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    Genetic Understanding of Locally Advanced Breast Cancer

    Scientific Abstract:
    Locally advanced breast cancer (LABC) is a primary breast cancer at least 5 cm in diameter (Stage IIIA/B). LABC has an extremely high risk for recurrence. The majority of tumors which respond poorly to treatment (primary chemotherapy or chemo-radiation followed by surgery), metastasize within a few years of clinical diagnosis and treatment. LABC patients experience a higher rate of treatment failure and mortality compared to patients with early stages of breast cancer. Importantly, LABC is a disproportionate source of breast cancer and mortality among minority and underserved women, constituting 30% of breast cancers in the U.S. and up to 70% in developing countries. We will investigate specific genetic determinants that are likely associated with unfavorable or favorable responses of LABC tumors to treatment by determining gene expression profiles of individual tumors from patients retrospectively and prospectively entered into an LABC clinical trial at NYU School of Medicine. Gene expression profiles will be examined for association with treatment response, resistance, maintenance of local disease or progression to metastasis. Specific Aims: To identify specific genes and gene expression profiles associated with treatment response, resistance, local disease and progression to metastatic disease in LABC, by studying pre-treatment tumor biopsies of patients accrued from a common clinical treatment protocol ongoing at NYUSM. Study Design. Central to the proposed research is the ongoing clinical trial on LABC at NYU. This trial involves pre-operative concurrent chemotherapy and radiation (RT) for LABC, assigning patients to two different treatment arms. Gene expression profiles in a cohort of approximately 100 multi-ethnic, multi-national women accrued over 3 years to the ongoing LABC clinical trial at NYUSM will be examined. Using this approach, specific genes and gene expression patterns that are associated with restriction of LABC to locally advanced disease or progression to metastatic cancer, as well as sensitivity or resistance of tumors to treatment, will be identified. Potential outcomes: There is very little research effort directed to LABC at the genetic and molecular levels. Since LABC is probably the most common stage of breast cancer at presentation worldwide and very high among disadvantaged U.S. women, an attempt to understand and ultimately tailor treatment can enormously impact on breast cancer mortality and the understanding of the transition of tumors from local disease to metastatic disease.

    Lay Abstract:
    Sponsor-Robert J. Schneider Postdoctoral applicant-Ksenia Karpisheva Title: Genetic Understanding of Locally advanced Breast Cancer LAY ABSTRACT Locally advanced breast cancer (LABC) is a primary breast cancer that measures at least 2 inches in diameter. Treatment of LABC involves chemotherapy or chemo-radiation followed by surgery. In those patients whose tumors respond poorly to treatment, metastasis often occurs within a few years from the time of diagnosis (new tumor deposits at distant sites in the body). LABC patients suffer a higher rate of treatment failure and higher mortality compared to women with early stages of breast cancer. In an age in which the common use of mammography screening has led to a clear shift to diagnosis of earlier stages of breast cancer, the incidence of LABC remains astonishingly high, constituting 30% of breast cancers among socially disadvantaged women in the United States and up to 70% or higher in developing counties. Thus LABC represents an inordinately large and unacceptable burden of suffering and death from breast cancer for disadvantaged and minority women in the U.S.. Little is known about the genetics of LABC and its likelihood to respond to different treatments. We propose to use LABC as a model for the understanding the genetic differences between LABC tumors that response to therapy versus those that do not, which progress from local disease to metastastatic disease. These studies seek to identify those genes expressed in LABC tumors that typify this form of breast cancer, and identify the genes that whose expression is associated with progression of LABC to metastasis. In addition, these studies seek to identify gene expression patterns linked to tumor response to therapy. In summary, these studies will investigate the genetic determinants of LABC and progression of disease to metastasis in order to understand its clinical presentation and to better predict the course of treatment for patients with LABC.