating fish oil. Aim 2B-Confirm that multiple postpartum preventative treatments do not interfere with fertility, abilit to nurse, or involution in subsequent pregnancies. Aim 3A-Assess for tumor suppressive effects of systemic NSAID treatment on the microenvironments of common sites of breast cancer metastasis such as lung and liver. Aim 3B-Address potential interactions with autoimmune disease by determining if systemic NSAID treatment during involution alters release of self-antigen. Significance: The goal is to provide data required to propose a large scale prevention trial where women at high risk for breast cancer would take a 'postnatal' pill during postpartum breast involution to reduce the tumor promotional attributes of this unique risk window, an important objective given the 6 million U.S. pregnancies per year.

描述（由申请人提供）：背景：所有女性在分娩后都有一个立即增加患乳腺癌风险的时期，无论年龄大小。对于那些在相对年轻的时候就有孩子的妇女来说，怀孕最终会提供长期的预防乳腺癌的保护。然而，年龄较大的第一次母亲终生患乳腺癌的风险增加。目前公认的妊娠相关乳腺癌（PABC）定义包括妊娠期间和产后1年内诊断的病例。然而，PABC的发病高峰出现在产后5-7年。此外，一些研究确定产后5年内的诊断是预后不良的独立预测因素，而怀孕期间的诊断则不是。这些数据确定了在完成妊娠后5年内诊断出的癌症为PABC的高风险子集，并为扩展PABC的定义以包括后期产后病例提供了重要的理论依据。乳腺癌是20-50岁女性的主要癌症，超过该年龄段其他5种癌症的总和。产次影响年轻女性乳腺癌的结局，诊断时分娩5年内的女性5年死亡率为34%，充分证明了对乳腺癌这一亚类的研究重点。在动物模型中，我们证明了将哺乳期腺体重塑到妊娠前状态所需的伤口愈合样程序是肿瘤促进的。此外，我们表明，非甾体类抗炎药可以抑制这些退化的致瘤属性。我们的总体目标是确定妇女产后乳房复旧是否代表减少PABC的机会之窗。鉴于产后人类乳房复旧的重要细节尚不清楚;我们的啮齿动物研究并未直接讨论基于NSAID的干预对女性的相关性。此外，我们缺乏适用于人体试验的安全性数据。在本提案中，我们确定了将我们的PABC预防战略转化为产后妇女所需的缺失数据，并提出了解决这些需求的具体目标。目的1a-在未受影响的产后/哺乳期后女性中进行0期研究，以证明正常人体退化是一种主要的细胞死亡程序，在大多数女性中，无论是否哺乳，分娩后都会迅速而完全地发生。我们将获得适当的乳房组织标本，并提供详细的产次和哺乳史。我们将 利用我们的临床前模型中鉴定的标志物，使用最先进的定量IHC检测乳腺活检检查产后人类乳腺退化。目的1b-将确认促肿瘤伤口愈合（如基质微环境）的存在，并鉴定来自经历正常产后复旧的女性的乳腺组织中促炎特征的存在及其初步机制。目的2A-扩展我们的临床前研究，以验证布洛芬在免疫活性PABC模型中的疗效，并通过评估鱼油研究可针对哺乳期妇女的化学预防策略。目的2B-确认多次产后预防性治疗不会干扰生育能力，护理能力或随后怀孕的复旧。目的3A-评估全身性NSAID治疗对乳腺癌常见转移部位（如肺和肝）微环境的肿瘤抑制作用。目的3B-通过确定退化期间全身性NSAID治疗是否改变自身抗原的释放来解决与自身免疫性疾病的潜在相互作用。重要性：其目标是提供所需的数据，以提出一项大规模的预防试验，其中乳腺癌高风险的妇女将在产后乳房退化期间服用“产后”药丸，以减少这一独特风险窗口的肿瘤促进属性，这是一个重要的目标。