Medical Policy

This document addresses the management of individuals with cancer using immunological techniques designed to detect tumor cells circulating in the blood to quantify circulating tumor cells. The CellSearch^® System (Menarini Silicon Biosystems, Florence, Italy) is an example of the technology.

Note: This document does not address circulating tumor DNA testing for cancer (liquid biopsy). For information related to that service, please refer to applicable guidelines used by the plan.

Note: For a high-level overview of this document, please see “Summary for Members and Families” below. 

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.

This document describes clinical studies and expert recommendations, and explains whether tests to detect circulating tumor cells in the blood are appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

Circulating tumor cell tests look for cancer cells in the blood that have spread from the original tumor. These tests are sometimes used in research to try to understand cancer progression in people with breast, prostate, or colorectal cancer. One example of this test is called the CellSearch System. While studies show that higher numbers of circulating tumor cells may be linked to shorter survival, no strong evidence shows that using these test results to guide treatment choices helps people live longer or feel better. The test is not part of routine cancer care. Medical groups do not recommend using circulating tumor cell tests. Unnecessary or unproven tests can lead to treatment that does not help.

What the Studies Show

Circulating tumor cells have been studied in breast, colorectal, and prostate cancer. Many studies show a link between higher numbers of these cells and worse outcomes, such as shorter time before the cancer worsens or shorter overall survival. For example, in people with breast cancer, having five or more circulating tumor cells per 7.5 mL of blood was linked to a shorter survival time. However, studies that used circulating tumor cell levels to guide treatment decisions did not show improved results. One large study (SWOG S0500) in people with breast cancer found that changing chemotherapy based on circulating tumor cell levels did not help people live longer. Another study found that choosing treatments based on circulating tumor cell counts did not reduce the use of chemotherapy or the side effects that come with it. In colorectal cancer, studies also show that higher circulating tumor cell levels are linked to shorter survival. But these studies did not test whether using the results to guide treatment improves health. In prostate cancer, circulating tumor cell levels are also linked with survival, but again, no studies show that using this test to make treatment decisions improves outcomes. Expert groups, such as the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN), do not recommend using circulating tumor cell tests to guide treatment. In other cancers like lung, bladder, or ovarian cancer, research is ongoing, and no circulating tumor cell test is approved for clinical use in these cases.

Is this clinically appropriate?

This test is not appropriate because it has not been proven to improve health. Although many studies show that higher numbers of circulating tumor cells are linked to worse outcomes, no studies have shown that using this test to choose or change treatment improves how long people live or how they feel. Expert guidelines do not support using circulating tumor cells.

(Return to Description/Scope)

Summary

The body of evidence for circulating tumor cell testing consists of prospective observational studies, randomized trials, and meta-analyses. Studies have consistently demonstrated that circulating tumor cell counts are prognostic in breast, colorectal, and prostate cancer, with elevated counts associated with shorter progression-free survival and overall survival. However, randomized clinical trials evaluating whether circulating tumor cell-guided treatment decisions improve individual outcomes have not consistently demonstrated improved outcomes. The SWOG S0500 trial in breast cancer found no survival benefit from early chemotherapy switching based on persistently elevated circulating tumor cells. A non-inferiority trial evaluating circulating tumor cell-driven treatment selection did not confirm the hypothesis that this approach would reduce chemotherapy use. Professional society guidelines do not recommend routine use of circulating tumor cells for treatment decisions. The clinical utility of circulating tumor cell quantification remains unproven.

Discussion

Circulating tumor cells are malignant cells found in peripheral blood originating from primary or metastatic tumors. Detection of circulating tumor cells has been associated with prognosis in individuals with certain types of cancer, primarily breast, colorectal, and prostate cancer. However, evidence is insufficient to demonstrate that clinical decisions based on circulating tumor cell levels improve quality or duration of life or decrease adverse events. The clinical utility of circulating tumor cell quantification remains unproven.

Breast Cancer

Prognostic Validity

Multiple studies have demonstrated that circulating tumor cell counts are prognostic in breast cancer. Early studies by Cristofanilli and colleagues (2004, 2005) and Hayes and colleagues (2006) established that participants with five or more circulating tumor cells per 7.5 mL blood at baseline or follow-up had significantly shorter progression-free survival and overall survival compared with those with fewer than five circulating tumor cells. These findings have been confirmed and extended by subsequent larger analyses.

Janni and colleagues (2025) conducted a global pooled analysis of individual participant-level data from 17 studies including 4436 participants with metastatic breast cancer with circulating tumor cell results at baseline and follow-up using CellSearch. Participants were grouped by circulating tumor cell status: negative/negative (n=913, 20.6%), negative/positive (n=325, 7.3%), positive/negative (circulating tumor cell responders; n=1189, 26.8%), and positive/positive (circulating tumor cell nonresponders; n=2009, 45.3%). Median overall survival by group was 45.6, 26.1, 32.3, and 17.3 months, respectively (p<0.0001). Circulating tumor cell responders had significantly lower mortality risk than nonresponders (hazard ratio [HR] 0.48; 95% confidence interval [CI], 0.44-0.53). Results were consistent across hormone receptor-positive/HER2-negative, HER2-positive, and triple-negative subtypes. The authors concluded that new randomized trials to define clinical utility of circulating tumor cell monitoring are urgently needed.

The meta-analysis of 49 studies by Zhang and colleagues (2012) confirmed that circulating tumor cell positivity was associated with increased risk of disease progression (HR, 1.78; 95% CI, 1.52-2.09) and death (HR,2.23; 95% CI, 2.09-2.60) in metastatic breast cancer. Pooled analyses of studies using CellSearch found that circulating tumor cell positivity significantly increased the likelihood of disease progression (HR, 1.85; 95% CI, 1.53-2.25) and death (HR, 2.45; 95% CI, 2.10-2.85). The authors reported that further study is needed to assess clinical utility.

In early-stage disease, Rack and colleagues (2014) analyzed circulating tumor cells using CellSearch in 2026 participants with early breast cancer before adjuvant chemotherapy and in 1,492 participants after chemotherapy. Prior to chemotherapy, circulating tumor cells were detected in 21.5% of participants. The presence of circulating tumor cells was associated with poor disease-free survival, and persisting circulating tumor cells after chemotherapy showed a negative influence on disease-free survival and overall survival. Study limitations included the short median follow-up of 35 months.

Clinical Utility

Despite established prognostic validity, randomized trials have not demonstrated that circulating tumor cell-guided treatment decisions improve individual outcomes.

Smerage and colleagues (2014) reported on overall survival of women enrolled in SWOG S0500, a phase III randomized trial. Participants who did not have increased circulating tumor cells at baseline remained on initial therapy until progression (Arm A; n=276). Participants with initially elevated circulating tumor cells that decreased after initial therapy were assigned to Arm B (n=165). Participants with persistently elevated circulating tumor cells (n=123) were randomized to continue initial therapy (Arm C1) or change to alternative chemotherapy (Arm C2). No difference in median overall survival was observed between Arm C1 and C2. Median overall survival for Arms A, B, and C were 35, 23, and 13 months, respectively. The authors concluded that failure to reduce circulating tumor cells within the first 3 to 4 weeks of starting first-line chemotherapy indicated poor prognosis and general chemotherapy resistance; however, early switching to an alternate chemotherapy regimen had no effect on overall survival.

Bidard and colleagues (2021) published a non-inferiority randomized controlled trial evaluating the impact of using circulating tumor cell count to manage first-line treatment decisions in 778 individuals with hormone receptor-positive, HER2-negative metastatic breast cancer. Participants were randomized to clinician-driven treatment choice (n=387) or circulating tumor cell-driven treatment choice (n=391). In the circulating tumor cell-driven arm, individuals with fewer than 5 circulating tumor cells per 7.5 mL received endocrine therapy and those with high counts received chemotherapy. Median progression-free survival was 13.9 months in the clinician-driven arm and 15.5 months in the circulating tumor cell-driven arm (HR, 0.94; 90% CI, 0.81-1.09), meeting non-inferiority criteria. However, there were not fewer individuals treated with chemotherapy in the circulating tumor cell arm (36.6% vs. 27.2%), and rates of chemotherapy-related adverse events were higher, not lower. The hypothesis that circulating tumor cell-guided selection would reduce chemotherapy use and adverse events was not confirmed.

Gerratana and colleagues (2025) conducted a biomarker analysis of the PACE phase II randomized trial evaluating 203 participants with hormone receptor-positive/HER2-negative metastatic breast cancer progressing on CDK4/6 inhibitors. Using CellSearch, participants were classified as Stage IV aggressive (five or more circulating tumor cells per 7.5 mL; 49%) or Stage IV indolent (fewer than five circulating tumor cells; 51%). Median progression-free survival was 3.5 months for aggressive compared to 5.7 months for indolent (HR, 1.69; 90% CI, 1.27-2.24; p<0.001). In the Stage IV aggressive subgroup, combination therapy with palbociclib showed benefit over fulvestrant alone (HR, 0.43; 90% CI, 0.25-0.71), whereas no benefit was observed in the Stage IV indolent subgroup (HR, 1.45; 90% CI, 0.87-2.40). The authors framed these findings as hypothesis-generating exploratory evidence of potential predictive value.

Guideline Recommendations

The American Society of Clinical Oncology has published recommendations for the use of biomarkers in breast cancer. For metastatic disease, the American Society of Clinical Oncology (Henry, 2022) concluded: "There are insufficient data to recommend routine use of circulating tumor cells to monitor response to therapy among individuals with metastatic breast cancer (Type: informal consensus; Evidence quality: low; Strength of recommendation: moderate)." For early-stage disease, the American Society of Clinical Oncology (Andre, 2022) issued a strong recommendation that clinicians should not use circulating tumor cells to guide decisions for adjuvant endocrine and chemotherapy.

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guideline For Breast Cancer (V1.2026) states that the clinical use of circulating tumor cells in metastatic breast cancer is not yet included in the guidelines for disease assessment and monitoring. The guideline cites the SWOG-S0500 randomized trial and concludes that "in spite of its prognostic ability, circulating tumor cell count has failed to show a predictive value."

Colorectal Cancer

Prognostic Validity

Studies have demonstrated that circulating tumor cell counts are prognostic in colorectal cancer. Cohen and colleagues (2008) conducted a prospective multicenter trial of 430 individuals with metastatic colorectal cancer. Participants were divided into unfavorable and favorable prognostic groups based on circulating tumor cell levels of three or more or fewer than three per 7.5 mL, respectively. Those with unfavorable baseline levels had shorter median progression-free survival (4.5 vs. 7.9 months; p=0.0002) and overall survival (9.4 vs. 18.5 months; p<0.0001). Conversion from unfavorable to favorable levels at 3 to 5 weeks was associated with significantly longer progression-free survival and overall survival. Baseline and follow-up circulating tumor cell levels remained strong predictors after adjustment for clinically significant factors.

Sastre and colleagues (2012) performed an ancillary study evaluating circulating tumor cell count as a prognostic marker in 180 individuals with metastatic colorectal cancer enrolled in a phase III trial assessing maintenance therapy. The median progression-free survival for participants with a circulating tumor cell count of three or more at baseline was 7.8 months compared to 12.0 months for those with fewer than three (p=0.0002). Median overall survival was 17.7 months for participants with elevated counts compared with 25.1 months for those with lower counts (p=0.0059).

Huang and colleagues (2015) published a meta-analysis of 11 studies containing 1,847 participants to evaluate if circulating tumor cells detected with CellSearch have prognostic utility in colorectal cancer. Detection of circulating tumor cells was associated with worse overall survival (HR, 2.00; 95% CI, 1.49-2.69) and progression-free survival (HR, 1.80; 95% CI, 1.52-2.13). Study limitations included heterogeneity and the retrospective nature of the analysis.

Jimenez-Fonseca and colleagues (2023) published a post-hoc analysis of data from two randomized controlled trials enrolling 589 individuals with previously untreated metastatic colorectal cancer. Circulating tumor cell count was determined at baseline using CellSearch. Median progression-free survival was 10.9 months in individuals with three or more circulating tumor cells and 12.0 months for those with fewer than three; the difference was not statistically significant (HR, 0.81; p=0.0549). However, median overall survival differed significantly (p<0.0001): 19.5 months in individuals with elevated counts compared to 32.9 months in those with lower counts. The study did not evaluate whether circulating tumor cell quantification would impact treatment decisions or individual outcomes.

Wullaert and colleagues (2025) conducted a prospective observational study (MIRACLE) of 188 participants with isolated, resectable colorectal liver metastases without neoadjuvant chemotherapy. Circulating tumor cells were enumerated using CellSearch before surgery and 3 weeks postoperatively. Circulating tumor cell detection occurred in 20% at baseline and 9% postoperatively. Baseline circulating tumor cells were not associated with 1-year recurrence-free survival. However, postoperative circulating tumor cell detection was significantly associated with shorter 1-year recurrence-free survival: 15% (95% CI, 4%-55%) compared to 53% (95% CI, 45%-62%) for circulating tumor cell-negative participants (log-rank p=0.0004). In multivariable analysis, postoperative circulating tumor cells remained prognostic (HR, 2.98; 95% CI, 1.56-5.71; p=0.0010). The study did not evaluate whether circulating tumor cell-guided treatment decisions improve outcomes.

Clinical Utility

Randomized controlled trials evaluating circulating tumor cell-informed treatment strategies in colorectal cancer are limited.

Guideline Recommendations

The NCCN Clinical Practice Guidelines For Colon Cancer And Rectal Cancer do not include any recommendations regarding circulating tumor cell testing.

Prostate Cancer

Prognostic Validity

Studies have demonstrated that circulating tumor cell counts are prognostic in prostate cancer. De Bono and colleagues (2008) conducted a multi-center prospective study of 231 individuals with castration-resistant prostate cancer with progressive metastatic disease starting a new line of chemotherapy. Participants were divided into unfavorable (five or more circulating tumor cells per 7.5 mL) or favorable (fewer than five) groups. Individuals with unfavorable pretreatment counts had shorter overall survival (median 11.5 vs. 21.7 months; HR, 3.3; p<0.0001). Unfavorable post-treatment counts also predicted shorter overall survival at all time points assessed. Overall survival was predicted better with circulating tumor cell counts than with prostate-specific antigen algorithms. Prognosis improved for those with unfavorable baseline counts who converted to favorable counts, and worsened for those with favorable baseline counts who converted to unfavorable counts.

Scher and colleagues (2015) examined circulating tumor cells alone and in combination with other biomarkers as a surrogate for overall survival in the COU-AA-301 randomized controlled trial of abiraterone acetate plus prednisone compared to prednisone alone in participants with metastatic castration-resistant prostate cancer previously treated with docetaxel. The final analysis consisted of 711 participants with both circulating tumor cell and lactate dehydrogenase data at week 12. At 12 weeks, the 2-year survival of participants with fewer than five circulating tumor cells (low risk) compared to those with five or more circulating tumor cells and lactate dehydrogenase levels greater than 250 U/L (high risk) was 46% and 2%, respectively. A limitation was that only 59% of enrollees had circulating tumor cell enumeration performed at week 12. The authors concluded that a biomarker panel demonstrated individual patient-level surrogacy and supports use as a clinical trial endpoint.

Clinical Utility

No randomized controlled trials have demonstrated that circulating tumor cell-guided treatment decisions improve outcomes in prostate cancer.

Guideline Recommendations

The NCCN Clinical Practice Guideline For Prostate Cancer does not include recommendations for circulating tumor cell enumeration for prognosis or monitoring. However, an international expert consensus (Nicolò, 2025) using a modified Delphi methodology with 37 experts found that circulating tumor cell enumeration is a validated prognostic biomarker in metastatic castration-resistant prostate cancer. The consensus noted that androgen receptor splice variant-7 testing in circulating tumor cells should be considered to help guide selection of therapy in the post-abiraterone/enzalutamide metastatic castration-resistant prostate cancer setting and is referenced in NCCN guidelines. For other solid tumors, the consensus concluded that the use of circulating tumor cells remains investigational, as more evidence is needed to support clinical utility.

Other Cancers

Studies have also been published evaluating circulating tumor cell levels as a diagnostic or prognostic marker for individuals with other types of cancer including melanoma (Hoshimoto, 2012a; Hoshimoto, 2012b), bladder (Guzzo, 2012; Jiang, 2021; Rink, 2011), gastric (Eskandarion, 2024; Huang, 2015b; Yang, 2018), lung (Tanaka, 2009; Krebs, 2011; Gao, 2018; Qian, 2018; Tong, 2018), pancreatic (Court, 2018; Okubo, 2017), thyroid (Ehlers, 2018), endometrial (Kiss, 2018), neuroblastoma (Liu, 2018), and ovarian (Liu, 2013; Huang, 2021) cancer. There are no FDA-cleared clinical tests for these indications, and none of the studies evaluated individual health care management decisions using circulating tumor cells.

The NCCN Clinical Practice Guideline For Neuroendocrine Tumors (V2.2025) discusses circulating tumor cells as investigational prognostic markers, noting that the presence of one or more circulating tumor cells per 7.5 mL blood was independently associated with worse progression-free survival and overall survival in individuals with metastatic neuroendocrine tumors. However, the guideline states that circulating tumor cells have not been incorporated into routine care, and a multinational consensus meeting concluded that no single currently available biomarker is sufficient as a diagnostic, prognostic, or predictive marker in individuals with neuroendocrine tumors.

The European Society of Gynaecological Oncology (ESGO), European Society for Medical Oncology (ESMO, and European Society of Pathology (ESP, 2024) consensus conference on ovarian cancer provided a Grade A recommendation that "routine monitoring for circulating tumour DNA and circulating tumour cells is not recommended" but should be encouraged within the context of research projects.

Conclusion

The clinical utility of quantifying circulating tumor cells remains unproven. Published data demonstrate prognostic validity but are inadequate to determine how such measurements would guide treatment decisions and whether those treatment decisions would result in improved outcomes.

Studies suggest that the presence of circulating tumor cells in individuals with metastatic carcinoma is associated with shortened survival. The CellSearch System is an immunological technique designed to detect circulating tumor cells in peripheral blood. Cells are tagged using antibody-coated magnetic beads that recognize cell surface antigens and labeled with fluorescent dyes, which can then be quantified by a semi-automated fluorescent-based microscopy system. The CellSearch System 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. There has also been some interest in the use of this test in individuals with a variety of other types of cancer. However, published studies have not established that changing routine clinical management based on circulating tumor cell measurement improves clinical outcomes across cancer types.

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. The American Cancer Society (ACS) estimated that in 2026 there would be about 321,910 American women diagnosed with invasive breast cancer, about 60,730 newly diagnosed cases of carcinoma in situ, and approximately 42,140 women would die from breast cancer.

Colorectal cancer is the third most common cancer found in men and women other than skin cancer in the United States. The ACS estimated that in 2026 there would be nearly 159,000 new cases of colorectal cancer diagnosed in the U.S. Colorectal cancer is expected to cause approximately 55,230 deaths in 2026.

Prostate cancer is the most common cancer, other than skin cancers, in American men and is the second leading cause of cancer death in men, behind only lung cancer. The ACS estimated that in 2026 there would be about 333,830 new cases of prostate cancer diagnosed in the United States and approximately 36,320 deaths from the disease.

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.

When services are also Investigational and Not Medically Necessary:

Peer Reviewed Publications:

1. 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 non-malignant diseases. Clin Cancer Res. 2004; 10(20):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, Jacot W, Kiavue N, et al. Efficacy of circulating tumor cell count-driven vs clinician-driven first-line therapy choice in hormone receptor-positive, ERBB2-negative metastatic breast cancer: the STIC CTC randomized clinical trial. JAMA Oncol. 2021; 7(1):34-41.
4. 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.
5. Court CM, Ankeny JS, Sho S, et al. Circulating tumor cells predict occult metastatic disease and prognosis in pancreatic cancer. Ann Surg Oncol. 2018; 25(4):1000-1008.
6. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumors cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351(8):781-791.
7. 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.
8. 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.
9. Ehlers M, Allelein S, Schwarz F, et al. Increased numbers of circulating tumor cells in thyroid cancer patients. Horm Metab Res. 2018; 50(8):602-608.
10. Eskandarion MR, Eskandarieh S, Tutunchi S et al. Investigating the role of circulating tumor cells in gastric cancer: a comprehensive systematic review and meta-analysis. Clin Exp Med. 2024; 24(1):59.
11. Gao W, Huang T, Yuan H, et al. Highly sensitive detection and mutational analysis of lung cancer circulating tumor cells using integrated combined immunomagnetic beads with a droplet digital PCR chip. Talanta. 2018; 185:229-236.
12. Gerratana L, Reduzzi C, Ren Y, et al. Circulating tumor cell dynamics after CDK4/6 inhibitor for hormone receptor-positive metastatic breast cancer: a biomarker analysis from the PACE phase II study. Clin Cancer Res. 2025; 31:4510-4517.
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. 2012; 30(1):44-48.
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; 12(14 Pt 1):4218-4224.
15. Hoshimoto S, Faries MB, Morton DL, et al. Assessment of prognostic circulating tumor cells in a phase III trial of adjuvant immunotherapy after complete resection of stage IV melanoma. Ann Surg. 2012a; 255(2):357-362.
16. Hoshimoto S, Shingai T, Morton DL, et al. Association between circulating tumor cells and prognosis in patients with stage III melanoma with sentinel lymph node metastasis in a phase III international multicenter trial. J Clin Oncol. 2012b; 30(31):3819-3826.
17. Huang C, Lin X, He J, Liu N. Enrichment and detection method for the prognostic value of circulating tumor cells in ovarian cancer: A meta-analysis. Gynecol Oncol. 2021; 161(2):613-620.
18. Huang X, Gao P, Song Y, et al. Meta-analysis of the prognostic value of circulating tumor cells detected with the CellSearch System in colorectal cancer. BMC Cancer. 2015a; 15:202.
19. Huang X, Gao P, Sun J. Clinicopathological and prognostic significance of circulating tumor cells in patients with gastric cancer: a meta-analysis. Int J Cancer. 2015b; 136(1):21-33.
20. Jacob K, Sollier C, Jabado N. Circulating tumor cells: detection, molecular profiling and future prospects. Expert Rev Proteomics. 2007; 4(6):741-756.
21. Janni W, Friedl TWP, Yab TC, et al. Clinical validity of repeated circulating tumor cell enumeration as an early treatment monitoring tool for metastatic breast cancer in the PREDICT global pooled analysis. Clin Cancer Res. 2025; 31:2196-2209.
22. Jiang H, Gu X, Zuo Z, et al. Prognostic value of circulating tumor cells in patients with bladder cancer: a meta-analysis. PLoS One. 2021; 16(7):e0254433.
23. Jiménez-Fonseca P, Sastre J, García-Alfonso P, et al. Association of circulating tumor cells and tumor molecular profile with clinical outcomes in patients with previously untreated metastatic colorectal cancer: a pooled analysis of the Phase III VISNÚ-1 and Phase II VISNÚ-2 randomized trials. Clin Colorectal Cancer. 2023; 22(2):222-230.
24. Kiss I, Kolostova K, Matkowski R, et al. Correlation between disease stage and the presence of viable circulating tumor cells in endometrial cancer. Anticancer Res. 2018; 38(5):2983-2987.
25. Krebs MG, Sloane R, Priest L, et al. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol. 2011; 29(12):1556-1563.
26. Liu JF, Kindelberger D, Doyle C, et al. Predictive value of circulating tumor cells (CTCs) in newly-diagnosed and recurrent ovarian cancer patients. Gynecol Oncol. 2013; 131(2):352-356.
27. Liu X, Zhang Z, Zhang B, et al. Circulating tumor cells detection in neuroblastoma patients by EpCAM-independent enrichment and immunostaining-fluorescence in situ hybridization. EBioMedicine. 2018; 35:244-250.
28. 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.
29. Okubo K, Uenosono Y, Arigami T, et al. Clinical impact of circulating tumor cells and therapy response in pancreatic cancer. Eur J Surg Oncol. 2017; 43(6):1050-1055.
30. Qian C, Wu S, Chen H, et al. Clinical significance of circulating tumor cells from lung cancer patients using microfluidic chip. Clin Exp Med. 2018; 18(2):191-202.
31. Rack B, Schindlbeck C, Jückstock J, et al; SUCCESS Study Group. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. 2014; 106(5):dju066.
32. 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.
33. Rink M, Chun FK, Minner S, et al. Detection of circulating tumour cells in peripheral blood of patients with advanced non-metastatic bladder cancer. BJU Int. 2011; 107(10):1668-1675.
34. Sastre J, Maestro ML, Gómez-España A, et al. Circulating tumor cell count is a prognostic factor in metastatic colorectal cancer patients receiving first-line chemotherapy plus bevacizumab: a Spanish Cooperative Group for the Treatment of Digestive Tumors study. Oncologist. 2012; 17(7):947-955.
35. 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.
36. Scher HI, Heller G, Molina A, et al. Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer. J Clin Oncol. 2015; 33(12):1348-1355.
37. Smerage JB, Barlow WE, Hortobagyi GN, et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol. 2014; 32(31):3483-3489.
38. 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.
39. Tong B, Xu Y, Zhao J, et al. Prognostic role of circulating tumor cells in patients with EGFR-mutated or ALK-rearranged non-small cell lung cancer. Thorac Cancer. 2018; 9(5):640-645.
40. Wullaert L, Jansen MPHM, Kraan J, et al. Circulating tumour cells and circulating tumour DNA in patients with resectable colorectal liver metastases (MIRACLE): a prospective, observational biomarker study. eClinicalMedicine. 2025; 87:103406.
41. Yang C, Zou K, Yuan Z, et al. Prognostic value of circulating tumor cells detected with the CellSearch System in patients with gastric cancer: evidence from a meta-analysis. Onco Targets Ther. 2018; 11:1013-1023.
42. Yang Y, Liu Z, Wang Q, et al. Presence of CD133-positive circulating tumor cells predicts worse progression-free survival in patients with metastatic castration-sensitive prostate cancer. Int J Urol. 2022; 29(5):383-389.
43. Zhang L, Riethdorf S, Wu G, et al. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res 2012; 18(20):5701-5710.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Andre F, Ismaila N, Allison KH, et al. Biomarkers for adjuvant endocrine and chemotherapy in early-stage breast cancer: ASCO guideline update. J Clin Oncol. 2022; 40(16):1816-1837.
2. Andre F, Ismaila N, Henry NL, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: ASCO clinical practice guideline update-integration of results from TAILORx. J Clin Oncol. 2019; 37(22):1956-1964.
3. Centers for Medicare and Medicaid Services (CMS). MolDX: phenotypic biomarker detection from circulating tumor cells L38584. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdId=38584&ver=9. Accessed on January 13, 2026.
4. Henry NL, Somerfield MR, Dayao Z, et al. Biomarkers for systemic therapy in metastatic breast cancer: ASCO guideline update. J Clin Oncol. 2022; 40(27):3205-3221.
5. Ledermann J, Matias-Guiu X, Fagotti A, et al. ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and, early, advanced and recurrent disease. Ann Oncol. 2024; 35(3):248-266.
6. NCCN Clinical Practice Guidelines in Oncology™ (NCCN). © 2026 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on January 13, 2026.
   • Breast Cancer (V1.2026). January 16, 2026.
   • Colon Cancer (V5.2024). Revised August 22, 2024.
   • Neuroendocrine Tumors (V2.2025).
   • Prostate Cancer (V1.2025). Revised December 4, 2024.
   • Rectal Cancer (V6.2024). Revised August 22, 2024.
7. Nicolò E, Reduzzi C, Pierga JY, et al. International expert consensus on the clinical integration of circulating tumor cells in solid tumors. Eur J Cancer. 2025; 231:116050.
8. 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=K103502. Accessed on January 13, 2026.

1. American Cancer Society. Available at: https://www.cancer.org/. Accessed on January 13, 2026.

AdnaTest BreastCancer
CellSearch System
Circulating Tumor Cells in the Blood for Prognosis of Cancer
FirstSight^CRC™
Immunostaining‑fluorescence in situ hybridization (iFISH)
Peptide-based nanomagnetic CTC isolation system (Pep@MNPs)
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.

Applicable to Commercial HMO members in California: When a medical policy states a procedure or treatment is investigational, PMGs should not approve or deny the request. Instead, please fax the request to Anthem Blue Cross Grievance and Appeals at fax # 818-234-2767 or 818-234-3824. For questions, call G&A at 1-800-365-0609 and ask to speak with the Investigational Review Nurse.

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member’s contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan.

© CPT Only – American Medical Association