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MolDX: EndoPredict Breast Cancer Gene Expression Test

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LCD ID
L37264
LCD Title
MolDX: EndoPredict Breast Cancer Gene Expression Test
Proposed LCD in Comment Period
N/A
Source Proposed LCD
DL37264
Original Effective Date
For services performed on or after 10/02/2017
Revision Effective Date
For services performed on or after 07/04/2021
Revision Ending Date
N/A
Retirement Date
N/A
Notice Period Start Date
05/20/2021
Notice Period End Date
07/03/2021
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42 Code of Federal Regulations (CFR) 410.32(a). Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions

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Coverage Guidance

Coverage Indications, Limitations, and/or Medical Necessity

This Medicare contractor will provide limited coverage for the EndoPredict® breast cancer gene expression test (Myriad Genetic Laboratories Inc., Salt Lake City, UT) for the management of post-menopausal women diagnosed with early-stage (TNM stage T1-3, N0-1) estrogen-receptor (ER) positive, Her2-negative breast cancer, who are either lymph node-negative or who have 1-3 positive nodes, and for whom treatment with adjuvant endocrine therapy (e.g., tamoxifen or aromatase inhibitors) is being considered. The test is used by physicians in the management of these patients by identifying those who have sufficiently low risk of distant recurrence (DR) at 10 years and may safely forego chemotherapy.

Summary of Evidence

In 2016, approximately 247,000 cases of breast cancer were diagnosed in the United States.1 Approximately 75% of early-stage breast cancers are estrogen receptor (ER)-positive and HER2-negative, leading to treatment with adjuvant endocrine therapy (e.g., tamoxifen or aromatase inhibitors) that significantly improves prognosis.2,3 Determining which patients with ER+/Her2- breast cancer will have a low enough risk of DR after 5 years of endocrine therapy to forgo adjuvant chemotherapy is a priority for physicians who manage these patients.

A 2012 meta-analysis by the Early Breast Cancer Trialist’s Collaborative Group demonstrated that all clinical risk groups of patients with early breast cancer experience a ~30% benefit from chemotherapy, in terms of decrease in DR rate.4 Therefore, patients with a low 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 treatment-related toxicity and long-term side effects.

Tumor size, grade, and nodal status are currently used for assessment of a patient’s distant recurrence risk 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 features and have become increasingly important for patients with ER+/Her2- breast cancer. These assays have become standard of care in the treatment of early stage breast cancer, to identify patients who have a low risk of DR such that chemotherapy would not provide an overall benefit, to directly predict chemotherapy benefit, and to help curtail costly overtreatment.

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. Patients with a risk under 10% are categorized as low risk. This 10% cutoff is a well-accepted standard used by many currently available breast prognostic tests and accepted by the American Society of Clinical Oncology (ASCO).5 In addition, while hormone receptor-positive early-stage breast cancer patients have a favorable prognosis overall, there is an ongoing risk of distant recurrence (DR) and death. 15,16 Women with node-negative disease who received 5 years of endocrine therapy have a 13% risk of recurrence 5-20 years after diagnosis.15 Studies have offered conflicting results on the efficacy of continuing endocrine therapy beyond five years. A series of randomized trials that compared the benefit of extended endocrine therapy (EET; 10 years total) versus the 5-year standard of care demonstrated that EET led to a modest clinical benefit in disease free survival, although many were confounded by the inclusion of patients who received adjuvant chemotherapy or by unknown hormone receptor status. 17-23

Recently presented results from the large, randomized, placebo-controlled NSABP-B42 trial showed that survival was not significantly improved with EET. 24 Finally, EET is associated with a risk of serious, potentially life-threatening toxicities and side effects that may impact quality of life, which must be balanced with the potential for increased survival. 25-27

Patients with hormone receptor-positive, HER2-negative breast cancer and their physicians face a challenging second treatment decision regarding continuation of endocrine therapy beyond 5 years. Current professional society guidelines state that women may consider EET beyond 5 years.

Because of the modest benefit possible, ASCO Guidelines suggest using clinical criteria, including assessing tolerability, for determining which patients should be given EET in the low-risk population of node-negative and limited node-positive patients. 28-29

Test Description and Intended Use

EndoPredict was developed in a training cohort of 964ER-positive and HER2-negative breast tumor samples.10 The EndoPredict test is composed of a 12 gene molecular score as well as clinicopathological features (tumor size and nodal status). Eight genes were selected as relevant for therapeutic decision making; they include proliferation-associated genes as well as estrogen receptor signaling-associated genes. The signature also includes three RNA normalization genes and one DNA contamination control gene. The 12 gene molecular score is calculated by the weighted expression of the 8 target genes, as normalized by the 3 normalization genes, as measured in formalin-fixed paraffin-embedded (FFPE) breast tumor tissue. The 12 gene molecular score is then combined with clinicopathologic features including tumor size and lymph node status to produce the EndoPredict (EPclin) score. Patients with an EPclin score of ≤3.3 are classified as low risk and those with an EPClin score >3.3 are classified as high risk. In addition to a clear bimodal result (low- or high-risk), the test report includes the patient’s 10-year risk of distant recurrence and the likelihood of distant recurrence 5-15 years after diagnosis.

EndoPredict is intended for use in FFPE breast tumor tissue from postmenopausal women diagnosed with early-stage (TNM stage T1-3, N0-1) ER-positive, Her2-negative breast cancer, who are either lymph node-negative or who have 1-3 positive nodes, and for whom treatment with adjuvant endocrine therapy (e.g., tamoxifen or aromatase inhibitors) is being considered. The test is used by physicians in the management of early-stage breast cancer by identifying those patients with a low-risk EPClin score, for whom the absolute benefit of adjuvant chemotherapy is unlikely to outweigh the risks.

Analytical Validation

This assays analytical validation is consistent with industry standards and MolDX criteria. 

Clinical Validation

The prognostic ability of EndoPredict has been validated by prospectively designed-retrospective studies in three different cohorts from phase III trials [The Austrian Breast & Colorectal Cancer Study Group (ABCSG)-6 and-8, and Arimidex, Tamoxifen, Alone or in Combination (ATAC)] involving more than 2,600 patients,7,10 satisfying a 1B level of evidence according to the classification for prognostic biomarkers proposed by Simon et al.11 These studies collectively demonstrate the ability of EndoPredict to predict the primary endpoint of distant metastases in both early and late time periods, to accurately classify patients into a low or high risk group, and to identify a low risk group with excellent 10 year outcomes after treatment with 5 years of endocrine therapy only.7,10,12-13 EndoPredict was determined to provide independent prognostic information compared to clinical and pathologic features alone.9 

Filipits et al. (2011) described the initial development and clinical validation of the 12 gene molecular score and EPclin scores.10 The 12 gene molecular score and EPclin scores were developed in a training cohort of 964 ER-positive, HER2-negative tumors from both node-positive and -negative patients treated with adjuvant endocrine therapy only. The design and calculation of the 12 gene molecular score and EPclin scores was prespecified. The threshold for EPclin to discriminate patients into low and high risk of distant recurrence was pre-defined at 3.3 which corresponded to a 10% DR risk at 10 years. Scores were then independently validated on 1702 patients from two large randomized phase III trials (ABCSG-6 and -8 trials), with ER+, HER2- breast cancer who received endocrine therapy only for 5 years and included both node-positive and node-negative patients. In Kaplan-Meier analysis, EPclin low risk patients had a 4% distant recurrence rate (both ABCSG cohorts), while EPclin high risk patients had a 28% (ABCSG-6) or 22% (ABCSG-8) rate of distant recurrence (HR= 7.97 (ABCSG-6) or 4.27 (ABCSG-8), both P<0.001), demonstrating the ability of EPclin to accurately classify patients into low and high risk groups.

Buus et al. (2016) published a clinical validation study of EndoPredict in a third cohort of patients using the same pre-defined EPclin threshold of 3.3 to discriminate low risk from high risk patients (as described in Filipits et al.).7 The study included 928 women from the ATAC trial who had ER-positive, HER2-negative breast cancer, both node-negative and node-positive, chemotherapy-naïve, treated with endocrine therapy. The EPclin score classified high and low risk patients with both node negative disease (5.9% DR for low risk vs. 20.0% DR for high risk, HR=3.9 (2.33-6.52) p<0.001) and node positive disease (5.0% vs. 36.9%, HR=9.49 (2.33-38.75) p<0.001). Overall, the EPclin score classified 58.8% of patients as low risk in this study. The authors concluded that the superior performance of EPclin compared with another widely used breast cancer prognostic test was partly due to the inclusion of clinical variables (nodal status and tumor size) in the EPclin score, but also due to an improved molecular signature that better predicts late events in years 5-10 (x2=59.3, p<0.001).

Dubsky et al. conducted two secondary analyses to evaluate the performance of EndoPredict in different subsets of the 1702 ER-positive, HER2-negative breast cancer patients from the ABCSG-6 and ABCSG-8 phase III trials.12-13 The EPclin score improved the classification of breast cancer compared to the prognosis assigned by standard guidelines that use clinical and pathological features (i.e., NCCN, German S3 and St. Gallen).12 Using clinical guidelines, 6-19% of patients were classified as low risk; however, EPclin classified 63% of all patients as low risk. Furthermore, 58-61% of patients classified as high- or intermediate-risk according to clinical guidelines were reclassified by EPclin as low risk; this group of patients had a 5% rate of distant metastasis at 10 years, confirming the accuracy of EndoPredict’s assessment of risk. Finally, EndoPredict was compared to standard clinical parameters for predicting distant metastases in both early (0-5y) and late (5-10y) time periods, which is an important consideration based on the fact that 50% of recurrences in women with ER+, Her2- breast cancer occur after 5 years.13 The EPclin low risk group had significantly improved clinical outcomes compared to the EPclin high risk group in both the early (0-5y; HR 4.82, p<.001)) and late (5-10y; HR 6.25, p<.001) timeframes. The EPclin score identified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% risk of late distant metastasis at 10 years.

A more recent, longer term study of the ABCSG6/8 cohorts evaluated the prognostic value of EndoPredict in women who were DR-free 5 years after diagnosis.30 Filipits et al suggests that women with low EndoPredict scores had reduced rates of DR, and the hazard ratio remained statistically significant even in the longer follow-up period from 5 to 15 years compared to those with high EndoPredict scores. The overall data demonstrated that EndoPredict could identify a difference in recurrence rates between EPclin high and low risk patients. A detailed breakdown of the findings (fig.2 of the study) identifies specific information related to the patients within the intended use of EndoPredict. A subset of the data (including the most robust data) limited to 5-10 years after ET demonstrates that EPclin –low risk patients are unlikely to have recurrence. In the subset of node negative women who did not have a recurrence by 5 years, the DR for low risk EndoPredict was 2.1% at 10 years, with a narrow confidence interval (CI) that does not exceed 4%. In the subset of node positive women who did not have a recurrence by 5 years, the DR for low risk EndoPredict was 1.7% at 10 years, with a narrow confidence interval that does not exceed 5%. However, these data omit later time points (years 10-15 of the study).

Clinical Utility

A retrospective analysis of the prospective use and impact of the EndoPredict assay in a clinical setting was published in 2013 by Müller et al.14 Samples from 167 women with primary invasive ER+, HER2- breast cancer were analyzed by EndoPredict performed at the molecular pathology laboratory (Institute of Pathology) at the Charite´ University Hospital in Berlin. The impact of EndoPredict on changes in therapy decisions was evaluated for 130 of the 167 patients, of whom 47.7% had low EPclin scores and 52.3% had high EPclin scores. There was a change in pre-test versus post-test therapy for 37.7% of patients with most of the changes due to reduction from combination therapy (chemotherapy plus endocrine) to endocrine therapy alone. Before the EndoPredict assay, 47 (36.2%) of patients had been scheduled for endocrine therapy alone and 83 (63.8%) had been scheduled for a combination of endocrine therapy and chemotherapy. After the EndoPredict results were available, the number of patients with endocrine therapy alone increased to 67 (51.5%). Changes in therapy were directionally aligned with the EPclin result as low or high risk. 

A 2011 meta-analysis of Oncotype DX decision data determined that the test changed adjuvant chemotherapy treatment decisions in 33.4 % of patients (8 studies, 1,437 patients).16 The observed change in treatment recommendations for 37.7% and 35.8% of patients after use of EndoPredict is therefore consistent with the expected clinical utility of similar established tests.

Summary of Analytical and Clinical Performance

General

Intended Use EndoPredict is intended for use in FFPE breast tumor tissue from postmenopausal women diagnosed with early stage (TNM stage T1-3, N0-1) ER-positive, Her2-negative breast cancer, who are either lymph node-negative or who have 1-3 positive nodes, and for whom treatment with adjuvant endocrine therapy (e.g., tamoxifen or aromatase inhibitors) is being considered.
Validated Specimen Type (s) Invasive primary female breast cancer FFPE tissue.

 

Analytical Performance

Description Results (with 95% Confidence Intervals if applicable)
Intermediate precision (between run precision)12 samples (2 low, 10 high, score range 2.1-5.9) were run 3 times for the inter-batch reproducibility. Each set of 12 samples was run on different days, in batches of 2 samples. Each time a set of 12 samples was run, the samples were randomly assigned into the batches of 2 samples. Thus, 6 batches were run for each set of samples, for a total of 18 batches. 2 QuantStudio instruments (for qRT-PCR) and 7 technicians (3 within the anatomic pathology laboratory and 4 within the RNA extraction and qRT-PCR laboratory) were involved. These samples were tested over a 17 day period, with each sample replicate tested on a different day than the other replicates for that sample. Two different lots of 96-well plates and positive control were utilized, and a single lot of mastermix and extraction reagents were utilized. Qualitative: 100% (36/36; 95% CI = 90.3-100%)
Quantitative: Standard deviation = 0.06 EPclin score units (upper 95% CI: 0.07)
Reproducibility (between sites) N/A. This test is only performed in one laboratory.
Minimum input quantity There is no minimum RNA concentration required for testing as determined by UV spectroscopy. Instead, a functional quantification of the RNA is performed by measuring the average Ct values of the 3 housekeeper genes. This average value must be between 19.0 and 27.0 for an EPclin score to be generated.
Limit of blank (LOB) Not empirically determined.
Limits of quantitation (LOQ) There is no pre-specified upper or lower limit for Ct values for any target or housekeeper gene. However, there is both an upper and lower limit for the averaged Ct value of the housekeeper genes (19.0-27.0).
Reportable range For the EPclin score, the reportable range of scores was determined in a cohort of 1,324 samples and is from 1.1 to 6.2.10
Interfering substances Contamination of ≤70% normal tissue did not significantly alter the EPclin score.18 Additionally, there are no known PCR inhibitors in breast resection tissue.
Specimen stability, primary (FFPE) Archival FFPE samples were tested in the validation studies of this assay, with samples over 10 years old tested and producing passing results.10
Specimen stability, intermediate (Isolated RNA) 6 samples (1 low risk, 5 high risk; score range 2.0 to 6.8) were tested over 4 weeks when stored at -80 °C, acceptance criteria = ±0.6 EP score units) 4 weeks at -80 °C
Reagent closed/shelf-life stability 4 reagents are considered critical: Versant Tissue Prep Kit (Siemens Healthcare Diagnostics); TaqPath 1-step RT-qPCR Master Mix (ThermoScientific); Positive control RNA (Agilent Technologies); and EndoPredict 96-well plate (Myriad GMBH). Manufacturer’s guidelines are followed for all reagent expirations.
Reagent open/in use stability

 

The prognostic ability of EndoPredict for 10 year distant recurrence has been validated in three different cohorts from phase III trials (ABCSG-6 and-8, and ATAC), involving more than 2,600 patients with ER-positive, HER2-negative, node-positive and –negative invasive breast cancer treated with endocrine therapy only.

 

Cohort Patient Subset No. Patients EPclin Low Risk Group EPclin High Risk Group HR and p-value
10-yr risk of DR (95% CI) 10-15 yr risk of DR (95% CI) 10-yr risk of DR (95% CI) (Between EPclin low/high risk groups)
ABCSG-610 All (Node Negative & Node Positive) 378 4% (1 – 8%) 55% 28% (20 – 36%) 7.97(3.56-17.83 p<0.001
ABCSG-810 1324 4% (2 – 5%) 65% 22% (15 – 29%) 4.27(2.74-6.67) p<0.001
ATAC7 928 5.8% (4.0 – 8.3) 59% 28.8% (24.3 – 33.9) 5.99(3.94-9.11) p<0.001
ABCSG-6&810* Node Negative 1165 5% (2.5 – 6.8) 78% 16% (10.0 – 22.8) 3.92(2.35-6.54) p<0.001
ATAC7 680 5.9% (4.0 – 8.6) 73% 20.0% (14.6 – 27.0) 3.90 (2.33-6.52) p<0.001
ABCSG-6&810* Node Positive 527 5.2% (1.0 – 9.2) 30% 28% (21.1 – 34.4) 4.70(2.16-10.22) p<0.001
ATAC7 248 5.0% (1.2 – 18.9) 19% 36.9% (30.2 – 44.5) 9.49 (2.33-38.75) p<0.001

*Subset analysis from Filipits et al. 2011

 A longer term study of the ABCSG6/8 cohorts evaluated the prognostic value of EndoPredict in women who were DR-free 5 years after diagnosis.

 

Low-Risk EPclin Score

High-Risk EPclin Score

Patient Group

5-10 Year DRFR*

95% CI

5-10 Year DRFR*

95% CI

All Patients

97.9%

96.8%, 99.0%

90.6%

87.6%, 93.6%

Node-Negative

97.9%

96.7%, 99.1%

94.1%

90.5%, 97.8%

Node-Positive

98.3%

95.9%, 100%

88.0%

83.8%, 92.5%

1-3 Positive Nodes

98.2%

95.8%, 100%

90.5%

86.2%, 94.9%

Table 1: DRFR (Distant Recurrence-Free Rate) at 10 years for patients who were distant recurrence free after 5 years, according to nodal status. Filipits et al. 2019, Supplementary Table S5.

Analysis of Evidence (Rationale for Determination)

The EndoPredict assay is reasonable and necessary to assist physicians in the management of early stage breast cancer by identifying those patients with a sufficiently low risk of 10-year distant recurrence who may safely forgo chemotherapy. While EndoPredict may help assess risk of late recurrence after ET is complete, it is not clear at this time if this test is useful for identifying which patients should receive EET.

This contractor believes the clinical utility of this test for determining which patients would benefit from EET is not clear based on these data. This test is indicated in node-negative and 1-3 node-positive patients. First, the data presented in Filipits et al. for 1-3 node-positive patients was not significant for the period studied (5-15 years), and the difference in DRFR was 84% vs 87% between the EPclin high and low groupWhile the difference between EPclin high and low groups are significant in node–negative patients for the duration of the study (96% vs 85% DRFR), a subset analysis (described above) of the best supported data (in the supplemental data, Table S5, shown above) shows that 5-10 years after ET therapy there is little difference in the performance of these patients; neither the EPclin high or low group would be defined as “high risk” (>10% risk of recurrence), and the difference in DRFR between these two groups is 97.9% vs. 94.1%. Based on this study, this contractor does not believe there is sufficient evidence that this test can clearly delineate patients who can benefit from EET (whose benefits are already known to be ‘modest’). Given that EET carries significant risk for adverse events, it is not clear how much, if any, weight an oncologist should place on EndoPredict results for determining the use of EET in patients who have not recurred after initial ET.

The assay is covered for women with T1-3, N0-1 breast cancer when the following criteria are met:

  • Patient is post-menopausal, and
  • Pathology (excisional or biopsy) reveals invasive carcinoma of the breast that is ER-positive, Her2-negative, and
  • Patient is either lymph node-negative or has 1-3 positive lymph nodes, and
  • Patient has no evidence of distant metastasis, and
  • Test result will be used to determine treatment choice between endocrine therapy alone vs. endocrine therapy plus chemotherapy.


Note: The EndoPredict test should not be ordered if a physician does not intend to  act upon the test result.

General Information

Associated Information

N/A

Sources of Information

N/A

Bibliography
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  3. Dowsett M, Forbes JF, Bradley R, et al. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015 Oct 3;386(10001):1341-52.
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  15. Pan H, Gray R, Braybrooke J, Davies C; EBCTCG. 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. N Engl J Med. 2017 Nov 9;377(19):1836-1846.
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  28. Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update. J Clin Oncol. 2019 Feb 10;37(5):423-438.
  29. Gradishar W, et al. NCCN clinical practice guidelines in oncology: breast cancer. Version 2.2019. Accessed March 10, 2020.
  30. Filipits, et al.: Prediction of Distant Recurrence using EndoPredict among Women with ER+, HER2- Node-Positive and Node-Negative Breast Cancer Treated with Endocrine Therapy Only. Clin Cancer Res 25:1-8, 2019.              

 

Revision History Information

Revision History DateRevision History NumberRevision History ExplanationReasons for Change
07/04/2021 R7

This LCD is being presented for notice.

Under CMS National Coverage Policy revised the section titles for CMS Internet-Only Manual, Pub. 100-02, §80 and §80.1.1 and deleted CMS Internet-Only Manual, Pub. 100-02, §80.2. Under Summary of Evidence changed 54% to 75% in the first paragraph. Corrected 2013 to 2011 in the last paragraph under the sub-category Clinical Utility. Under Analysis of Evidence (Rationale for Determination) removed the scoring for the level of evidence. Formatting, punctuation and typographical errors were corrected throughout the LCD.

  • Provider Education/Guidance
11/07/2019 R6

This LCD is being revised in order to adhere to CMS requirements per chapter 13, section 13.5.1 of the Program Integrity Manual, to remove all coding from LCDs. There has been no change in coverage with this LCD revision. Regulations regarding billing and coding were removed from the CMS National Coverage Policy section of this LCD and placed in the related Billing and Coding: MolDX: EndoPredict Breast Cancer Gene Expression Test A56963 article.

  • Provider Education/Guidance
08/29/2019 R5

All coding located in the Coding Information section has been moved into the related Billing and Coding: MolDX: EndoPredict Breast Cancer Gene Expression Test A56963 article and removed from the LCD.

At this time 21st Century Cures Act will apply to new and revised LCDs that restrict coverage which requires comment and notice. This revision is not a restriction to the coverage determination; and, therefore not all the fields included on the LCD are applicable as noted in this policy.

  • Provider Education/Guidance
01/10/2019 R4

Revised Validated Specimen Type in table under "Summary of Analytical and Clinical Performance" and bulleted list under Analysis of Evidence.

  • Reconsideration Request
08/16/2018 R3

Corrected the reference link in reference #1 in Bibliography section.

  • Typographical Error
02/26/2018 R2 The Jurisdiction "J" Part B Contracts for Alabama (10112), Georgia (10212) and Tennessee (10312) are now being serviced by Palmetto GBA. The notice period for this LCD begins on 12/14/17 and ends on 02/25/18. Effective 02/26/18, these three contract numbers are being added to this LCD. No coverage, coding or other substantive changes (beyond the addition of the 3 Part B contract numbers) have been completed in this revision.
  • Change in Affiliated Contract Numbers
01/29/2018 R1 The Jurisdiction "J" Part A Contracts for Alabama (10111), Georgia (10211) and Tennessee (10311) are now being serviced by Palmetto GBA. The notice period for this LCD begins on 12/14/17 and ends on 01/28/18. Effective 01/29/18, these three contract numbers are being added to this LCD. No coverage, coding or other substantive changes (beyond the addition of the 3 Part A contract numbers) have been completed in this revision.
  • Change in Affiliated Contract Numbers

Associated Documents

Attachments
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Related National Coverage Documents
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Public Versions
Updated On Effective Dates Status
05/13/2021 07/04/2021 - N/A Currently in Effect You are here
Some older versions have been archived. Please visit the MCD Archive Site to retrieve them.

Keywords

  • Endopredict
  • Breast

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