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Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Breast Cancer

Policy Number: MP-180

 

Latest Review Date: November 2019

Category: Medicine/Laboratory/Pathology

Policy Grade: B

POLICY:

Effective for dates of service January 4, 2020 and after:

The Oncotype DX®, EndoPredict, the Breast Cancer IndexSM, and Prosigna, may be considered medically necessary to determine recurrence risk for deciding whether or not to undergo adjuvant chemotherapy in women with primary, invasive breast cancer meeting ALL of the following characteristics:

  • Unilateral tumor; AND
  • Hormone receptor positive (that is, estrogen receptor [ER]-positive or progesterone receptor [PR]-positive); AND
  • Human epidermal growth factor receptor (HER2)-negative; AND
  • Tumor size 0.6-1 cm with moderate/poor differentiation or unfavorable features OR tumor size > 1 cm; AND
  • Node negative (lymph nodes with micrometastases [≤ 2 mm in size] are considered node negative for this policy statement); AND
  • Who will be treated with adjuvant endocrine therapy, (e.g., tamoxifen or aromatase inhibitors); AND
  • When the test result will aid the patient in making the decision regarding chemotherapy (i.e., when chemotherapy is a therapeutic option); AND
  • When ordered within six months following diagnosis, because the value of the test for making decisions regarding delayed chemotherapy is unknown.

The Mammaprint assay may be considered medically necessary to determine recurrence risk for deciding whether or not to undergo adjuvant chemotherapy in women with primary, invasive breast cancer meeting ALL of the following characteristics:

  • Unilateral tumor; AND
  • Hormone receptor positive (that is, estrogen receptor [ER]-positive or progesterone receptor [PR]-positive); AND
  • Human epidermal growth factor receptor (HER2)-negative; AND
  • Stage T1 or T2 or operable T3 at high clinical risk (see Policy Guidelines); AND
  • one to three positive nodes; AND
  • Who will be treated with adjuvant endocrine therapy, (e.g., tamoxifen or aromatase inhibitors); AND
  • When the test result will aid the patient in making the decision regarding chemotherapy (i.e., when chemotherapy is a therapeutic option); AND
  • When ordered within six months following diagnosis, because the value of the test for making decisions regarding delayed chemotherapy is unknown.

All other indications for the Oncotype DX®, EndoPredict, the Breast Cancer IndexSM, Prosigna, and Mammaprint®, including determination of recurrence risk in breast cancer patients with positive lymph nodes or patients with bilateral disease, or to consider length of treatment with tamoxifen, is considered not medically necessary and investigational.

Use of a subset of genes from the Oncotype Dx® for predicting recurrence risk in patients with noninvasive ductal carcinoma in situ (i.e. Oncotype DX® Breast DCIS Score) to inform treatment planning following excisional surgery is considered not medically necessary and investigational.

The use of BluePrint in conjunction with MammaPrint® or alone is considered not medically necessary and investigational.

The use of gene expression assays in men with breast cancer is considered not medically necessary and investigational.

POLICY GUIDELINES:

In the MINDACT trial (Cardoso 2016), low versus high clinical risk was determined using the Adjuvant! Online tool (version 8.0 with HER2 status, www.adjuvantonline.com). The Adjuvant tool includes factors for age, comorbidities, ER status, tumor grade and size and number of positive nodes. In MINDACT, ER-positive, HER2-negative, node-positive patients were classified as high clinical risk if they met any of the following additional criteria:

  • Grade: well differentiated; tumor size, <= 2 cm or 2.1 to 5 cm; OR
  • Grade: moderately differentiated; tumor size, any size: OR
  • Grade: poorly differentiated or undifferentiated; tumor size, any size

Effective for dates of service January 1, 2019 through January 3, 2020:

The Oncotype DX®, EndoPredict, the Breast Cancer IndexSM, Prosigna, and Mammaprint® may be considered medically necessary to determine recurrence risk for deciding whether or not to undergo adjuvant chemotherapy in women with primary, invasive breast cancer meeting ALL of the following characteristics:

  • Unilateral tumor; AND
  • Hormone receptor positive (that is, estrogen receptor [ER]-positive or progesterone receptor [PR]-positive); AND
  • Human epidermal growth factor receptor (HER2)-negative; AND
  • Tumor size 0.6-1 cm with moderate/poor differentiation or unfavorable features OR tumor size > 1 cm; AND
  • Node negative (lymph nodes with micrometastases [≤ 2 mm in size] are considered node negative for this policy statement); AND
  • Who will be treated with adjuvant endocrine therapy, (e.g., tamoxifen or aromatase inhibitors); AND
  • When the test result will aid the patient in making the decision regarding chemotherapy (i.e., when chemotherapy is a therapeutic option); AND
  • When ordered within six months following diagnosis, because the value of the test for making decisions regarding delayed chemotherapy is unknown.

All other indications for the Oncotype DX®, EndoPredict, the Breast Cancer IndexSM, Prosigna, and Mammaprint®, including determination of recurrence risk in breast cancer patients with positive lymph nodes or patients with bilateral disease, or to consider length of treatment with tamoxifen, is considered not medically necessary and investigational.

Use of a subset of genes from the Oncotype Dx® for predicting recurrence risk in patients with noninvasive ductal carcinoma in situ (i.e. Oncotype DX® Breast DCIS Score) to inform treatment planning following excisional surgery is considered not medically necessary and investigational.

The use of other gene expression assays (including, but not limited to, Mammostrat, the BreastOncPx, NexCourse Breast IHC4, and BreastPRS) for any indication is considered not medically necessary and investigational.

The use of BluePrint in conjunction with MammaPrint® or alone is considered not medically necessary and investigational.

The use of gene expression assays in men with breast cancer is considered not medically necessary and investigational.


Effective for dates of service January 18, 2017 through December 31, 2018:

The use of the 21-gene reverse transcriptase-polymerase chain reaction (RT-PCR) assay* (i.e., Oncotype DX®) to determine recurrence risk for deciding whether or not to undergo adjuvant chemotherapy may be considered medically necessary in women with primary, invasive breast cancer meeting ALL of the following characteristics:

  • Unilateral tumor; and
  • Hormone receptor positive (that is, estrogen receptor [ER]-positive or progesterone receptor [PR]-positive); and
  • Human epidermal growth factor receptor (HER2)-negative; and
  • Tumor size 0.6-1 cm with moderate/poor differentiation or unfavorable features OR tumor size > 1 cm; and
  • Node negative (lymph nodes with micrometastases [< 2 mm in size] are considered node negative for this policy statement); and
  • Who will be treated with adjuvant endocrine therapy, e.g., tamoxifen or aromatase inhibitors; and
  • When the test result will aid the patient in making the decision regarding chemotherapy (i.e., when chemotherapy is a therapeutic option); and
  • When ordered within 6 months following diagnosis, because the value of the test for making decisions regarding delayed chemotherapy is unknown.

*The 21-gene RT-PCR assay Oncotype DX® should only be ordered on a tissue specimen obtained during surgical removal of the tumor and after subsequent pathology examination of the tumor has been completed and determined to meet the above criteria (i.e., the test should not be ordered on a preliminary core biopsy). The test should be ordered in the context of a physician-patient discussion regarding risk preferences when the test result will aid in making decisions regarding chemotherapy.

For patients who otherwise meet the above characteristics but who have multiple ipsilateral primaries, a specimen from the tumor with the most aggressive histological characteristics should be submitted for testing. It is not necessary to conduct Oncotype DX testing on each tumor; treatment is based on the most aggressive lesion.

Use of EndoPredict, the Breast Cancer IndexSM, and Prosigna to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy may be considered medically necessary in women with primary, invasive breast cancer with the same characteristics as noted in the above criteria for Oncotype DX®.

All other indications for the 21-gene RT-PCR assay (i.e., Oncotype DX®), EndoPredict, the Breast Cancer IndexSM, and Prosigna, including determination of recurrence risk in breast cancer patients with positive lymph nodes or patients with bilateral disease, or to consider length of treatment with tamoxifen, is considered not medically necessary and investigational.

Use of a subset of genes from the 21-gene RT-PCR assay for predicting recurrence risk in patients with noninvasive ductal carcinoma in situ (i.e., Oncotype DX® Breast DCIS Score) to inform treatment planning following excisional surgery is considered not medically necessary and investigational.

The use of other gene expression assays (including, but not limited to, MammaPrint, Mammostrat, the BreastOncPx, NexCourse Breast IHC4, and BreastPRS) for any indication is considered not medically necessary and investigational.

Use of 70-gene signature (MammaPrint®) for any indication is considered not medically necessary and investigational.

The use of BluePrint in conjunction with MammaPrint® or alone is considered not medically necessary and investigational.

The use of gene expression assays in men with breast cancer is considered not medically necessary and investigational.


Effective for dates of service July 1, 2014 through January 17, 2017:

The use of the 21-gene RT-PCR assay (i.e., Oncotype DX®) to determine recurrence risk for deciding whether or not to undergo adjuvant chemotherapy may be considered medically necessary in women with breast cancer meeting all of the following characteristics:

  • Unilateral tumor;
  • Hormone receptor positive (that is ER-positive or PR-positive);
  • HER2-negative;
  • Tumor size 0.6-1 cm with moderate/poor differentiation or unfavorable features OR tumor size > 1 cm;
  • Node negative (lymph nodes with micrometastases (< 2 mm in size) are considered node negative for this policy statement);
  • Who will be treated with adjuvant endocrine therapy, e.g., tamoxifen or aromatase inhibitors;
  • When the test result will aid the patient in making the decision regarding chemotherapy (i.e., when chemotherapy is a therapeutic option); AND
  • When ordered within 6 months following diagnosis, since the value of the test for making decisions regarding delayed chemotherapy is unknown.

The 21-gene RT-PCR assay Oncotype DX® should only be ordered on a tissue specimen obtained during surgical removal of the tumor and after subsequent pathology examination of the tumor has been completed and determined to meet the above criteria (i.e., the test should not be ordered on a preliminary core biopsy). The test should be ordered in the context of a physician-patient discussion regarding risk preferences when the test result will aid in making decisions regarding chemotherapy.

For patients who otherwise meet the above characteristics but who have multiple ipsilateral primaries, a specimen from the tumor with the most aggressive histological characteristics should be submitted for testing, as this is how prognosis is clinically determined. It is not necessary to conduct Oncotype DX® testing on each tumor.

All other indications for the 21-gene RT-PCR assay (i.e., Oncotype DX®) including determination of recurrence risk in breast cancer patients with positive lymph nodes or patients with bilateral disease is considered not medically necessary and investigational.

Use of a subset of genes from the 21-gene RT-PCR assay for predicting recurrence risk in patients with noninvasive ductal carcinoma in situ (i.e., Oncotype DX® DCIS) to inform treatment planning following excisional surgery is considered not medically necessary and investigational.

The use of other gene expression assays (including, but not limited to, MammaPrint, Mammostrat, the Breast Cancer Index, the BreastOncPx, NexCourse Breast IHC4, Prosigna, BreastPRS, and EndoPredict) for any indication is considered not medically necessary and investigational.

The use of gene expression assays in men with breast cancer is considered not medically necessary and investigational.

The use of gene expression assays to molecularly subclassify breast cancer (e.g., BluePrint®) is considered not medically necessary and investigational.

The use of gene expression assays for quantitative assessment of ER, PR, and HER2 overexpression (e.g., TargetPrint®) is considered not medically necessary and investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Laboratory tests have been developed that detect the expression, via messenger RNA, of many different genes in breast tumor tissue and combine the results into a prediction of distant recurrence risk for women with early-stage breast cancer. Test results may help providers and patients decide whether to include adjuvant chemotherapy in the postsurgical management of breast cancer, to alter treatment in patients with ductal carcinoma in situ (DCIS), or to recommend extended endocrine therapy in patients who are recurrence-free at five years. This report summarizes the evidence for five tests, which are organized by indication: Oncotype DX, EndoPredict, Breast Cancer Index, MammaPrint, and Prosigna.

For all tests and all indications, relevant outcomes include disease-specific survival and changes in disease status.

Newly Diagnosed Breast Cancer

Most women with newly diagnosed breast cancer in the United States present with early-stage or locally advanced (i.e., nonmetastatic) disease. However, almost a third of women who are disease-free after initial local and regional treatment develop distant recurrences during follow-up. Current breast cancer treatment regimens involve systemic adjuvant chemotherapy, hormonal therapy, biologic therapy, or a combination, depending on patients’ baseline levels of recurrence risk, hormonal markers, and risk tolerance.

Women whose tumors are positive for human epidermal growth factor receptor 2 (HER2) should receive adjuvant therapy with a HER2-directed therapy (trastuzumab with or without pertuzumab). Decision making about adjuvant biologic therapy for women with HER2-positive cancer is not discussed here. This review focuses three decision points:

  1. The decision to pursue adjuvant chemotherapy following locoregional therapy, with or without neoadjuvant chemotherapy, based on predicted risk of recurrence, for women who are hormone receptor-positive but HER2-negative. The use of adjuvant chemotherapy reduces the risk of breast cancer recurrence, but carries risks of systemic toxicity. The risk: benefit ratio must be considered for each patient, with a higher likelihood of net health benefits for patients with a greater baseline predicted risk of recurrence. Some of the individual considerations are discussed below. HER2 expression independently confers an unfavorable prognosis, but assessing the independent effects of HER2 is complicated in the presence of targeted therapy; therefore, we focused specifically on patients without HER2 expression.

  1. The decision to pursue extended adjuvant endocrine therapy from five to ten years for women who are hormone receptor-positive but HER2-negative and who have survived without recurrence to five years. For patients with hormone receptor-positive tumors, the use of adjuvant endocrine therapy (tamoxifen and/or an aromatase inhibitor, with or without ovarian suppression) for five to ten years after an initial diagnosis has support in clinical practice. The 2019 guidelines from the National Comprehensive Cancer Network (v.1.2019) do not recommend extended endocrine therapy, but state that aromatase inhibitors or tamoxifen may be considered following five years of endocrine therapy for certain women, depending on menopausal status and prior treatment history. The guidelines also note that optimal duration of aromatase inhibitors is uncertain. In 2018, The American Society for Clinical Oncology’s (ASCO) updated its guidelines from 2014 on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. The update included a qualifying statement that none of the studies used to develop the recommendations showed improvements in overall survival with extended therapy, and that the recommendations are based on benefits that include prevention of distant recurrence and prevention of second breast cancers. Therefore, the decision to receive extended therapy should involve the weighing of recurrence risk against potential therapy risks and side effects. Recommendations based on nodal status are as follows:
  • "Many women with node-negative breast cancer are potential candidates for and may be offered extended AI therapy for up to a total of 10 years of adjuvant endocrine therapy based on considerations of recurrence risk using established prognostic factors. However, as recurrence risk is lower, the benefits are likely narrower for such patients. Women with low-risk node-negative tumors should not routinely be offered extended therapy.
  • Women with node-positive breast cancer should be offered extended AI therapy for up to a total of 10 years of adjuvant endocrine therapy."

  1. The decision to pursue adjuvant radiotherapy in women with ductal carcinoma in situ (DCIS). Adjuvant radiotherapy reduces the risk of local recurrences but has not been shown to change the risk of distant recurrence or mortality. There may be a group of patients for whom the reduction in risk for local recurrence may not be large enough to justify the risks of radiotherapy.

Selection of Adjuvant Chemotherapy Based on Risk of Recurrence

An important part of treatment planning for women with breast cancer involves determining which patients could benefit from adjuvant cytotoxic chemotherapy. For example, for women with early-stage, invasive breast cancer (i.e., cancer extending beyond the basement membrane of the mammary ducts into adjacent tissue), adjuvant cytotoxic chemotherapy consistently provides approximately a 30% relative risk reduction in ten-year breast cancer mortality regardless of patients’ baseline prognosis. However, the absolute benefit of chemotherapy depends on the underlying or baseline risk of recurrence. Women with the best prognosis have tumors that are small, early stage, estrogen receptor (ER)-positive, and lymph node to negative. (The table below shows recurrence risk for estrogen receptor‒positive cancers for patients followed in the International Breast Cancer Study Group. Patients may have received no adjuvant treatment, or adjuvant tamoxifen and/or adjuvant chemotherapy.) These women have an approximately 15% 10-year risk of recurrence with tamoxifen alone; which means that approximately 85% of these patients could avoid the toxicity of adjuvant cytotoxic chemotherapy if they could be accurately identified. Conventional risk classifiers (e.g., Adjuvant! Online) estimate recurrence risk by considering criteria such as tumor size, type, grade, and histologic characteristics; hormone receptor status; and number of affected lymph nodes. Consensus guidelines for defining receptor status exist. However, no single classifier is considered a criterion standard. As a result, a substantial number of patients are treated with chemotherapy who fail to benefit. Better predictors of recurrence risk could help women’s decision making, some who may prefer to avoid chemotherapy if assured that their risk is low.

Table 1. Effect of Nodal Involvement, Tumor Size, and Grade on Annual Recurrence Hazard in Estrogen Receptor-Positive Breast Cancers

 

Recurrence, Hazard (SE), %

 

Years

Nodes

0-5

5-10

10-15

15-20

20-25

0

5.8 (0.5)

3.3 (0.4)

2.0 (0.4)

2.1 (0.4)

1.1 (0.4)

1 to 3

9.5 (0.6)

5.8 (0.6)

3.0 (0.5)

3.5 (0.7)

1.5 (0.6)

≥4

17.2 (0.9)

10.9 (1.2)

5.9 (1.2)

3.8 (1.2)

1.3 (0.9)

Size

         

≤2 cm

7.0 (0.4)

4.8 (0.4)

2.9 (0.4)

2.7 (0.5)

1.5 (0.5)

>2 cm

12.9 (0.6)

6.1 (0.6)

2.9 (0.5)

2.7 (0.5)

1.1 (0.5)

Grade

         

1

5.8 (0.6)

4.9 (0.7)

3.6 (0.7)

4.0 (0.9)

0.7 (0.5)

2

9.6 (0.5)

6.3 (0.5)

2.8 (0.4)

2.7 (0.5)

1.8 (0.5)

3

14.1 (0.8)

4.1 (0.6)

2.5 (0.6)

2.4 (0.7)

0.4 (0.4)

Adapted from Colleoni et al (2016). SE: standard error

Number of events occurring within a time interval divided by the total years of follow-up during the interval accrued by patients at risk during the interval. Patients may have received no adjuvant treatment or have been treated with adjuvant tamoxifen and/or adjuvant chemotherapy.

Selection of Extended Endocrine Therapy

Randomized controlled trials have established that five years of tamoxifen improves mortality in women with hormone receptor-positive breast cancer. A 2011 individual patient data meta-analysis by the Early Breast Cancer Trialists' Collaborative Group, including 20 trials (n=21,457) found that five years of tamoxifen in estrogen receptor‒positive disease reduced the recurrences by almost 50% over ten years; breast cancer mortality was decreased by 29% through 15 years.

Early randomized trials of extended tamoxifen treatment had mixed findings: Tormey et al (1996; total N=194 patients), the National Surgical Adjuvant Breast and Bowel Project (Fisher et al, 2001; total N=1172 patients), and the Scottish Cancer Trials Breast Group (Stewart et al, 2001; total N=342 patients). However, more recent available trial evidence suggests that ten years of tamoxifen in pre- or postmenopausal women is associated with improved survival (see table below).

Randomized controlled trials published have shown that extended endocrine therapy decreases the risk of recurrence. The ATLAS trial, which compared five and ten years of tamoxifen and the subsequent aTTom trial (reported in abstract form) included women who were hormone receptor-positive and had completed five years of tamoxifen. Five years of extended tamoxifen was associated with improvements in breast cancer-specific mortality in both ATLAS and ATTom; however, only ATLAS showed improvements in overall survival (see table below).

Several trials have compared survival outcomes in women using extended aromatase inhibitors vs placebo following several years of tamoxifen, and two trials compared the use of extended aromatase inhibitors for different durations (three years vs six years and two and a half years vs five years) (see table below). No differences in overall survival were detected between the aromatase inhibitor groups and with the placebo groups. Differences in breast cancer-specific survival were inconsistent. Differences in disease specific survival and overall survival were not detected among patients receiving aromatase inhibitors for different lengths of time.

Guidelines for Extended Endocrine Therapy

For patients with early-stage, invasive breast cancer that is hormone receptor-positive, the use of endocrine therapy (tamoxifen and/or aromatase inhibitor, with or without ovarian suppression) for the initial five years following initial diagnosis has support in national guidelines. Support for extended endocrine therapy beyond the initial five years is inconsistent across various guidelines.

The latest guidelines from the American Society for Clinical Oncology (2014) discuss extended endocrine therapy for breast cancer have recommended an additional five years of tamoxifen for premenopausal women and five years of aromatase inhibitors for postmenopausal women. National Comprehensive Cancer Network guidelines (v.1.2019) do not recommend extended endocrine therapy, but state that aromatase inhibitors or tamoxifen may be considered following five years of endocrine therapy. The guidelines also note that the optimal duration of aromatase inhibitors is uncertain.

Adverse Events From Extended Endocrine Therapy

Adverse events from extended tamoxifen include increased risk of thromboembolic disease (deep vein thrombosis, pulmonary embolism) and endometrial cancer. The ATLAS trial reported relative risks of 1.9 (95% CI, 1.1 to 3.1) for pulmonary embolus and 1.7 (95% CI, 1.3 to 2.3) for endometrial cancer. Adverse events from extended aromatase inhibitors include musculoskeletal side effects (e.g., carpal tunnel syndrome, bone pain, bone fractures). In meta-analyses comparing tamoxifen and aromatase inhibitors, results showed an increased risk in cardiovascular events with aromatase inhibitors relative to tamoxifen. Women treated with aromatase inhibitors have also experienced higher fracture rates compared with women treated with tamoxifen.

Table 2. Randomized Trials Evaluating Adjuvant Extended Endocrine Therapies for Hormone Receptor-Positive Breast Cancer

Study

Population

Comparators

Breast Cancer-Specific Mortality

Overall Mortality

     

Event RR (95% CI)

p

Event RR (95% CI)

p

Extended tamoxifen

         

ATLAS (2013)

6846 women with ER-positive, early breast cancer, after 5 y of tamoxifen

Continue tamoxifen to 10 y (n=3428) vs stop tamoxifen at 5 y (n=3418)

0.83 (0.72 to 0.96) (331/3428 vs 397/3418)

0.01

0.87 (0.78 to 0.97)

722 (639/3428 vs 722/3418)

0.01

aTTom (2013)

6953 women with ER-positive or untested breast cancer, after 5 y of tamoxifen

Continue tamoxifen to 10 y (n=3468) vs stop tamoxifen at 5 y (n=3485)

10 years

392/3468 intervention vs 442/3485 control

Years 5-9

1.03 (0.84 to 1.27)

After year 9

0.77 (0.64 to 0.92)

0.05

10 years

849/3468 intervention vs 910/3485 control

Years 5-9

1.05 (0.90 to 1.22)

After year 9

0.86 (0.75 to 0.97)

0.1

Extended aromatase inhibitor

         

ABCSG (2007)

856 post-menopausal women with ER- and/or PR-positive breast cancer, after 5 y of tamoxifen

Anastrozole for 3 y (n=386) vs no further therapy (n=466)

   

5 years

10.3% anastrozole vs 11.7% control

Event HR (95% CI)

0.89 (0.59 to 1.34)

0.57

     

Breast Cancer-Specific Survival

Overall Survival

IDEAL

(2018)

1824 postmenopausal women with ER- and/or PR positive early breast cancer, after 5 y endocrine therapy

Letrozole for 2.5 y

(n=909) or 5 y

(n=915)

Median 6.6 Years · 2.5 y: 82.0% · 5 y: 83.3%

0.5

Median 6.6 Years · 2.5 y: 89.4%

· 5 y: 88.6%

NS

DATA

(2017)

1912 postmenopausal women with ER- and/or PR positive early breast cancer, after 2-3 y TAM

Anastrozole for 3 y (n=955) or 6 y (n=957)

5 Years · 3 y: 79.4% · 6 y: 83.1%

0.06

5 Years

· 3 y: 90.4%

· 6 y: 90.8%

0.6

NCIC CTG MA.17 trial (2003, 2005)

5187 post-menopausal women with ER- and/or PR-positive early breast cancer, after 5 y tamoxifen

Continue letrozole to 10 y (n=2593) vs stop tamoxifen at 5 y (n=2594)

48 Months

94.4% letrozole vs 89.8% placebo

Event HR

0.58 (0.45 to 0.76)

<0.001

48 Months

96% letrozole vs 94% placebo

Event HR

0.76 (0.48 to 0.21)

40 Months

95.4% letrozole vs 95% placebo

Event HR

0.82 (0.57 to 1.19)

0.25

0.3

NSABP (2008)

1598 post-menopausal women with ER- and/or PR-positive early breast cancer, after 5 y of tamoxifen

Planned comparison: 5 y exemestane vs 5 y placebo. Accrual stopped (n=1598 randomized), and crossover allowed after results of NCIC CTG available:

Exemestane: 783 randomized, 560 continued after unblinding)

Placebo: 779 randomized, 334 crossed over to exemestane after unblinding

48 Months

ITT: 91% exemestane vs 89% placebo

0.07

   

ABCSG: Austrian Breast and Colorectal Cancer Study Group; CI: confidence interval; DATA: Different Durations of Adjuvant Anastrozole Therapy; ER: estrogen receptor; HR: hazard ratio; IDEAL: Investigation on the Duration of Extended Adjuvant Letrozole; ITT: intention to treat; NCIC CTG: National Cancer Institute Clinical Trials Group; NS: not significant; NSABP: National Surgical Adjuvant Breast and Bowel Project; PR: progesterone receptor; RR: rate ratio; TAM: tamoxifen.

In addition to the trials published in full length form, two trials presented in early 2017 evaluating extended endocrine therapy in postmenopausal women (NSABP-42 [NCT00382070]: ten years vs five years of letrozole and IDEAL [NTR3077] ten years vs 7.5 years of letrozole) did not meet their primary end points.

Decision Framework for Evaluating Breast Cancer Biomarkers

Simon et al Framework

Many studies have investigated individual biomarkers or combinations of biomarkers associated with breast cancer outcomes. Determining which studies constitute sufficient evidence that the test or biomarker is likely to be clinically useful depends on attributes of the test such as its performance and the quality of the study generating the results. Simon et al (2009) has described a framework to evaluate prognostic biomarker evidence. Study designs such as prospective clinical trials or previously conducted clinical trials with archived tumor samples constitute stronger evidence than studies with less planned and systematic patient recruitment and data collection. Randomized trials allow the determination of treatment-biomarker interactions that may be clinically important. In some clinical scenarios, demonstration of a treatment-biomarker interaction is not critical, because the decision to withhold chemotherapy in a low-risk group (to avoid chemotherapy-related morbidity) does not require the presence of a biomarker-treatment interaction. The study must generate an absolute estimate of outcome in the patient group of interest that would result in a change in management (e.g., withholding of chemotherapy), and the study must have sufficient precision (narrow confidence intervals). Results of the same test across studies should show consistency of results and more than one study demonstrating the desired result should be available. Simon has proposed that at least two Simon Category B studies showing results consistent with clinical utility are necessary to demonstrate adequate evidence of a biomarker. Simon also proposed that while “further confirmation in a separate trial of the results gained from a category A prospective trial is always welcome, compelling results from such a trial would be considered definitive and no other validating trial would be required.”

KEY POINTS:

The most recent literature update for all indications was performed through September 16, 2019.

Summary of Evidence

For all tests and all indications, relevant outcomes include disease-specific survival and changes in disease status.

Early-Stage Node-Negative Invasive Breast Cancer

For the evaluation of breast cancer-related gene expression profiling tests for the management of all early-stage breast cancer populations, study populations considered had positive hormone receptor status, and negative HER2 status. Studies retrospectively collecting tumor samples from prospective trials that provide at least five-year distant recurrence rates or at least five-year survival rates in node-negative women were included in this part of the evidence review.

Oncotype DX (21-Gene Assay)

For individuals who have early-stage node-negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with Oncotype DX (21-gene assay), the evidence includes multiple prospective clinical trials and prospective-retrospective studies. Patients classified as low risk with Oncotype DX have a low risk of recurrence in which avoidance of adjuvant chemotherapy is reasonable (average risk at 10 years, 3%-7%; upper bound of the 95% CI, 6% to 10%). These results have been demonstrated with stronger study designs for evaluating biomarkers. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

EndoPredict

For individuals who have early-stage node-negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with EndoPredict, the evidence includes three prospective-retrospective studies and observational studies. The studies revealed that a low score was associated with a low absolute risk of ten-year distant recurrence (average risk at ten years for the two larger studies, 3%-6%; upper bound of the 95% CI, 6% to 9%). Over half of patients in these studies were classified at low risk. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Breast Cancer Index

For individuals who have early-stage node-negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with the Breast Cancer Index, the evidence includes findings from two prospective-retrospective studies and a registry-based observational study. The findings from the two prospective-retrospective studies showed that a low-risk Breast Cancer Index score is associated with low ten-year distant recurrence rates (average risk at ten years, 5%-7%; upper bound of the 95% CI, 8% to 10%). The findings from the registry-based observational study also showed low ten-year distant recurrence rates. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

MammaPrint (70-Gene Signature)

For individuals who have early-stage node-negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with MammaPrint (70-gene signature), the evidence includes a prospective-retrospective study, a study using a cancer registry cohort, and an RCT providing evidence for clinical utility. The prospective-retrospective study reported high ten-year distant metastases-free survival for the low-risk group treated with tamoxifen (93%; 95% CI, 88% to 96%), but not as high survival for the low-risk group not treated with tamoxifen (83%, 95% CI, 76% to 88%). Although the registry study showed a low risk of ten-year distant recurrence, the source is not considered high quality. The RCT (MINDACT) showed five-year distance recurrence rates below the 10% threshold among patients identified as low risk. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Prosigna

For individuals who have early-stage node-negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with Prosigna, the evidence includes two prospective-retrospective studies evaluating the prognostic ability of Prosigna. Both studies showed a low absolute risk of distant recurrence in patients with low-risk scores (average risk at ten years, 3%-5%; upper bound for the study providing CI, 6%). The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Early-Stage Node-Positive Invasive Breast Cancer

For decisions on management of early-stage node-positive disease, Oncotype DX, EndoPredict, MammaPrint, and Prosigna were evaluated. Only studies presenting minimum five-year distant recurrence rates or five-year survival rates were included in this part of the evidence review.

Oncotype DX (21-Gene Assay)

For individuals who have early-stage node-positive invasive breast cancer who are considering adjuvant chemotherapy who receive gene expression profiling with Oncotype DX (21-gene assay), the evidence includes two prospective-retrospective studies and a prospective study. The prospective-retrospective studies showed that Oncotype DX stratifies node-positive patients into high and low risk for distant recurrence-free survival. However, only one of the studies reported CIs for estimates and those are very wide. The prospective study included patients with node-negative and node-positive breast cancer. The authors reported that subgroup analyses of patients with node-positive breast cancer who were classified as low risk experienced higher rates of survival than patients classified as high risk, though no rates were provided. There is a wide range of survival improvements over which individual patients would elect or refuse adjuvant chemotherapy, but accurate risk estimates are needed to inform patient decisions. The evidence is insufficient to determine the effects of the technology on health outcomes.

EndoPredict

For individuals who have early-stage node-positive invasive breast cancer who are considering adjuvant chemotherapy who receive gene expression profiling with EndoPredict, the evidence includes two prospective-retrospective analyses. In a study, the ten-year distant recurrence rate in low-risk EPclin score patients was estimated to be 5% (95% CI, 1% to 9%). In the other study, ten-year distant recurrence rate in low-risk EPclin score patients was estimated to be 5%, but the upper bound of the 95% CI was close to 20%. To establish that the test has potential for clinical utility, it should be able to identify a low-risk group with a recurrence risk that falls within a range that is clinically meaningful for decision-making about avoiding adjuvant chemotherapy. The evidence is insufficient to determine the effects of the technology on health outcomes.

MammaPrint (70-Gene Signature)

For individuals who have early-stage node-positive invasive breast cancer who are considering adjuvant chemotherapy who receive gene expression profiling with MammaPrint (70-gene signature), the evidence includes a clinical utility study and an observational study. The study of clinical utility only reported five-year results and may not identify a group with sufficiently low risk. The observational study reported that the low-risk group experienced a low rate of ten-year distant recurrence; however, the standard error around the rate did not meet the threshold benefit of less than 10%. The evidence is insufficient to determine the effects of the technology on health outcomes.

Prosigna

For individuals who have early-stage node-positive invasive breast cancer who are considering adjuvant chemotherapy who receive gene expression profiling with the Prosigna ROR score, the evidence includes a single prospective-retrospective study. The ten-year distant recurrence rate in low-risk Prosigna ROR patients with a single positive node is roughly twofold the rate in low-risk ROR score node-negative patients. However, in the single available study, the upper bound of the 95% CI for ten-year distant recurrence in node-positive patients classified as ROR score low-risk was about 13%, which approaches the range judged clinically informative in node-negative patients. The predicted recurrence rates require replication. To establish that the test has potential for clinical utility, it should be able to identify a low-risk group with a recurrence risk that falls within a range that is clinically meaningful for decision-making about avoiding adjuvant chemotherapy. The evidence is insufficient to determine the effects of the technology on health outcomes.

Ductal Carcinoma In Situ

The Oncotype DX Breast DCIS Score is the only assay investigated for patients with ductal carcinoma in situ (DCIS).

Oncotype DX Breast DCIS Score

For individuals who have DCIS considering radiotherapy who receive gene expression profiling with the Oncotype DX Breast DCIS Score, the evidence includes a prospective-retrospective study and a retrospective cohort study. Although the studies have shown that the test stratifies patients into high- and low-risk groups, they have not yet demonstrated with sufficient precision that the risk of disease recurrence in patients identified with a Breast DCIS Score is low enough to consider changing the management of DCIS. The evidence is insufficient to determine the effects of the technology on health outcomes.

Extended Endocrine Therapy

For this indication, Oncotype DX, EndoPredict, Breast Cancer Index, MammaPrint, and Prosigna were evaluated. Studies retrospectively collecting tumor samples from prospective trials that provided ten-year distant recurrence rates or ten-year survival rates were included in this part of the evidence review. Studies comparing genetic assays with clinical risk prediction tools were also included.

Oncotype DX (21-Gene Assay)

For individuals who have early-stage node-positive invasive breast cancer who are considering adjuvant chemotherapy who receive gene expression profiling with Oncotype DX (21-gene assay), the evidence includes two prospective-retrospective studies and a prospective study. The prospective-retrospective studies showed that Oncotype DX stratifies node-positive patients into high and low risk for distant recurrence-free survival. However, only one of the studies reported CIs for estimates and those are very wide. The prospective study included patients with node-negative and node-positive breast cancer. The authors reported that subgroup analyses of patients with node-positive breast cancer who were classified as low risk experienced higher rates of survival than patients classified as high risk, though no rates were provided. There is a wide range of survival improvements over which individual patients would elect or refuse adjuvant chemotherapy, but accurate risk estimates are needed to inform patient decisions. The evidence is insufficient to determine the effects of the technology on health outcomes.

EndoPredict

For individuals who have early-stage node-negative invasive breast cancer who are distant recurrence-free at five years who are considering extending endocrine treatment who receive gene expression profiling with EndoPredict, the evidence includes two analyses of archived tissue samples from two previously conducted clinical trials. The studies showed low distant recurrence rates in patients classified as low risk with EndoPredict. The ability of the test to reclassify patients assessed with a clinical prediction tool was not reported. Additional prospective trials or retrospective-prospective studies of archived samples reporting on the association between risk score and survival are needed for confirmation of results from the single study. More importantly, clarity is needed about how the test would inform clinical practice. The evidence is insufficient to determine the effects of the technology on health outcomes.

Breast Cancer Index

For individuals who have early-stage node-negative invasive breast cancer who are distant recurrence-free at five years who are considering extending tamoxifen treatment who receive gene expression profiling with the Breast Cancer Index, the evidence includes three analyses of archived tissue samples from two previously conducted clinical trials and a retrospective cohort study. The analyses showed low distant recurrence rates and high distant recurrence-free survival rates in patients classified as low risk with the test. Two studies suggested that, in addition to having a more favorable prognosis, low-risk patients may receive less benefit from extended endocrine therapy. The ability of the test to reclassify patients assessed with a clinical prediction tool was not reported. Clarity about how the test would inform clinical practice is needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

MammaPrint (70-Gene Signature)

individuals who have early-stage node-negative invasive breast cancer who are distant recurrence-free at five years who are considering extending tamoxifen treatment who receive gene expression profiling with MammaPrint (70-gene signature), the evidence includes a retrospective-prospective study. Analyses on patients classified as ultralow risk (a subgroup of the low-risk group) showed that this ultralow-risk group experienced high 10- and 20-year breast cancer-specific survival rates. Additional studies are needed to confirm the results of this single study. The ability of the test to reclassify patients assessed with a clinical prediction tool was not reported. Clarity about how the test would inform clinical practice is needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

Prosigna

For individuals who have early-stage node-negative invasive breast cancer who are distant recurrence-free at five years who are considering extending tamoxifen treatment who receive gene expression profiling with Prosigna, the evidence includes several studies from previously conducted clinical trials examined in three publications. The studies showed low distant recurrence rates in patients classified as low risk with the test. A reclassification result suggested that the test may offer little improvement over clinical predictors alone. Clarity about how the test would inform clinical practice is needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

Adjuvant Chemotherapy for Node-Negative Breast Cancer

Current guidelines from the National Comprehensive Cancer Network (NCCN) for breast cancer (v.3.2019) provide a summary table assessing multigene assays to inform the addition of adjuvant systemic chemotherapy to adjuvant endocrine therapy (page BINV-N). The table shows that several genetic assays can be used to identify patients with node-negative breast cancer and low recurrence risk scores who may derive little benefit from chemotherapy. The NCCN category of evidence and consensus for the following assays is: level 1 for Oncotype DX and MammaPrint, and level 2A for Prosigna, EndoPredict, and the Breast Cancer Index. In the table, NCCN states that all the tests are prognostic, but only the Oncotype DX is predictive of response to chemotherapy in patients with node-negative breast cancer and is the preferred testing of the Network panel. In addition to the summary table, the following recommendation appears in an algorithm:

“Strongly consider 21-gene RT-PCR assay” for node-negative, ER+ [estrogen receptor-positive], HER2- [human epidermal growth factor receptor 2-negative] breast cancer with “pT1, pT2, or pT3; and pN0” and tumor less than 0.5 cm. “Other prognostic multigene assays may be considered to help assess risk of recurrence but have not been validated to predict response to chemotherapy.”

Adjuvant Chemotherapy for Node-Positive Breast Cancer

The table discussed above in the NCCN guidelines for breast cancer (v.3.2019) also provides information on the use of genetic assays to inform recurrence risk for patients with node-positive (one to three nodes) breast cancer. The level of evidence and consensus for MammaPrint for this population is one and the level of evidence and consensus for Oncotype DX, and EndoPredict for this population is 2A. In addition to the summary table, the following recommendation appears in an updated algorithm:

“Consider multigene assay to assess prognosis and determine chemotherapy benefit” for node-positive, ER+, HER2- breast cancer with “pN1mi (≤2 mm axillary node metastasis) or N1 (<four nodes). “There are few data regarding the role of multigene assays in women with four or more ipsilateral axillary lymph nodes. Decisions to administer adjuvant chemotherapy for this groups should be based on clinical factors.” For N1mi and N1, “multigene assays are prognostic and not proven to be predictive of chemotherapy benefit but can be used to identify a low risk population that when treated with proper endocrine therapy may derive little absolute benefit from chemotherapy.”

Extended Endocrine Therapy

The latest NCCN guideline (v.3.2019) provides a flow chart on adjuvant endocrine therapy (aromatase inhibitors [A1] or tamoxifen) recommendations and considerations, based on menopausal status at diagnosis and after five years of therapy, and on prior therapy history (page BINV-K). The following table summarizes the content of the flow chart:

Table. NCCN Recommendations and Considerations for Extended Endocrine Therapy

Menopausal Status at Diagnosis

Therapy History

Current Menopausal Status

Recommendations or Considerations

Premenopausal

--Tamoxifen 5 years (cat 1)

--A1 5 years (cat 1)

Postmenopausal

--Rec A1 5 more years (cat 1)

--Consider tamoxifen 5 more years

Premenopausal

--Tamoxifen 5 years (cat 1)

--A1 5 years (cat 1)

Premenopausal

--Consider tamoxifen 5 more years

No further endocrine therapy

Postmenopausal

A1 5 years (cat 1)

Postmenopausal

Consider A1 5 more years

Postmenopausal

A1 2 to 3 years (cat 1)

Postmenopausal

Rec tamoxifen to complete 5 years (cat 1)

Postmenopausal

Tamoxifen 2 to 3 years

Postmenopausal

--Rec A1 to complete 5 years (cat 1)

--Rec up to 5 years of A1 (cat 2B)

Postmenopausal

Tamoxifen 4.5 to 6 years

Postmenopausal

--Rec A1 5 more years (cat 1)

--Consider tamoxifen to complete 10 years

Postmenopausal

No A1 therapy (contraindicated or declined)

Postmenopausal

--Rec tamoxifen 5 years (cat 1)

--Consider tamoxifen up to 10 years

A1: aromatase inhibitor; NCCN: National Comprehensive Cancer Network; rec: recommend; cat: category

American Society of Clinical Oncology

In 2017, the American Society of Clinical Oncology updated its guidelines on the use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer and published a focused update of those guidelines in 2019. The ASCO also updated endorsement of the Cancer Care Ontario recommendations on the Role of Patient and Disease Factors in Adjuvant Systemic Therapy Decision Making for Early-Stage, Operable Breast Cancer in 2019. The recommendations are consistent with the table below. The table below shows the gene expression profiling biomarkers found to have demonstrated clinical utility to guide decisions on the need for adjuvant systemic therapy in women with early-stage invasive breast cancer and known estrogen and progesterone and HER2 status. The guidelines did not endorse any test for decision making to determine the length of tamoxifen treatment.

Table. Guidelines for Estrogen and Progesterone Receptor-Positive and HER2-Negative Breast Cancer

Test

Recommendation

QOE

SOR

Node-negative

Oncotype DX

"For patients older than 50 years and whose tumors have Oncotype DX recurrence scores of less than 26, and for patients age 50 years or younger whose tumors have Oncotype DX recurrence scores of less than 16, there is little to no benefit from chemotherapy. Clinicians may offer endocrine therapy alone."

High

Strong

"For patients age 50 years or younger with Oncotype DX recurrence scores of 16 to 25, clinicians may offer chemoendocrine therapy"

Intermediate

Moderate

"Patients with Oncotype DX recurrence scores of greater than 30 should be considered candidates for chemoendocrine therapy"

High

Strong

"..oncologists may offer chemoendocrine therapy to patients with Oncotype DX scores of 26 to 30"

Insufficient

Moderate

EndoPredict

Clinician may use the 12-gene risk score to guide decisions on adjuvant systemic chemotherapy

Intermediate

Moderate

Breast Cancer Index

Clinician may use the Breast Cancer Index to guide decisions on adjuvant systemic therapy

Intermediate

Moderate

MammaPrint

Clinician may use the 70-gene assay to guide decisions on adjuvant systemic therapy in women with high clinical risk per MINDACT categorization

Clinician should not use the 70-gene assay to guide decisions on adjuvant systemic therapy in women with low clinical risk per MINDACT categorization

High

Strong

Prosigna

Clinician may use the PAM50 risk of recurrence score, in conjunction with other clinicopathologic variables, to guide decisions on adjuvant systemic therapy

High

Strong

Node-positive (1-3 nodes)

MammaPrint

Clinician may use the 70-gene assay to guide decisions on adjuvant systemic therapy in women with high clinical risk per MINDACT categorization

High

Moderate

HER2: human epidermal growth factor receptor 2; QOE: quality of evidence; SOR: strength of recommendation.

St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer

In 2017, an international expert Panel, including members from the United States, convened for the 15th St. Gallen International Breast Cancer Conference. The Panel reviewed current evidence on locoregional and systemic therapies for early breast cancer. The table below summarizes relevant recommendations.

Table. Therapies by Breast Cancer Diagnosis

Breast Cancer Group

Recommendation

Adjuvant chemotherapy for patients with node-negative breast cancer

The Panel endorsed the following gene expression assays for guiding the decision on adjuvant chemotherapy in node-negative cancers: 21-gene recurrence score, the 70-gene signature, the PAM50 ROR score, the EPclin score, and the Breast Cancer Index.

Adjuvant chemotherapy for patients with node-positive breast cancer

“The Panel did not uniformly endorse the use of gene expression signatures for making treatment decisions regarding adjuvant chemotherapy in node-positive cases.”

Extended endocrine therapy for patients recurrence free at five years

“The Panel did not recommend the use of gene expression signatures for choosing whether to recommend extended adjuvant endocrine treatment, as no prospective data exist and the retrospective data were not considered sufficient to justify the routine use of genomic assays in this setting.”

U.S. Preventive Services Task Force

Not applicable.

KEY WORDS:

Microchip array, tumor gene expression, breast cancer, Oncotype test, Oncotype™ DX, MammaPrint®, Breast Cancer Gene Expression Ratio, Mammostrat, THEROS Breast Cancer Index, 12 gene expression test, colon cancer, BreastOncPx, PAM50 Breast Cancer Intrinsic Classifier, Geneoptix, NexCourse, TargetPrint, BluePrint, Prosigna Breast Cancer Assay, Oncotype DX Breast DCIS, 21 gene RT-PCR assay, 21 gene reverse transcriptase polymerase chain reaction

APPROVED BY GOVERNING BODIES:

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Oncotype DX® and other tests listed herein are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

In 2007, MammaPrint® (Agendia) was cleared for marketing by the FDA through the 510(k) process for the prediction of breast cancer metastasis. In 2015, MammaPrint® was cleared for marketing by the FDA through the 510(k) process for use in fresh-frozen, paraffin-embedded breast cancer tissue.

In 2013, Prosigna® was cleared for marketing by the FDA through the 510(k) process. Moreover, the FDA determined that Prosigna® was substantially equivalent to MammaPrint®.

FDA product code: NYI.

Currently, the Breast Cancer IndexSM (Biotheranostics) and EndoPredict® (distributed by Myriad) are not FDA-approved.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CODING:

CPT codes:

81479

Unlisted molecular pathology procedure

81599

Unlisted multianalyte assay with algorithmic analysis

84999

Unlisted chemistry procedure

The following code is for use with Breast Cancer Index Assay:

81518

Oncology (breast), mRNA, gene expression profiling by real-time RT-PCR of 11 genes (7 content and 4 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithms reported as percentage risk for metastatic recurrence and likelihood of benefit from extended endocrine therapy (Effective 01/01/2019)

The following CPT multi-analyte assay with algorithmic analysis (MAAA) code is for use with Oncotype DX:

81519

Oncology (breast), mRNA, gene expression profiling by real-time RT-PCR of 21 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as recurrence score

The following code is for use with the Prosigna Breast Cancer Assay:

81520

Oncology (breast), mRNA gene expression profiling by hybrid capture of 58 genes (50 content and 8 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a recurrence risk score (Effective 01/01/2018)

The following code is for use with Mammaprint:

81521

Oncology (breast), mRNA, microarray gene expression profiling of 70 content genes and 465 housekeeping genes, utilizing fresh frozen or formalin-fixed paraffin-embedded tissue, algorithm reported as index related to risk of distant metastasis (Effective 01/01/2018)

The following code is for use with Endopredict:

81522

Oncology (breast), mRNA gene expression profiling (Effective 1/1/2020)

The following code is for use with Onctotype DX Breast DCIS Score Test:

0045U

Oncology (breast ductal carcinoma in situ), mRNA, gene expression profiling by real-time RT-PCR of 12 genes (7 content and 5 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as recurrence score. (Effective 07/01/2018)

HCPCS:

S3854

Gene expression profiling panel for use in the management of breast cancer treatment (Reinstated 07/01/16)

PREVIOUS CODING:

CPT codes:

0008M

Oncology (breast), mRNA analysis of 58 genes using hybrid capture, on formalin-fixed paraffin-embedded (FFPE) tissue, prognostic algorithm reported as a risk score (Deleted 12/31/17)

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POLICY HISTORY:

Medical Policy Group, June 2004 (4)

Medical Policy Administration Committee, July 2004

Available for comment August 11-September 24, 2004

Medical Policy Group, July 2005 (1)

Medical Policy Group, December 2005 (4)

Available for comment January 28-March 13, 2006

Medical Policy Group, January 2007 (4)

Medical Policy Administration Committee, January 2007

Available for comment January 30-March 8, 2007

Medical Policy Group, July 2007 (4)

Medical Policy Group, February 2008 (2)

Medical Policy Administration Committee, February 2008

Available for comment February 21-April 4, 2008

Medical Policy Group, February 2009 (3)

Medical Policy Administration Committee, February 2009

Available for comment February 6-March 23, 2009

Medical Policy Group, December 2009 (1)

Medical Policy Administration Committee, December 2009

Available for comment December 29, 2009-February 11, 2010

Medical Policy Group, June, 2011 (1): Update to Description, Key Points Coding and References; Added tests BreastOncPx and PAM50 to Policy as investigational and to Key Words

Medical Policy Administration Committee, August 2011

Available for comment August 11 – September 26, 2011

Medical Policy Panel, December 2012

Medical Policy Group, January 2013 (1): Update to Descriptions, Policy, Key Points, Key Words, and References related to addition of bilateral disease as investigational Oncotype statement; addition of newer assay considered investigational and addition of Oncotype for DCIS as investigational; removed and archived policy statement prior to December 2009.

Medical Policy Administration Committee, February 2013

Available for comment February 21 through April 7, 2013

Medical Policy Group, July 2013 (1): Update to Policy section with clarifying (included, but not limited to) phrase added to ‘use of other gene assays’; update to Key Words with addition of TargetPrint and BluePrint gene assays; update to Coding section with addition of 81479 and 81599 to policy.

Medical Policy Administration Committee, July 2013

Medical Policy Group, May 2014 (1): Added new code 0008M related to Prosigna Breast Cancer Assay, which is a non-covered and investigational indication; effective 07/01/14

Medical Policy Panel, July 2014

Medical Policy Group, July 2014 (1): Update to Policy, Key Points and References with addition of noncoverage statements related to breast cancer in men and new tests BluePrint and TargetPrint; removed the “non-fixed” verbiage from criteria for unilateral tumor related to Oncotype Dx

Medical Policy Administration Committee, August 2014

Available for comment August 8 through September 22, 2014

Medical Policy Group, November 2014: 2015 Annual Coding update. Added code 81519 to current coding

Medical Policy Panel, July 2015

Medical Policy Group, July 2015 (3): Updates to Description, Key Points, Approved Governing Bodies, and References. No change to policy statements.

Medical Policy Group, November 2015: 2016 Annual Coding Update. Moved HCPCS code S3854 from current coding to previous coding

Medical Policy Panel, November 2016

Medical Policy Panel, December 2016

Medical Policy Group, January 2017 (3): Updates to Description, Key Points, Coding, & References; Policy statements also updated to reflect adding coverage criteria for EndoPredict, the Breast Cancer Index, and Prosigna; use of MammaPrint and BluePrint remains investigational; no other policy statement changes made

Medical Policy Administration Committee, January 2017

Available for comment January 18 through March 3, 2017

Medical Policy Panel, August 2017

Medical Policy Group, September 2017 (3): 2017 Updates to Description, Key Points, Approved by Governing Bodies & References; removed Policy statements for dates of service prior to July 1, 2014; No change in current policy statements

Medical Policy Panel, November 2017

Medical Policy Group, December 2017 (3): 2017 Updates to Description, Key Points, Approved by Governing Bodies & References; no change in policy statement

Medical Policy Group, December 2017: Annual Coding Update 2018. Added new CPT codes 81520 and 81521 effective 1/1/18 to Current Coding.

Medical Policy Group, June 2018: Quarterly Coding Update July 2018. Added new CPT code 0045U to Current Coding. Added Key Word Oncotype DX Breast DCIS.

Medical Policy Panel, November 2018

Medical Policy Group, December 2018 (9): 2018 Updates to Description, Key Points, References; Policy Statement updated to include Mammaprint in the list of tests which may be considered medically necessary; Key words added: 21 gene RT-PCR assay, 21 gene reverse transcriptase polymerase chain reaction; moved deleted code 0008M to previous coding section, added code 81518, 81521 to current coding section.

Medical Policy Administration Committee, January 2019.

Available for comment January 1, 2019 through February 15, 2019.

Medical Policy Panel, June 2019

Medical Policy Group, July 2019 (9): 2019 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Panel, November 2019

Medical Policy Group (9): 2019 Updates to Description, Key Points, and References. Added CPT code 81522 (for use with Endopredict) to Current coding section. Change to policy statement as follows: A medically necessary statement was added for Mammaprint for decisions regarding adjuvant chemotherapy in node-positive women.

Medical Policy Administration Committee, December 2019.

Available for comment November 20, 2019 through January 3, 2020


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.