BlueCross BlueShield of Tennessee Medical Policy Manual

Circulating Tumor DNA (Liquid Biopsy) and Circulating Tumor Cells


Detection and quantification of circulating tumor DNA (ctDNA) also referred to as ‘liquid biopsy’, and circulating tumor cells (CTCs) in peripheral blood, has been proposed as a noninvasive alternative to tissue biopsy. The presence of CTCs (e.g., CellSearch® CTC) and ctDNA (e.g., Oncotype SEQ™, Guardant360®) has been documented in multiple tumor types, such as breast, prostate, lung, and colorectal carcinomas.

Both normal and tumor cells release DNA fragments into the blood. Studies have shown variable results for clinical sensitivity and it is not known to what degree genetic variances detected by ctDNA are representative of the primary tumor.

For individuals who have cancer or are at high risk of developing cancer who receive identification and quantification of CTCs, cutoff levels that should be used to signal a change in patient management are unknown.




The uncertainties concerning clinical validity preclude conclusions about whether genetic variance analysis by ctDNA can replace analysis of tissue samples. The evidence is insufficient to determine the effects of the technology on health outcomes, therefore using liquid biopsy or the analysis of circulating tumor cells as a method to predict or manage any type of cancer remains investigational at this time.


Alemar, J., & Schuur, E. R. (2013). Progress in using circulating tumor cell information to improve metastatic breast cancer therapy. Journal of Oncology, 2013, article ID 2013: 702732. (Level 2 evidence) 

Bidard, F. C., Mathiot, C., Delaloge, S., Brain, E., Giachetti, S., de Cremoux, P., et al. (2010). Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Annals of Oncology, 21 (4), 729-733. (Level 3 evidence - Industry sponsored)

BlueCross BlueShield Association. Medical Policy Reference Manual (5:2018) Circulating Tumor DNA and Circulating Tumor Cells for Cancer Management (Liquid Biopsy) Retrieved June 11, 2018 from BlueWeb. (37 articles and/or guidelines reviewed)

Hou, J. M., Greystoke, A., Lancashire, L., Cummings, J., Ward, T., Board, R., et al. (2009). Evaluation of circulating tumor cells and serological cell death biomarkers in small cell lung cancer patients undergoing chemotherapy. The American Journal of Pathology, 175 (2), 808-816. (Level 4 evidence - Independent study)

Husain, H., and Valculescu, V. (2017, October) Cancer DNA in the circulation, the liquid biopsy. JAMA Insights, 318 (13), 1272-3. (Level 5 evidence)

Iinuma, H., Watanabe, T., Mimori, K., Adachi, M., Hayashi, N., Tamura, J., et al. (2011, April). Clinical significance of circulating tumor cells, including cancer stem-like cells, in peripheral blood for recurrence and prognosis in patients with Dukes’ stage B and C colorectal cancer. Journal of Clinical Oncology, 29 (12), 1508-1556. (Level 2 evidence)

Mao, C., Yuan, J., Yang, Z., Wu, X., and Tang, J. (2015, May) 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)

Matsusaka, S., Chin, K., Ogura, M., Suenaga, M., Shinozaki, E., Mishima, Y., et al. (2010). Circulating tumor cells as a surrogate marker for determining response to chemotherapy in patients with advanced gastric cancer. Cancer Science, 101 (4), 1067-1071. (Level 3 evidence - Industry sponsored)

Merker, J., Oxnard, G., Compton, C., Diehn, M., Hurley, P., Lazar, A., et al. (2018, March) Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. Received March 6, 2018 (Journal of Clinical Oncology) from

Mirza, S., Jain, N., and Rawal, R. (2017, March) Evidence for circulating cancer stem-like cells and epithelialmesenchymal transition phenotype in the pleurospheres derived from lung adenocarcinoma using liquid biopsy. Tumour Biology;36(3). Abstract retrieved June 20, 2017 from PubMed database.

National Comprehensive Cancer Network (2018, April) NCCN Guidelines® Non-small cell lung cancer V4.2018. Retrieved June 11, 2018 from the National Comprehensive Cancer Network.

Palmeto, GBA. (2018, February) Local Coverage Determination (LCD): MolDX: Circulating Tumor Cell Marker Assays (L35071). Retrieved June 11, 2018 from

Plaks, V., Koopman, C. D., & Werb, Z. (2013, November). Circulating tumor cells. Science, 341 (6151). (Level 3 evidence)

Qiu, M., Wang, J., Xu, Y., Ding, X., Li, M., Jiang, F., et. al., (2015, January) Circulating tumor DNA is effective for the detection of EGFR mutation in non-small cell lung cancer: a meta-analysis. Cancer Epidemiology, Biomarkers &  Prevention; 24(1):206-12. Abstract retrieved June 20, 2017 from PubMed database.

Rack, B., Schindlbeck, C., Jückstock, J., Andergassen, U., Hepp, P., Zwingers, T., et al. (2014, May). Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. Oxford Journal, 106 (5), 1-11. (Level 3 evidence)

Satelli, A., Brownlee, Z., Mitra, A., Meng, Q., & Li, S. (2015, January). 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. (2004, January). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K031588. Retrieved January 4, 2012 from 

U. S. Food and Drug Administration. (2005, January). Center for Devices and Radiological Health. 510(k) Premarket Notification Database. K040898. 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 3 evidence - Independent study)

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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