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.
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| Poggi, Matthew M; Danforth, David N; Sciuto, Linda C et al. (2003) Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial. Cancer 98:697-702 |
