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

摘要 摘要导管原位癌(DCIS)被认为是浸润性乳腺的非专性先兆。 癌症(IBC)。筛查乳房X光检查的使用大大增加了对乳房疾病的发现 DCIS在过去的2-30年里。约5%-14%的DCIS患者被诊断为DCIS并接受 保留乳房的治疗，无论有没有放射治疗，都会发生同侧IBC，1-6%的人会发生 对侧IBC，为期10年。然而，自然历史研究表明，在 在缺乏治疗的情况下，14-53%的DCIS病例如果随访长达30年就会发展为IBC。 DCIS的治疗是多种多样的，许多DCIS患者要么治疗不足，要么治疗过度。 阐明DCIS病变中可检测到的与IBC风险相关的分子变化 迫切需要发展，因为这不仅有助于降低IBC的发展风险，而且 也是为了防止IBC风险较低的患者过度治疗。在这方面，一个多基因 表达分析包括与增殖相关的基因以及PR和GSTM1 最近被证明可以预测患有DCIS的女性继发同侧IBC的风险。同样， 免疫组织化学检测的p16、COX-2和Ki67的表达也与 随着IBC发病风险的增加。然而，这些发现需要得到证实。此外， 对基因的评估可能会产生新的预测(并最终预测)标记 全球范围内的表达模式。在这方面，非编码的microRNAs(MiRNAs) RNA是基因表达的主要调节者，被认为对发育有贡献 浸润性癌症。在此背景下，我们的首要目标是促进及早发现 有IBC发展风险的DCIS患者。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 年首次诊断为DCIS的7275名大型人口多中心队列患者 以社区为基础的健康计划，并遵循后续IBC发展，以确定并随后 验证与后续IBC风险相关的miRNA表达变化，以评估IBC的风险 与先前确定的2组标记相关联(Oncotype DX DCIS评分； P16、COX-2和Ki67蛋白表达)，并检验临床因素之间的关系 以及随后发生IBC的风险，这是迄今为止规模最大的此类研究。我们的分子流行病学研究， 它建议将最先进的技术应用于存档的DCIS FFPE样本，用于 在大型多中心检测与IBC发病风险相关的分子变化 最初被诊断为DCIS的以人群为基础的女性队列，有可能导致 将有助于完善对需要加强监测和管理的妇女的识别 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.