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.

This policy provides limited coverage of the Prosigna breast cancer gene signature assay to patients that meet the following criteria consistent with the 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 change 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).

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