This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Locally advanced breast cancer (LABC), defined as a tumor >5 cm or one which shows chest wall or skin involvement, has become rare in the general population of individuals with reasonable health care. However, in the under-served population it remains relatively common. Current therapy consists of pre-operative biopsy then pre-operative chemotherapy followed by excision of the tumor. This allows the tumor-specific markers to be discovered and the effectiveness of the chemotherapy regimen to be assessed. Experience suggests that the pathological response of the tumor to the primary chemotherapy can be used as a surrogate endpoint for survival: for a group, the 'better' the initial treatment the better the survival measures of overall survival (OS) and disease-free survival (DFS). Adding radiation as part of the initial treatment helps improve the response to initial treatment locally to complement the effects of chemotherapy with 5-FU to kill micrometastatic disease elsewhere in the body, as these investigators have shown previously. Correlation with pretreatment biopsy showed that p53 over-expression was the only independent predictive factor for pathological response consistent with the poor performance of 5-FU with such disease. In the case of tissue that over-expresses p53, taxanes are a better choice. Treatment of tumors positive for HER-2/neu is improved with the addition of Trastuzumab to the regimen. These observations led to the current study. With the goal of maximizing the response to the initial treatment, and therefore of maximizing measures of survival, patients will be sorted into 4 groups depending on whether their tumors are positive or not for p53 and positive or not for HER-2/neu. p53-negative tumors will be treated with Capecitabine and p53-positive with Paclitaxel. HER-2/neu-positive tumors will be treated with Trastuzumab. All patients will receive radiotherapy. This study brings the state-of-the-art in anti-cancer treatment to a group of people who are typically underserved within the community. The investigators have developed this protocol fully to employ earlier studies of similar populations with this disease and stage. The study will test the feasibility of managing treatments targeting specific tumor characteristics and will allow a comparison with the results of earlier trials where targeting was not employed. Secondary objectives will be to accumulate core biopsies before and after treatment and to look at quality of life. However, this is a trial where targeted treatment is being used with drugs that are expected to make a difference. This makes this trial unusual and valuable. Thus far, patient outcomes have conformed with expectations.
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