Targeted Prevention of Postpartum-Related Breast Cancer (PRBC)

产后相关乳腺癌（PRBC），本文定义为五年内诊断的乳腺癌（BC） 预示着预后不佳虽然初次生育年龄小和多胎分娩降低了晚发性BC的风险， 二十多年来，分娩会暂时增加雌激素受体（ER）+和ER-BC的风险， 在产后5年达到高峰（经产与未经产：HR=1.80，95%CI=1.63-1.99）。峰值风险是均匀的 在有BC家族史的女性中更高（经产与未经产：HR=3.53，95%CI=2.91-4.29）， 第一胎年龄偏大的妇女（p交互作用=0.03）。在临床前模型中，产后退化（PPI）， 在断奶后使乳房恢复到非泌乳状态的促炎过程与激活 环氧合酶-2（考克斯-2），它增加了三尖杉脂素的产生，并导致免疫反应。 抑制的、促癌的“伤口愈合”微环境，其驱动BC进展;在这些模型中， 用非甾体抗炎药（NSAID）治疗抑制PRBC的发展。在妇女中， 产后正常乳腺组织和BBD活组织检查的特征在于显著的炎症。我们和 其他人已经报道了患有良性乳腺疾病（BBD）的NSAID使用者中BC的风险显著降低， 这表明对有PRBC风险的妇女有潜在的预防益处。我们提出了3个目的来检验假设 PPI失调会增加BBD和PRBC风险， PPI可以降低BC风险。在目标1中，我们将定义和验证PPI特异性免疫签名 评分以区分年轻的未经产妇女和经产妇女的正常乳腺组织（5年内获得）， 出生，年龄匹配）使用240个捐赠给科门组织库（KTB）的样本。我们还将测量 这些妇女的一个亚组（n=100）的冷冻组织中的类花生酸，包括前列腺素E2。我们将定义 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 风险在目标2中，我们将细化并独立测试基于8的PRBC免疫签名得分是否 先前定义的标记物联合AUC=0.76可预测先前未检测的BBD活检的风险（75 病例组和75例对照组。我们将比较来自女性的707个BC中的PRBC免疫特征评分 年龄40岁或以下，按产次状态、分子亚型分类，并校正潜在混杂因素。在目标3中， 将进行一项机会之窗临床试验，以测试每天81毫克阿司匹林的6周疗程是否可以 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。这一重要和创新的建议旨在 明确PRBC发病机制的统一机制，这将为制定 使用免疫靶向和/或抗炎剂短期、耐受性良好的预防策略 防止BC。

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.