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, 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). This is a collaborative study in which the normal contralateral breast is being studied in women with ipselateral breast cancer. The contralateral breast is being studied by breast duct lavage and breast duct endoscopy, including targeted endoscopic sampling of the epithelium, and the ductal epithelial cells are characterized cytologically, by gene expression profiling and protein lysate array, and for chromosomal abnormalitites by comparative genomic hybridization. The protocol is active, and twenty seven subjects have been enrolled, and 48 ducts have been studied. The subjects were predominantly postmenopausal, with infiltrating ductal carcinoma (77.8 %) and were previously treated with chemotherapy (48.2 %) and tamoxifen (29.6 %). Forty eight percent of all ducts studied did not produce nipple aspirate fluid, but were easily accessed for lavage and endoscopy. Adequate cellular material for diagnosis was obtained by ductal lavage for 20 patients (74.7 %). Cellular atypia was present in 6 ducts from 5 subjects, and 5/6 had intraductal lesions on endoscopy. Endoscopy was performed on 36 ducts (26 patients). Sixteen ducts (13 pts) were normal, and 20 ducts (13 pts) contained intraductal lesions, most commonly intraductal adhesions or fibrous bridging. Endoscopic targeted intraductal sampling was performed 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 and placed in separate Eppendorf caps, allowing comparative cytologic and molecular analyses. Application of targeted sampling to the identification of breast stem cells is being evaluated. Followup repeat ductal lavage and ducal endoscopy was easily performed at 6-14 months in four subjects with atypia. Importantly, this showed essentially complete resolution of the intraductal lesions and the atypia. The presence of cellular atypia in the contralateral breast was therefore dynamic, and suggests reconsideration of cytologic changes as endpoints in chemoprevention trials aimed at the high risk population. These findings further indicate that breast duct endoscopy with targeted intraductal sampling provides a more comprehensive evaluation of the high risk breast ducts and ductal epithelium. This may be valuable for risk assessment and defining the carcinogenic pathway, and provide for a model incorporating endoscopy with sampling and molecular markers to allow short-term analysis of chemoprevention drugs. Molecular analyses including gene expression profiling, DNA methylation, proteomic, and comparative genomic hybridization are planned for samples in this study. This study was awarded an NCI Intramural Bench-to Bedside Award to support the conduct of the trial. b.) 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).
| Freedman, R J; Aziz, N; Albanes, D et al. (2004) Weight and body composition changes during and after adjuvant chemotherapy in women with breast cancer. J Clin Endocrinol Metab 89:2248-53 |
| Danforth Jr, David N; Cowan, Kenneth; Altemus, Rosemary et al. (2003) Preoperative FLAC/granulocyte-colony-stimulating factor chemotherapy for stage II breast cancer: a prospective randomized trial. Ann Surg Oncol 10:635-44 |
| 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 |
