Targeted Prevention of Postpartum-Related Breast Cancer (PRBC)

产后相关乳腺癌(PRBC)，这里定义为五年内确诊的乳腺癌(BCS) 出生后，预示着预后不佳。尽管初产和多胎的年龄越早，晚发BCS的风险越低， 分娩会在20多年内短暂增加雌激素受体(ER)+和ER-BCS的风险， 风险高峰出现在产后5年(产后与未分娩：HR=1.80，95%CI=1.63~1.99)。高峰风险平分秋色 在有BC家族史的妇女中更高(分娩与未分娩：HR=3.53，95%CI=2.91-4.29)， 初产年龄偏大的妇女(p交互作用=0.03)。在临床前模型中，产后复旧(PPI)、 在断奶后将乳房恢复到非哺乳状态的促炎过程与激活有关 环氧合酶-2(COX-2)，它增加前列腺素的产生，导致免疫 抑制的、致癌的“伤口愈合”微环境推动了BC的进展；在这些模型中， 使用非类固醇抗炎药(NSAIDs)治疗可抑制PRBC的发展。在女性中， 产后正常乳腺组织和BBD活检的特点都是明显的炎症。我们和 其他人报告说，患有良性乳腺疾病(BBD)的非甾体抗炎药使用者患BC的风险显著降低， 这表明，对有患PRBC风险的妇女来说，这是一种潜在的预防性益处。我们提出了3个目的来检验这一假设 PPI失调会增加BBD和PRBC的风险，以及对有害炎症的抑制 遵循PPI可以降低BC风险。在目标1中，我们将定义和验证PPI特定的免疫签名 年轻未产妇和临产妇女正常乳腺组织的分值(5年内获得 出生，年龄匹配)使用了240个捐赠给Komen组织库(KTB)的样本。我们还将衡量 在这些妇女的子组(n=100)的冰冻组织中发现了二十烷类化合物，包括前列腺素E2。我们将定义 与PPI免疫签名得分相关的因素，假设得分较高可能表明PRBC增加 风险。在目标2中，我们将提炼并独立测试基于8的PRBC免疫签名分数 先前定义的具有组合AUC=0.76的标记物预测先前未检测的BBD活检的风险(75 病例和75例配对对照)。我们将比较707名女性BCS的PRBC免疫签名得分 年龄在40岁或以下，根据胎次、分子亚型，并调整了潜在的混杂因素。在目标3中，我们 将进行一次机会窗临床试验，以测试每天服用81毫克阿司匹林6周的疗程是否 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乳腺癌风险标记物。这项重大而创新的建议旨在 明确了PRBC发病机制的统一性，为进一步研究PRBC的发病机制奠定了基础。 使用免疫靶向和/或消炎剂的短期、耐受性良好的预防策略 为了防止公元前。

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.