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    Research Grants Awarded

    Molecular Biomarkers to Predict Local Recurrence of Breast Cancer

    Study Section:
    Risk, Prevention and Epidemiology

    Scientific Abstract:
    The use of breast-conserving surgery (BCS) for the treatment of early-stage breast cancers has been increasing and the ability to identify patients at high risk of local recurrence is highly desirable for guiding treatment decisions. Currently, relatively few recurrence risk factors have been identified; those known risk factors, which are based on clinical and histological features of tumor tissue, have limited predictive power. It is known that molecular genetic changes often precede morphologic evidence of malignant transformation. Thus, early molecular genetic alterations in breast tissue surrounding the tumor are likely to be more sensitive tools for the identification of patients at increased risk of local recurrence than current histological criteria. Hypothesis: Local recurrence of breast cancer in patients who are diagnosed with early-stage (stage 0-II) breast cancer and who underwent BCS is due to extended "field cancerization" in breast tissue surrounding the tumor. Thus, detecting such molecular alterations in the morphologically normal breast tissue surrounding the tumor will be predictive of local recurrence. Specific aims: (1) determine the relationship between telomere shortening in the epithelial cells of normal breast tissue surrounding the tumor and the risk of local recurrence; (2) determine the relationship between allele imbalance/loss of heterozygosity (LOH) in the normal breast tissue surrounding the tumor in chromosomes 3p, 9, 11q, 16q and 17 and the risk of local recurrence; (3) determine the relationship between the levels of Ki-67 expression (cell proliferation marker) in the normal breast tissue surrounding the tumor and the risk of local recurrence. Study design: We will conduct a nested case-control study of women who are diagnosed with early-stage breast cancer between 1970 and 2000. Cases are patients who had local recurrences of breast cancer after surgery treatment. Controls are breast cancer patient who had no local recurrence and are matched to cases on year of surgery, age at diagnosis, disease stage and type of treatment. Telomere length, frequency of LOH and levels of Ki-67 expression in epithelial cells of normal breast tissue surrounding the tumor will be determined and compared between cases and controls. Potential outcomes and benefits of the research: The proposed study will determine whether molecular alterations in the normal breast tissue surrounding the tumor will be predictive of local recurrence of breast cancer. We expect that women with shorter telomeres, higher frequencies of LOH and higher level of cell proliferation in the normal breast tissue surrounding the tumor will have an increased risk of local recurrence. The study has the potential to identify new sensitive molecular markers that predict local recurrence and may provide new molecular tools to guide the selection of the most appropriate local and systemic treatment for many individual breast cancer patients.

    Lay Abstract:
    The use of breast-conserving surgery (BCS) for the treatment of early-stage breast cancers has been increasing and new research is urgently needed to develop better tools for the identifying patients most likely to benefit from this treatment. In practical terms this means identifying molecular markers for predicting whether new tumors will grow in the remaining breast (the risk of local recurrence). Currently, relatively few recurrence risk factors have been identified; those known risk factors have limited predictive power since they are based on clinical and histological features of tumor tissue. Molecular markers may be more promising because it is known that detectable molecular and/or genetic changes often precede morphologic evidence of malignant transformation. Previous studies have shown that early genetic alterations can be detected in the normal appearing breast tissue that surrounds visible tumors. However, it remains to be determined whether genetic alterations in breast tissue surrounding the tumor will predict the risk of local breast cancer recurrence. We hypothesize that local recurrence of breast cancer in patients who are diagnosed with early-stage (stage 0-II) breast cancer and who underwent BCS is due to the presence of early ?cancerous? genetic alterations in the morphologically normal breast tissue surrounding the tumor. Thus, detecting any of these early ?cancerous? genetic alterations in the morphologically normal breast tissue surrounding the tumor will be good predictors of local recurrence. We propose to conduct a nested case-control study to examine the breast tissue surrounding the tumor for the relationship between three molecular markers, telomere length, loss of heterozygosity (LOH) and degree of cell proliferation (Ki-67 expression), and the risk of local recurrence. Cases are breast cancer patients who had local recurrences of breast cancer after surgery treatment. Controls are breast cancer patient who had no local recurrence and are matched to cases on year of surgery, age at diagnosis, disease stage and type of treatment. Telomere length, frequency of LOH and levels of of Ki-67 expression in breast tissue surrounding the tumor will be determined and compared between cases and controls. We expect that women with shorter telomeres, higher frequencies of LOH or higher level of cell proliferation in this surrounding normal breast tissue will have an increased risk of local recurrence. The proposed study will have the potential to identify sensitive molecular markers that predict local recurrence and may provide new molecular tools to guide the selection of the most appropriate local and systemic treatment for individual breast cancer patients.