Characterization and Regulation of High Risk and Maligna

高风险和恶性疾病的特征和监管

• 批准号: 7331396
• 负责人: DAVID DANFORTH
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7331396
• 关键词: Characterization; Regulation; Risk; Maligna; Characterization; Regulation; Risk; Maligna

Characterization and Regulation of High Risk and Malignant Breast Epithelium.Breast cancer commonly develops in the epithelial cells lining the breast milk ducts. An understanding of the characteristics of high risk epithelium and their regulation is critical for defining the carcinogenic pathway, for risk assessment, and for selecting and monitoring for chemoprevention therapy. To provide a more comprehensive evaluation of the high risk duct and ductal epithelium, and facilitate molecular characterization of ductal epithelial cells, two clinical trials and correlative studies are being conducted: a.) Protocol 02-C-0077, Characterization of High Risk Breast Duct Epithelium by Cytology, Breast Duct Endoscopy, and cDNA Gene Expression Profile (DN Danforth, PI). b.) Protocol 02-C-0144, Establishment of Normal Breast Epithelial Cell Cultures, and a High Risk Cell Line and Tissue Repository from Breast Tissue from Women at High Risk for Breast Cancer (DN Danforth, PI). Both protocols are active and accruing subjects. Protocol 02-C-0077 studies, by ductal lavage and ductal endoscopy, the ducts and ductal epithelium of women at increased risk for breast cancer (represented by the contralateral breast in women with ipselateral breast cancer) and normal subjects (not at increased risk for breast cancer, to serve as controls). Thirty-six women have been studied, 29 high risk subjects and 7 normal volunteers. Cytologic analysis of ductal epithelial cells revealed cellular atypia in 9 subjects. Ductal endoscopy was performed on 46 ducts and revealed a spectrum of structural changes in 23 ducts, including, fibrous bridging, yellow sessile lesions, and a papillary lesion, providing important clarification of cytologic findings. This study also demonstrated the feasibility of performing repeated ductal lavage and endoscopy for followup evaluation of cellular atypia in these high risk ducts, which was performed at 6 - 14 months. Thus study has defined a new method for ductal epithelial sampling of normal and high risk ducts - endoscopic targeted intraductal sampling with brush, coil, and aspiration sampling devices. Multiple samples from different sites within the duct can be collected. Ductal epithelial samples of high cellularity (> 20,000 epithelial cells) with relatively pure ductal epithelial content (>91% purity) are obtained, allowing selective and comparative cytologic and molecular analyses. The findings from this study provide important evidence that breast duct endoscopy with targeted intraductal sampling provides a more comprehensive evaluation of the high risk breast duct and ductal epithelium. Molecular analyses including gene expression profiling, DNA methylation, proteomic, and comparative genomic hybridization are planned for samples in this study. The protocol is being amended to study all major high risk categories, including women with a family history of breast cancer, a Gail Index > 1.67, and breast cancer mutation carriers. Intraductal sampling will also be used to identify mammary gland stem cells as part of the Breast Cancer Stamp Fund Initiative ("Isolation, Propagation, Characterization, and Imaging of Breast Cancer Stem Cells in these subjects to Improve Early Diagnosis and Therapy of Breast Cancer" Barbara K. Vonderhaar, Ph.D., Coordinating PI). Findings for the ductal lavage and ductal endoscopy study have been published (DN Danforth, et al. Jour Surg Oncol, 2006, In Press). This study was awarded an NCI Intramural Bench-to Bedside Award to support the conduct of the trial.The second protocol, 02-C-0144, (Establishment of Normal Breast Epithelial Cell Cultures, and a High Risk Cell Line and Tissue Repository from Breast Tissue from Women at High Risk for Breast Cancer (DN Danforth, PI), is also a collaborative study which will promote identification and understanding of phenotypic, metabolic, and molecular changes which occur in high risk or premalignant breast epithelial cells.

高风险和恶性乳房上皮的表征和调节。在母乳管道内的上皮细胞中通常发展。对高风险上皮的特征及其调节的理解对于定义致癌途径，风险评估以及选择和监测化学预防疗法至关重要。为了更全面地评估高风险导管和导管上皮，并促进了导管上皮细胞的分子表征，正在进行两项临床试验和相关研究： b。）方案02-C-0144，建立正常的乳房上皮细胞培养物，以及来自乳腺癌高风险的乳房组织的高风险细胞系和组织仓库（DN Danforth，PI）。这两个方案都是主动和应计的主题。方案02-C-0077研究，通过导管灌洗和导管内窥镜检查，妇女的导管和导管上皮增加乳腺癌风险增加（iPselal乳腺癌女性的对侧乳房代表）和正常受试者（不适用于乳腺癌的风险增加，可以用作对照的乳腺癌）。已经研究了36名妇女，29名高风险受试者和7名正常志愿者。导管上皮细胞的细胞学分析显示9名受试者的细胞异型。导管内窥镜检查在46个导管上进行，并显示23个导管的结构变化谱，包括纤维桥，黄色的无缝病变和乳头状病变，提供了重要的细胞学发现。这项研究还表明，在这些高风险管道中进行重复进行导管灌洗和内窥镜检查以对细胞异型的随访评估，这是在6-14个月进行的。因此，研究定义了一种新方法，用于使用刷子，线圈和吸入采样装置进行正常风险管道和高风险管道的导管靶向靶向靶向性。可以收集来自管道内不同位点的多个样品。获得具有相对纯的导管上皮含量（> 91％纯度）的高细胞（> 20,000个上皮细胞）的导管上皮样品，从而可以选择性和比较细胞学和分子分析。这项研究的发现提供了重要的证据，表明具有靶向导管内采样的乳腺导管内窥镜检查提供了对高风险乳腺导管和导管上皮细胞的更全面评估。在这项研究中，计划样品，计划样品，计划对分子分析，包括基因表达分析，DNA甲基化，蛋白质组学和比较基因组杂交。该方案正在修订，以研究所有主要的高风险类别，包括具有乳腺癌家族史的女性，盖尔指数> 1.67和乳腺癌突变携带者。导管内采样还将用于鉴定乳腺干细胞作为乳腺癌邮票基金倡议的一部分（“这些受试者中乳腺癌干细胞的分离，传播，表征和成像，以改善乳腺癌的早期诊断和治疗”芭芭拉·K·沃德哈尔（Barbara K. Vonderhaar），博士学位，pi）。导管灌洗和导管内窥镜研究的发现已发表（DN Danforth等人Jour Surg Oncol，2006年，印刷中）。 This study was awarded an NCI Intramural Bench-to Bedside Award to support the conduct of the trial.The second protocol, 02-C-0144, (Establishment of Normal Breast Epithelial Cell Cultures, and a High Risk Cell Line and Tissue Repository from Breast Tissue from Women at High Risk for Breast Cancer (DN Danforth, PI), is also a collaborative study which will promote identification and understanding of phenotypic, metabolic, and molecular changes which发生在高风险或前乳房上皮细胞中。