BlueCross BlueShield of Tennessee Medical Policy Manual

Breast Cancer Gene Expression Assays

Does Not Apply to Commercial Genetic Testing Program effective 6/1/2018


Commercial products and laboratory tests have been developed that detect the expression of many different genes in breast tumor tissue and combine the results into a prediction of distant recurrence risk (return of detectable cancer in another part of the body) for women with early-stage breast cancer.  Test results may help determine whether to include adjuvant chemotherapy in post-surgical management of breast cancer.

For women with early-stage invasive breast cancer with positive hormone receptor status and negative human epidermal growth factor receptor 2 (HER2) several tests have been proposed for gene expression profiling as a means to predict recurrence. Most women with newly diagnosed, early-stage or nonmetastatic breast cancer are disease-free after initial local and regional treatment. However, almost a third of women develop metastasis by the 5 – 10 year follow-up.

Examples of gene expression assays for breast cancer:



Regulatory Status

Breast Cancer Index

6-11 gene predictor for risk of late recurrence at 5 to 10 years

Not FDA approved


12-gene molecular score for early and late reoccurrence

To date, the FDA has chosen not to require regulatory review of this test


70 gene analysis; provides low-high risk classification for 10 year prognosis

cleared for marketing by the FDA through the 510(k) process

Oncotype DX® for Breast Cancer

21-gene assay; Recurrence Score® of 0-00 provides 10 year prognosis information

To date, the FDA has chosen not to require regulatory review of this test


(PAM 50)

digital analysis system based on prediction of 50 gene microarray; giving a numerical value of 0-100 that correlates with the probability of recurrence within 10 years.

cleared for marketing by the FDA through the 510(k) process





Tests intended to assess estrogen receptor, progesterone receptor and HER2 status, such as TargetPrint®, and tests that do not provide a specific recurrence risk are outside the scope of this policy. 


American Society of Clinical Oncology. (2017). Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer. Retrieved January 16, 2018 from

Blok, E.J., Bastiaannet, E., van den Hout, W.B., Liefers, G.J., Smit, V.T., Kroep, J.,R., & van de Velde, C.J.H. (2018). Systematic review of the clinical and economic value of gene expression profiles for invasive early breast cancer available in Europe. Cancer Treatment Reviews, 62, 74-90. (Level 1 evidence)

BlueCross BlueShield Association. Evidence Positioning System. (11:2017). Assays of genetic expression in tumor tissue as a technique to determine prognosis in patients with breast cancer (2.04.36). January 25, 2019 from (71 articles and/or guidelines reviewed)

Cardosa, F., van’t Veer, L.J., Bogaerts, J., Slaets, L., Viale, G., Delaloge, S., et al. (2016). 70-gene signature as an aid to treatment decisions in early-stage breast cancer. New England Journal of Medicine, 375 (8), 717-729. (Level 1 evidence) Centers for Medicare and Medicaid Services. Palmetto GBA (2019, January) MolDX: Breast cancer index genetic assay (LCD ID: L35631). Retrieved January 25, 2019 from https:/// Centers for Medicare and Medicaid Services. Palmetto GBA (2019, January) MolDX: Breast cancer assay: Prosigna (LCD ID: L36125). Retrieved January 25, 2019 from https:/// 

Dubsky, P., Brase, J., Jakesz, R., Rudas, M., Singer, C., Greil, R., et al. (2013). The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. British Journal of Cancer, 109, 2959-2964. (Level 2 evidence)

Müller, B., Keil, E., Lehmann, A., Winzer, K., Richter-Ehrenstein, C., Prinzler, J., et al. (2013). The EndoPredict gene expression assay in clinical practice - performance and impact on clinical decisions. PLOS One, 8 (6), e68252. (Level 4 evidence)

National Comprehensive Cancer Network. (2018, October). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Breast cancer. Version 3.2018. Retrieved November 2, 2018 from the National Comprehensive Cancer Network.

National Institute for Health and Care Excellence. (2013). Gene expression profiling and expanded immunohistochemistry tests for guiding adjuvant chemotherapy decisions in early breast cancer management: MammaPrint, Oncotype DX, IHC4 and Mammostrat. Retrieved January 6, 2017 from

Sestak, I., Buus, R., Cuzick, J., Dubsky, P., Kronenwett, R., Denkert, C., et al. (2018, April). Comparison of the performance of 6 prognostic signatures for estrogen receptor-positive breast cancer: a secondary analysis of a randomized clinical trial. JAMA Oncology, 4 (4), 545-553. Abstract retrieved November 26, 2018 from PubMed database.

Sgroi, D., Sestak, I., Cuzick, J., Zhang, Y., Schnabel, A., Schroeder, B., et al. (2013). Prediction of late distant recurrence in estrogen receptor positive breast cancer patients: prospective comparison of the breast cancer index (BCI), Oncotype DX recurrence score and IHC4 in TransATAC. Lancet Oncology, 14 (11), 1067-1076.  (Level 4 evidence)

Tan, W., Yang, M., Zhou, F., and Shen, W. (2018). Predicting the response to neoadjuvant therapy for early-stage breast cancer: tumor-, blood-, and imaging-related biomarkers. Cancer Research and Management, 10, 4333-4347. (Level 2 evidence)

U. S. Food and Drug Administration. (2007, June). Center for Devices and Radiologic Health, Premarket Notification Database. K141142 (MammaPrint®). Retrieved November 26, 2018 from

U. S. Food and Drug Administration. (2015, May). Center for Devices and Radiologic Health, Premarket Notification Database. K141771 (Prosigna™). Retrieved November 26, 2018 from

Xin, L., Liu, Y.H., Martin, T.A., & Jiang, W.G. (2017). The era of multigene panels comes? The clinical utility of OncotypeDX and MammaPrint. World Journal of Oncology, 8 (2), 34-40. (Level 2 evidence)

Zhang, Y., Schnabel, C., Schroeder, B., Jerevall, P., Jankowitz, R., Fornander, T., et al. (2013). Breast cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for early and late - distant recurrence. Clinical Cancer Research, 19 (15), 4196-4205. Abstract retrieved January 9, 2017 from PubMed database.




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