Laboratory Section - Detection of Circulating Tumor Cells in the Management of Patients with Cancer

IMPORTANT REMINDER

Regence Medical Policies are developed to provide guidance for members and providers regarding coverage in accordance with contract terms. Benefit determinations are based in all cases on the applicable contract language. To the extent there may be any conflict between the Medical Policy and contract language, the contract language takes precedence.

PLEASE NOTE: Contracts exclude from coverage, among other things, services or procedures that are considered investigational or cosmetic. Providers may bill members for services or procedures that are considered investigational or cosmetic. Providers are encouraged to inform members before rendering such services that the members are likely to be financially responsible for the cost of these services.

Description

Studies have suggested that the presence of circulating tumor cells in patients with metastatic carcinoma is associated with short survival. Quantifying circulating tumor cells might be a useful technique to provide an immediate assessment of response to chemotherapy rather than relying on changes in imaging studies (e.g., CT scans). Finally, the presence of circulating tumor cells has been investigated as an additional prognostic factor in women with breast cancer without metastases, which could be used to determine the need for additional adjuvant chemotherapy. The CellSearch System (Veridex) is an example of such a technology. The technique involves identification of the circulating tumor cells, which are tagged using antibody coated magnetic beads that recognize cell surface antigens. The cells are then labeled with fluorescent dyes, which can then be quantified by a semiautomated fluorescent-based microscopy system.

Veridex LLC, a Johnson & Johnson company, markets the CellSearch System. It uses automated instruments manufactured by Immunicon Corp. for sample preparation (Cell Tracks® AutoPrep) and analysis (CellSpotterAnalyzer®), together with supplies, reagents, and epithelial cell control kits manufactured by Veridex. According to information on the manufacturer’s Web site (www.veridex.com), the CellSearch system became available in the United States in December 2004. The technology has received U.S. Food and Drug Administration (FDA) clearance through the 510(k) process.

Policy/Criteria

Detection and quantification of circulating tumor cells is considered investigational in the management of patients with cancer.

Scientific Background

The number of circulating tumor cells is associated with prognosis in patients with metastatic breast cancer. These cells can be separated and quantified using immunologic methods that detect epithelial cells. Cristofanilli and colleagues reported results from a multicenter prospective trial of 177 patients with measurable metastatic breast cancer who were followed for 38.7 weeks or longer. (2) Using the CellSearch System (Veridex LLC), they measured the number of circulating tumor cells before initiating a new line of therapy and at first follow-up (4.5 +/- 2.4 weeks after baseline sample). They also tested 145 normal subjects and 200 patients with benign breast diseases.

The authors report detecting two or fewer epithelial cells per 7.5 mL of blood in all normal subjects and in patients with benign breast diseases. Using a statistically validated threshold of 5 cells per 7.5 mL of blood, they found that patients below threshold at baseline (n=90; 51%) had longer median progression-free (7.0 versus 2.7 months; p<0.001) and overall survival (greater than 18 months versus 10.1 months; p<0.001) than those above threshold (n=87; 49%). Survival duration of a subgroup (n=33) with values above threshold at baseline but below threshold at first follow-up (i.e., after the first cycle of therapy) was similar to that of patients below threshold at baseline. This subgroup’s median survival also was significantly longer than survival of those who remained above threshold despite therapy. Multivariate analysis showed that being below threshold for level of circulating tumor cells was the most statistically significant independent predictor of longer progression-free and overall survival of all parameters studied, including hormone receptor status, HER-2/neu status, site of metastases, etc.

The Cristofanilli study is the first prospective study using the CellSearch System to predict prognosis of patients with metastatic breast cancer. However, predicting risk or prognosis does not directly improve health outcomes. To complete the causal chain, there must be evidence that patient management decisions based on risk level or prognosis increase the duration or quality of life or decrease adverse events. At this time, evidence is lacking that treatment decisions based on the number of circulating tumor cells improves outcomes for patients with metastatic breast cancer.

Cristofanilli and colleagues note, "This study did not address whether patients with an elevated number of circulating tumor cells might benefit from other therapies. Whether such patients might benefit from other therapies is under investigation." Apparently, studies are underway to complete the causal chain and develop this prognostic test into a predictive tool to guide patient management. Data for the subgroup above threshold at baseline who fell below threshold at first follow-up suggest it may identify responders sooner than currently possible with imaging modalities (approximately 4 weeks versus 2–3 months). This may permit earlier changes in the treatment regimen for non-responders and thus, might improve outcomes.

In an accompanying editorial, Braun and Marth note that evidence is also lacking that measuring circulating tumor cells is useful either to predict prognosis or guide treatment decisions for patients with breast cancer that has not metastasized who are receiving adjuvant systemic therapy after local treatment. (3) The possibility of curing breast cancer is substantially greater among patients with early stage disease than after it has metastasized. Thus, tests are also needed to accurately predict response and guide adjuvant therapy in early stage patients. In the adjuvant, neoadjuvant (i.e., presurgery) and metastatic disease settings, many groups are investigating genomic methods to predict prognosis and responses to treatment. (See Laboratory, Policy No. 42.) If ongoing studies demonstrate the CellSearch System can reliably guide treatment decisions for patients with metastatic breast cancer, future trials comparing this test to genomic methods may also be important.

Several abstracts were presented at the 2005 annual meeting of the American Society of Clinical Oncology. In separate abstracts, Budd, Stopeck, and Beveridge reported that the detection of circulating tumor cells in a total of 161 patients with metastatic breast cancer treated with systemic therapy was associated with a poor outcome, and potentially could be used as a sign of treatment failure. (4-6)

Although the bulk of the literature is related to metastatic breast cancer, studies have also been performed on other metastatic cancers as well as cancer that has not metastasized. These include prostate, esophageal, gastrointestinal cancers and melanoma. Studies for these tumors are more preliminary than those for metastatic breast cancer.

An updated search of the MEDLINE database through September 5, 2008 failed to return any randomized clinical trials that allow scientific conclusions to be made concerning the clinical utility of CTC data in the management of cancer Studies continue to report the association of circulating tumor cells with prognosis and/or response to therapy in metastatic and early breast cancer and in other malignancies. (7-8) For example, Nole and colleagues tested 80 patients with metastatic breast cancer for circulating tumor cell levels before starting a new treatment and after four weeks, eight weeks, at the first clinical evaluation, and every two months, thereafter. Forty-nine patients had 5 or more cells at baseline. At the multivariate analysis, baseline number of circulating tumor cells was associated with progression-free survival (hazard ratio [HR] 2.5; 95% confidence interval [CI] 1.2–5.4). The risk of progression for patients with 5 or more circulating tumor cells at the last available blood draw was five times the risk of patients with 0–4 circulating tumor cells at the same point (HR 5.3; 95% CI: 2.8–10.4). Patients with rising or persistent counts of 5 or more circulating tumor cells at last available blood draw showed a statistically significant higher risk of progression with respect to patients with less than 5 circulating tumor cells at both blood draws. The authors concluded that circulating tumor cell basal value is a predictive indicator of prognosis, that changes in circulating tumor cell levels during therapy may indicate a clinical response, and that testing circulating tumor cell levels during targeted treatments might substitute for other parameters to determine response to therapy.

None of the studies identified have evaluated the clinical impact (clinical utility) through prospective use of this assay in clinical care. The 2007 American Society of Clinical Oncology update of recommendations for the use of tumor markers in breast cancer indicated that the measurement of circulating tumor cells should not be used to make the diagnosis of breast cancer or to influence any treatment decisions in those with breast cancer. (9)

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 2.04.37
2. 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):781-91
3. Braun S, Marth C. Circulating tumor cells in metastatic breast cancer – toward individualized treatment? N Engl J Med 2004;351(8):824-6
4. Budd GT, Cristofanilli M, Ellis MJ et al. Monitoring circulating tumor cells (CTC) in non measurable metastatic breast cancer (MBC). 2005 ASCO Annual Meeting; abstract 503-accessible at www.asco.org  (Verified 09/05/08)
5. Stopeck A, Cristofanilli M, Budd GT. Circulating tumor cells– not serum tumor markers–predict survival in metastatic breast cancer. 2005 ASCO Annual Meeting; abstract 9516-accessible at: www.asco.org  (Verified 09/05/08)
6. Beveridge RA, Robert NJ, Desai S et al. Early assessment of circulating tumor cell results in a community-based practice. 2005 ASCO Annual Meeting; abstract 621–accessible at: www.asco.org  (Verified 5/31/07)
7. Nole F, Munzone E, Zorzino L et al. Variation of circulating tumor cell levels during treatment of metastatic breast cancer: prognostic and therapeutic implications. Ann Oncol 2007 Dec 4 [Epub ahead of print]
8. 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):7053-8
9. Harris L, Fritsche H, Mennel R et al. American Society of Clinical Oncology 2007 Update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007;25(33):5287-312

Cross References

Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis In Patients With Breast Cancer, Regence Medical Policy Manual, Laboratory, Policy No. 42

Laboratory Section Table of Contents