MolDX: Breast Cancer Index® (BCI) Gene Expression Test

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

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.eg., 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 patient’s 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 (0-5years) 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

* 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

* 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, 21.3–13.88; 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, 1.62–3.27; 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

* 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 BCI—the 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

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 of Evidence: High
Weight of Evidence: 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.

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21. Centers for Disease Control and Prevention. ACCE Model List of 44 Targeted Questions Aimed at a Comprehensive Review of Genetic Testing. 2010; https://www.cdc.gov/genomics/gtesting/acce/acce_proj.htm. Accessed 01/25/2021.