measurment of tumor volume and weight, microscopically-directed analysis of tumor extent, and 
molecular analysis of tumor and adjacent normal tissues to compare the extent of gene tranfer between 
tumor cells and adjacent normal cells. More extensive tumor seeding will likely require repeated treatments 
with retroviral vector in order to achieve a therapeutic response, particularly since large tumors may be 
composed predominantly of slowly dividing cells which may require repeated exposure of the tumor cells 
to retroviral vector. 
Overall Aims and Objectives: 
Based on preclinical data (see preliminary studies) we hypothesize that breast targeted antisense 
retroviral vectors may be effective agents in the treatment of metastatic breast cancer. The study is designed 
to test this hypothesis and specifically provide information on the following aspects of this therapy: 
1. Is there effective uptake and expression of retroviral vector into malignant breast cancer cells which are 
growing within meningeal, pleural, or peritoneal fluid ? 
2. Is the breast-targeted retroviral vector specifically expressed within breast cancer cells or do other cells 
express the MMTV-based transcription unit in an unexpected fashion ? 
3. Is there toxicity associated with infusion of viral vector in patients with metastatic breast cancer ? 
4. Is there an effective reduction in the number of malignant cells following retroviral vector-based therapy 
of carcinomatous meningitis, malignant pleuritis, or malignant ascites ? 
2. Background and Significance 
I. Breast Cancer and Metastasis 
Breast Cancer is the most common type of cancer and the second leading cause of cancer deaths in 
women. New breast cancers are diagnosed in 150,000 women each year and approximately 50% of these 
women will ultimately die of this disease. Although many women can be cured if the cancer is detected 
prior to metastasis, the survival rate for patients with metastatic breast cancer remains low. Patients who 
present with widely metastatic disease have rapid disease progression and a poor prognosis, but many 
patients who present with local disease will develop metastatic disease over the course of 10-20 years. 
Although some genetic markers can at least partially predict patients which are likely to develop metastatic 
disease, it is still impossible to absolutely predict patient prognosis and response to therapy (1-10). Thus 
even well-implemented early detection programs may not completely irradicate the eventual development of 
metastasis in some patients. A particular therapeutic problem are those patients with breast cancer which 
has metastasized to mesothelial-lined spaces such as meninges, peritoneum, or pleura. Carcinomatous 
meningitis, metastasis to the meninges involving the cerebral spinal fluid (CSF), is a life-threatening 
problem for which there is no sure and reliable therapy. 
Breast cancer is a major cause of death in women. Although the disease is often indolent for long 
periods, metastasis ultimately occurs in about 50% of patients and this is thought to be responsible for 
death in most patients. Metastasis can occur at numerous sites and is frequently multifocal, involving 
several organs. One fairly common pattern of metastasis involves the spread of malignant cells into 
mesothelial-lined spaces which results in malignant ascites, pleural effusion, or carcinomatous meningitis. 
The clinical manifestations of disease progression are different at each site. Malignant ascites involves the 
accumulation of malignant breast cancer cells within the peritoneal cavity, and progression is manifested 
by increasing weight, increasing abdominal girth, increasing quantities of fluid obtained by paracentesis, 
increasing numbers of cytologically malignant cells within the fluid, difficult food ingestion, and renal 
dysfunction. Malignant pleural effusion progression is manifested by increasing quantities of fluid noted 
on chest X-ray, dyspnea, increasing quantities of fluid obtained by thoracentesis, and increasing numbers 
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