NSAIDs During Postpartum Involution for Breast Cancer Chemoprevention

描述(申请人提供)：背景：所有妇女在分娩后患乳腺癌的风险都会立即增加，无论她们的年龄。在年龄相对较小就有孩子的女性中，怀孕最终确实能为预防乳腺癌提供长期保护。然而，年龄较大的第一次生育的母亲患乳腺癌的风险终生增加。目前公认的妊娠相关乳腺癌(PABC)的定义包括怀孕期间和产后一年内确诊的病例。产后5~7岁为产后高发期。此外，几项研究发现，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。这些数据将妊娠完成后5年内确诊的癌症确定为PABC的高危亚组，并为将PABC的定义扩大到包括产后病例提供了重要的理由。乳腺癌是20-50岁女性的主要癌症，超过了这个年龄段其他5种顶级癌症的总和。产次对年轻女性乳腺癌的预后有影响，确诊时生育5年内的女性5年内死亡率为34%，这充分证明了对这类乳腺癌的研究重点是正确的。在动物模型中，我们证明了创伤修复类程序需要将哺乳能力腺体重塑到怀孕前的状态，这是促进肿瘤的。此外，我们还发现非甾体抗炎药可以抑制肿瘤退化的这些致癌属性。我们的总体目标是确定女性产后乳房退缩是否代表了降低PABC的机会之窗。鉴于人类产后乳房退化的重要细节尚不清楚；我们的啮齿动物研究没有直接解决基于非甾体抗炎药的干预对妇女的相关性。此外，我们缺乏适用于人体试验的安全数据。在这项提案中，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/哺乳后妇女中进行0期研究，以证明正常的人类退化是一种主导的细胞死亡程序，在大多数妇女分娩后迅速而完全地发生，无论她是否哺乳。我们将获得具有详细产次和哺乳史的合适的乳房组织标本。我们会 利用我们临床前模型中确定的标志物，在乳房活检组织上使用最先进的定量IHC分析来检查产后人类乳房退化。目的1b-将证实在经历正常产后复旧的妇女的乳腺组织中存在类似于基质微环境的促肿瘤愈合的创面愈合，并鉴定其存在，并初步探讨其机制。目的2A-扩大我们的临床前研究，以验证布洛芬在免疫功能良好的PABC模型中的有效性，并通过评估鱼油来研究可针对哺乳期妇女的化学预防策略。目标2B-确认多种产后预防性治疗不会干扰生育能力、哺乳能力或在后续怀孕中的退化。目的3A-评价全身非甾体抗炎药治疗对乳腺癌常见转移部位如肺、肝等微环境的抑制作用。目的3B-通过确定复苏期全身性非类固醇激素治疗是否改变自身抗原的释放，解决与自身免疫性疾病的潜在相互作用。意义：目标是提供所需的数据，以提出一项大规模预防试验，在该试验中，乳腺癌高危女性在产后乳房退化期间服用“产后”避孕药，以减少这一独特风险窗口的肿瘤促进属性，鉴于美国每年有600万例怀孕，这是一个重要的目标。

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.