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Tumor Cells Circulate in the Peripheral Blood of All Major Carcinomas but Not in Healthy Subjects Or Patients with Nonmalignant Diseases

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Tumor Cells Circulate in the Peripheral Blood of All Major Carcinomas but Not in Healthy Subjects Or Patients with Nonmalignant Diseases Vol. 10, 6897–6904, October 15, 2004 Clinical Cancer Research 6897 Tumor Cells Circulate in the Peripheral Blood of All Major Carcinomas but not in Healthy Subjects or Patients With Nonmalignant Diseases W. Jeffrey Allard,1 Jeri Matera,1 Conclusions: The CellSearch system can be standard- M. Craig Miller,1 Madeline Repollet,1 ized across multiple laboratories and may be used to deter- mine the clinical utility of CTCs. CTCs are extremely rare in Mark C. Connelly,1 Chandra Rao,1 1 2 healthy subjects and patients with nonmalignant diseases Arjan G. J. Tibbe, Jonathan W. Uhr, and but present in various metastatic carcinomas with a wide 1 Leon W. M. M. Terstappen range of frequencies. 1Immunicon Corporation, Huntingdon Valley, Pennsylvania; and 2Cancer Immunobiology Center and Departments of Microbiology, University of Texas Southwestern Medical Center at Dallas, INTRODUCTION Dallas, Texas There are accumulating reports of the isolation and char- acterization of circulating tumor cells [CTCs (1–18)]. The find- ings that CTCs can be found in patients before the primary ABSTRACT tumor is detected, CTCs are found in a significant proportion of Purpose: The purpose of this study was to determine the patients when a carcinoma recurs, and CTCs persist in some accuracy, precision, and linearity of the CellSearch system patients after removal of the primary tumor have been the and evaluate the number of circulating tumor cells (CTCs) impetus for continued studies of these tumor cells. Evidence that per 7.5 mL of blood in healthy subjects, patients with non- CTCs are derived from clones in the primary tumor (16) sug- malignant diseases, and patients with a variety of metastatic gests that they may reflect the tumor burden at all stages of carcinomas. tumor progression. Thus, in addition to a potential role in early Experimental Design: The CellSearch system was used diagnosis and prognostication, CTCs may play a major role in to enumerate CTCs in 7.5 mL of blood. Blood samples characterizing genetic and immunophenotypic changes with tu- spiked with cells from tumor cell lines were used to establish mor progression, thereby helping to guide targeted therapy (17, analytical accuracy, reproducibility, and linearity. Preva- 18). A particularly important attribute of a blood test is that it is lence of CTCs was determined in blood from 199 patients safe and can be performed frequently, whereas repeated invasive with nonmalignant diseases, 964 patients with metastatic procedures including bone marrow aspiration may provide lim- carcinomas, and 145 healthy donors. ited patient compliance. Results: Enumeration of spiked tumor cells was linear A major problem in the field is that different techniques over the range of 5 to 1,142 cells, with an average recovery have been used to isolate and characterize CTCs (1, 7, 19–23). > of 85% at each spike level. Only 1 of the 344 (0.3%) It is not known to what extent these assays differ in sensitivity, > healthy and nonmalignant disease subjects had 2 CTCs reproducibility, and specificity for detection of CTCs in neo- per 7.5 mL of blood. In 2,183 blood samples from 964 plastic and nonneoplastic diseases. Therefore, it is difficult to metastatic carcinoma patients, CTCs ranged from 0 to compare results from different laboratories without answers to ؎ 23,618 CTCs per 7.5 mL (mean, 60 693 CTCs per 7.5 mL), the above-mentioned questions. > and 36% (781 of 2,183) of the specimens had 2 CTCs. The purpose of the present study is to show that by the use > Detection of 2 CTCs occurred at the following rates: 57% of a cellular preservative to prevent CTC degradation and the (107 of 188) of prostate cancers, 37% (489 of 1,316) of breast CellSearch system consisting of semiautomated equipment and cancers, 37% (20 of 53) of ovarian cancers, 30% (99 of 333) prepackaged kits for the isolation and identification of CTCs it of colorectal cancers, 20% (34 of 168) of lung cancers, and is possible to obtain highly reproducible quantitative results 26% (32 of 125) of other cancers. from different laboratories and to prove that CTCs are rarely present in patients with nonneoplastic diseases. Accuracy, precision, and linearity of the CellSearch system were determined, and the number of CTCs per 7.5 mL of blood in healthy subjects, patients with nonmalignant diseases, and Received 2/26/04; revised 6/4/04; accepted 7/6/04. The costs of publication of this article were defrayed in part by the patients with a variety of metastatic carcinomas was evaluated. payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. MATERIALS AND METHODS Note: Supplementary data for this article can be found at Clinical Patients and Blood Collection. Blood was drawn at Cancer Research Online (http://clincancerres.aacrjournals.org). multiple geographically dispersed locations from healthy female Requests for reprints: W. Jeffrey Allard, Immunicon Corporation, 3401 Masons Mill Road, Suite 100, Huntingdon Valley, PA 19006. Phone: volunteers, women with nonmalignant diseases, and patients 215-830-0777, ext. 193; E-mail: [email protected]. with a variety of metastatic carcinomas into evacuated 10-mL ©2004 American Association for Cancer Research. blood draw tubes containing EDTA (Becton Dickinson, Frank- Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2004 American Association for Cancer Research. 6898 Circulating Tumor Cells in Cancer and Noncancer Subjects lin Lakes, NJ) or the CellSave Preservative Tube (Veridex LLC, remaining plasma were aspirated. The staining reagents were Raritan, NJ). Specimens drawn into EDTA tubes had a cellular then added in conjunction with a permeabilization buffer to preservative manually added immediately after the blood draw fluorescence label the immunomagnetically labeled cells. After (24, 25). The CellSave Preservative Tube is an evacuated blood incubation on the system, the magnetic separation was repeated, draw tube containing EDTA as anticoagulant and a cellular and excess staining reagents were aspirated. In the final proc- preservative. Samples were maintained at room temperature and essing step, the cells were resuspended in the MagNest Cell processed within 72 hours of blood collection. All patients were Presentation Device (Veridex LLC). This device consists of a enrolled using institutional review board-approved protocols chamber and two magnets that orient the immunomagnetically and provided informed consent. Blood was always drawn from labeled cells for analysis using the CellSpotter Analyzer. cancer patients either before or a minimum of 7 days after the Sample Analysis. The MagNest is placed on the Cell- administration of intravenous therapy. Results of the control Spotter Analyzer, a four-color semiautomated fluorescence mi- group were reported previously (26). The healthy volunteers had croscope. Image frames covering the entire surface of the car- no known illness or fever at the time of draw, no history of tridge for each of the four fluorescent filter cubes are captured. Ն malignant disease, and were 35 years old to provide a cohort The captured images containing objects that meet predetermined age-matched with the cancer population. The women with non- criteria are automatically presented in a web-enabled browser malignant diseases included those with benign breast diseases as from which final selection of cells is made by the operator. The well as other nonmalignant diseases. These subjects had no criteria for an object to be defined as a CTC include round to Ն known history of cancer and were 25 years old. oval morphology, a visible nucleus (DAPI positive), positive Cell Culture and Cell Spiking. The breast cancer cell staining for cytokeratin, and negative staining for CD45 (23, line SKBR-3 was cultured in flasks containing RPMI 1640 27). Results of cell enumeration are always expressed as the supplemented with 10% fetal calf serum and subsequently har- number of cells per 7.5 mL of blood. vested using trypsin. The cell suspensions were only used when Accuracy, Sensitivity, and Linearity of Circulating Tu- their viability as assessed by trypan blue exclusion exceeded mor Cell Detection. The following procedure was used to 90%. To determine the actual cell number, a 50-␮L aliquot of estimate the accuracy, sensitivity, and linearity of the the SKBR-3 cells was permeabilized and fluorescence labeled CellSearch system. Five 7.5-mL aliquots of blood collected into by adding 200 ␮L of PBS containing 0.05% saponin and 10 ␮L CellSave Preservative Tubes from each of five healthy donors of anticytokeratin monoclonal antibody conjugated to phyco- were prepared. The five aliquots from each donor were spiked erythrin at a final concentration of 0.5 ␮g/mL. After a 15-minute incubation at room temperature, 200 ␮L of buffer and 20 ␮Lof with different numbers of SKBR-3 cells to produce separate fluorescent beads (Beckman-Coulter, Inc., Miami, FL) contain- tubes with approximately 1,142, 286, 71, 18, or 4 cells per 7.5 ing approximately 20,000 total beads were added. Duplicate mL of blood. The 25 tubes were then processed and analyzed by tubes containing beads only were run on a flow cytometer a single operator according to the sample preparation and sam- (FACSCalibur; BD Biosciences, San Jose, CA) until 100% of ple analysis protocols. the sample was aspirated. This provided an accurate estimate of Assay Imprecision. Blood from a healthy donor was the number of beads present in 20 ␮L. The experimental tubes collected into CellSave tubes and dispensed into eight aliquots were then tested in triplicate on the flow cytometer until 10,000 of 7.5 mL. A 50-␮L volume containing 58 SKBR-3 cells was beads were counted in each tube. Using the known number of added to four of the tubes of blood, and a 50-␮L volume beads per unit volume, the concentration of cells was deter- containing 319 cells was added to the remaining four tubes.
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