It has been suggested that the small fraction of tumor cells capable of initiating local or distant recurrence exhibit properties of stem cells, and that identification and molecular characterization of putative cancer stem cells will lead to better outcomes through targeted cancer stem cell therapies in appropriately selected patients. Clinical studies examining the predictive and prognostic significance of these cells have been limited by several factors, including variable methods for isolating single cells from tissues, the need for multiple markers to distinguish committed from undifferentiated cells, and the availability of fresh tissue from patients for study. Originating from the primary tumor, circulating tumor cells (in the blood) and disseminated tumor cells (in the bone marrow) are attractive cancer stem cell candidates, and practical clinical surrogates for cancer stem cell study because they exist as single cells, and can be quantified using available FDA approved technology. Therefore, we propose a translational strategy to examine primary, circulating, and disseminated tumor cells from breast cancer patients to test our central hypothesis that circulating and disseminated tumor cells present in the blood and bone marrow of non-metastatic breast cancer patients represent cancer stem cells which are precursors to distant metastases and potential targets for novel treatment. Our hypothesis is based on preliminary data from an ongoing IRB-approved clinical protocol that demonstrates disseminated tumor cells in the bone marrow of patients with non-metastatic breast cancer are positive for the expression of cancer stem cell markers of tumor initiating capacity;CD44+CD24- and aldehyde dehydrogenase-1 (ALDH1). Translational aims are based on three IRB protocols and tailored to the material collected, treatment approach, and patient population in each trial. The translational work represents an established multidisciplinary collaboration between Massimo Cristofanilli, MD Breast Medical Oncology, James Reuben, PhD, Hematopathology, and Wendy Woodward, MD-PhD, Clinical and Experimental Breast Radiation Oncology. The goals are 1) Measure CTCs and DTCs in patients without metastatic disease, assess these cells for stem cell features and correlate these to outcome and ALDH1 staining in the primary;2) Measure CTCs and primary tumor stem cells in patients receiving neoadjuvant chemotherapy and correlate response to therapy between these measures as well as transplant and culture primary biopsy material for molecular studies;3) Determine key mediators of ?-catenin and Notch-1 crosstalk in radioresistance of cancer stem cells, and test inhibition of these pathways as radiosensitizers. In these studies we hope to demonstrate that CTCs/DTCs are prognostic and predictive surrogates for cancer stem cells that are easily accessible for examination on the single cell level. This approach could be used to select patients for individualized therapy using targeted sensitizing agents based on the proposed preclinical studies.

Public Health Relevance

Approximately 30-40% of patients who appear clinically free of cancer at distant sites harbor hidden cancer cells [1, 2] and failure to eliminate them with chemotherapy, surgery and/or radiation allows for eventual spread of the disease [3, 4]. Cancer cells have been detected in the blood and bone marrow of patients and it is believed that some of these cells may indeed be cancer stem cells;which initiate cancer growth in other places in the body. Our experiments intend to prove that these cells are indeed cancer stem cells and we also hope to identify means of eliminating them by directly targeting their unique properties. Understanding cancer stem cell properties and ways to eliminate them will eventually lead to preventative therapy, ensuring that all hidden cancer cells are destroyed before they spread and grow. 1. Clare, S.E., et al., Prognostic significance of occult lymph node metastases in node-negative breast cancer. Ann Surg Oncol, 1997. 4(6): p. 447-51. 2. Braun, S., et al., Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med, 2000. 342(8): p. 525-33. 3. Folkman, J., Tumor angiogenesis: therapeutic implications. N Engl J Med, 1971. 285(21): p. 1182-6. 4. Clarke, M., et al., Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet, 2005. 366(9503): p. 2087-106.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-RPRB-O (O2))
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Kagan, Jacob
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University of Texas MD Anderson Cancer Center
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