This policy provides limited coverage of the [Prosigna Breast Cancer Gene
Signature
Assay](https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm?ID=K130010)
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).

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