This contractor will provide limited coverage for the Oncotype DX DCIS assay
(Genomic Health, Inc., Redwood City, CA) for women diagnosed with DCIS who are
planning on having breast conserving surgery and considering adjuvant
radiation therapy.

Ductal carcinoma _in situ_ (DCIS) is a heterogeneous group of neoplastic
lesions confined to the breast ducts and lobules. It is one of the most
commonly diagnosed breast conditions, accounting for approximately 20% of
newly diagnosed breast cancers in the United States.1 Women diagnosed with
DCIS are at risk for local recurrence, which may be either DCIS or progression
to invasive breast carcinoma. The management of patients with DCIS is an area
of controversy and historically treatment has included both surgical excision
and radiation therapy.2 Following surgical excision alone, local recurrences
occur in approximately 25% to 30% of women by 10 years.3 The addition of
radiation therapy has been reported to reduce local recurrence risk by
approximately 50% but has not been demonstrated to prolong overall or disease
free-survival.3 In an observational study of patients diagnosed with DCIS from
1988 to 2011, prevention of invasive in-breast recurrence with radiation
therapy after lumpectomy did not improve 10-year breast cancer-specific
mortality compared with lumpectomy alone.4 Therefore, treating all women with
radiation therapy following surgical excision may represent overtreatment for
many, especially given that the majority of cases do not recur following
surgery alone. Clinical and pathologic features do not reliably predict the
risk of recurrence; therefore, validated biomarkers are needed that identify
patients at low risk of local recurrence for whom less treatment is indicated
and conversely distinguish patients at high risk of progression to invasive
disease for whom more intensive treatment regimens are appropriate.  
  
 **Oncotype DX** **** **DCIS Score**  
  
 **Test Description**  
  
The DCIS Score is a ribonucleic acid (RNA) based assay measuring the
expression of 5 proliferation genes, progesterone receptor (PR), GSTM1 and 5
reference genes (Figure 1) with results reported as a numerical score along
with accompanying interpretive information. The assay is performed on formalin
fixed paraffin-embedded (FFPE) tissue blocks containing DCIS. The DCIS Score
was developed based upon analyses of multiple correlative science studies
comparing gene expression profiles between invasive and DCIS tumor samples.5
An algorithm was developed using scaling and category cut-points based on the
analysis of the DCIS Score result in a separate cohort of DCIS patients.6

**  Figure 1: Genes Comprising the DCIS Score.**

**Proliferation Group**

|

**Hormone Receptor Group**

|

**Reference Group**  
  
---|---|---  
  
  * Ki67
  * STK15
  * Survivin
  * CCNB1 (cyclin B1)
  * MYBL2

|

  * PR
  * GSTM1

|

  * ACTB ( -actin)
  * GAPDH
  * RPLPO
  * GUS
  * TFRC

  
  
**Test Performance**

Initial validation of the DCIS Score result was performed in a prospectively
designed study of archived tumor specimens from 327 patients who participated
in the previously described E5194 trial, a prospective cooperative group trial
that evaluated 5- and 10-year ipsilateral breast event (IBE) rates after local
excision alone in a selected population of patients with DCIS.7,8 The study
met its primary objective, as the DCIS Score result was predictive of the
10-year risk of any IBE. The DCIS Score result as a continuous variable was
significantly associated with developing an IBE (hazard ratio [HR]/50
units=2.31, 95% CI = 1.15-4.49; p = 0.02). Using 3 pre-specified risk groups
(low < 39, intermediate 39-54, and high  55), the 10-year risk of any IBE
(DCIS or invasive carcinoma) was 10.6% in the low risk group compared to 26.7%
in the intermediate risk group and 25.9% in the high risk group; the risk
stratification between the 3 groups was significant (log rank p = 0.006). The
risk for developing ipsilateral invasive carcinoma was only 3.7% in the low
risk group compared to 19.2% in the high risk group (log rank p = 0.003).
Approximately 70% of all patients enrolled in the study were in the low risk
group. In multivariable analyses, the DCIS Score result, tumor size, and
menopausal status were identified to be statistically significant predictors
of the risk of local recurrence (p  0.02). The HR for the score remained
unchanged after adjusting for tumor size and menopausal status thereby
demonstrating that the DCIS Score result provides independent prognostic
information beyond these risk factors.  
  
The second prospectively designed clinical validation study of the Oncotype
DX Breast DCIS Score Assay was conducted in a population-based cohort of
women diagnosed with DCIS and treated with breast conserving therapy alone
from 1994-2003 in Ontario, Canada.9 The final study cohort included 718
patients of whom 571 had negative surgical margins. Median follow-up was 9.6
years. The study found the DCIS Score result to independently predict and
quantify local recurrence risk. In the primary analysis, the DCIS Score result
was significantly associated with any local recurrence in estrogen receptor
positive patients (HR/50 units = 2.26, 95% CI = 1.41-3.59; p < 0.001) as well
as all patients regardless of estrogen receptor status (HR = 2.15; 95% CI =
1.43-3.22; p < 0.001). For the same pre-specified risk groups (low < 39,
intermediate 39-54, and high  55), the 10-year risk of a local invasive
carcinoma recurrence was 8.0% in the low risk group compared with 20.9% and
15.5% in the intermediate and high risk groups, respectively; the risk
stratification between the 3 groups was significant (p = 0.03). The risk of
developing a DCIS local recurrence was 5.4% in the low risk group compared
with 14.1% and 13.7% in the intermediate and high risk groups, respectively (p
= 0.002). In multivariable analysis, the DCIS Score result was a significant
predictor of local recurrence (HR/50 units = 1.68, 95% CI = 1.08-2.62; p =
0.02) and provided independent recurrence risk information beyond clinical and
pathologic measures including age at diagnosis, tumor size, grade, necrosis,
multifocality, and subtype. The primary analyses were restricted to patients
with clear margins; however, secondary analysis included all patients
regardless of surgical margins. The HR in the expanded cohort, adjusting for
margin status and other clinical and pathological features, was 2.11 (95% CI =
1.43-3.09; p < 0.001) indicating that the DCIS Score result effectively risk-
stratifies patients regardless of margin status.  
  
The analytical and clinical performance of the Oncotype DX DCIS assay is
summarized below.  

Intended Use | To assess the average 10 year rate for any ipsilateral breast
event (DCIS or invasive carcinoma) in women diagnosed with DCIS who had breast
conserving surgery with negative margins and are considering adjuvant
radiation therapy.  
---|---  
Validated Specimen Type(s) | FFPE tissue  
  
**Analytical Performance**

**Description** | **Results**  
---|---  
Precision, within RNA extract  
(2 operator; 2 runs on different days; 2 manufacturing reagent lot; 5 PCR
robots; 9 PCR detection systems; 75 paired RNA extracts run all in CLIA lab;
expected score range 3-86*) | **Within RNA Extracts**  
**DCIS Score Category** | **N** | **STD**  
Low | 36 | 1.04  
Int-High | 39 | 1.09  
Precision, between tumor block sections (2 operator; 2 runs on different days;
2 manufacturing reagent lot; 5 PCR robots; 9 PCR detection systems; 39 unique
tumor blocks run all in CLIA lab; expected score range 3-86*) | **Between
Consecutive Tumor Block Sections**  
**DCIS Score Category** | **N** | **STD**  
Low | 19 | 2.11  
Int-High | 20 | 3.96  
Analytical sensitivity: Minimum input | Total RNA: 110 ng extracted from tumor
tissue  
Critical reagent closed/shelf-life stability (GHI conducted shelf-life
stability unless stated otherwise) | Reverse Transcription Kit  
Stability from date of receipt through the manufacturer's labeled expiration
date with 12 months of on-site storage at -20 C  5 C  
GSP pool (gene specific primers for reverse transcription)  
9 months at -20 C  5 C  
Reverse Transcription Positive control  
2 years at -80 C  10 C  
P3 Plate  
9 months -80 C  10 C  
Human gDNA (quantitative PCR positive control)  
6 months at +5 C  3 C  
Quantitative PCR Master Mix  
18 months from date of manufacturing  
at -20 C  5 C  
Critical reagent open/in use stability (GHI conducted operational stability
unless stated otherwise) | Reverse Transcription Kit  
Use within 2 shifts after opening kit and prior to manufacturer's labeled
expiration date at -20 C  5 C  
GSP pool (gene specific primers for reverse transcription)  
Freeze thaw no more 10x  
Reverse Transcription Positive control  
Single Use Tube  
P3 Plate  
Freeze thaw no more than 10x  
Use within 1 day 5 C  3 C  
Human gDNA (quantitative PCR positive control)  
6 months at +5 C  3 C  
Quantitative PCR Master Mix  
3 months after thaw at 5 C  3 C  
Up to 3 hours prior to qPCR plate assembly at room temperature (18 C to 25
C)  
Assembled Quantitative PCR plates  
24 hours at room temperature (18 C to 25 C)  
Specimen stability, primary | FPET slice in tube 6 months at room temperature  
(18 C to 25 C)  
Specimen stability, intermediate (extracted RNA) | Within 1 day 5 C  3 C  
Within 5 days -20 C  5 C  
Within 365 days at -80 C  10 C  
Specimen stability, intermediate (cDNA Sample plate) | Within 3 months at -20
C  5 C  
  
* DCIS Score risk groups were specified prior to first clinical validation study (DCIS Score: Low <39, Intermediate 39-54, High 54). Actual range of DCIS scores for samples used for precision studies were DCIS Score Low 3-37 and DCIS Score Int-High 40-86.

**Clinical Performance**

The Oncotype DX DCIS Score is a continuous measure that provides predicted
risks of an ipsilateral breast event for individual patients over a continuum
of gene expression, reflecting the continuous nature of tumor biology.
Statistics, such as sensitivity and specificity, were designed to evaluate the
general predictive ability of binary (dichotomous) predictors of the presence
or absence of a disease or condition, rather than prediction of the risk of a
future event, and have limitations in the assessment of continuous predictors
of risk.10,11,12 A more appropriate statistical assessment of the predictive
accuracy of the DCIS Score for risk groups is demonstrated by the width of the
95% confidence intervals for estimates of 10-year risk of an IBE within each
risk group, shown in the table below.  
  
The Oncotype DX DCIS Score was validated in 2 clinical studies encompassing
the indicated patient population. Both clinical validation studies were
conducted under IRB-approved protocols with pre-specified analytical and
quality acceptance criteria, statistical analysis plans, and endpoints. All
clinical studies were conducted on the platform (device) after assay
performance requirements (above) were specified and independently validated.

**Description** | **Results**  
---|---  
Solin et al., 20138  
(n = 327 patients) | Rakovitch et al., 20159  
(n = 571 patients)  
Hazard ratio/50 units | 2.31a  
(95% Cl = 1.15 - 4.49)  
p = 0.02 | 2.15b  
(95% Cl = 1.43 - 3.22)  
p < 0.001  
**Number (%) of patients** |  
Low DCIS Score | 230 (70%) | 355 (62%)  
Intermediate/High DCIS Score | 97 (30%) | 216 (38%)  
**10-year Risk of Local Recurrence (95% CI)** |  
Low DCIS Score | 10.6%  
(6.9-16.2%) | 12.7%  
(9.5-16.9%)  
Intermediate/High DCIS Score | 26.2%  
(18.1-37.0%) | 30.1%  
(23.9-37.5%)  
Overall Proportion with IBEc | 46/327 (14.1%) | 100/571 (17.5%)  
  
aAdjusted for tamoxifen use (pre-specified primary analysis)  
bNo covariate adjustment; all patients (irrespective of ER status) with
negative resection margins  
clpsilateral breast event (DCIS or invasive carcinoma)

**Decision Impact and Health Economic Studies**  
A prospective multicenter clinical utility study evaluating the impact of the
DCIS Score result upon treatment recommendations for radiation therapy (XRT)
has been reported.13 Eligible women had newly diagnosed histologically
documented DCIS and were candidates for breast conserving therapy. Physicians
completed standardized questionnaires that captured their estimates of local
recurrence risk and treatment recommendations for XRT, prior to and after
receiving the DCIS Score results. A total of 115 evaluable patients from 10 US
centers were included in final analyses. Study results found a significant
change in the proportion of patients receiving recommendations for XRT pre- vs
post-DCIS Score result (P = 0.008; McNemar's test). Pre-assay, 73.0% of
patients were recommended to receive XRT; this was reduced to 59.1% post-
assay. Overall integration of the DCIS Score result into clinical management
decisions resulted in a 31.3% change in XRT recommendations. Changes in
treatment were bidirectional, indicating that the information was useful both
for identifying patients at lower risk of recurrence for whom XRT may be
omitted, as well as those at higher risk who may be appropriate candidates for
more intensive modalities.

In a second prospective multicenter clinical utility study,14 27 surgeons and
27 radiation oncologists at 13 US centers provided estimates of local
recurrence risk and XRT recommendations for 127 patients, before and after
DCIS Score results were known. Baseline characteristics of this patient cohort
were similar to those of the first clinical utility study. Post-assay, 26.4%
of recommendations changed overall, representing 22.0% of recommendations by
radiation oncologists and 30.7% of recommendations by surgeons. The DCIS Score
result was the most frequently cited reason for post-assay treatment
recommendations.

Young et al. reported a retrospective health economic study from a single
center involving 38 patients for whom the DCIS Score assay had been ordered.15
In this cohort, 26 patients (68%) had DCIS Score results and local recurrence
risk considered low enough to omit radiation from their course of therapy. The
authors concluded that the assay has the potential to be cost-saving to the
healthcare system and spare many patients from the adverse effects associated
with radiation therapy. A cost-effectiveness modeling study comparing the
Oncotype DX Breast DCIS Score Assay to standard clinical assessment to
determine treatment recommendation for radiation therapy has been reported by
Alvarado et al.16 The study found that on average, the assay was more cost-
effective than the clinical assessment strategy by approximately
$1000/patient, with similar life expectancies (17.15 vs 17.11, respectively)
and quality-adjusted life-years (QALYs) (16.777 vs 16.789).  
  
 **Criteria for Coverage**  
  
The Oncotype DX DCIS assay is covered only when the following clinical
conditions are met:

  * Pathology (excisional or core biopsy) reveals ductal carcinoma in situ of the breast (no pathological evidence of invasive disease), **and**
  * FFPE specimen with at least 0.5 mm of DCIS length, **and**
  * Patient is a candidate for and is considering breast conserving surgery alone as well as breast conserving surgery combined with adjuvant radiation therapy, **and**
  * Test result will be used to determine treatment choice between surgery alone vs. surgery with radiation therapy, **and**
  * Patient has not received and is not planning on receiving a mastectomy.

_Level of Evidence_

Quality - Moderate

Strength - Limited

Weight - Limited

This contractor recognizes that evidence of clinical utility for the Oncotype
DX DCIS assay for women diagnosed with DCIS who are planning on having breast
conserving surgery and considering adjuvant radiation therapy is promising at
the current time.  However, this contractor believes the ongoing collection
studies with data elements identified below will generate sufficient data to
demonstrate the utility of this assay in women with DCIS. Continued coverage
is dependent bi-annual data submission and defined endpoints.

The MolDX Contractor expects Genomic Health to:

  * Ensure that healthcare providers who order the DCIS Score understand the appropriate patient population for testing and how to interpret test results; **and**
  * Report utilization by DCIS Score risk category on a bi-annual basis; **and**
  * Continue data development providing further evidence of clinical utility for the DCIS Score. During coverage with data development, evidence will be generated from Medicare patients receiving the DCIS Score. The nature and extent of this data is dependent on the volume of testing, specific disease context, and data elements required to support the test's utility. De-identified data should be collected through HIPAA-compliant mechanisms.
  * For the DCIS Score, collected data elements include:
    * Date of DCIS diagnosis
    * DCIS pathology including:
      * Histologic subtype
      * Pathological grade
      * Size
      * Presence of necrosis
      * Multi-focality as reported on pathology report
      * ER, PR and Her-2 Neu Status as reported on pathology report
  * Treatment received (local: surgery +/- radiation, systemic: hormonal therapy)
  * Any ipsilateral recurrence during the period of data development (DCIS and/or Invasive cancer recurrences).

Provide bi-annual data updates to include:

  * Number of tested patients for which data is being collected
    * Completeness of the collected data elements
    * Updates on the analysis supporting test utility including:
      * Proportion of DCIS score Low Risk patients receiving breast conserving surgery alone
      * Proportion of High-Risk and Intermediate-Risk DCIS score receiving radiation therapy.
      * 3-year ipsilateral recurrence rates in DCIS score Low Risk patients receiving breast-conserving surgery alone
      * 3-year ipsilateral recurrence rates for DCIS score Intermediate and High Risk patients receiving breast-conserving surgery plus radiation.
      * Clinical management (i.e., adjuvant radiation procedures) for patients who are low or high risk by the DCIS assay is consistent with the post-test strategy described below for at least 80% of tested patients

**Oncotype DX  DCIS assay** | **Post-Test Diagnostic Strategy to Consider**  
---|---  
Low Risk | No XRT  
High Risk | XRT  
  
  * Analysis of collected data to demonstrate that:
  *     * Ipsilateral breast recurrence at 3 years is  6% in DCIS Low Risk patients treated with breast conserving surgery alone, and
    * Local recurrence rate in DCIS Low Risk patients after treatment with breast conserving surgery alone is not statistically significantly greater than breast cancer recurrences from the DCIS Intermediate and High risk groups receiving radiation
  * Data analysis described above should be: 
    * Independently verified;
    * Made public, either in a peer reviewed publication or online, within one year of completion.