This document addresses the immunological techniques designed to detect epithelial cells circulating in the blood to quantify circulating tumor cells. The CellSearch^™ System (Veridex, LLC, Warren, New Jersey) is an example of such a technology.

Investigational and Not Medically Necessary:

Detection of circulating tumor cells in the blood is considered investigational and not medically necessary in the management of individuals with cancer.

Breast Cancer

Cristofanilli and colleagues (2004) reported on a prospective multi-center study of 177 subjects with metastatic breast cancer who were tested for levels of circulating tumor cells (CTCs) both at the time a new line of therapy was initiated and at the first follow-up visit. Of all the variables studied (i.e., hormone receptor status, HER2/neu status, site of metastasis), the levels of CTCs at baseline and at the first follow-up visit were the most significant predictors of progression-free survival (PFS) and overall survival (OS). The authors noted their study was not designed to determine whether those with an elevated number of CTCs might benefit from other therapies.

Cristofanilli and colleagues (2005), in a follow-up analysis, focused on a subset of the initial study, consisting of 83 subjects with newly diagnosed measurable metastatic breast cancer about to start first line systemic therapy. The purpose of this analysis was to investigate whether the presence of CTCs predicts treatment efficacy, PFS, and OS in individuals with newly diagnosed metastatic breast cancer. Subjects with five CTCs in 7.5 ml blood at baseline or first follow-up (four weeks) were found to have a worse prognosis than those with less than five CTCs at baseline (baseline: median PFS, 4.9 v 9.5 months, respectively; median OS, 14.2 v 18 months, respectively; first follow-up: median PFS, 2.1 v 8.9 months, respectively; median OS, 11.1 v 18 months, respectively).

Hayes and colleagues (2006) analyzed additional follow-up data and CTC levels at subsequent follow-up visits. CTCs were measured in 177 individuals with metastatic breast cancer at baseline, and three to five, six to eight, nine to 14, and 15 to 20 weeks after the initiation of therapy. Median PFS times for those with less than five CTCs from each of the five follow-up points were 7.0, 6.1, 5.6, 7.0, and 6.0 months, respectively. For those with greater than or equal to five CTCs, median PFS from these same time points was significantly shorter: 2.7, 1.3, 1.4, 3.0, and 3.6 months, respectively. Median OS for individuals with less than five CTCs from the five blood draw time points was greater than 18.5 months. For those with greater than or equal to five CTCs, median OS from these same time points was significantly shorter: 10.9, 6.3, 6.3, 6.6, and 6.7 months, respectively.

Budd and colleagues (2006) compared the use of CTCs to radiology for prediction of OS. The median OS of 13 (9%) subjects with radiologic nonprogression and greater than or equal to five CTCs was significantly shorter than that of the 83 (60%) subjects with radiologic nonprogression and less than five CTCs (15.3 versus 26.9 months; P = 0.0389). The median OS of the 20 (14%) subjects with radiologic progression and less than five CTCs was significantly longer than the 22 (16%) subjects with greater than or equal to five CTCs that showed progression by radiology (19.9 versus 6.4 months; P = 0.0039).

In 2007, Cristofanilli and colleagues compared the prognostic significance of CTCs with measures of tumor burden and phenotypic subtype of disease. In a retrospective analysis, 151 individuals with metastatic breast cancer were studied. CTCs were isolated and counted in whole blood using the CellSearch System. The median age of subjects was 53 years, and 44% had greater than 5 CTCs. The median OS rates for negative versus positive CTCs were 29.3 months and 13.5 months respectively. The authors noted that the prognostic value was independent of measure of tumor burden and type and line of therapy, and phenotypic subtype of the disease.

In a small prospective single institution trial, Tewes and colleagues (2009) examined CTCs from the blood of 32 out of 42 individuals with metastatic breast cancer before and during therapy to determine the ability of this technique to predict therapy response. Ten individuals could not be monitored as six were lost to follow-up and four died. The overall detection rate for CTCs was 52%. The test appeared to predict a therapy response in 78% of cases and was thought to have correlated with OS. The authors noted that it was difficult to draw any conclusions regarding the prognostic value of CTCs and more individuals will be evaluated.

Bidard and colleagues (2010), in a prospective study, investigated whether CTC detection had a prognostic impact on nonmetastatic breast cancer. A total of 115 women diagnosed with large operable or locally advanced nonmetastatic breast cancer participated in this trial. Baseline CTC detection rates were low, with 23% and 10% of the women having at least one and two CTC/7.5 ml prior to chemotherapy, respectively. After a median follow-up of 36 months clinical outcomes were reanalyzed. Of 115 women, 14 (12%) had metastatic relapses and 9 (8%) died. CTC detection before chemotherapy was found to be an independent prognostic factor for both distant metastasis-free survival (DMFS) [DMFS; P = 0.01, relative risk (RR) = 5.0, 95% confidence interval (CI) 1.4-17] and OS (OS; P = 0.007, RR = 9, 95% CI 1.8-45). CTC detection after chemotherapy was of less significance (P = 0.07 and 0.09, respectively). The authors noted that other trials combined with CTC detection, such as the GeparQuattro trial conducted by the German Breast Group, are needed to confirm results.

Riethdorf and colleagues (2010), in the GeparQuattro clinical trial, studied the detection and characterization of CTCs in the peripheral blood before and after neoadjuvant therapy (NT) for nonmetastatic breast cancer. The trial incorporated NT approaches (epirubicin/cyclophosphamide prior to randomization to docetaxel alone, docetaxel in combination with capecitabine, or docetaxel followed by capecitabine) and additional trastuzumab treatment for those with HER2-positive tumors. The CellSearch^™ system was used for CTC detection and further evaluation of HER2 expression. Blood samples of 213 subjects with nonmetastatic breast cancer before NT and 207 subjects after NT prior to surgery were examined. Study results included the detection of greater than or equal to one CTC/7.5 ml in 46 of 213 subjects (21.6%) before NT and in 22 of 207 subjects (10.6%) after NT (P = 0.002). Twenty (15.0%) which were initially CTC-positive were CTC-negative after NT and 11 (8.3%) cases were CTC-positive after NT, even though no CTCs were detected before NT. The detection of CTCs did not correlate with characteristics of primary tumors. In addition, there was no association between tumor response to NT and CTC detection. HER2-overexpressing CTCs were observed in 14 of 58 CTC-positive subjects (24.1%), including eight with HER2-negative primary tumors and three after treatment with trastuzumab. CTCs which were scored as HER2-negative or weakly HER2-positive before or after NT were present in 11 of 21 subjects with HER2-positive primary tumors. HER2 overexpression on CTC appeared to be restricted to ductal carcinomas and associated with high tumor stage (P = 0.002).

Fehm and colleagues (2010) assessed HER2 CTC testing in 254 individuals with metastatic breast cancer from nine German university breast cancer centers in a prospective, open labeled, non-randomized study . Both the CellSearch assay and AdnaTest BreastCancer^™ (Adnagen AG, Langenhagen, Germany) were used to assess the HER2 status of CTCs. Using the CellSearch assay, it was determined that 122 of 245 (50%) subjects had greater than or equal to five CTCs, and HER2-positive CTCs were observed in 50 (41%). Using the AdnaTest BreastCancer, it was demonstrated that 90 of 229 (39%) subjects were CTC positive and the HER2 positivity rate was 47% (42 of 90). The percentage of breast cancer cases with HER2-negative primary tumors but HER2-positive CTCs was 32% (25 of 78) and 49% (28 of 57) using the CellSearch assay and AdnaTest BreastCancer, respectively. Concordance between the HER2 status shown by either the CellSearch assay or AdnaTest BreastCancer could only be evaluated in 62 subjects who were CTC positive with both tests. In considering only those individuals who had CTCs on both tests (n = 62), concordant results regarding HER2 positivity were obtained in 50% of the cases (31/62). The authors noted that the overall agreement between the tests was low at 64% and both assays should have been able to detect HER2-positive CTCs. In addition, a "potential drawback" of the study was that biopsy of the metastatic tissue was optional and only performed on 30 of 252 subjects; since most of these subjects were CTC negative, "no meaningful comparison could be performed."

The American Society of Clinical Oncology (ASCO) (Harris, 2007) issued updated recommendations for the use of tumor marker tests in the prevention, screening, treatment and surveillance of breast cancer. ASCO's 2007 recommendations for CTC assays for breast cancer include:

• "The measurement of CTCs should not be used to make the diagnosis of breast cancer or to influence any treatment decisions in patients with breast cancer.
• The use of the CellSearch Assay in patients with metastatic breast cancer cannot be recommended until additional validation confirms the clinical value of this test."

The Southwest Oncology Group (SWOG) initiated, in 2006, a partially blinded and randomized phase III trial designed to test the strategy of changing chemotherapy versus maintaining chemotherapy for women with metastatic breast cancer who have elevated CTCs at a first follow-up assessment (SWOG Protocol S0500). This trial is currently still recruiting participants and outcome results are not yet available.

Colorectal Cancer 

Sastre and colleagues (2008) attempted to correlate the presence of CTCs with common clinical and morphological variables. Blood samples were collected from 97 subjects with colorectal cancer and 30 healthy volunteers. Quantification of CTCs was performed using the CellSearch System. Three of the 97 subjects with colorectal cancer were excluded from this analysis due to spoiled blood samples. Positive CTCs were detected in 34 of the remaining 94 individuals (36.2%). Correlation was not found among positive CTCs and location of primary tumor, increased carcinoembryonic antigen level, increased lactate dehydrogenase level or grade of differentiation. The stage of the disease did correlate with positive CTCs (20.7% in stage II, 24.1% in stage III and 60.7% in stage IV, P = 0.005). There were no CTCs found in the group of healthy volunteers. The authors concluded CTC detection by CellSearch is a highly reproducible method that correlates with stage but not with other clinical and morphological variables in those with colorectal cancer and further studies are needed.

Cohen and colleagues (2008), in a prospective multi-center clinical trial, studied individuals with metastatic colorectal cancer to determine if CTCs could predict clinical outcomes. CTCs were counted in the peripheral blood of 430 individuals with metastatic colorectal cancer at baseline and after starting first-, second-, or third-line therapy. Study subjects were divided into unfavorable and favorable prognostic groups based on CTC levels of three or more or less than three CTCs/7.5 mL, respectively. Those with unfavorable compared with favorable baseline CTCs had shorter median PFS (PFS; 4.5 v 7.9 months; P = .0002) and OS (OS; 9.4 v 18.5 months; P < .0001). Differences continued at 1 to 2, 3 to 5, 6 to12, and 13 to 20 weeks after therapy. Conversion of baseline unfavorable CTCs to favorable at three to five weeks was associated with significantly longer PFS and OS compared with subjects with unfavorable CTCs at both time points (PFS, 6.2 v 1.6 months; P = .02; OS, 11.0 v 3.7 months; P = .0002). Among non progressing subjects, favorable compared with unfavorable CTCs within one month of imaging was associated with longer survival (18.8 v 7.1 months; P < .0001). Baseline and follow-up CTC levels remained strong predictors of PFS and OS after adjustment for clinically significant factors. Limitations of this study, as noted by the authors, included individuals undergoing different lines of therapy, which could potentially influence the ability to generalize results to any one group, individuals had the flexibility to determine the exact date of their blood draws and computed tomography scans, and the percentage of persons with unfavorable CTCs at baseline and overall CTC yield is less than in other epithelial malignancies such as breast cancer.

Prostate Cancer 

Cho and colleagues (2007), in a small preliminary study, analyzed enhancer of zeste homolog 2 (EZH2) messenger ribonucleic acid (mRNA) in CTCs in peripheral blood as a marker in subjects with metastatic prostate cancer. EZH2 is a type of transcriptional repressor, which is reportedly overexpressed in prostate cancer. The sensitivity of this test for detection of EZH2 mRNA was determined by serial dilutions of a human prostate cancer cell line. Blood samples were collected from 20 individuals with metastatic or localized prostate cancer and 10 healthy volunteers. It was noted that EZH2 mRNA in circulating tumor cells was over-expressed in those with metastatic prostate cancer. The authors concluded that EZH2 mRNA in circulating tumor cells could be a promising marker for detecting early metastasis in prostate cancer, but more specific and sensitive techniques for the detection of CTCs are needed to avoid mononuclear cell contamination.

Danila and colleagues (2007) evaluated CTC numbers in individuals with progressive castration-resistant metastatic prostate cancer who were being considered for different hormonal and cytotoxic therapies. In this study, CTCs were isolated from the blood samples of 120 subjects with the disease. Their probability of survival over time was estimated by the Kaplan-Meier method. Sixty-nine (57%) individuals had five or more CTCs and 30 (25%) had two cells or less. Higher CTC numbers were found in those with bone metastases compared to those with soft tissue disease and in individuals who had received prior cytotoxic chemotherapy compared to those who had not. CTC counts were correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. The authors noted that baseline CTC was predictive of survival, with no threshold effect and prospective studies will need to be conducted to assess the role of these and future markers for pretreatment stratification in large scale trials.

DeBono and colleagues (2008) conducted a multi-center prospective study designed to establish the relationship between post treatment CTC counts and OS in castration-resistant prostate cancer (CRPC). Secondary objectives included determining the prognostic utility of CTC measurement before initiating therapy, and the relationship of CTC to prostate-specific antigen (PSA) changes and OS at these and other time points. Two hundred thirty-one individuals with CRPC with progressive metastatic disease starting a new line of chemotherapy prior to treatment and monthly thereafter were evaluated. They were divided into two groups consisting of those having either unfavorable (>5 CTC/7.5 mL) or favorable (<5 CTC/7.5 mL) CTC counts. Individuals in the unfavorable pretreatment CTC (57%) had shorter OS (median OS, 11.5 versus 21.7 months; Cox hazard ratio, 3.3; P < 0.0001). Unfavorable post treatment CTC counts also predicted shorter OS at 2 to 5, 6 to 8, 9 to 12, and 13 to 20 weeks (median OS, 6.7-9.5 versus 19.6-20.7 months; Cox hazard ratio, 3.6-6.5; P < 0.0001). OS was predicted better with CTC counts than with PSA algorithms at all time points. The prognosis for those with unfavorable baseline CTC counts who converted to favorable CTC counts improved (6.8 to 21.3 months), while the prognosis for those with favorable baseline CTC counts who converted to unfavorable CTC counts worsened (>26 to 9.3 months). This study was limited by non randomization and additional evaluation in the form of randomized clinical trials is needed to determine the clinical utility of CTC measurement in the management of CRPC.

Other Cancers 

Studies have also been published evaluating CTC levels as a diagnostic or prognostic marker for individuals with other types of cancer including bladder (Guzzo, 2009), advanced gastric (Matsusaka, 2010), and lung (Tanaka, 2009) cancer. There are no FDA cleared tests for these indications, and none of the studies evaluated individual health care management decisions using CTCs.

Conclusion 

The clinical utility of quantifying CTCs is unproven. Published data is inadequate to determine how such measurements should guide treatment decisions and whether these treatment decisions result in beneficial outcomes. Therefore, detection of CTCs in the blood for management of cancer is considered investigational and not medically necessary.

Breast cancer is the most common cancer among women, other than skin cancer. After lung cancer, it is the second leading cause of cancer death in women. In 2010, it was estimated that about 207,090 American women would be diagnosed with invasive breast cancer and about 39,840 women would die from the disease (American Cancer Society, 2010).

Colorectal cancer is the third most common cancer found in men and women other than skin cancer in the United States. In 2010, it was estimated that about 101,700 new cases of colon cancer and 39,510 new cases of rectal cancer would be diagnosed in the United States. Combined, they would cause about 49,380 deaths (American Cancer Society, 2011).

Prostate cancer is the most common cancer, other than skin cancers, in American men. In 2010, it was estimated that about 217,730 new cases of prostate cancer would be diagnosed in the United States and that 32,050 men would die from the disease. It is the second leading cause of cancer death in American men, behind only lung cancer (American Cancer Society, 2010).

Studies suggest the presence of CTCs in individuals with metastatic carcinoma is associated with shortened survival. Immunological techniques designed to detect epithelial cells (CD45-, EpCAM+, and cytokeratins 8, 18+, 19+) circulating in the blood can quantify CTCs. The CellSearch System is an example of such a technology. The technology received U.S. Food and Drug Administration (FDA) clearance through the 510(k) process for monitoring of metastatic breast cancer in 2004, for monitoring of metastatic colorectal cancer in 2007 and for monitoring of metastatic prostate cancer in 2008. In addition, there has been some interest for the use of this test in individuals with nonmetastatic breast cancer, bladder cancer, advanced gastric cancer, and metastatic lung cancer. Published studies have failed to demonstrate a correlation between measurement of circulating tumor cells and improved individual health outcomes.

Metastatic: Spread of a disease from the organ or tissue of origin to another part of the body.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Allard WJ, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with non-malignant diseases. Clin Cancer Res. 2004; 10:6897-6904.
2. Balic M, Dandachi N, Hofmann G, et al. Comparison of two methods for enumerating circulating tumor cells in carcinoma patients. Cytometry B Clin Cytom. 2005; 68(1):25-30.
3. Bidard FC, Mathiot C, Delaloge S, et al. Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Ann Oncol. 2010; 21(4):729-733.
4. 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.
5. Cho KS, Oh HY, Lee EJ, Hong SJ. Identification of enhancer of zeste homolog 2 expression in peripheral circulating tumor cells in metastatic prostate cancer patients: a preliminary study. Yonsei Med J. 2007; 48(6):1009-1014.
6. 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.
7. Cristofanilli M, Broglio KR, Guarneri V, et al. Circulating tumor cells in metastatic breast cancer: biologic staging beyond tumor burden. Clin Breast Cancer. 2007; 7(6):471-479.
8. Cristofanilli M, Budd GT, Ellis MJ et al. Circulating tumors cells, disease progression, and survival in metastatic breast cancer. N Eng J Med 2004; 351:781-791.
9. Cristofanilli M, Hayes DF, et al. Circulating tumor cells; a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 2005; 23:1420-1430.
10. Danila DC, Heller G, Gignac GA, et al. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res. 2007; 13(23):7053-7058.
11. 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.
12. Fehm T, Müller V, Aktas B, et al. HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat. 2010; 124(2):403-412.
13. Guzzo TJ, McNeil BK, Bivalacqua TJ, et al. The presence of circulating tumor cells does not predict extravesical disease in bladder cancer patients prior to radical cystectomy. Urol Oncol 2009. [Epub ahead of print]
14. 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; 1 2(14 Pt 1):4218-4224.
15. Jacob K, Sollier C, Jabado N. Circulating tumor cells: detection, molecular profiling and future prospects.Expert Rev Proteomics. 2007; 4(6):741-756.
16. Matsusaka S, Chìn K, Ogura M, et al. Circulating tumor cells as a surrogate marker for determining response to chemotherapy in patients with advanced gastric cancer. Cancer Sci. 2010; 101(4):1067-1071.
17. Mocellin S, Hoon D, Ambrosi A, et al. The prognostic value of circulating tumor cells in patients with melanoma: a systematic review and meta-analysis. Clin Cancer Res. 2006; 12(15):4605-4613.
18. Riethdorf S, Fritsche H, Muller V, et al.  Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the cellsearch system. Clin Cancer Res. 2007; 13(3):920-928.
19. Riethdorf S, Müller V, Zhang L, et al. Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res. 2010; 16(9):2634-2645.
20. 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.
21. Tanaka F, Yoneda K, Kondo N, et al. Circulating tumor cell as a diagnostic marker in primary lung cancer. Clin Cancer Res. 2009; 15(22):6980-6986.
22. Tewes M, Aktas B, Welt A, et al. Molecular profiling and predictive value of circulating tumor cells in patients with metastatic breast cancer: an option for monitoring response to breast cancer related therapies. Breast Cancer Res Treat. 2009;115(3):581-590.

Government Agency, Medical Society, and Other Authoritative Publications: 

1. American Cancer Society. How many men get prostate cancer? Revised 12/13/2010. Available at: http://www.cancer.org/cancer/prostatecancer/overviewguide/prostate-cancer-overview-key-statistics. Accessed on March 23, 2011.
2. American Cancer Society. How many people get colorectal cancer? Revised 03/08/2011. Available at: http://www.cancer.org/Cancer/ColonandRectumCancer/OverviewGuide/colorectal-cancer-overview-key-statistics. Accessed on March 23, 2011.
3. American Cancer Society. How many women get breast cancer? Revised 09/24/2010. Available at: http://www.cancer.org/Cancer/BreastCancer/OverviewGuide/breast-cancer-overview-key-statistics. Accessed on March 23, 2011.
4. Harris L, Fritsche H, Mennel, et al. American Society of Clinical Oncology. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007; 25(33):5287-5312.
5. Southwest Oncology Group, Treatment decision making based on blood levels of tumor cells in women with metastatic breast cancer receiving chemotherapy. SWOG Protocol S0500. NLM Identifier: NCT00382018. Last updated March 17, 2011. Available at: http://clinicaltrials.gov/ct/show/NCT00382018. Accessed on March 23, 2011.
6. U.S. Food and Drug Administration 510(k) Premarket Notification Database. CellSearch Circulating Tumor Cell Kit, Veridex, LLC. Summary of Safety and Effectiveness. No. K103502. Rockville, MD: FDA. December 21, 2010. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm?ID=35381. Accessed on March 23, 2011.

CellSearch System
Circulating Tumor Cells in the Blood for Prognosis of Cancer
Veridex (CellSearch) System

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.