Vermont Breast Cancer Molecular Characterization Laboratory

 描述（由申请人提供）：过去 30 年来，乳腺癌筛查和治疗的进步降低了美国乳腺癌死亡率。然而，随着筛查性乳房X光检查的广泛采用，早期乳腺癌诊断数量急剧增加，但并未被晚期乳腺癌诊断数量的下降所抵消。越来越多的证据表明，如果不通过筛查发现，很大一部分通过筛查检测到的乳腺癌永远不会在临床上出现。尽管对于过度诊断的严重程度存在广泛的争论，但人们普遍认为，迫切需要新的方法来区分筛查检测到的惰性病例和可能危及生命的病例。肿瘤微环境在乳腺癌进展中的作用已得到越来越多的认识。多项证据表明，乳腺肿瘤的发生受到肿瘤微环境中恶性乳腺上皮细胞和非肿瘤细胞之间的活跃信号传导的严重影响。我们提案的目标是确定肿瘤微环境特征，通过微创方法预测早期筛查检测乳腺癌的侵袭性。我们将利用和完善最先进的技术，根据间期和症状检测的浸润性乳腺癌的肿瘤微环境中特定细胞群的细胞组成和基因表达来表征侵袭性特征。然后，我们将确定筛查检测到的早期乳腺癌中这些侵袭性肿瘤微环境特征的存在是否与进展相关。我们将从佛蒙特州乳腺癌监测系统 (VBCSS) 获取 800 份福尔马林固定、石蜡包埋标本的回顾性数据进行分析，该系统收集了自 1996 年以来佛蒙特州所有接受乳腺成像的女性的综合患者、放射学、病理学、治疗和结果数据。VBCSS 拥有一个庞大的现有存储库，包含 1,200 多个集中审查的 DCIS 标本，并可访问超过佛蒙特州诊断病例的 10,000 份浸润性乳腺癌样本。我们还将通过佛蒙特州癌症中心组织生物库前瞻性地收集新鲜样本，该样本库也与 VBCSS 的综合数据相关联。侵袭性和惰性肿瘤微环境特征的识别将促进针对预后良好的女性子集开发更保守的治疗策略，并为预后不良的病例提出治疗干预的新靶标。我们组建了一支多学科研究团队，在细胞和分子癌症生物学、病理学、癌症筛查和流行病学方面拥有全国公认的专业知识，以及基于联盟的富有成效的合作研究的长期记录。佛蒙特州乳腺癌分子表征实验室将为该联盟提供科学领导力、技术资源，并可访问与 VBCSS 丰富数据相关的回顾性和前瞻性收集的乳腺标本大型存储库。

 DESCRIPTION (provided by applicant): Advances in breast cancer screening and treatment have reduced breast cancer mortality in the US over the past 30 years. However, the widespread adoption of screening mammography has been accompanied by dramatic increases in early stage breast cancer diagnoses that have not been offset by declines in advanced stage disease. Accumulating evidence suggests that a substantial fraction of screen-detected breast cancers would never have emerged clinically if not detected through screening. While there is extensive debate regarding the magnitude of overdiagnosis, there is widespread consensus that new approaches are urgently needed to distinguish indolent screen-detected cases from those that may be life threatening. The role of the tumor microenvironment in breast cancer progression has been increasingly recognized. Several lines of evidence indicate that breast tumorigenesis is critically influenced by active signaling between malignant breast epithelial cells and non-neoplastic cells of the tumor microenvironment. The goal of our proposal is to identify tumor microenvironment signatures that predict the aggressiveness of early stage, screen-detected breast cancers by minimally invasive methods. We will leverage and refine state-of-the-art technologies to characterize aggressive signatures based on the cellular composition and gene expression of specific cell populations within the tumor microenvironment of interval- and symptom-detected invasive breast cancers. We will then determine whether the presence of these aggressive tumor microenvironment signatures in early stage, screen-detected breast cancer is associated with progression. We will obtain retrospective data on 800 formalin-fixed, paraffin-embedded specimens for analysis from the Vermont Breast Cancer Surveillance System (VBCSS), which has collected integrated patient, radiology, pathology, treatment, and outcomes data on all women undergoing breast imaging in the state of Vermont since 1996. The VBCSS has a large existing repository of over 1,200 centrally-reviewed DCIS specimens and access to over 10,000 invasive breast cancer specimens for cases diagnosed in the state of Vermont. We will also engage in prospective collection of fresh specimens via the Vermont Cancer Center Tissue Biobank, which is also linked to the integrated data of the VBCSS. The identification of aggressive and indolent tumor microenvironment signatures will promote the development of more conservative treatment strategies for the subset of women with favorable prognosis and suggest novel targets for therapeutic intervention in cases with unfavorable prognosis. We have assembled a multidisciplinary research team with nationally recognized expertise in cellular and molecular cancer biology, pathology, cancer screening, and epidemiology, as well as a long track record of productive consortium-based collaborative research. The Vermont Breast Cancer Molecular Characterization Laboratory will provide the consortium with scientific leadership, technical resources, and access to a large repository of retrospective and prospectively collected breast specimens linked to the rich data of the VBCSS.