LCD L36811

Coverage Guidance

Title XVIII of the Social Security Act (SSA), §1862(a)(1)(A), states that no Medicare payment shall be made for items or services that “are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.”

42 Code of Federal Regulations (CFR) §410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions.

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests and §80.1.1 Certification Changes

Indications and Limitations of Coverage

This policy provides limited coverage of the Prosigna® Breast Cancer Gene Signature Assay to patients that meet the following criteria consistent with the United States (U.S.) Food and Drug Administration (FDA) indications for use:

• Post-menopausal female either

• ER+, lymph node-negative, stage I or II breast cancer; or

• ER+, lymph node-positive (1-3 positive nodes), stage II breast cancer.

Claims for Prosigna® testing will be denied when testing does not meet all of the above criteria.

Background

Women with early breast cancer and up to 3 locally positive lymph nodes whose tumor is estrogen-receptor positive will usually receive anti-hormonal therapy such as tamoxifen or aromatase inhibitors. U.S. (NCCN) and international (St. Gallen) guidelines predicate the decision for adjuvant chemotherapy on the size and grade of the breast cancer and other factors including genomic assays that provide additional information on risk of recurrence (Hernandez-Ava, et al., 2013). According to a 2014 review, “Prognostic factors provide an indication of whether a patient needs subsequent therapy.” (Paoletti & Hayes, 2014). Similarly, another 2014 review article states, “Efforts should be focused on reducing chemotherapy in patients unlikely to benefit.” (Rampurwala, et al., 2014). Accordingly, Medicare has covered breast cancer gene signature prognostic/predictive tests since 2006.

The PAM50 breast cancer gene signature test was developed in the late 1990s, and initial studies showed a strong correlation with breast cancer recurrence and with complete pathologic response to neoadjuvant chemotherapy (Parker, et al., 2009). While test results are reported on a scale of 1-100 as a Risk of Recurrence (ROR) score, the underlying algorithm is also able to classify cases into the luminal A and B, Her2neu, and triple-negative subtype classifications.

The Nanostring nCounter® nucleic acid analysis system replicates the PAM50 algorithm, as an FDA cleared kit, the Prosigna® Breast Cancer Gene Signature Assay (FDA, 2013). The Prosigna® package insert was most recently updated in January 2015 (FDA, 2015) reflecting additional studies (Sestak, et al., 2014). Notably, the Prosigna® platform and the original PAM50 platform have a 0.997 correlation (Dowsett, et al., 2013).

For the FDA, the Prosigna® test was validated in a large population of post-menopausal, estrogen-receptor positive women based on 1,017 cases of the TransATAC study (Dowsett, et al., 2013). The study showed a strong correlation with long-term breast cancer recurrence and added substantial additional prognostic information over a clinical treatment score based on standard clinical variables. This study was replicated in an independent population, also on the Prosigna® test, using 1,620 samples from the ABCSG8 trial (Gnant, 2014). A separate analysis of these trials validated prediction of distant recurrence in years 5-10 after initial diagnosis (Sestak, et al., 2014) and has been incorporated in the FDA labeling (FDA, 2015). The Prosigna® test is issued as separate reports, consistent with FDA review and labeling, for node-negative and node-positive (1-3 node) populations. Analytic performance, precision, reproducibility, and analysis of the clinical validations are provided in the FDA labeling (FDA, 2013; FDA, 2015).

Clinical utility of this breast cancer gene signature has also been assessed. The study of Martin, et al. (2015), showed a 20% decision impact on decisions for or against adjuvant chemotherapy in an all-comers population of 200 new cases of incident breast cancer, when Prosigna® test information became available after all other clinical information had been considered. The net rates of selecting adjuvant chemotherapy for low, intermediate, and high risk cases was similar to that observed in a meta-analysis of Oncotype DX decision data (Carlson & Roth, 2013). Additional support for the use of these test results in treatment decisions comes from Parker, et al. (2009), in which there was a strong association with neoadjuvant chemotherapy response. Low-scoring cases have a very low chance of complete pathological response to neoadjuvant chemotherapy, while high-scoring cases approach a 50% chance of complete pathological response. The same findings have been observed for other breast cancer gene signatures based on prognostic algorithms (Chang, et al., 2008).

Summary of Evidence

N/A

Analysis of Evidence

N/A

Associated Information

Documentation Requirements

The patient's medical record must contain documentation that fully supports the medical necessity for services included within this LCD. (See “Coverage Indications, Limitations, and/or Medical Necessity") This documentation includes, but is not limited to, relevant medical history, physical examination, and results of pertinent diagnostic tests or procedures.

Documentation supporting the medical necessity should be legible, maintained in the patient's medical record, and must be made available to the MAC upon request.

Bibliography

• Carlson JJ, Roth JA. The impact of Oncotype DX breast cancer assay in clinical practice: A systematic review and meta-analysis. Breast Cancer Res Treat. 2013;141:13-22.

• Chang JC, Makris A, Gutierrez MC, et al. Gene expression patterns in formalin-fixed, paraffin-embedded core biopsies predict docetaxel chemosensitivity in breast cancer patients. Breast Cancer Res Treat. 2008;108:233-240.

• Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 Risk of Recurrence score with Oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol. 2013;31(22):2783-2790.

• FDA (2013). 510(k) Summary: K130010. Prosigna Breast Cancer Prognostic Gene Signature Assay. Accessed 04/08/2025.

• FDA (2015) Package Insert: Prosigna Breast Cancer Prognostic Gene Signature Assay. Version 04, 18 pages. link: https://www.prosigna.com/resources/ Accessed 04/08/2025.

• Gnant M, Filipits M, Greil R, et al. Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: Using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol. 2013;25:339-345.

• Hernandez-Aya LF, Gonzalez-Angulo AM. Adjuvant systemic therapies in breast cancer. Surg Clin North Am. 2013; 93(2):473–491.

• Martin M, Gonzalez-Rivera M, Morales S, et al. Prospective study of the impact of the Prosigna assay on adjuvant clinical decision-making in unselected patients with estrogen receptor positive, human epidermal growth factor receptor negative, node negative early-stage breast cancer. Curr Med Res Opin. 2015;31(6):1129-1137.

• Paoletti C, Hayes DF. Molecular testing in breast cancer. Ann Rev Med. 2014;65:95-110.

• Parker JS, Mullins M, Cheang MCU, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160-1167.

• Rampurwala M, Rocque GB, Burkard ME. Update on adjuvant chemotherapy for early breast cancer. Breast Cancer: Basic and Clinical Research. 2014;8:125-134.

• Sestak I, Cuzick J, Dowsett M, et al. Prediction of late distant recurrence after 5 years of endocrine treatment: A combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and Arimidex, Tamozigen alone or in combination randomized trials using the PAM50 risk of recurrence score. J Clin Oncol. 2014;33:916-922.