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: 8908279
• 负责人: VIRGINIA F. BORGES
• 金额: $ 53.26万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8908279
• 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; 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：无论年龄大小，所有女性在分娩后都有一段增加患乳腺癌风险的直接时期。在相对年轻的年龄生育的妇女中，怀孕最终确实提供了长期预防乳腺癌的保护。然而，年龄较大的第一次母亲一生中患乳腺癌的风险更高。目前接受的妊娠相关乳腺癌（PABC）的定义包括在怀孕期间和产后1年内诊断的病例。然而，PABC的高峰发生在产后5-7年。此外，几项研究发现，产后5年的诊断是预后不良的独立预测因素，而孕期的诊断则不是。这些数据确定在妊娠结束后5年内诊断出的癌症是PABC的高风险子集，并为将PABC的定义扩大到包括后期产后病例提供了重要的依据。乳腺癌是20-50岁女性的主要癌症，超过了该年龄段其他5种癌症的总和。胎次影响年轻妇女乳腺癌的预后，在诊断为分娩后5年内的5岁妇女中有34%的死亡率，充分证明了对这一乳腺癌亚群的研究重点是合理的。在动物模型中，我们证明了将泌乳腺重塑到怀孕前状态所需的类似伤口愈合的程序对肿瘤有促进作用。此外，我们发现非甾体抗炎药可以抑制这些复发的致瘤性属性。我们的总体目标是确定女性产后乳房复发是否代表了减少PABC的机会之窗。鉴于产后人类乳房退化的重要细节尚不清楚；我们的啮齿动物研究并没有直接解决以非甾体抗炎药为基础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。在本建议中，我们确定了将我们的PABC预防策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/哺乳期妇女中进行0期研究，以证明正常的人类退化是一个主要的细胞死亡程序，在大多数妇女分娩后，无论她是否哺乳期，都会迅速而彻底地发生。我们将获得适当的乳房组织标本，详细的胎次和哺乳史。我们将