Circulating tumor cells (CTCs) are an important predictor of survival in metastatic breast cancer patients. When CTCs undergo epithelial-mesenchymal transition (EMT), resulting in a loss of epithelial markers, they may escape conventional detection, according to data presented at the annual CTRC-AACR San Antonio Breast Cancer Symposium, USA.
"Our data suggest that current CTC detection methods may underestimate the most important subpopulation of CTCs, which are involved in tumour dissemination," said Michal Mego, a scientist at the National Cancer Institute in the Slovak Republic. The research was conducted while Mego was an International Union Against Cancer Scholar in the Morgan Welch Inflammatory Breast Cancer Research Program and Clinic at The University of Texas M. D. Anderson Cancer Center.
The presence of an increased number of CTCs is associated with poor prognosis in breast cancer patients, Mego explained. Cells with this EMT phenotype are probably involved in tumour dissemination and represent tumour initiating cells. Identification of therapeutic targets on these cells could lead to eradication of micrometastatic disease in breast cancer, as well as in other epithelial tumors.
"When we retrospectively evaluated the outcome of breast cancer patients, we observed that there were subgroups of patients, such as those with brain metastasis, triple negative or inflammatory breast cancer, who had poor prognosis and low or undetectable CTCs by conventional methods," Mego said. "We found that the low or undetectable CTCs were due to the existence of a subpopulation of cancer cells that undergoes a process of EMT."
When epithelial cells undergo EMT, they lose their epithelial receptors. As a result, they are no longer detected by current detection assays. In addition, these cancer cells become resistant to chemotherapy or radiation therapy, according to Mego.
"This observation led us to hypothesize that EMT CTCs are responsible for tumour dissemination," Mego said. "Hence, we developed a novel detection method that would be capable of identifying EMT CTCs in peripheral blood from breast cancer patients."
In this prospective study, Mego and colleagues used approximately 5 mL of peripheral blood from patients with varying stages of breast cancer and isolated the CTCs using magnetic beads coated with monoclonal antibodies. Using a polymerase chain reaction, they then isolated RNA to detect genes that are involved in EMT.
Patients who had triple-negative breast cancer more commonly overexpressed EMT genes compared to non-triple-negative patients.
"Our data indicate that a subpopulation of CTCs with EMT really exists, and that these cells are more commonly detected in patients with poor prognosis such as those with triple-negative breast cancer or in patients pretreated by neoadjuvant chemotherapy who have developed resistance to therapy," Mego said. "A novel detection method such as ours that is capable of detecting CTCs after EMT could add new important prognostic information, and could be useful for monitoring treatment efficacy."
Mego and colleagues also initiated a confirmatory study in metastatic breast cancer patients as well as in prostate and colorectal cancer patients to confirm their findings. These studies were aimed to identify therapeutic targets on these cells.
Ongoing research at The University of Texas M. D. Anderson Cancer Center and the National Cancer Institute in the Slovak Republic will continue to focus on the detection of CTCs with tumour-initiating properties, as well as the identification of potential therapeutic targets for CTCs. Trastuzumab treatment based on detection of HER-2/neu amplification on CTCs represents proof of this new concept of targeted therapy, according to Mego.
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