This Medicare contractor will provide limited coverage for the Breast Cancer
Index (BCI) gene expression test (Biotheranostics, Inc., San Diego, CA). The
BCI test is used by physicians to provide a genomic-based estimate of distant
recurrence risk when considering addition of chemotherapy, and/or late distant
recurrence risk and endocrine responsiveness when considering extension of
endocrine therapy, depending upon when in the continuum of care testing is
requested.

The BCI test is covered for postmenopausal women with invasive breast cancer
when the following criteria are met:

  * Pathology reveals invasive carcinoma of the breast that is estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) and Human Epidermal Growth Factor Receptor 2 negative (HER2-); and
  * Patient has early-stage disease {Tumor, Node, Metastasis (TNM) stage T1-3, pN0-N1, M0} and
  * Patient has no evidence of distant breast cancer metastasis (i.e., non-relapsed); and
  * Test results will be used in determining treatment management of the patient for chemotherapy and/or endocrine therapy.

_Adjuvant therapy decisions initially and at 5 years in ER+_ _(or PR+)/HER2-_
_node negative breast cancer_

In 2017, approximately 253,000 patients were expected to be diagnosed with
invasive breast cancer in the United States,1 of which approximately 90% are
diagnosed with early-stage disease. Hormone-receptor positive (HR+) breast
cancer is the most common subtype of breast cancer (~80% of cases1) and has
the most favorable prognosis overall.1 Standard-of-care treatment for HR+
disease includes primary adjuvant anti-estrogen therapy with tamoxifen, an
aromatase inhibitor (AI), or a sequence of these. In addition to anti-estrogen
therapy, 2 key treatment decisions are priorities in the management of early
stage breast cancer. The first decision is whether the patient is of
sufficient risk of recurrence to recommend systemic adjuvant chemotherapy. In
addition, while HR+ early-stage breast cancer patients have a favorable
prognosis overall, there is an ongoing risk of distant recurrence (DR) beyond
year 5 (late recurrence), and 75% of deaths occur more than 5 years post-
diagnosis. As such, the second key decision is whether to recommend extension
of endocrine therapy beyond the initial primary adjuvant therapy. For each
treatment decision, physicians and patients must weigh whether the potential
benefit from the additional treatment regimen is likely to outweigh the risks
of serious toxicities and side effects.

 _Improving Patient Stratification for Addition of Adjuvant Chemotherapy_

Adjuvant chemotherapy has been shown to improve outcomes in patients with
early stage HR+ breast cancer. In a meta-analysis of 100,000 women across 123
randomized trials,2 the Early Breast Cancer Trialists Collaborative Group
(EBCTCG) reported that patients with early-stage breast cancer experience an
approximately 30% reduction in DR rate or benefit from adjuvant chemotherapy.
Notably, this analysis also showed that proportional risk reduction was not
affected by traditional clinical and pathologic factors (e.g., nodal status,
tumor size, tumor grade). Patients, therefore, with a limited underlying risk
of DR will have a lower absolute benefit from chemotherapy, compared to
patients with a high underlying risk of DR. For each patient, the expected
absolute benefit of chemotherapy needs to be weighed against the 2-3% chance
of fatal, life-threatening, or life-changing toxicities.3  
  
Standard clinical and pathologic factors (e.g., tumor size, grade, and nodal
status) are commonly used for assessment of a patients risk of DR to make
decisions about the addition of chemotherapy to endocrine therapy. However,
molecular tests have been shown to improve prognostic accuracy compared to
standard clinical and pathologic features and have become increasingly
important for patients with early-stage HR+/HER2- breast cancer to identify
patients who have a low risk of DR such that chemotherapy would not provide an
overall benefit. In determining the cutoff to identify low risk patients,
breast cancer prognostic tests commonly use a threshold of a 10% risk of DR at
10 years. Identification of a group of patients with a risk of DR<10% is a
well-accepted standard used by many currently available breast prognostic
tests and accepted by the American Society of Clinical Oncology (ASCO). 3, 4
National Comprehensive Cancer Network (NCCN) guidelines recommend the use of
clinical characteristics, tumor stage, and pathology as the initial basis for
deciding on the use of adjuvant endocrine and chemotherapy treatment. These
guidelines also recommend consideration of gene expression testing in N0 and
N1 patients who are potential candidates for adjuvant treatment .5

 _Additional Genomic Tools to Weigh Risk-Benefit with Extended Endocrine
Therapy_

In studies of HR+ patients treated with primary adjuvant endocrine therapy,
patients who were DR-free after 5 years had an approximately 10% risk of
recurrence during years 5-10.4,6 The critical question of whether longer
durations of endocrine therapy would provide additional clinical benefit led
to a series of randomized trials that compared the benefit of extended
endocrine therapy (EET; 10 years total) versus the 5-year standard of care.
The results of these trials demonstrated that EET led to a modest clinical
benefit, with statistically significant increases in disease-free survival
(3-4% absolute benefit; 10-40% relative risk reduction) in most trials.7-12
Analyses of the numbers needed to treat (NNT) from these trials demonstrate
that approximately 70-100 patients need to be treated to prevent 1 DR. While
only a small percentage of patients benefit from EET, all patients are at risk
of experiencing side effects, which include several serious toxicities such as
endometrial cancer, pulmonary embolism, ischemic heart disease and even death
in some trials for tamoxifen, and higher rates of osteoporosis, bone
fractures, thrombotic events with AIs. In addition to serious safety concerns,
prolonged endocrine therapy has numerous lower grade side effects and
tolerability challenges that can have a substantial impact on quality of life
such as arthralgia, joint pain, and musculoskeletal symptoms with AIs, and hot
flashes, fatigue, vaginal dryness, and mood swings with tamoxifen.8,10,13,14
Side effects and tolerability issues commonly lead to treatment nonadherence
or discontinuation of endocrine therapy or EET, causing worse patient
outcomes.15

The large randomized trials have demonstrated that EET is associated with a
10-40% relative reduction in risk of DR.7-12,16 The risk of serious toxicities
(e.g., spinal fractures, thrombotic events, and endometrial cancers that lead
to deaths) have been reported in ~1-2% of patients treated with EET. If the
28% relative risk reduction from the National Surgical Adjuvant Breast and
Bowel Project (NSABP). B-42 is applied to a group of patients with a 7% risk
of late DR, the absolute benefit of treatment is at most 2%, which is
approximately equivalent to the risk of serious treatment-related toxicities.
Therefore, a 7% cutoff for assessing risk versus benefit may be applied, such
that if a biomarker identifies patients with a 7% or lower risk of late DR,
the likelihood of benefit from EET is unlikely to outweigh the risks of
serious toxicities.

 **Test Description and Intended Use**

The Breast Cancer Index (BCI) is a molecular assay that evaluates the
differential expression (qRT-PCR) of 11 genes: 7 informational genes that
interrogate multiple cell-signaling pathways associated with breast cancer
recurrence [proliferative Molecular Grade Index (MGI) and estrogen signaling
(HoxB13/IL17BR or H/I)], and 4 RNA normalization (reference) genes. The test
provides both prognostic and predictive results reported as 1) individualized
risk of DR as a percentage based on a BCI Score. Specific risk estimates are
generated for the risk of overall DR (0-10 years after diagnosis) and late DR
(5-10 years after diagnosis) in patients who are recurrence-free at year 5,
and 2) the test separately reports a categorical output of H/I High versus Low
for likelihood of endocrine response, with a High H/I ratio associated with
endocrine responsive disease.

BCI is used for the management of postmenopausal women diagnosed with early-
stage (TNM stage T1-3, pN0-N1, M0), non-relapsed, ER and/or PR-positive ,
HER2-negative breast cancer, who are being treated with primary adjuvant
endocrine therapy. The test is used by physicians to provide a genomic-based
estimate of distant recurrence risk and endocrine responsiveness to identify
patients:

  * who have sufficiently low risk of distant recurrence over 10 years, wherein the absolute benefit of adjuvant chemotherapy is unlikely to outweigh the risks of serious toxicities; and/or
  * who are distant recurrence-free and have a sufficiently low residual risk of late distant recurrence (post-5 years from diagnosis) wherein the absolute benefit of extension of endocrine therapy is unlikely to outweigh the risks of complications and nonadherence to therapy.

BCI is tested once per patient lifetime on formalin-fixed, paraffin-embedded
(FFPE) tissue from the primary tumor specimen obtained prior to adjuvant
treatment.

 **Clinical Validation**

 _Evidence supporting the clinical validity of risk assessment for newly-
diagnosed patients considering adjuvant chemotherapy_

The prognostic ability of BCI for identifying patients at low risk of both
early (0-5 years) and cumulative overall DR (0-10 years) in the absence of
adjuvant chemotherapy was validated in prospective-retrospective studies in
randomized trial cohorts that included ER+ and/or PR+, LN- patients who were
treated with adjuvant tamoxifen or AI therapy (Tables 1 and 2).

 **Table 1: Risk of early DR (years 0-5), by BCI risk group in clinical
validation studies**

 **Cohort**|  **Patient subset**|  **No. of Pts**|  **BCI Low Risk**|  **BCI
Intermediate Risk**|  **BCI High Risk**|  **Hazard ratio (96% CI)**  
---|---|---|---|---|---|---  
 **% of Pts**|  **Risk of DR between 0-5y (95% CI)**|  **% of Pts**|  **Risk
of DR between 0-5y (95% CI)**|  **% of Pts**|  **Risk of DR between 0-5y (95%
CI)**|  **Intermediate vs Low risk groups**|  **High vs Low risk groups**|
**P value**  
Stockholm RCT*| Node negative| 317| 64%| 2.0% (0.0-4.0%)| 20%| 4.8%
(0.0-9.9%)| 16%| 12.2% (2.6-21.0%)| 2.31  
(0.52-10.3)| 6.19  
(1.75-21.92)| P=0.0063  
TransATAC RCT*| Node negative| 665| 59%| 1.3% (0.5-3.1%)| 25%| 5.6%
(2.9-10.5%)| 16%| 18.1% (12.0-27.0%)| 3.13  
(1.03-24.30)| 8.59  
(3.03-24.30)| P<0.0001  
Multi-institutional*| Node negative| 358| 55%| 4.1% (1.3-6.9%)| 22%| 7.7%
(1.6-13.5%)| 23%| 24.5% (14.6-33.3%)| 6.55  
(2.89-14.88)| 6.55  
(2.89-14.88)| P<0.0001  
  
* Distant recurrence-free survival data were converted to distant recurrence rates to allow for comparison between studies.  
** Hazard ratios in the Stockholm randomized study were based on 0-15yr
analysis  
Pts, patients.

 **Table 2: Risk of overall DR (years 0-10), by BCI risk group in clinical
validation studies**

 **Cohort**|  **Patient subset**|  **No. of Pts**|  **BCI Low Risk**|  **BCI
Intermediate Risk**|  **BCI High Risk**|  **Hazard ratio (96% CI)**  
---|---|---|---|---|---|---  
 **% of Pts**|  **Risk of DR between 0-10y (95% CI)**|  **% of Pts**|  **Risk
of DR between 0-5y (95% CI)**|  **% of Pts**|  **Risk of DR between 0-10y (95%
CI)**|  **Intermediate vs Low risk groups**|  **High vs Low risk groups**|
**P value**  
Stockholm RCT*| Node negative| 317| 64%| 4.8% (1.7-7.8%)| 20%| 11.7%
(3.1-19.5%)| 16%| 21.1% (8.5-32.0%)| 2.23  
(0.91-5.45)| 4.79  
(2.18-10.5)**| P=0.0063  
TransATAC RCT*| Node negative| 665| 59%| 4.8% (3.0-7.6%)| 25%| 18.3%
(12.7-25.8%)| 16%| 29.0% (21.1-39.1%)| 2.89  
(1.55-5.40)|

4.86  
(2.58-9.17)

| P<0.0001  
Multi-institutional*| Node negative| 358| 55%| 6.6% (2.9-10.0%)| 22%| 23.3%
(12.3-33.0%)| 23%| 35.8% (24.5-45.5%)| 3.54  
(1.67-7.48)|

6.81  
(3.47-13.34)

| P<0.0001  
  
* Distant recurrence-free survival data were converted to distant recurrence rates to allow for comparison between studies.  
** Hazard ratios in the Stockholm randomized study were based on 0-15yr
analysis  
Pts, patients.

Development of the 11-gene BCI assay was based on a combination of H/I and MGI
using patients from the untreated arm of the Stockholm prospective trial as
the training set (n=283). Scores and pre-specified risk groups were then
validated in a prospective-retrospective study including 317 ER+, LN- patients
treated with primary adjuvant tamoxifen from the Stockholm trial.17 The BCI
Low Risk group had only a 6% risk of death due to breast cancer over a 20 year
follow-up (years 0-20). Multivariate analyses adjusted for clinicopathologic
factors (e.g., patient age, tumor size, tumor grade) showed that BCI was the
only significant predictor of DR during years 0-10 (hazard ratio, 5.44; 95%
CI, 21.313.88; P=0.0004). Further independent validations were performed on a
well-annotated multi-institutional cohort of 358 ER+, LN- patients,17 and in a
prospective-retrospective study evaluating 665 ER+, LN- patients from the
translational cohort of the prospective, randomized, controlled ATAC
trial.17,18 In a multivariate analysis, BCI was a significant prognostic
factor for risk of DR from years 0-10 (HR, 2.30; 95% CI, 1.623.27; P<0.0001)
that included the CTS (a prognostic algorithm based on classic clinical and
pathologic factors of tumor size/grade, LN status, patient age, and
treatment).18 These studies collectively demonstrate the ability of BCI to
significantly stratify patients based on risk of DR, and to identify a low
risk group (55-64% of patients across studies) with excellent 10 year outcomes
(4.8-6.6% DR rate) when treated with a regimen of 5 years of endocrine therapy
only. BCI was also determined to provide independent prognostic information
compared to clinical and pathologic features alone.

 _Evidence supporting the clinical validity of risk assessment for patients
who are distant recurrence-free at year 5 considering extended endocrine
therapy_

Evaluation of BCI prognostic performance for late DR was performed in ER+
and/or PR+, LN- patients who were treated with no more than 5 years of
adjuvant tamoxifen or AI therapy and were DR-free at 5 years (Table 3).

 **Table 3: Risk of late DR (years 5-10) in patients who were disease free
following 5 years of adjuvant endocrine therapy, by BCI risk group in
validation studies**

 **Cohort**|  **Patient subset**|  **No. of Pts**|  **BCI Low Risk**|  **BCI
Intermediate Risk**|  **BCI High Risk**|  **Hazard ratio (95% CI)**  
---|---|---|---|---|---|---  
 **% of Pts**|  **Risk of DR between 0-10y (95% CI)**|  **% of Pts**|  **Risk
of DR between 0-5y (95% CI)**|  **% of Pts**|  **Risk of DR between 0-10y (95%
CI)**|  **Intermediate vs Low risk groups**|  **High vs Low risk groups**|
**P value**  
Stockholm RCT*| Node negative| 285| 65%| 2.8% (0.3-5.2%)| 20%| 7.2%
(0.1-13.8%)| 15%| 10.1% (0.2-19.1%)| 2.2  
(0.72-6.73)**| 4.04  
(1.46-11.14)**| P=0.0152  
TransATAC RCT*| Node negative| 596| 61%| 3.5% (2.0-6.1%)| 25%| 13.4%
(8.5-20.5%)| 14%| 13.3% (7.4-23.4%)| 2.93  
(1.37-6.29)|

2.97  
(1.23-7.13)

| P<0.0001  
Multi-institutional*| Node negative| 312| 58%| 2.5% (0-5.0%)| 22%| 16.9%
(6.5-26.2%)| 20%| 15.0% (5.5-23.6%)| 6.9  
(2.17-22.02)|

7.03  
(2.17-22.84)

| P<0.0002  
  
* DR-free survival was converted to DR rates to allow for comparison between studies.   
** Hazard ratios in the Stockholm randomized study were based on 5-15yr
analysis  
Pts, patients

Validation studies for prediction of late DR included 285 ER+, LN- patients
that were DR-free following treatment with primary adjuvant tamoxifen, 312
patients that were DR-free following treatment with primary adjuvant
treatment, and 596 patients that were DR-free following treatment with primary
adjuvant treatment.17 These studies collectively demonstrate the ability of
BCI to significantly stratify patients based on risk of late DR, and to
identify a low risk group (58-65% of patients across studies) with excellent
outcomes in the extended timeframe (<3.5% DR rate from years 5-10 in all
studies) when treated with a regimen of 5 years of endocrine therapy only,
with a risk of DR that is sufficiently low that the likelihood of benefit from
5 additional years of endocrine therapy is outweighed by the probability of
complications and treatment nonadherence.

In addition to the above data regarding patients with lymph node negative
disease, 15 year follow-up data has been reported in patients with lymph node
positive disease limited to 1-3 nodes (N1 disease) in a study of 402 women
with breast cancer.19 Subjects were followed up to 15 years with median
follow-up time of 12 years. In the low risk group, the 15 year risk of
recurrence was 1.3% (95% CI, 0.0%3.7%), while in the high risk group the risk
of recurrence was 29.0% (95% CI 23.2%34.4%). Subset analyses examining test
performance after stratification by HER2 status (HER2+ vs HER2-) and number of
positive nodes showed similar test performance across groups.

 _Evidence supporting the clinical validity of prediction of benefit from
endocrine therapy_

In addition to stratification of patients based on risk of DR, the BCI assay
also reports results from the estrogen signaling biomarker component of
BCIthe HoxB13/IL17BR gene expression ratio (H/I). The H/I ratio has been
shown to be predictive of benefit from endocrine therapies in 3 prospective
randomized study cohorts (N=1514; Table 4).17,18 In each of these studies, a
statistically significant interaction between H/I and endocrine treatment was
demonstrated. Thus, in all 3 studies, H/I had statistically significant
ability to identify patients likely to benefit from endocrine therapy versus
those patients not likely to benefit.

 **Table 4: Summary of predictive treatment benefit by H/I categorization**

 **Study Cohort**|  **Endocrine Treatment**|  **Relative Risk Reduction by
Endocrine Treatment**|  **Interaction P Value**  
---|---|---|---  
Stockholm (n=600)| Adjuvant tamoxifen vs. untreated|

H/I-High HR: 0.35 (0.19-0.65); p=0.0005  
H/I-Low HR: 0.67 (0.36-1.24), p=0.2

| 0.003  
TransATAC (n=665)| Adjuvant anastrozole vs. tamoxifen|

H/I-High HR: 0.51 (0.27-0.97); p=0.04  
H/I-Low HR: 1.33 (0.65-2.71), p=0.4

| 0.004  
MA.17 (n=249)| Extended letrozole vs. placebo|

H/I-High OR: 0.33 (0.15-0.73); p=0.006  
H/I-Low OR: 0.58 (0.25-1.36), p=0.21

| 0.03  
  
H/I was validated in the extended (> 5 years) treatment setting in a cohort of
patients from the MA.17 trial.18 H/I predicted which patients benefited from
treatment with an AI between years 5-10 post-diagnosis. The reduction in risk
of recurrence with extended letrozole (an AI) was 16.5% for patients with High
H/I (p=0.007), while patients with a Low H/I did not statistically benefit
from the extended AI therapy (p=0.35).

Level of Evidence

Quality of Evidence  Moderate  
Strength  High  
Weight - Moderate

Numerous prior Medicare coverage decisions have considered the evidence in the
hierarchical framework of Fryback and Thornbury,20 where Level 2 addresses
diagnostic accuracy, sensitivity, and specificity of the test; Level 3 focuses
on whether the information produces change in the physician's diagnostic
thinking; Level 4 concerns the effect on the patient management plan and Level
5 measures the effect of the diagnostic information on patient outcomes. To
apply this same hierarchical framework to analyze an in vitro diagnostic test,
we utilized the ACCE Model Process for Evaluating Genetic Tests.21 The
practical value of a diagnostic test can only be assessed by taking into
account subsequent health outcomes. When a proven, well-established
association or pathway is available, intermediate health outcomes may also be
considered. For example, if a particular diagnostic test result can be shown
to change patient management and other evidence has demonstrated that those
patient management changes improve health outcomes, then those separate
sources of evidence may be sufficient to demonstrate positive health outcomes
from the diagnostic test.

Consensus guidelines on the treatment of early stage breast cancer suggest the
consideration of multiple approaches to treatment of varying levels of
intensity. The potential benefits of available treatment options must be
balanced against potential harms, and magnitude of likely benefit of treatment
is in part dependent upon the probability of disease recurrence. Evidence
shows that the BCI test both predicts disease recurrence, and for some
patients also predicts response to adjuvant therapy. Moreover, NCCN guidelines
explicitly recommend the use of not only clinical characteristics, tumor
stage, and pathology, but also consideration of the inclusion of a gene
expression classifier.