Breast cancer patients who received chemotherapy prior to surgery had heightened levels of cancer-initiating stem cells in their bone marrow, and the level of such cells correlated to a tumor's lymph node involvement, according to research from The University of Texas M. D. Anderson Cancer Center.
James Reuben, Ph.D., associate professor in the Department of Hematopathology, will present the findings in an oral presentation at the upcoming American Society of Clinical Oncology's annual meeting. It's the first prospective study to investigate the presence of breast cancer stem cells of primary breast cancer patients. The results suggest the need for additional biological therapies, as well as a potential and promising new direction for the study of micro-metastasis.
It's estimated that 30-40 percent of locally advanced breast cancer patients who appear disease-free after neoadjuvant treatment actually harbor undetectable, distant micro-metastasis, explained Reuben.
Reuben describes cancer stem cells as tumor cells found in the bone marrow that are capable of self-renewal, thus a potential catalyst for recurrence and metastasis.
"Until now, the concept of cancer stem cells and their resistance to chemotherapy has been described in the lab in animal models. With this study, we are characterizing cancer stem cells and consistently identifying them in breast cancer patients for the first time," said Reuben, the study's first author. "Our research showed a higher presence of cancer stem cells correlated with more advanced disease, suggesting that they may one day be a prognostic factor for identifying those at greatest risk for metastasis and recurrence."
Cancer stem cells are a small but important component of circulating (found in peripheral blood) and disseminating (found in the bone marrow) tumor cells, both already shown to be independent prognostic factors for breast cancer, in that they are self-renewing. Cancer stem cells have been described in previous preclinical models, but before now, have been extremely difficult to detect and characterize in cancer patients.
The study enrolled 90 M. D. Anderson breast cancer patients from September 2006 to October 2008. Bone marrow aspirations were performed in all women at the time of their surgery. Of the 90 women, 29 (32 percent) had undergone neoadjuvant chemotherapy, and eight of the 29 had been treated with anti HER2 targeted therapy. All other patients had early-stage disease, and, therefore, did not need chemotherapy prior to surgery. Of the bone marrows collected, 61 were analyzed for estrogen receptor and HER-2 status, as well as expression of the transcription factor Notch-1.
Using multi-color flow cytometry methods capable of detecting multiple markers and receptors on the surface of cells the researchers found patients who received neoadjuvant therapy featured a significantly higher presence of breast cancer stem cells and higher percentage of specific markers that are associated with breast cancer stem cells, compared to patients with early-stage disease.
"As the cancer stem cells were concentrated in patients who had already received therapy, our research indicates their true resilience and lack of sensitivity to chemotherapy, as well as demonstrates a need for a more comprehensive study of micro-metastasis and molecular markers that target these illusive cells," said Reuben. "While intriguing, this is still early research and more research is needed to determine the true relationship between cancer stem cells, progression- and disease-free survival in breast cancer patients."
The researchers also found the level of Notch-1 was lower in neoadjuvant treated patients and inversely correlated between the level of its expression and the percentage of breast cancer stem cells, suggesting that Notch signaling may play an integral role in the development of breast cancer stem cells.
Reuben will present the node status research at his oral presentation in the Clinical Science Symposium session on Saturday, May 30 at 2:15 p.m.
According to Massimo Cristofanilli, M.D., associate professor in M. D. Anderson's Department of Breast Medical Oncology, these findings provide a direction for immediate concept and design of adjuvant clinical study.
"Although early, the research stands highlights the concept that chemotherapy alone does not cure a significant number of primary breast cancer patients, and gives us an indication for a new line of therapeutic intervention that focuses on new biological agents that target cancer stem cells," said Cristofanilli, also a senior author on the study. "The research also presents a strong case for obtaining bone marrow specimens from locally advanced breast cancer patients undergoing surgery after neo-adjuvant therapy, with the rationale that it will lead to better monitoring of patients who may need additional treatment."
Such studies are currently ongoing in collaboration with Anthony Lucci, M.D., associate professor in the Department of Surgery, also an author on the study, Reuben said. Also, based on these initial findings, a clinical trial with a Notch inhibitor is in development at M. D. Anderson.
The study was funded, in part by grants from the State of Texas, National Cancer Institute, and the Morgan Welch Inflammatory Breast Cancer Research Program and Clinic.
In addition to Reuben, Cristofanilli and Lucci, other authors on the all-M. D. Anderson study include: Gabriel Hortobagyi, M.D., professor and chair of the Department of Breast Medical Oncology; Wendy Woodward, M.D., Ph.D., assistant professor in the Department of Radiology; Savitri Krishnamurthy, M.D., associate professor in the Department of Pathology; and Bang-Ning Lee, Ph.D., assistant professor; Hui Gao, Ph.D., post-doctoral fellow, Changping Li, M.D., post-doctoral fellow, and Evan Cohen, B.S., graduate student, all of the Department of Hematopathology.
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