Molecular markers of risk of subsequent invasive breast cancer in women wth ductal carcinoma in situ

摘要 导管原位癌（DCIS）被认为是浸润性乳腺癌的非专性前兆 癌症（IBC）。筛查性乳房X光检查的使用已导致乳腺癌的检出率大幅增加。 DCIS在过去的2-3年。大约5-14%的诊断为DCIS并接受治疗的患者 保乳治疗，有或没有放射，发展同侧IBC和1-6%的发展， 对侧IBC在10年内。然而，自然历史研究表明，在 如果没有治疗，如果随访长达30年，14-53%的DCIS病例会发展为IBC。 DCIS的治疗是可变的，许多DCIS患者要么治疗不足，要么治疗过度。 阐明与IBC风险相关的DCIS病变中可检测到的分子变化 发展是迫切需要的，因为这不仅有助于减少发展国际生物伦理委员会的风险， 还可以防止过度治疗IBC风险较低的患者。在这方面，多基因 表达分析，包括与增殖相关的基因，以及PR和GSTM 1， 最近显示可预测DCIS女性随后患同侧IBC的风险。同样地， 化学检测的p16、考克斯-2和Ki 67表达也与肿瘤的发生有关。 增加了IBC发展的风险。然而，这些调查结果需要确认。此外，委员会认为， 新的预后（并最终预测）标记物可能出现在基因评估中。 在全球范围内的表达模式。在这方面，非编码的microRNA（miRNAs） RNA是基因表达的主要调节因子，被认为有助于发育 侵袭性癌症在此背景下，我们的总体目标是促进早期发现 DCIS患者有发生IBC的风险。为此，在我们以前工作的基础上，我们 建议使用临床数据和存档的福尔马林固定石蜡包埋（FFPE）组织， 一项大型、基于人群的多中心队列研究，包括7，275例最初诊断为DCIS的患者， 以社区为基础的健康计划，并遵循随后的IBC发展，以确定，然后 验证与后续IBC风险相关的miRNA表达变化，以评估IBC风险 与先前鉴定的2组标志物（Oncotype DX DCIS评分; p16、考克斯-2和Ki 67蛋白表达），并检查临床因素之间的关联 和随后IBC的风险进行了迄今为止规模最大的此类研究。我们的分子流行病学研究， 其建议将最先进的技术应用于存档的DCIS FFPE标本， 在一个大型多中心研究中检测与IBC发生风险相关的分子变化 最初诊断为DCIS的女性人群队列有可能导致 采取有助于确定需要加强监测的妇女的方法， 早期积极治疗。

ABSTRACT Ductal carcinoma in situ (DCIS) is considered to be a non-obligate precursor of invasive breast cancer (IBC). Use of screening mammography has led to a substantial increase in detection of DCIS over the past 2-3 decades. About 5-14% of patients diagnosed with DCIS and treated with breast-conserving therapy, with or without radiation, develop an ipsilateral IBC and 1-6% develop a contralateral IBC over a period of 10 years. However, natural history studies have shown that, in the absence of treatment, 14-53% of DCIS cases develop IBC if followed for up to ~30 years. Treatment of DCIS is variable, and many DCIS patients are either under- or over-treated. Elucidation of the molecular changes detectable in DCIS lesions that are associated with risk of IBC development is critically needed, as this may help not only to reduce risk of development of IBC but also to prevent overtreatment of patients with lower risk of IBC. In this regard, a multigene expression assay, consisting of genes related to proliferation, as well as PR and GSTM1, was recently shown to predict risk of subsequent ipsilateral IBC in women with DCIS. Similarly, immunohistochemically-detected expression of p16, COX-2, and Ki67 has also been associated with increased risk of IBC development. However, these findings require confirmation. Furthermore, novel prognostic (and ultimately predictive) markers may emerge from assessment of gene expression patterns on a global scale. In this regard, microRNAs (miRNAs), which are noncoding RNAs that are master regulators of gene expression, are thought to contribute to the development of invasive cancer. Against this background, our overarching goal is to facilitate early detection of patients with DCIS at risk of IBC development. To this end, building upon our previous work, we propose to use clinical data and archived formalin-fixed paraffin-embedded (FFPE) tissue from a large, population-based multi-center cohort of 7,275 patients initially diagnosed with DCIS in community-based health plans and followed for subsequent IBC development, to identify and then validate miRNA expression changes associated with risk of subsequent IBC, to evaluate risk of IBC in association with 2 previously identified sets of markers (Oncotype DX DCIS score; positivity for p16, COX-2, and Ki67 protein expression), and to examine the association between clinical factors and risk of subsequent IBC in the largest such study to date. Our molecular epidemiologic study, which proposes to apply state-of-the art technologies to archived DCIS FFPE specimens for the detection of molecular changes associated with risk of IBC development in a large, multi-center population-based cohort of women initially diagnosed with DCIS, has the potential to lead to approaches that will help to refine identification of women who need enhanced surveillance and early aggressive treatment.