Mobile Site ›
Communique Print the PDF of this entire issue

The CellSearch Assay for Circulating Tumor Cells:

An Advance in Cancer Prognosis and Treatment


Subscribe

Receive notification when new Communiqué articles are published:

January 2011

Background

The management of cancer has evolved greatly over the past century. Important developments that have contributed to decreased cancer morbidity and mortality include surgery, chemotherapy, radiotherapy, and screening programs that lead to earlier tumor detection. Unfortunately, the war on cancer is far from won. There were approximately 51,000 colorectal-, 40,000 breast-, and 32,000 prostate-cancer deaths in 2010 and almost all were due to the development of metastatic disease.

In the late 1800s, a number of physicians including Stephen Paget and Thomas Ashworth,1, 2 hypothesized that tumor metastases were the result of tumor cells dislodging from the primary tumor, circulating in the peripheral bloodstream, and seeding distant sites. These cells were referred to as circulating tumor cells. Since that time cancer researchers have demonstrated the critical role that these cells play in metastasis.

In recent years, tools have been developed to detect circulating tumor cells. The availability of such tools improves our ability to monitor treatment in patients with metastatic cancer. Currently, the only US Food and Drug Administration (FDA)-cleared system for detecting circulating tumor cells in peripheral blood is the CellSearch system (Veridex LLC). The system is FDA cleared for the detection of circulating tumor cells in patients with metastatic breast, prostate, and colorectal cancer. This review will discuss how the system works and how it can be used to provide prognostic information and monitor treatment of metastatic cancer.

Cancer Metastasis

Depending on the type of cancer, approximately one-half of patients will present with either regional or distant clinically detectable metastases. The metastatic process is important to consider since most cancer deaths occur as a result of metastatic disease. Cancer metastasis consists of a series of separate, yet related, steps that must occur in order for a tumor cell to metastasize.3 As a tumor begins to form, nutrients are initially supplied by simple diffusion through the cell wall. Proliferation of the mass continues through the secretion of angiogenic factors that allow for the growth of a capillary network to supply the tumor’s increasing need for nutrients. Migration through the body occurs when the mass reaches a lymphatic channel or blood vessel, and then tumor cells detaches from that mass and enter the lymphatic or blood vessel. Once in circulation, the tumor cells are transported throughout the body, finally coming to rest against a vessel wall. The tumor cells seep into the surrounding tissue through events similar to those in the migration process. Finally, the newly growing microtumor establishes a new vascular network through angiogenic processes and formation of a new tumor site is complete. While these steps describe the most general overview of the metastatic process, many other factors may be involved including loss of cell to cell adhesion, motility of tumor cells, epithelial-mesenchymal transition, and heterogeneous cell populations in the primary tumor.

Studies have suggested that tumors shed approximately 1 million circulating tumor cells per gram of tumor tissue.4 While this would seem to indicate that the metastatic process would progress quickly, the development of distant metastases is quite inefficient. In fact, within 24 hours after tumor cells are released into circulation, less than 0.1% of the cells are still viable, and less than 0.01% of the viable cells survive to produce metastases.5 Therefore, approximately 1 tumor cell may be present in the circulation per 100,000 to 10 million peripheral blood mononuclear cells.6 Ultimately, the search for circulating tumor cells becomes a test of the ability of an assay to find a needle in a haystack.

Cancer patients are most commonly monitored for metastatic disease by periodic clinical surveillance using radiologic imaging techniques (computerized tomography [CT], positron emission tomography [PET], magnetic resonance imaging [MRI], etc), biomarkers, and clinical findings. A new method of monitoring patients with breast, colorectal, or prostate cancer includes screening for circulating tumor cells. The CellSearch Circulating Tumor Cell assay is the first and only assay to date cleared by the FDA to use circulating tumor cell analysis to determine prognosis in patients with metastatic disease. These tests are offered by Mayo Medical Laboratories as #89089 Circulating Tumor Cells (CTC) for Breast Cancer by CellSearch, Blood, #89162 Circulating Tumor Cells (CTC) for Colorectal Cancer by CellSearch, Blood, and #60142 Circulating Tumor Cells (CTC) for Prostate Cancer by CellSearch, Blood.

The assay allows the capture and enumeration of tumor cells circulating in peripheral blood in a standardized format.7 Clinical trial studies have shown that this type of testing offers useful information for the physician to monitor progression of disease or response to treatment. Studies have also demonstrated that detection and quantitation of circulating tumor cells is an independent predictor of progression-free and overall survival in patients with metastatic cancer and provides valuable prognostic information sooner to support patient care decisions.8-10

Figure 1

Figure 1. The CellTracks AutoPrep system automates and standardizes the preanalytical specimen preparation step that captures and stains circulating tumor cells for analysis.
Used with permission. © Veridex, LLC 2010

The CellSearch Circulating Tumor Cell Assay System

The CellSearch Circulating Tumor Cell system (Veridex LLC) uses a combination of immunomagnetic labeling and automated digital microscopy to identify and enumerate the number of circulating tumor cells in a peripheral blood specimen. It consists of a CellTracks AutoPrep system (Figure 1), which isolates the circulating tumor cells, and a CellTracks Analyzer, which differentiates the tumor cells from nonspecific cells and debris. The process begins with a 7.5 mL peripheral blood specimen from the patient. Blood is collected using the Circulating Tumor Cell Collection Kit (supply T630) and the specimen must be promptly shipped to assure processing within 96 hours of collection. Once in the laboratory, the whole blood specimen is centrifuged and placed on the CellTracks AutoPrep system (Figure 1). The plasma is aspirated to waste and the remaining cellular component is mixed with buffer and ferrofluid reagent conjugated with monoclonal epithelial cell adhesion molecule (EpCAM) antibodies. The ferrofluid/antibody complex attaches specifically to epithelial cells. Magnets then attract the ferrofluid-bound cells to the side of the tube, the remaining fluid and any unlabeled cells are aspirated and the magnets are removed. The remaining cells are then resuspended in buffer. The CellSearch system uses 3 stains to help distinguish epithelial cells from contaminating leukocytes and nonspecific debris: 4’-6-diamidino-2-phenylindole (DAPI) stains the nuclei of cells and helps identify viable cells, phycoerythrin (PE)-labeled cytokeratin (CK) antibodies (CK 8, 18, and 19) recognize epithelial cells, allophycocyanin (APC)-labeled CD45 antibodies identify contaminating leukocytes. The resulting epithelial-enriched fluid is then placed in a cell presentation device (MagNest) that attracts the magnetically labeled epithelial cells to the surface of the cartridge. The cartridge is placed on the CellTracks Analyzer, a fluorescence-based microscopy system that scans the surface of the cartridge to acquire cell images to visualize DAPI-labeled nuclei, PE-labeled CK, and APC-labeled CD45. A gallery of images is reviewed by a technologist who identifies tumor cells based on the circulating tumor cell phenotype showing positive DAPI and CK staining with an absence of CD45 staining (Figure 2a). All other staining combinations represent circulating nontumor cells (eg, leukocytes) or noncellular debris (Figure 2b).

Figure 2a

Figure 2a These images considered classic examples of circulating tumor cells ( CK-PE+, DAPI+, CD45-APC-) as seen on the CellSearch analyzer.

Figure 2b

Figure 2b This image demonstrates events that are not circulating tumor cells.
A. Detached nuclei B. Control cell carryover C. Dual positive-staining leukocyte D. Noncellular debris E. Leukocyte

Circulating Tumor Cells and the CellSearch System in Metastatic Cancer

As noted above, the CellSearch system is FDA cleared for detection of circulating tumor cells in patients with metastatic breast, prostate, and colorectal cancer. The following sections will discuss the evidence that shows the clinical utility of the CellSearch system for each of these patient populations.

Metastatic Breast Cancer

In 2010, an estimated 209,060 new cases of breast cancer were diagnosed in the United States and there were approximately 40,230 deaths from this disease.11 Of newly diagnosed cases of breast cancer, 5% of patients will have metastatic breast cancer at diagnosis, and another 30% will ultimately develop metastatic disease. Primary tumor metastasis is the leading cause of breast cancer-related death and detection of the presence of circulating tumor cells in the blood of cancer patients may be an important indicator of the potential for metastatic disease and poor prognosis. Therefore, recent efforts that focus on the ability of an assay that can be performed on a peripheral blood sample to consistently enumerate, track, and characterize circulating tumor cells in cancer patients holds promise to determine patient prognosis and to monitor response to treatment.

A multicenter, prospective, longitudinal clinical trial using the CellSearch system was conducted between 2001 and 2003, and the results published in 4 scientific publications.8,10,13,14 Results were used to determine whether the number of circulating tumor cells predicted disease progression and survival in metastatic breast cancer patients. The trial included 177 patients with metastatic disease as defined by standard imaging techniques. A baseline circulating tumor cell count was determined prior to start of new therapy and a follow-up count was determined approximately 3 to 4 weeks after the start of therapy. Progression-free survival was determined from the time of the baseline blood draw to identifiable disease progression based on CT scans or clinical indications. Overall survival was measured from baseline blood draw to the time of death.

Kaplan-Meier analyses were performed to determine whether circulating tumor cell counts could predict progression-free and overall survival. Patients were separated into 2 groups based on their circulating tumor cell count. The favorable group (n = 90) represented patients with a baseline circulating tumor cell count <5, while the unfavorable group (n = 87) represented patients with a baseline count ≥ 5. The median progression-free survival was approximately 7.0 months for the favorable group and 2.7 months for the unfavorable group, which was statistically significant (P = 0.0001) (Figure 3a). Circulating tumor cell enumeration was also shown to be a predictive marker of overall survival. When comparing the favorable and unfavorable groups, the median overall survival was shown to be significantly (P<0.0001) longer in the favorable group than in the unfavorable group (21.9 versus 10.9 months [Figure 3b]). The data from this clinical trial led to FDA clearance in 2004 of the CellSearch assay for the capture and enumeration of circulating tumor cells in metastatic breast cancer patients.

Figure 3a

Figure 3a Progression-free survival of metastatic breast cancer patients with <5 or ≥5 circulating tumor cells at baseline (n=177)
Used with permission. © Veridex, LLC 2010

Figure 3b

Figure 3b Overall survival of metastatic breast cancer patients with <5 or ≥5 circulating tumor cells at baseline (n=177)
Used with permission. © Veridex, LLC 2010

Monitoring circulating tumor cell levels during the course of treatment has also been shown to provide additional prognostic information. The most striking result of 1 study showed that patients with ≥5 circulating tumor cells at both baseline and at the end of treatment had significantly shorter median progression-free survival (1.8 months) and overall survival (4.1 months) than patients in all other groups. Patients with <5 circulating tumor cells at each time point had the longest median progression-free and overall survival (7.2 and 22.6 months, respectively). Interestingly, patients with ≥5 circulating tumor cells at baseline, which decreased to <5 at the end of treatment had significantly longer median progression-free and overall survival than patients who maintained counts of at least 5 at all time points (Figure 4a and 4b).

Figure 4a

Figure 4a A reduction in circulating tumor cells to <5 after the initiation of therapy predicts longer progression-free survival in metastatic breast cancer patients
Used with permission. © Veridex, LLC 2010

Figure 4b

Figure 4b A reduction in circulating tumor cells to <5 after the initiation of therapy predicts longer overall survival whereas an increase in circulating tumor cells count to 5 or above predicts shorter overall survival in metastatic breast cancer patients.
Used with permission. © Veridex, LLC 2010

Several clinical and biomarker parameters were evaluated by univariate Cox regression analysis to determine which features were predictors of progression-free and overall survival at baseline. The number of circulating tumor cells (<5 versus ≥ 5), line of therapy (first versus second), and type of therapy (chemotherapy versus hormonal, immunotherapy versus chemotherapy) were univariate predictors of progression-free survival. These 3 features, as well as time to metastasis, estrogen receptor/progesterone receptor (ER/PR) status, and baseline Eastern Cooperative Oncology Group (ECOG) status, used to record the physical status of patients (2 versus 1 versus 0) (Table)15 were univariate predictors of overall survival. When these features were evaluated in a multivariate model, the type of therapy (hazard ratio [HR] = 1.74), circulating tumor cell number (HR = 1.69), and line of therapy (HR = 1.52) were independent predictors of progression-free survival. All 6 of the features in the overall survival multivariate model were independent predictors, which included circulating tumor cell number (HR = 2.62), ER/PR status (HR = 0.57), baseline ECOG status (HR = 1.58), time to metastasis (HR = 0.97), line of therapy (HR = 2.33), and type of therapy (HR = 1.78). Since circulating tumor cell counts at baseline and prior to the first imaging studies have been shown to predict overall and progression-free survival, this analysis may provide a more accurate assessment of prognosis when used in conjunction with surveillance imaging techniques as compared with imaging alone.

ECOG Performance Status15
Grade ECOG
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours
3
Capable of only limited self care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self care. Totally confined
to bed or chair
5
Dead

Table. This assessment is a tool used by adult oncologists and researchers to assess a patient’s quality of life and physical disability, determine appropriate care plans and treatment, and establish prognosis. This information is provided by the Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair

Metastatic Colorectal Cancer

In 2010, an estimated 142,570 new cases of colorectal cancer were diagnosed in the United States with approximately 51,370 deaths due to colorectal cancer.11 Of the new cases, nearly 20% had metastatic colorectal cancer when diagnosed and nearly one-third will develop metastases during clinical follow-up. Therefore, approximately 75,000 new patients are being treated for metastatic colorectal cancer every year.12

A multicenter, prospective clinical trial was conducted between 2004 and 2006 to determine whether circulating tumor cell enumeration could predict colorectal cancer disease progression and survival.16,17 Prior to initiation of a new line of therapy, 430 patients with measurable metastatic colorectal cancer were enrolled. Measurable disease was defined as a minimum of one 2-cm lesion to a maximum of 10 lesions. Imaging methods were determined for each patient as per the current standard of care defined by the patient’s physician. All lesions seen at baseline were followed using the same method for all successive studies, either CT or MRI of the chest, abdomen, and pelvis. A baseline circulating tumor cell count was established prior to the start of therapy and follow-up counts were determined every 3 to 4 weeks. Progression-free survival was measured from the time of baseline blood draws until the time of detectable disease progression based on CT or MRI scans and clinical findings. Overall survival was determined from the time of baseline blood draws to the time of death.

The majority of patients (413 of 430) had a baseline blood draw, and a Kaplan-Meier curve was generated to evaluate progression-free and overall survival between 2 patient cohorts based on baseline circulating tumor cell counts. Unlike the metastatic breast cancer trial, which used a cutoff of ≥5 circulating tumor cells to place patients in the unfavorable group, the metastatic colorectal cancer trial used a cutoff of ≥3. The favorable group (n = 305) in the metastatic colorectal cancer trial consisted of patients with a <3 circulating tumor cell count at baseline, while the unfavorable group (n = 108), consisted of patients with a cell count ≥3. Based on the baseline cell counts, Kaplan-Meier analyses were performed in the 2 patient cohorts. The results of this study showed that progression-free and overall survival were significantly higher in patients in the favorable group. The median progression-free survival was 7.9 months for the favorable group versus 4.5 months for the unfavorable group (P = 0.0002) (Figure 5a) and the median overall survival (Figure 5b) was longer for the favorable group when compared to the unfavorable group (18.5 versus 9.4 months, respectively [P<0.0001]). The information from this clinical trial led to FDA clearance of the CellSearch assay in 2007 for the capture and enumeration of circulating tumor cells in metastatic colorectal cancer patients.

Figure 5a

Figure 5a Progression-free survival of metastatic colorectal cancer patients with <3 or ≥3 circulating tumor cells at baseline (n=413)
Used with permission. © Veridex, LLC 2010

Figure 5b

Figure 5b Overall survival of metastatic colorectal cancer patients with <3 or ≥3 circulating tumor cells at baseline (n=413)
Used with permission. © Veridex, LLC 2010

Monitoring circulating tumor cell levels during the course of treatment has also shown to provide additional prognostic information (Figure 6). The results from studies have shown that a reduction of circulating tumor cells to less than 3 after the start of therapy predicts a longer progression-free survival in metastatic colorectal cancer patients. Those patients with less than 3 circulating tumor cells for each time point had a longer median progression-free survival (8.1 months) and overall survival (18.6 months) than those patients with an increase above 3 circulating tumor cells (progression-free survival = 7.2 months, overall survival=11.7 months). Patients with 3 or more circulating tumor cells at each time point had the worst prognosis and had the shortest median progression-free and overall survival (2.2 and 3.9 months, respectively) compared with the other 3 groups. Interestingly, patients with ≥3 circulating tumor cells at baseline in whom there was a reduction in the cell count to <3 at the last draw showed significantly longer progression-free (7.2 months) and overall survival (11.7 months) compared with the group that had an increase from <3 circulating tumor cells at baseline to ≥3 cells at last draw (median progression-free survival = 4.3 months, overall survival = 7.1 months) (Figure 6a and 6b).

Figure 6a

Figure 6a A reduction in circulating tumor cells to <3 after the initiation of therapy predicts longer progression-free survival in metastatic colorectal cancer patients
Used with permission. © Veridex, LLC 2010

Figure 6b

Figure 6b A reduction in circulating tumor cells to <3 after the initiation of therapy predicts longer overall survival whereas an increase in circulating tumor cells count to 3 or above predicts shorter overall survival in metastatic colorectal cancer patients
Used with permission. © Veridex, LLC 2010

Similar to the clinical trial performed on metastatic breast cancer, several clinical and biomarker parameters were evaluated by univariate Cox regression analysis to determine which features at baseline were independent predictors of overall and progression-free survival. The number of circulating tumor cells (<3 versus ≥3), age (<65 versus ≥65 years), ECOG status (0 versus 1 versus 2), line of therapy (first versus second versus third), bevacizumab therapy, irinotecan therapy, and oxaliplatin therapy were all predictors of progression-free and overall survival. When these features were evaluated in a multivariate model, all 7 parameters were independent predictors of progression-free survival. Baseline circulating tumor cell counts (HR = 1.76) and line of therapy (HR = 1.59) were the best predictors of a worse progression-free survival and bevacizumab, irinotecan, and oxaliplatin therapies were predictors of having better progression-free survival (HR = 0.65, 0.76, and 0.57, respectively). Baseline circulating tumor cell counts were found to be the strongest predictor of worse overall survival (HR = 2.46), while baseline ECOG status (HR = 1.84), age at baseline (HR = 1.84), and line of therapy (HR = 1.59) were found to be independent predictors of overall survival. Bevacizumab therapy was the only feature to be a strong independent predictor of better overall survival (HR = 0.68). Since circulating tumor cell counts at baseline and prior to the first imaging studies were shown to predict overall and progression-free survival, this analysis may provide a more accurate assessment of prognosis when used in conjunction with routine surveillance imaging techniques compared to imaging alone.

Metastatic Prostate Cancer

In the United States in 2010, there were approximately 217,730 new cases of prostate cancer with 32,050 deaths.11 Of the new cases, nearly 4% had evidence of metastatic disease at diagnosis.

A multicenter, prospective clinical trial was conducted between 2004 and 2006 to determine whether the number of circulating tumor cells predicted disease progression and overall survival.9,18 The patient sample in this trial consisted of patients with hormone-resistant, androgen-independent, or castration-resistant tumors. A patient with a castration-resistant tumor is defined as a prostate cancer patient who has had 2 consecutive increases in prostate-specific antigen values despite hormone treatment.

The clinical trial enrolled 231 patients with metastatic prostate cancer who, despite treatment, had an increase in prostate-specific antigen level. Baseline circulating tumor cell counts were determined prior to initiation of a new line of therapy. Most patients (221 of 231) had 1 or more blood draws to monitor circulating tumor cell counts and prostate-specific antigen levels every 4 to 6 weeks after baseline. Progression-free survival was determined by identifying continued increases in prostate-specific antigen values, radiologic imaging evidence of disease progression, or other clinical signs. Overall survival was determined from baseline draw until time of death or until last contact with the patient.

Two hundred nineteen of the 231 patients had a baseline blood draw. A Kaplan-Meier curve was generated to evaluate the difference in progression-free and overall survival between 2 groups of patients based on their baseline circulating tumor cell counts (Figure 7a and 7b). The favorable group (n = 94), consisted of patients with <5 circulating tumor cells identified at baseline. The unfavorable group (n = 125), consisted of patients with a ≥5 circulating tumor cells count. Median progression-free survival was slightly longer (P = 0.0009) for the favorable group (5.8 months) when compared to the unfavorable group (4.2 months).

Figure 7a

Figure 7a Progression-free survival of metastatic prostate cancer patients with <5 or ≥5 circulating tumor cells at baseline (n=219)
Used with permission. © Veridex, LLC 2010

Figure 7b

Figure 7b Overall survival of metastatic prostate cancer patients with <5 or ≥5 circulating tumor cells at baseline (n=219)
Used with permission. © Veridex, LLC 2010

Median overall survival was significantly longer (P<0.0001) for the favorable group when compared to the unfavorable group (21.7 months versus 11.5 months). This information and other data within the same clinical trial led to FDA clearance of the CellSearch assay for the capture and enumeration of circulating tumor cells in metastatic prostate cancer patients in 2008.

Monitoring circulating tumor cells levels during the course of treatment has also shown to provide additional prognostic information. The results from studies have shown that a reduction of circulating tumor cells to below 5 after the start of therapy predicted longer progression-free survival in metastatic prostate cancer patients. Patients who had ,<5 circulating tumor cells for all time points had the longest median progression-free survival (6.5 months) and overall survival (>26 months) of all groups. Patients who had ≥5 circulating tumor cells for all time points had the worst prognosis and had the shortest median progression-free survival (2.5 months) and overall survival (6.8 months) than the other 3 groups. Interestingly, patients with ≥5 circulating tumor cells at baseline who had a reduction in circulating tumor cells to <5 at the last draw showed significantly longer progression-free survival (7.3 months) and overall survival (21.3 months) than the group that had an increase of circulating tumor cells from <5 circulating tumor cells at baseline to ≥5 at last draw (median progression-free survival = 4.2 months, overall survival = 9.3 months).

Several clinical and biomarker parameters were evaluated by univariate Cox regression analysis to determine which features were predictors of overall and progression-free survival at baseline. Number of circulating tumor cells at baseline (<5 versus ≥5), baseline ECOG status (0 versus 1 versus 2) (Table), baseline hemoglobin, baseline lactate dehydrogenase (LDH), line of therapy (first through sixth), and type of therapy (taxotere) were predictors of progression-free survival on univariate analysis. These 6 parameters and baseline alkaline phosphatase were also univariate predictors of overall survival. When these features were evaluated in a multivariate model, baseline hemoglobin (HR = 0.88 per g/dL), baseline LDH (HR = 1.0007 per IU/mL), and type of therapy (HR = 0.63) were independent predictors of progression-free survival at baseline. Independent predictors of overall survival at baseline included baseline circulating tumor cell counts (HR = 1.93), ECOG status (HR = 1.46), hemoglobin (HR = 0.81 per g/dL), and LDH (HR = 1.002 per IU/mL).

These parameters, as well as prostate-specific antigen reduction from baseline (≥30% versus <30%), were evaluated by multivariate Cox regression analysis again at 2 to 5 weeks, 6 to 8 weeks, 9 to 12 weeks, and 13 to 20 weeks after initiation of therapy. Interestingly, the most independent predictors were found at the 6- to 8-week blood draw. Prostate-specific antigen reduction was found to be a strong predictor of progression-free survival during the 4 follow-up visits (HR = 1.40, 1.88, 2.23, and 1.97 for weeks 2 to 5, 6 to 8, 9 to12, and 13 to 20, respectively). Having a circulating tumor cell count less than 5 versus an unfavorable circulating tumor cell count greater than 5 was found to be the strongest predictor of progression-free survival (HR = 1.48, 2.14, 1.74, and 2.95) and overall survival (HR = 2.91, 2.13, 3.94, and 3.75) for almost all of the 4 follow-up visits. Since circulating tumor cell counts and prostate-specific antigen reduction rates have been shown to predict overall survival during the course of treatment, Kaplan-Meier analyses were performed to determine whether a combination of circulating tumor cell analysis and prostate-specific antigen reduction rates could better predict overall survival during treatment. The results from this analysis showed that patients with ≥5 circulating tumor cells at any time point after initiation of therapy were much more likely to have shorter overall survival than those with <5 circulating tumor cells, regardless of their prostate-specific antigen reduction measurement from baseline. This analysis also showed that a reduction in prostate-specific antigen from baseline was predictive of overall survival and circulating tumor cell analysis was much more accurate than prostate-specific antigen reduction measurements (Figure 8a and 8b).

Figure 8a

Figure 8a A reduction in circulating tumor cells to <5 after the initiation of therapy predicts longer progression-free survival in metastatic prostate cancer patients
Used with permission. © Veridex, LLC 2010

Figure 8b

Figure 8b A reduction in circulating tumor cells to <5 after the initiation of therapy predicts longer overall survival whereas an increase in circulating tumor cells count to ≥5 predicts shorter overall survival in metastatic prostate cancer patients
Used with permission. © Veridex, LLC 2010

Conclusion

Circulating tumor cells play an important role in the metastatic disease process and our true understanding of their relevance is growing. The ability to capture and enumerate circulating tumor cells will play an increasingly important role in the management of patients with metastatic breast, colorectal, and prostate cancer. Recent studies have also demonstrated the potential clinical utility of the CellSearch assay for patients with urothelial cancer,19 lung cancer,20 and melanoma.21 Studies are under way that explore the use of circulating tumor cell counts in localized breast22, prostate23, and colorectal cancer.24 Additional studies are needed to determine the utility of this technology for guiding the proper patient treatment. Several trials are currently under way, including one from the Southwest Oncology Group, SWOG-S0500 trial,25 which is investigating a strategy of changing or maintaining therapy based on circulating tumor cell levels in patients with metastatic breast cancer. These trials should answer the question of whether changing treatment based on an elevated or increasing circulating tumor cell count alone is warranted.

Authored by: Michael Campion, Jesse Voss, and Kevin Halling, MD, PhD

Mayo Clinic has no equity in or license to Veridex, LLC, nor does Mayo Clinic receive any financial incentive from Veridex, LLC. Any perception of endorsement is unintended.

References

  1. Pantel K, Brakenhoff RH: Dissecting the metastatic cascade. Nat Rev Cancer 2004;4(6):448-456
  2. Fidler IJ: The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 2003;3(6):453-458
  3. Chambers AF, Groom AC, MacDonald IC: Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002;2(8):563-572
  4. Chang YS, di Tomaso E, McDonald DM, et al: Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci U S A 2000;97(26):14608-14613
  5. Fidler IJ. Metastasis: quantitative analysis of distribution and fate of tumor embolilabeled with 125 I-5-iodo-2’-deoxyuridine. J Natl Cancer Inst 1970;45(4):773-782
  6. Ross AA, Cooper BW, Lazarus HM, et al: Detection and viability of tumor cells in peripheral blood stem cell collections from breast cancer patients using immunocytochemical and clonogenic assay techniques. Blood 1993;82(9):2605-2610
  7. Allard WJ, Matera J, Miller MC, et al: Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004;10(20):6897-6904
  8. Cristofanilli M, Budd GT, Ellis MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004;351(8):781-791
  9. de Bono JS, Scher HI, Montgomery RB, et al: Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 2008;14(19):6302-6309
  10. Hayes DF, Cristofanilli M, Budd GT, et al: Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 2006;12(14 Pt 1):4218-4224
  11. American Cancer Society Cancer Facts and Figures. Available at: http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-and-figures-2010. Accessed 11/22/2010
  12. Surveillance Epidemiology and End Result Cancer Statistics Review 1975-2007. Available at: http://seer.cancer.gov/csr/1975_2007/browse_csr.php?section = 6&page = sect_06_table.12.html. Accessed 11/22/2010
  13. Cristofanilli M, Hayes DF, Budd GT, et al: Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 2005;23(7):1420-1430
  14. Budd GT, Cristofanilli M, Ellis MJ, et al: Circulating tumor cells versus imaging--predicting overall survival in metastatic breast cancer. Clin Cancer Res 2006;12(21):6403-6409
  15. Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
  16. Cohen SJ, Punt CJ, Iannotti N, et al: Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 2008;26(19):3213-3221
  17. Cohen SJ, Punt CJ, Iannotti N, et al: Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol 2009;20(7):1223-1229
  18. Scher HI, Jia X, de Bono JS, et al: Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol 2009;10(3):233-239
  19. Naoe M, Ogawa Y, Morita J, et al: Detection of circulating urothelial cancer cells in the blood using the CellSearch System. Cancer 2007;109(7):1439-1445
  20. Okumura Y, Tanaka F, Yoneda K, et al: Circulating tumor cells in pulmonary venous blood of primary lung cancer patients. Ann Thorac Surg 2009;87(6):1669-1675
  21. Steen S, Nemunaitis J, Fisher T, Kuhn J: Circulating tumor cells in melanoma: a review of the literature and description of a novel technique. Proc (Bayl Univ Med Cent) 2008;21(2):127-132
  22. Biggers B, Knox S, Grant M, et al: Circulating tumor cells in patients undergoing surgery for primary breast cancer: preliminary results of a pilot study. Ann Surg Oncol 2009;16(4):969-971
  23. Helo P, Cronin AM, Danila DC, et al: Circulating prostate tumor cells detected by reverse transcription-PCR in men with localized or castration-refractory prostate cancer: concordance with CellSearch assay and association with bone metastases and with survival. Clin Chem 2009;55(4):765-773
  24. Sastre J, Maestro ML, Puente J, et al: Circulating tumor cells in colorectal cancer: correlation with clinical and pathological variables. Ann Oncol 2008;19(5):935-938
  25. Hayes DF, Smerage J. Is there a role for circulating tumor cells in the management of breast cancer? Clin Cancer Res 2008;14(12):3646-3650

Key