Locally advanced breast cancer (LABC) is defined as a primary breast cancer that measures at least 2 inches in diameter, often with lymph node involvement. Remarkably, even at this stage it has rarely spread to form additional tumors in distant sites in the body. Treatment of LABC involves primary chemotherapy or chemoradiation followed by surgery. In those patients whose tumors respond poorly to treatment, metastasis occurs within a few years from the time of diagnosis (new tumor deposits at distant sites in the body). LABC patients therefore suffer a higher rate of treatment failure and breast cancer deaths compared to women with early stages of breast cancer. In an age in which there is a clear shift to diagnosis of earlier stages of breast cancer resulting from mammography screening, the incidence of LABC remains astonishing as it constitutes up to 30% of breast cancers among socially disadvantaged women in the United States and up to 70% or higher in developing counties. LABC therefore represents an inordinately large and unacceptable burden of suffering and death from breast cancer for underserved and minority women in the United States and worldwide, which has rarely, if ever, been properly addressed. One of the reasons it remains poorly studied is because of well-established cultural and social barriers these patients encounter in accessing care, entering clinical trials, and adhering to prescribed treatment. As a consequence, little is known about the profile of LABC among different ethnic groups and its likelihood to respond to different treatments. This lack of knowledge warrants prompt attention from the scientific community.

In collaboration with our active survivor/advocate group, we have chosen to address this understudied area of breast cancer, possibly the most common stage at presentation of breast cancer worldwide. We are convinced that improvements in our understanding of the management, treatment, and minimization of the complications of LABC should be a very high research priority. This area represents an enormous potential for future intervention and reduction in the high level of death for breast cancer worldwide. The opportunity was therefore pursued for establishing a clinical research network of academic institutions in five distinct international sites capable of delivering the same standardized preoperative therapy and surgery. The five international institutions were chosen based on the following criteria: (1) access to a patient population where LABC is common; (2) competence and qualifications to conduct ethical clinical research; and (3) commitment to a common clinical and research program over the next 5 years. With input from the survivor/advocate group, the Principal Investigators have leveraged their complementary expertise in clinical and scientific research to create a convergence of cutting edge technology and clinical applications. The research priorities identified require specific expertise in behavioral, epidemiological, genetic, immunological, molecular, and possibly ethnic aspects of LABC.

Consequently, a parallel network of participating U.S. research teams was created from different institutions interested in studying LABC based on the following criteria: (1) best scientific qualifications for each of the research priorities identified with the input of the survivors/advocate team; (2) synergistic aspects of specialization, and (3) commitment to participate in this research. These two networks constitute the matrix of the proposed Center of Excellence (COE). Specifically, the COE will conduct an international clinical trial in association with laboratory studies to understand the progression of LABC from local disease to metastatic disease, by asking how LABCs that respond to identical therapy differ from those that are unresponsive and progress to metastatic disease. Although focused on LABC, this COE will generate results important for all invasive breast cancers because the transition from local to metastatic disease is a central problem in breast cancer. The active participation of a unique team of survivors/advocates in the design and preparation of this proposal has maintained the scope of the research "patient focused," and it has already made the process invaluable to the team of investigators involved. We believe that by studying LABC from an international perspective that includes the United States that the common features involved in response to treatment or progression of advanced disease are likely to be more readily discernable.

In view of the nearly complete lack of coordinated research effort in LABC, which is the most common stage of breast cancer worldwide and a very high component of breast cancer among underserved and minority U.S. women, the proposed COE represents an organized attempt to finally address the "global breast cancer problem." Since this study will examine results related to treatment outcome and compare them to genetic, molecular, and immunological profiles of the same patients, it is anticipated that by the completion of Year 5 this research will have a large impact on the treatment of LABC and possibly also affect the management of other invasive forms of breast cancer.