Circulating tumor cells (CTCs) were discovered nearly 150 years ago but have only recently been recognized as a feature of most solid tumors due to their extremely low concentration in the peripheral circulation. Several technologies have been developed to isolate and analyze CTCs, which can now be routinely accessed for clinical information. The most mature of these (the CELLSEARCH system) uses immunomagnetic selection of epithelial cell adhesion molecule to isolate CTCs for analysis. Studies using this system have demonstrated that categorization of patients into high and low CTC groups using a validated decision point is prognostic in patients with metastatic breast, colorectal, or prostate cancer. Initial attempts to use CTC counts to guide therapeutic decisions appeared to yield positive results and key concepts in clinical application of CTC information, including the CTC cutoff, predictive value in disease subtypes, and comparison to current evaluation methods, have been demonstrated. Clinical studies of the impact of CTC counts in routine clinical practice are ongoing; however, recent published evidence on the clinical use of CTCs in metastatic breast cancer continues to support these concepts, and experience in the community oncology setting also suggests that CTC enumeration can be useful for therapy management. 1. Introduction In the United States nearly 40,000 deaths are attributed to metastatic breast cancer (MBC) annually [1]. Once breast cancer has metastasized it is usually fatal [2]; however, intensive research into the causes of breast cancer and the development of an array of effective targeted therapeutics has improved survival for these women. Appropriate management of treatment is important to make best use of these new therapeutics. Circulating tumor cell (CTC) analysis is a promising tool to address the need for better disease management, potentially improving both survival and quality of life for MBC patients. 2. History and Initial Clinical Application CTCs represent the hematogenous phase of metastasis [3]. They were initially observed over 150 years ago as a leukemia-like manifestation of cancer [4] with very high concentrations of malignant cells in the peripheral circulation. Most instances of metastatic solid tumors are not accompanied by high concentrations of CTCs, so these cells were not a focus of tumor biology research or clinical application until contemporary studies demonstrated the frequent presence of CTCs in patients with solid tumors, albeit at very low concentrations [5–7]. Importantly, CTCs are essentially
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