Circulating tumor cells (CTCs) are cells that have detached from a primary tumor and circulate in the bloodstream. CTCs may constitute seeds for subsequent growth of additional tumors (metastasis) in different tissues.
The detection of CTCs may have important prognostic and therapeutic implications but because their numbers can be very small, these cells are not easily detected [1]. A report published in the September 2009 issue of the Journal of Clinical Oncology suggests that detection of circulating tumor cells helps guide treatment and can impact quality of life for breats cancer patients.[2]
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Circulating tumor cells (CTCs) are cells that have detached from a primary tumor and circulate in the bloodstream. CTCs may constitute seeds for subsequent growth of additional tumors (metastasis) in different tissues.
In 1869 Thomas Ashworth obeserved circulating tumor cells in the blood of a man with metastatic cancer. He postulated that “cells identical with those of the cancer itself being seen in the blood may tend to throw some light upon the mode of origin of multiple tumours existing in the same person”. A thorough comparison of the morphology of the circulating cells to tumor cells from different lesions led Ashworth to conclude that “One thing is certain, that if they [CTC] came from an existing cancer structure, they must have passed through the greater part of the circulatory system to have arrived at the internal saphena vein of the sound leg” [1]. Cancer research has demonstrated the critical role circulating tumor cells play in the metastatic spread of carcinomas [2]. Technology with the requisite sensitivity and reproducibility to detect CTC in patients with metastatic disease was developed only recently [3][4][5][6][7].
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[[File:|thumb|200px|Figure 1: cell number of various blood cells in whole blood versus CTC]] The detection of CTCs may have important prognostic and therapeutic implications but because their numbers can be very small, these cells are not easily detected [8]. Circulating tumor cells are found in frequencies in the order of 1-10 CTC per mL of whole blood in patients with metastatic disease. For comparison, a mL of blood contains a few million white blood cells and a billion red blood cells, see figure 1. This low frequency means that a key component of methods to detect CTC is the enrichment method.
[[File:|thumb|600px|Figure 2: Kaplan Meier Analysis of overall survival before starting a new line of therapy for patients with metastatic breast, colorectal and prostate cancer. Patients were divided into those with Favorable and Unfavorable CTC (Unfavorable: >5 CTC/7.5mL for breast and prostate, >3 CTC/7.5mL for colon) [9]]] To date, a variety of research methods have been developed to isolate and enumerate CTC [10]. The only FDA cleared methodology for enumeration of CTC in whole blood is the CellSearch system [11]. Extensive clinical testing done using this method shows that presence of CTC is a strong prognostic factor for overall survival in patients with metastatic breast, colorectal or prostate cancer, see figure 2 [12][13][14][15][16][17][18]
Blood is sampled in an EDTA tube with an added preservative. Upon arrival in the lab, 7.5mL of blood is centrifuged and placed in a preparation system. This system first enriches the tumor cells immunomagnetically by means of ferrofluidic nanoparticles conjugated to epithelial cell adhesion molecule (EpCAM). Subsequently it stains the sample with a nuclear stain, and fluorescent antibody conjugates against CD45 and cytokeratin 8, 18 and 19 (CK). The sample is scanned on an analyzer, which takes images of the nuclear stain, the cytokeratin stain and the CD45 stain. A trained operator looks at the images of cells to identify those cells that are positive for the nuclear stain and the cytokeratin stain and negative for the CD45 stain. If the cell meets these criteria, the operator judges whether the morphology is suitable for a tumor cell. If the total number of tumor cells found is 5 or more, a sample is positive. In studies done on prostate, breast and colon cancer patients, median survival of metastatic patients with positive samples is about half the median survival of metastatic patients with negative samples.
Morphological appearance is judged by human operators and is therefore subject to large inter operator variation [19]. Several CTC enumeration methods exist which use morphological appearance to identify CTC, which may also apply different morphological criteria. A recent study in prostate cancer showed that many different mophological definitions of circulating tumor cells have similar prognostic value, even though the absolute number of cells found in patients and normal donors varied by more than a decade between different morphological definitions [20].
Some drugs are particularly effective against cancers which fit certain requirements. For example Herceptin is very effective in patients who are Her2 positive, but much less effective in patients who are Her2 negative. Once the primary tumor is removed, biopsy of the current state of the cancer through traditional tissue typing is not possible anymore.[21] Often tissue sections of the primary tumor, removed years prior, are used to do the typing. Further characterisation of CTC may help determining the current tumor phenotype. FISH assays has been performed on CTC to as well as determination of IGF-1R, Her2, Bcl-2, [ERG (gene)|ERG], PTEN, AR status using immunofluorescence.[22][23][24][25][26][27]
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