BlueCross BlueShield of Tennessee Medical Policy Manual

Circulating Tumor DNA Multi-Panel Testing and Circulating Tumor Cells (Liquid Biopsy)


Liquid biopsy refers to the analysis of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) as a method of noninvasively characterizing tumors and tumor genome from the peripheral blood. This method may be used to test for single genes, when appropriate, or multiple genes using a panel.

Both malignant and nonmalignant cells release small fragments of DNA into the blood, which is referred to as cell-free DNA. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor or metastases. Analysis of circulating tumor DNA allows multiple samples of blood to be analyzed over time to monitor the molecular changes taking place in a tumor. 

Intact circulating tumor cells (CTCs) are released from a primary tumor and/or a metastatic site in to the blood stream. The half-life of a CTC is short, approximately 1 – 2 hours. The primary reason for detecting CTCs is prognostic, through quantification of circulating levels.

Various laboratories are developing liquid biopsy assays.  For many of these assays, analytical validity studies have not been performed.

Note:  This policy does not address using circulating tumor DNA liquid biopsy for single-gene testing.





Insufficient data are available to determine if the analysis of circulating tumor cells (e.g., CellSearch®) improves health outcomes.


Aggarwal, C., Thompson, J.C., Black, T.A., Katz, S.I., Fan, R., Yee, S.S., et al. (2018). Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer. JAMA Oncology, doi: 10.1001/jamaoncol.2018.4.05. [Epub ahead of print]. Abstract retrieved May 14, 2019 from PubMed database.

American Society of Clinical Oncology / College of American Pathologists. (2018, March). Circulating tumor DNA analysis in patients with cancer: ASCO / CAP Joint Review. Received March 6, 2018 from

BlueCross BlueShield Association. Evidence Positioning System. (10:2018). Circulating tumor DNA for management of non-small cell lung cancer (liquid biopsy) (2.04.143). Retrieved March 11, 2019 from  (77 articles and/or guidelines reviewed)

BlueCross BlueShield Association. Evidence Positioning System. (1:2019). Circulating tumor DNA and circulating tumor cells for cancer management (liquid biopsy) (2.04.141). Retrieved March 11, 2019 from  (36 articles and/or guidelines reviewed)

Boysen, A.K., Schou, J.V., & Spindler, K.G. (2018). Cell-free DNA and preoperative chemoradiotherapy for rectal cancer: a systematic review. Clinical & Translational Oncology, doi: 10.1007/s12094-018-1997-y. [Epub ahead of print]. Abstract retrieved May 13, 2019 from PubMed database. Centers for Medicare & Medicaid Services. Palmetto, GBA. (2018, September). MolDX: Circulating Tumor Cell Marker Assays. (LCD IDL35071). Retrieved March 11, 2019 from

eviCore healthcare. (2019, July). Lab management guidelines for CellSearch circulating tumor cell count for breast cancer prognosis. Retrieved March 11, 2019 from (5 articles and/or guidelines reviewed)

eviCore healthcare. (2019, July). Lab management guidelines for liquid biopsy testing - solid tumors. Retrieved March 11, 2019 from (21 articles and/or guidelines reviewed)

Khetrapal, P., Lee, M.W.L., Tan, W.S., Dong, L., de Winter, P., Feber, A., & Kelly, J.D. (2018). The role of circulating tumour cells and nucleic acids in blood for the detection of bladder cancer: A systematic review. Cancer Treatment Reviews, 66, 56-63. Abstract retrieved May 13, 2019 from PubMed database.

Lanman, R., Mortimer, S., Zill, O., Sebisanovic, D., Lopez, R., Blau, S., Collisson, E., et al. (2015). Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PLoS One, 10 (10), e0140712. (Level 3 evidence)

Levy, B., Hu, Z., Cordova, K., Close, S., Lee, K. & Becker, D. (2016). Clinical utility of liquid diagnostic platforms in non-small cell lung cancer.The Oncologist, 21, 1121-1130. (Level 2 evidence)

Mao, C., Yuan, J., Yang, Z., Wu, X., & Tang, J. (2015). Blood as a substitute for tumor tissue in detecting EGFR mutations for guiding EGFR TKIs treatment of non-small cell lung cancer. Medicine, 94 (21), e775. (Level 1 evidence)

National Comprehensive Cancer Network (2019, January). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-small cell lung cancer V3.2019. Retrieved March 11, 2019 from the National Comprehensive Cancer Network.

Petit, J., Carroll, G., Gould, T., Pockney, P., Dun, M., & Scott, R.J. (2019). Cell-free DNA as a diagnostic blood-based biomarker for colorectal cancer: a systematic review. Journal of Surgical Research, 236, 184-197. Abstract retrieved May 13, 2019 from PubMed database.

Satelli, A., Brownlee, Z., Mitra, A., Meng, Q., & Li, S. (2015). Circulating tumor cell enumeration using a combination of EpCAM and Cell-surface vimentin based methods for monitoring breast cancer therapeutic response. Clinical Chemistry, 61 (1), 259-266. (Level 3 evidence)

U. S. Food and Drug Administration. (2005, January). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K040898 (CellSearch™). Retrieved January 4, 2012 from

Wang, S., Du, H., & Li, G. (2017). Significant prognostic value of circulating tumor cells in esophageal cancer patients: A meta-analysis. Oncotarget, Advance Publications, 2017, 1-12. (Level 2 evidence)

Wu, Z. X., Liu, Z., Jiang, H. L., Pan, H. M., & Han, W. D. (2016). Circulating tumor cells predict survival benefit from chemotherapy in patients with lung cancer. Oncotarget, 7 (41), 67586-67596. Abstract retrieved February 17, 2017 from PubMed database.

Zheng, Y., Zhang, C., Wu, J., Cheng, G., Yang, H., Hua, L., et al. (2016). Prognostic value of circulating tumor cells in castration resistant prostate cancer: A meta-analysis. Urology Journal, 13 (6), 2881-2888. Abstract retrieved February 17, 2017 from PubMed Database.




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