EndoPredict TechnicalSpecifications

Myriad EndoPredict® Technical Specifications
Myriad Genetic Laboratories, Inc. Effective Date: Jan 17, 2017
TEST RESULTS SHOULD BE USED ONLY AFTER REVIEW OF THE FOLLOWING SPECIFICATIONS:
Indications and Use Gene Molecular Score. The molecular score is then combined
Intended Use with tumor size and lymph node status to generate an EPclin
This assay is intended for in vitro analysis of FFPE Risk Score and a 10-year risk of distant recurrence.4-7
resection tissue of primary female invasive breast cancer
(estrogen receptor positive, HER2 negative), for the Performance Characteristics/Limitations
determination of the 10-year risk of distant recurrence The 12-Gene Molecular Score is calculated based upon
(metastatic disease). the RNA expression of 8 target genes and 3 normalization
genes, with 1 control gene used to assess DNA contamination.
Summary and Explanation The molecular score can be combined with specific clinical
Breast cancer is the most frequently diagnosed cancer data (tumor size and lymph node status) to genereate an EPclin
in U.S. women (246,000 new cases annually), and is the Risk Score.4 Both scores were trained in a large, multi-site
second leading cause of cancer-related death.1 Approximately cohort of 964 treatment-naïve FFPE primary breast resection
1 in 8 U.S. women, or 12%, will develop invasive breast samples.4 A Cox proportional hazards model was used to fit a
cancer over the course of their lifetime.1 Breast cancer is a linear combination of the 12-Gene Molecular Score, tumor
heterogeneous disease and is often classified based on the stage and lymph node status, generating an EPclin Risk Score.
status of the human epidermal growth factor receptor 2 The EPclin Risk Score is calculated, according the model, as:
(HER2) protein, as well as two hormone receptors (HR), EPclin Risk Score = (0.35 * tumor size) + (0.64 * lymph node
which are the estrogen receptor (ER) and progesterone status) + (0.28 * 12-Gene Molecular Score) [tumor size: 1
receptor. Based on the expression of these proteins, which (T1ab, ≤1 cm), 2 (T1c, >1 but <2 cm), 3 (T2, >2 but < 5 cm),
can inform medical management, newly diagnosed breast 4 (T3, >5 cm); lymph node status: 1 (no positive nodes), 2 (1-
cancer patients are stratified into three groups: HR- 3 positive nodes)]. Both the 12-Gene Molecular Score and
positive/HER2-negative, HER2-positive, or triple negative EPclin Risk Score have been subsequently validated in
(HR-negative and HER2-negative). Patients with HR- multiple independent cohorts.4-7
positive/HER2-negative invasive breast cancer have the most
favorable 5-year outcomes, followed by patients with HER2- Clinically Reportable Range
postive, and then triple negative disease.2 Based on the analysis of 1,324 treatment-naïve FFPE
Patients specifically with ER-positive/HER2-negative primary breast resection tumor samples, a clinically reportable
invasive breast cancer respond well to adjuvant anti-hormone range was determined for the EPclin Risk Score from 1.1
therapy drugs that block the estrogen receptor. Additional use through 6.2.4,8 Scores out of the validated range may lead to
of adjuvant chemotherapy can be considered for patients with test cancelation and/or follow-up with the referring healthcare
high risk features; however, not all patients have the same provider (see Interpretive Criteria).
potential for chemotherapy benefit.3 EndoPredict® is a
molecular test that identifies a large population of patients Analytical Precision, Linearity and Detection Limit
(55%-65% of patients tested in clinical trials) with excellent A set of 12 samples was tested, with 3 replicates for
10-year outcomes that can safely forgo adjuvant each sample, and the standard deviation of the EPclin Risk
chemotherapy.4-7 The EndoPredict Clinical (EPclin) Risk Score was determined to be 0.06 score units.8 The signature
Score is generated from the combination of molecular and was originally validated to require a minimal input of RNA
clinical data (described in more detail below) and has been input to generate a crossing threshold (Ct) value of at least 34.0
shown to be a significant and independent predictor of breast for normalization genes and 38.0 for target genes.4 In regards
cancer distant recurrence and adds significant prognostic to RNA input linearity, the test reproduces valid results from
information to clinical information alone.4-7 a housekeeper mean of 19-27.8
Description of Method Quality Control Measures

Acceptable sample types for testing are formalin-fixed A minimum of one no-RNA control and one normal
paraffin-embedded (FFPE) tissue from blocks or slides of human RNA control, with a previously determined score, are
primary invasive breast tumor resection specimens (estrogen analyzed concurrently with each sample. Additionally, one
receptor positive, HER2 negative). Blocks must have a portion DNA contamination control is measured with each sample
of the lesion with ≥30% invasive tumor on the diagnostic H&E replicate. Controls are analyzed to verify technical
slide, with at least 5-20 µm of remaining unstained tissue for consistency.
testing. In cases where blocks are not available, one 2-5 µm
H&E slide followed by 1-2 consecutive 5-10 µm unstained Test Interference
slides may be acceptable. Samples frozen prior to fixation are Systemic treatment prior to resection of the primary
not appropriate for analysis. Blocks (or slides) are shipped breast tumor (e.g., neoadjuvant chemotherapy, radiation
overnight with an ice pack to Myriad Genetic Laboratories, treatment) can effect test performance, potentially resulting in
Inc. for analysis. Upon receipt, sample barcodes, which are inaccurate test results. Patients receiving systemic treatments
scanned and tracked, are applied to each block (or slide). prior to resection are not suitable candidates for testing.
Unused tissue is returned to the provider upon the completion
of testing. Limitations and Sample Rejection Criteria
For testing, the H&E slide from each case is evaluated Performance characteristics for the test have not been
by an anatomic pathologist, who determines the location and established for tissues other than FFPE invasive female breast
amount of tumor per slide. Using the H&E stained slides as a cancer primary resection samples, which are estrogen receptor
guide, tumor tissue is macrodissected from the unstained positive and HER2 negative. This test has not been validated
sections and total RNA is extracted from the excised in non-invasive samples, tumors that are not estrogen receptor
tissue. Quantitative RT-PCR is then used to measure, in positive and HER2 negative, patients currently undergoing
triplicate, the expression of 8 signature genes, and 3 hormone replacement therapy, patients that received systemic
normalization genes, with 1 control gene to assess DNA treatment prior to resection, nor in male breast cancer tumors.4
contamination. These molecular data are used to generate a 12- Samples in non-validated tissues will not be accepted for
PB 135.1
Myriad EndoPredict® Technical Specifications
Myriad Genetic Laboratories, Inc. Effective Date: Jan 17, 2017
TEST RESULTS SHOULD BE USED ONLY AFTER REVIEW OF THE FOLLOWING SPECIFICATIONS:
testing. Samples with less than the 30% minimum invasive References
tumor may also lead to test cancelation.
Primary breast tumors with invasive ductal, invasive 1. Howlader N, Noone AM, Krapcho M, et al. SEER
lobular, mixed histology (with both invasive ductal and Cancer Statistics Review, 1975-2013, National Cancer
invasive lobular characteristics), and primary invasive breast Institute, based on November 2015 SEER data. 2016.
tumors with no specified histology are all acceptable for http://seer.cancer.gov/csr/1975_2013/
testing. In case of bilateral breast cancer, the most 2. Chen L, Linden HM, Anderson BO, et al. Trends in 5-
aggressive/invasive tumor should be tested. Patients with a year survival rates among breast cancer patients by
previous history of breast cancer are suitable for testing, as
hormone receptor status and stage. Breast Cancer Res
long as the tested sample is not a recurrence of a previous
Treat. 2014; 147(3): 609-16.
primary tumor. Samples that are recurrences of previous
primary breast cancers are not suitable for testing. This test 3. National Comprehensive Cancer Network (NCCN).
was validated in a mixed cohort of pre/post-menopausal NCCN Clinical Practice Guidelines in Oncology:
women,4 and therefore both pre- and post-menopause patients Breast Cancer. 2016; Version 2.
are acceptable for testing. 4. Filipts M, Rudas M, Jakesz R, et al. A new molecular
Two clinical parameters are required for calculation of predictor of distant recurrence in ER-positive HER2-
the EPclin Risk Score, which are tumor size/stage and the negative breast cancer adds independent information to
number of positive lymph nodes. Only primary tumors that are conventional clinical risk factors. Clin Cancer Res.
T stage ≤3 are acceptable for testing. Samples with 0-3
2011; 17(18):6012-20.
positive lymph nodes are acceptable for testing (further
validations are required for samples with ≥4 positive lymph 5. Buus R, Sestak I, Kronenwett R, et al. Comparison of
nodes). Samples lacking sufficient clinical information or EndoPredict and EPclin with Oncotype DX Recurrence
samples with clinical variables that are unsuitable for testing Score for prediction of risk of distant recurrence after
may lead to test cancelation and/or follow-up with the Endocrine therapy. J Natl Cancer Inst. 2016; 108(11).
referring healthcare provider. 6. Dubsky P, Filipits M, Jakesz R, et al. EndoPredict
The FFPE tissue preservation process may cause RNA improves the prognostic classification derived from
degradation resulting in insufficient quantity or quality of common clinical guidelines in ER-positive, HER-
RNA for analysis. Samples with insufficient RNA quantity negative early breast cancer. Ann Oncol. 2013;
and/or quality may lead to test cancelation and/or follow-up 24(3):640-7.
with the referring healthcare provider. 7. Martin M, Brase JC, Calvo L, et al. Clinical validation of
Results of this analysis should be used in conjunction the EndoPredict test in node-positive, chemotherapy-
with information available from clinical evaluation and other treated ER+/HER2- breast cancer patients: results from
diagnostic procedures. the GEICAM 9906 trial. Breast Cancer Res. 2014;
16(2):R38.
Interpretive Criteria 8. Data on File. 2017.
The EPclin Risk Score will be reported, along with the
10-year risk for distant recurrence, for the submitted sample.
The following criteria should be used to interpret the reported
score.
EPclin Risk Scores from 1.1 through 3.3

Scores within this range are clinically validated and will
be reported. Patients with scores in this range have a low 10-
year risk for distant recurrence. The estimated 10-year risk of
recurrence will be provided for patients based upon the EPclin
Risk Score.
EPclin Risk Scores from 3.4 through 6.2

EPclin Risk Scores within this range are clinically
validated and will be reported. Patients with scores in this
range have a high 10-year risk for distant recurrence. The
estimated 10-year risk of recurrence will be provided for
patients based upon the EPclin Risk Score.
EPclin Risk Scores less than 1.1 or greater than 6.2

Based upon 1,324 samples, a reportable range for
EPclin Risk Scores was established from 1.1 through 6.2.4,7
Scores outside of this range have not been validated and may
lead to test cancelation and/or follow-up with the referring
healthcare provider.
PB 135.1

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EndoPredict TechnicalSpecifications

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Myriad EndoPredict® Technical Specifications

Myriad Genetic Laboratories, Inc. Effective Date: Jan 17, 2017

Description of Method Quality Control Measures

EPclin Risk Scores from 1.1 through 3.3

EPclin Risk Scores from 3.4 through 6.2

EPclin Risk Scores less than 1.1 or greater than 6.2

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