Medical Policy: 02.04.59 

Original Effective Date: August 2016 

Reviewed: August 2018 

Revised: December 2018 

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

The selection of individuals with invasive breast cancer who may be candidates for adjuvant chemotherapy is complex and the current tools available for recurrence risk assessment are limited and do not allow for great accuracy in the selection of appropriate individuals who would and would not benefit from treatment with adjuvant chemotherapeutic agents. More precise identification of these individuals could improve outcomes through more appropriate chemotherapy use, mitigation of unnecessary treatment and decreased adverse chemotherapy related events.

 

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 genotypical women with early stage breast cancer. Test results may help providers and patients decide whether to include adjuvant chemotherapy in postsurgical management of breast cancer, to alter treatment in patients with ductal carcinoma in situ (DCIS), or to recommend extended endocrine therapy in patient's invasive breast cancer who are recurrence-free at 5 years.

 

Most geno typical women with newly diagnosed breast cancer in the United States present with early-stage or locally advanced (i.e. non-metastatic) disease. However, almost a third of geno typical 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 patient’s baseline level of recurrence risk, hormonal markers and risk tolerance.

 

This review focuses on 3 decision points:

  1. The decision to pursue adjuvant chemotherapy following locoregional therapy, with or without noadjuvant chemotherapy, based on the 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. HER2 expression independently confers on unfavorable prognosis, but assessing the independent effects of HER2 is complicated in the presence of targeted therapy.
  2. The decision to pursue extended adjuvant endocrine therapy from 5 to 10 years for women who are hormone receptor-positive and who have survived without recurrence for 5 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 5 to 10 years after an initial diagnosis has support in clinical practice. The 2018 guidelines from the National Comprehensive Cancer Network (NCCN) do not recommend extended endocrine therapy, but state that aromatase inhibitors or tamoxifen may be considered following 5 years of endocrine therapy. The guidelines also note that optimal duration of aromatase inhibitors is uncertain. The American Society of Clinical Oncology (ASCO) 2018 update to its guideline on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer recommended that women with node-positive breast cancer receive extended therapy, including an AI (aromatase inhibitor), for up to a total of 10 years of adjuvant endocrine therapy.
  3. The decision to pursue adjuvant radiotherapy in women with ductal carcinoma in situ (DCIS). Adjuvant radiotherapy reduces the risk of local recurrence 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 geno typical women with breast cancer involves determining which patients could benefit from adjuvant chemotherapy. For example, for genotypical women with early stage invasive breast cancer (i.e. cancer extending beyond the basement membrane of the mammary ducts into adjacent tissue), adjuvant chemotherapy provides approximately a 30% relative risk reduction in 10 year breast cancer mortality regardless of prognosis. However, the absolute benefit of chemotherapy depends on the underlying or baseline risk of recurrence. Geno typical women with the best prognosis have tumors that are small, early stage, are estrogen receptor (ER)-positive, and lymph node-negative. Patients may have received no adjuvant treatment, or adjuvant tamoxifen and/or adjuvant chemotherapy. These genotypical women have an approximately 15% 10 year risk of recurrence with tamoxifen alone; approximately 85% of these patients could avoid the toxicity of adjuvant 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 node. Consensus guidelines for defining receptor status exist, however, no single classifier is considered a criterion standard, and several common criteria have qualitative or subjective components that add variability to risk estimates. As a result, a substantial number of patients are treated with chemotherapy who fail to benefit. Better predictors of baseline risk could help genotypical women's decision making, some who may prefer to avoid chemotherapy if assured their risk is low.

 

Selection of Extended Endocrine Therapy

Randomized controlled trials have established that 5 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 (total N=21,457 patients) found that 5 years of tamoxifen in estrogen receptor – positive disease reduced the risk of recurrence by almost 50% over 10 years on the relative scale; breast cancer mortality was decreased by 29% through 15 years.

 

Randomized controlled trials published have shown that extended endocrine therapy decreases the risk of recurrence. The ATLAS trial, which compared 5 and 10 years of tamoxifen and the subsequent aTTom trial (reported in abstract form), included women who were hormone receptor-positive and had completed 5 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.

 

Several trials have compared survival outcomes in women using extended aromatase inhibitors versus placebo following several years of tamoxifen, and 2 trials compared the use of extended aromatase inhibitors for different durations (3 years versus 6 years and 2.5 years versus 5 years). No differences in overall survival were detected between the aromatase inhibitor groups compared 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 an aromatase inhibitor, with or without ovarian suppression) for the initial 5 years following initial diagnosis has support in national guidelines. Support for extended endocrine therapy beyond the initial 5 years is inconsistent among various guidelines.

 

The latest updated guidelines (2018) from American Society of Clinical Oncology (ASCO) discussing extended endocrine therapy for breast cancer recommends that women with node- positive breast cancer receive extended therapy including an AI (aromatase inhibitor), for up to a total of 10 years of adjuvant endocrine treatment (additional 5 years). This recommendation on extended adjuvant AI therapy was based on the benefits that include prevention of distant recurrence and prevention of second breast cancers. The NCCN guideline (2018) for invasive breast cancer do not recommend extended endocrine therapy, but state that aromatase inhibitors (AI) or tamoxifen may be considered following 5 years of endocrine therapy. The guidelines also note that optimal duration of aromatase inhibitors is uncertain.

 

Adverse Effects from Extended Endocrine Therapy

Adverse effects from extended tamoxifen include increased risk of thromboemobolic disease (deep vein thrombosis and 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%, 1.3 to 2.3) for endometrial cancer. Adverse effects from extended aromatase inhibitors include musculoskeletal side effects (for example carpal tunnel syndrome, bone pain, and bone fractures). In meta-analysis comparing tamoxifen and aromatase inhibitors (AI), results showed an increased risk in cardiovascular events with aromatase inhibitors related to tamoxifen. Women treated with aromatase inhibitors (AI) have also experienced higher fracture rates compared with women treated with tamoxifen.

 

Clinical Uses of Gene Expression Signatures for Breast Cancer

In other clinical scenarios involving breast cancer, accurate assessment of prognosis may affect the decision to offer certain treatments. Several groups have identified panels of gene expression markers (signatures) that appear to predict the baseline risk of invasive breast cancer recurrence after surgery, radiotherapy and endocrine therapy (for hormone receptor-positive tumors).  Several gene expression tests commercially available in the United States are listed in the below table. If these panels are more accurate risk predictors than current classifiers, they could be used to aid decision making on adjuvant treatments without greatly affecting disease free survival and overall survival (OS). This review focuses on gene expression profiling (GEP) panels that have prognostic or predictive ability in individuals with early stage invasive breast cancer with known estrogen receptor and progesterone receptor and human epidermal growth factor receptor (HER2) status.  The proposed clinical utility of these tests varies by clinical context:

  • Prognosis and/or prediction of treatment response in patients with node-negative, early stage, hormone receptor-positive, HER2-negative invasive breast cancer who will receive adjuvant hormonal therapy for the purpose of determining whether patients can avoid adjuvant cytotoxic chemotherapy.
  • Prognosis and/or prediction of treatment response in patients with node-positive (1-3 nodes), hormone receptor-positive, early stage, HER2-negative invasive breast cancer who will receive adjuvant hormonal therapy for the purpose of determining whether patients can avoid adjuvant cytotoxic chemotherapy.
  • Prognosis and/or prediction of treatment response in patients with node-negative, early stage hormone receptor-positive, HER2-negative invasive breast cancer, receiving adjuvant hormonal therapy, who have survived without progression to 5 years post-diagnosis, for the purpose of determining whether patients will continue adjuvant hormonal therapy.
Gene Expression Tests Reporting Recurrence Risk for Breast Cancer
Test Manufacturer Description
BluePrint Agendia 80 gene expression assay that classifies breast cancer into basal type, luminal type, or HER2 type

This test is marketed as an additional stratifier into a molecular subtype after risk assessment with MammaPrint

Breast Cancer Index bioTheranostics (San Diego, CA) Combines molecular grade index and the HOXB13:IL17BR Index using reverse transcriptase polymerase chain reaction identifies 2 groups as low or high risk for distant recurrence
EndoPredict Myriad (Salt Lake City, UT) 12 gene real time reverse transcriptase polymerase chain reaction gene expression molecular score alone (EP) or EP is combine with the clinical parameters of tumor size and number positive lymph nodes (EPclin), resulting in classification of EP low, EP high, EPClin low or EPclin high risk for distant recurrence
MammaPrint Agendia (Irvine, CA) 70 gene DNA microarray; identifies 2 groups as low or high risk for distant recurrence
Mammostrat Breast Cancer Test Clarient Diagnostic Services Uses five immunohistochemical markers
Oncotype DX Breast Genomic Health (Redwood City, CA) 21 gene reverse transcriptase polymerase chain reaction identifies 3 groups as low, intermediate and high risk for distant recurrence
Oncotype DX DCIS Genomic Health (Redwood City, CA)

Uses information from 12 (7 cancer related and 5 reference genes) of the 21 genes assayed in the standard Oncotype DX Breast (21-gene expression profile) for early breast cancer to predict 10 year risk of local recurrence (DCIS or invasive carcinoma).

 

The stated purpose is help guide treatment decision making in women with DCIS treated by local excision, with or without adjuvant tamoxifen therapy.

Prosigna NanoString Technologies (Seattle, WA) Gene expression profile is assessed by the nCounter digital platform system to determine similarity with prototypic profiles of prediction analysis for microarray 50 gene set genes for breast cancer; identifies 3 categorical ROR (risk of relapse) groups (ROR low, ROR intermediate, ROR high)
TargetPrint Agendia Microarray based gene expression test that offers a quantitative assessment of ER, PR and HER2 overexpression in breast cancer

This test is marketed to be used in conjunction with MammaPrint and BluePrint

MGI: Molecular Grade Index; PAM50: prediction analysis of microarray 50 gene set; RT-PCR: reverse transcriptase polymerase chain reaction.

 

Decision Framework for Evaluating Breast Cancer Biomarkers

Many studies have investigated individual biomarkers or combination of biomarkers associated with breast cancer outcomes. Determining which studies constitute sufficient evidence that the test or biomarker is like 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) have described a framework to evaluate prognostic biomarker evidence. Study designs, such 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 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 outcomes in the patient group of interest that would result in a change of 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 the consistency of results and more than 1 study demonstrating the desired result should be available. Simon has proposed at least 2 Simon category B studies showing results consistent with clinical utility are necessary to demonstrate adequate evidence of a biomarker.  Simon also proposes 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.”  

 

Breast Cancer-Specific Outcomes

The main outcome of interest is distant recurrence free-survival. Distant recurrence is a hallmark of advanced breast cancer and thus more informative of overall survival than disease-free survival. Disease-free survival also includes local recurrence, which has a much better treatment prognosis than distant disease.

 

Historically, 10 year distant recurrence has been the outcome of interest for assessing prognostic tests used to select women with early stage breast cancer who can avoid treatment with adj uvant chemotherapy. In 2012, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted a patient data meta-analysis of 123 trials (N > 100,000 women) which compared various chemotherapy regimens to no chemotherapy for early stage breast cancer. The pooled results showed that women receiving chemotherapy experienced significantly lower rates of distant recurrence compared with woman not receiving chemotherapy for up to 5 years; however, during the 5 to 10 year follow-up period, recurrence rates were similar between the two groups. This suggests that the benefit of chemotherapy can be observed with 5 years of follow-up. As a result, we have altered our requirement for duration of follow-up from 10 years to 5 years when assessing prognosis in women considering adjuvant chemotherapy.  

 

Decisions to undergo or forgo adjuvant therapy (chemotherapy or endocrine) depend on how a geno typical women values the potential benefit of lower recurrence risk relative to harms of treatment. The balance of benefits and harms determines the thresholds that inform decisions. Most geno typical women will accept substantial adverse effects for even modest benefit.

 

Assays of Genetic Expression in Tumor Tissue

Clinical Context and Test Purpose

The purpose of assays of genetic expression in tumor tissue in patients with early stage node-negative or node-positive invasive breast cancer considering adjuvant chemotherapy; in patients with ductal carcinoma in situ (DCIS) considering radiotherapy; and in patients with early stage node-negative invasive breast cancer, recurrence free at 5 years considering extended endocrine therapy, is to determine risk of recurrence, which informs decisions about potential breast cancer treatment.

 

Interventions

The interventions of interest are assays of genetic expression in tumor tissue: Blue Print, Breast Cancer Index, EndoPredict, MammaPrint, Mammostrat Breast Cancer Test, Oncotype DX Breast, Oncotype DX DCIS, Prosigna and TargetPrint.

  • BluePrint: Is an 80 gene expression assay that classifies breast cancer into basal type, luminal type, or HER2 type. The test is marketed as an additional stratifier into a molecular subtype after risk assessment with MammaPrint. This assists the physician in determining a patient’s individual risk for metastasis and/or recurrence and which patients can safely forego chemotherapy.
  • Breast Cancer Index (BCI): Risk of Recurrence is intended for use in patients diagnosed with estrogen receptor positive (ER+), lymph node negative early stage invasive breast cancer. BCI provides the individualized risk of late distant recurrence of breast cancer years 5-10. Breast Cancer Index is a quantitative molecular assessment of estrogen signaling pathways HoxB13/IL17BR with a five gene molecular grade index (MGI) (BUB1B, CENPA, NEK2, RACGAP1, RRM2, H/I).  This information may be used by the treating physician to guide therapy decisions by identifying which patients are sufficiently low risk of recurrence so that they can safely forgo chemotherapy. A numerical result is reported on a continuous curve delineated by high/low risk categories.
  • EndoPredict: Combines a breast tumor 12 gene expression signature with clinical features of the tumor (tumor size and nodal status) to predict the 10 year distant recurrence rate. This information may be used by the treating physician to guide therapy decisions by identifying which patients are sufficiently low risk of recurrence so that they can safely forgo chemotherapy.
  • MammaPrint: Is a 70 gene breast cancer recurrence assay that utilizes FFPE (formalin-fixed paraffin-embedded) breast tumor tissue to analyze and predict whether existing cancer has the ability to metastasize. Breast cancer recurrence and/or metastasis is partly dependent on the activation and suppression of certain genes located within the primary breast tumor. This information may be used by the treating physician to guide therapy decisions by identifying which patients are sufficiently low risk of recurrence so that they can safely forgo chemotherapy.
    • MammaPrint provides a numerical index with a range of -1 to +1, that is overlayed with a binary low risk/high risk clinical classification system.
      • Low Risk Results: 10% chance of cancer recurrence within 10 years without any additional adjuvant treatment, either hormonal therapy or chemotherapy.
      • High Risk Results: 29% chance of cancer recurrence within 10 years without any additional adjuvant treatment, either hormonal therapy or chemotherapy.
  • Mammostrat Breast Cancer Test: Uses five immunohistochemical markers (SLC7A5, HTF9C, P53, NDRG1 and CEACAM5) to stratify patients regarding recurrence risk and may inform treatment decisions. The Mammostrat test measures the levels of the five immunohistochemical markers into a risk index score and the individual is assigned to a risk category high, moderate or low.
  • Oncotype DX Breast: Is an assay that measures the expression of 21 genes (16 cancer genes and 5 reference genes) in RNA extracted from samples of tissue from a primary breast tumor. The initial indications for the 21-gene expression profile (Oncotype DX Breast) was for patients newly diagnosed with stage I or II disease that is node negative and estrogen receptor (ER) positive, invasive breast cancer who would be treated with tamoxifen. Primary validation studies enrolled node-negative geno typical women. More recently, Genomic Health has expanded their indication to include all stage II disease and IIIa (tumor ≤2 cm with spread to axillary lymph nodes or 2-5 cm without lymph node involvement) and ductal carcinoma in situ (DCIS). 
    • Results from the Oncotype DX 21-gene expression profile are combined into a Recurrence Score (RS) which is reported as a number between 0 and 100. A lower score means the cancer has a lower chance of returning, and a higher score means that there is a higher chance of the cancer returning. The score also  provides patients and doctors with important information regarding the potential benefit of adding chemotherapy to hormonal therapy. A low score indicates that the patient will receive minimal benefit from chemotherapy, whereas a patient with a high score may have significant benefit from chemotherapy.
    • Oncotype DX Breast cancer test provides information in addition to standard measurements (such as tumor size, tumor grade and lymph node status) that doctors have traditionally used to estimate how likely a patient’s cancer is to return, and to help make treatment decisions. Each report also includes quantitative, single gene scores for ER, PR and HER2 expression. The report can guide more informed treatment decisions with information to answer critical questions in early stage breast cancer:
      • Quantifies a patient’s 10 year risk of distant recurrence, assuming 5 years of hormonal therapy.
      • Predicts the likelihood of chemotherapy benefit across the range of Recurrence Score results, with higher scores indicating a greater likelihood of chemotherapy benefit.
      • Provides an individualized, quantitative risk assessment that reflects the patient’s unique tumor biology, rather than just a high or low binary result.
      • Personalized treatment decision that goes beyond clinical and pathological factors such as age, tumor size and tumor grade.
  • Oncotype DX DCIS: Uses information from 12 (7 cancer related and 5 reference genes) of the 21 genes assayed in the standard Oncotype DX Breast test (21-gene expression profile) for early breast cancer to predict 10 year risk of local recurrence (DCIS or invasive carcinoma). The stated purpose is help guide treatment decision making in  women with DCIS treated by local excision, with or without adjuvant tamoxifen therapy.
  • Prosigna: Is based on PAM50, the 50-gene classifier algorithm that is performed on the NanoString nCounter DX Analysis System using RNA extracted FFPE (formalin-fixed paraffin-embedded) breast tumor tissue previously diagnosed as invasive breast carcinoma. The algorithm uses a 50-gene expression profile to assign breast cancer to one of four PAM50 molecular subtypes determined by the tumors molecular profile. This qualitative assay utilizes gene expression data, weighted together with clinical variables to generate a numerical value on a 0 to 100 scale that correlates with the probability of distant recurrence within 10 years. This information may be used by the treating physician to guide therapy decisions by identifying which patients are sufficiently low risk of recurrence so that they can safely forgo chemotherapy. The Prosigna Breast Cancer Prognostic Gene Signature Assay is indicated in women with hormone receptor positive and lymph node negative invasive breast cancer. 
  • TargetPrint: Is a microarray based gene expression test that offers a quantitative assessment of ER, PR and HER2 overexpression in breast cancer. The test is marketed to be used in conjunction with MammaPrint and BluePrint. This assists the physician in determining a patient’s individual risk for metastasis and/or recurrence and which patients can safely forego chemotherapy.

 

Comparators

The comparators of interest for all assays are clinical risk prediction algorithms. For adjuvant chemotherapy, a conventional risk classifier (e.g. Adjuvant! Online) estimates recurrence risk by considering criteria such as tumor size, type, grade and histologic characteristics; hormone receptor status; and lymph node status. No single classifier is considered a criterion standard. Several common criteria have qualitative or subjective components that add variability for risk estimates.

 

Outcomes

Outcomes of interest for all assays are disease specific survival and change in disease status.

  • If patients with early stage invasive breast cancer are classified as low risk for distance recurrence, patients may be able to forgo adjuvant chemotherapy safely.
  • If patients with DCIS are classified as low risk for distant recurrence, they may be able to safely forgo radiotherapy.
  • If patients with invasive breast cancer who are recurrence free for 5 years are classified as low risk for distant recurrence, patients may be able to safely forego extended endocrine therapy. 

 

Timing

For patients with early stage invasive breast cancer, the assays would be performed following the diagnosis of early stage node negative or node positive invasive breast cancer, whenpatients are considering adjuvant chemotherapy.

 

For patients with DCIS, the assays would be performed following the diagnosis of DCIS when patients are considering radiotherapy (RT).

 

For patients with early stage invasive breast cancer who are recurrence-free for 5 years, the assays would be performed when patients are considering extended endocrine therapy.

 

Early Stage Node-Negative Invasive Breast Cancer Considering Adjuvant Chemotherapy

Oncotype DX Breast (21 Gene Assay)

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

In 2011, Tang et. al. compared the prognostic and predictive utility of two tools (Oncotype DX Recurrence Score (RS) and Adjuvant! [developed using SEER registry data and results from the Early Breast Cancer Clinical Trialists’ overview analyses to estimate outcome and benefit from adjuvant hormonal therapy and chemotherapy]) in node-negative, ER-positive breast cancer.  RS and Adjuvant! results were available from 668 tamoxifen-treated NSABP B-14 patients: 227 tamoxifen-treated NSABP B-20 patients, and 424 chemotherapy-plus-tamoxifen-treated B-20 patients. Adjuvant! results were also available from 1952 B-20 patients. The primary endpoint was distant recurrence-free interval (DRFI). Cox proportional hazards models were used to compare the prognostic and predictive utility of RS and Adjuvant!. Both RS (p<0.001) and Adjuvant! (p=0.002) provided strong independent prognostic information in tamoxifen-treated patients. Combining RS and individual clinicopathologic characteristics provided greater prognostic discrimination than combining RS and the composite Adjuvant!. In the B-20 cohort with RS results (n=651), RS was significantly predictive of chemotherapy benefit (interaction p=0.031 for DRFI, p=0.011 for overall survival [OS], p=0.082 for disease-free survival [DFS]), but Adjuvant! was not (interaction p=0.99, p=0.311 and p=0.357, respectively). However, in the larger B-20 sub-cohort (n=1952), Adjuvant! was significantly predictive of chemotherapy benefit for OS (interaction p=0.009) but not for DRFI (p=0.219) or DFS (p=0.099). Prognostic estimates can be optimized by combining RS and clinicopathologic information instead of simply combining RS and Adjuvant!. The authors concluded RS should be used for estimating relative chemotherapy benefit.

 

Sparano et. al. (2015), performed a prospective trial involving women with hormone-receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase-polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicating a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence). Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease-free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6). The authors concluded, among patients with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone.

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

 

Low-Risk Threshold (Recurrence Score ≤ 10)

Evidence for clinical validity has shown that patients within the low risk threshold for Oncotype DX may consider safely forgoing adjuvant chemotherapy with tight precision, and thereby avoid negative effects of the therapy.

 

Intermediate-Risk Threshold (Recurrence Scores 11-25)

Sparano et. al. (2018) performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score (21 gene expression assay) of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show non-inferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine versus chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. The authors concluded, adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger.

 

Summary

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% confidence interval (CI), 6% to 10%). These results have demonstrated with stronger study designs for evaluating biomarkers. The evidence is sufficient to determine that the technology results in meaningful improvement in the net health outcome.

 

EndoPredict

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

In 2011, Filipits et. al. assessed patients from two previously large randomized phase III trials.   
According to current guidelines, molecular tests predicting the outcome of breast cancer patients can be used to assist in making treatment decisions after consideration of conventional markers. We developed and validated a gene expression signature predicting the likelihood of distant recurrence in patients with estrogen receptor (ER)–positive, HER2-negative breast cancer treated with adjuvant endocrine therapy. RNA levels were assessed by quantitative reverse transcriptase PCR in formalin fixed, paraffin-embedded tumor tissue were used to calculate a risk score (Endopredict, EP) consisting of eight cancer-related and three reference genes. EP was combined with nodal status and tumor size into a comprehensive risk score, EPclin. Both prespecified risk scores including cutoff values to determine a risk group for each patient (low and high) were validated independently in patients from two large randomized phase III trials [Austrian Breast and Colorectal Cancer Study Group (ABCSG)-6: n = 378, ABCSG-8: n = 1,324]. In both validation cohorts, continuous EP was an independent predictor of distant recurrence in multivariate analysis (ABCSG-6: P = 0.010, ABCSG-8: P < 0.001). Combining Adjuvant!Online, quantitative ER, Ki67, and treatment with EP yielded a prognostic power significantly superior to the clinicopathologic factors alone [c-indices: 0.764 versus 0.750, P = 0.024 (ABCSG-6) and 0.726 versus 0.701, P = 0.003 (ABCSG-8)]. EPclin had c-indices of 0.788 and 0.732 and resulted in 10-year distant recurrence rates of 4% and 4% in EPclin low-risk and 28% and 22% in EPclin high-risk patients in ABCSG-6 (P < 0.001) and ABCSG-8 (P < 0.001), respectively. The authors concluded, the multigene EP risk score provided additional prognostic information to the risk of distant recurrence of breast cancer patients, independent from clinicopathologic parameters. The EPclin score outperformed all conventional clinicopathologic risk factors.

 

Buus et. al. (2016), compared the prognostic information provided by Oncotype DX recurrence score (RS) and EndoPredict (EPclin) for 10 year distant recurrence risk (DR). They used likelihood ratio χ² and Kaplan-Meier survival analyses to compare prognostic information provided by EP, EPclin, RS, and the clinical treatment score (CTS) of clinicopathologic parameters in 928 patients with ER+ disease treated with five years' anastrozole or tamoxifen. Comparisons were made for early (0-5 years) and late (5-10 years) DR according to nodal status. All statistical tests were two-sided. In the overall population, EP and EPclin provided substantially more prognostic information than RS (LRχ(2): EP = 49.3; LRχ(2): EPclin = 139.3; LRχ(2): RS = 29.1), with greater differences in late DR and in node-positive patients. EP and EPclin remained statistically significantly prognostic when adjusted for RS (LRχ(2): EP+RS vs RS = 20.2; LRχ(2): EPclin+RS vs RS = 113.8). Using predefined cut-offs, EPclin and RS identified 58.8% and 61.7% patients as low risk, with hazard ratios for non-low vs low risk of 5.99 (95% confidence interval [CI] = 3.94 to 9.11) and 2.73 (95% CI = 1.91 to 3.89), respectively. The authors concluded, this study has confirmed the independent prognostic ability of EP and EPclin in postmenopausal women with ER positive/HER2 negative primary disease. EPclin provided more prognostic information than RS partly because of its integration with node and tumor size information but also because of a superior molecular component able to predict late events better than RS.

 

In 2018, Sestak et. al. conducted a within-patient comparison of the prognostic value of 6 multigene signatures in women with early ER-positive breast cancer who received endocrine therapy for 5 years. This retrospective biomarker analysis included 774 postmenopausal women with ER-positive ERBB2 (formerly HER2)-negative breast cancer. This analysis was performed as a preplanned secondary study of data from the Anastrozole or Tamoxifen Alone or Combined randomized clinical trial comparing 5-year treatment with anastrozole vs tamoxifen with 10-year follow-up data. The signatures included the Oncotype Dx recurrence score, PAM50-based Prosigna risk of recurrence (ROR), Breast Cancer Index (BCI), EndoPredict (EPclin), Clinical Treatment Score, and 4-marker immunohistochemical score. Data were collected from January 2009, through April 2015. The primary objective was to compare the prognostic value of these signatures in addition to the Clinical Treatment Score (nodal status, tumor size, grade, age, and endocrine treatment) for distant recurrence for 0 to 10 years and 5 to 10 years after diagnosis. Likelihood ratio (LR) statistics were used with the χ2 test and C indexes to assess the prognostic value of each signature. In this study of 774 postmenopausal women with ER-positive, ERBB2-negative disease (mean [SD] age, 64.1 [8.1] years), 591 (mean [SD] age, 63.4 [7.9] years) had node-negative disease. The signatures providing the most prognostic information were the ROR (hazard ratio [HR], 2.56; 95% CI, 1.96-3.35), followed by the BCI (HR, 2.46; 95% CI, 1.88-3.23) and EPclin (HR, 2.14; 95% CI, 1.71-2.68). Each provided significantly more information than the Clinical Treatment Score (HR, 1.99; 95% CI, 1.58-2.50), the recurrence score (HR, 1.69; 95% CI, 1.40-2.03), and the 4-marker immunohistochemical score (HR, 1.95; 95% CI, 1.55-2.45). Substantially less information was provided by all 6 molecular tests for the 183 patients with 1 to 3 positive nodes, but the BCI (LR χ2 = 9.2) and EPclin (LR χ2 = 7.4) provided more additional prognostic information than the other signatures. The authors concluded, women with node-negative disease, the ROR, BCI and Epclin were significantly more prognostic for overall and late distant recurrence. For women with 1-3 positive nodes, limited indendent information was available from any test. These data might help oncologists and patients to choose the most appropriate test when considering chemotherapy use and/or extended endocrine therapy.

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

 

No decision impact studies were identified that provide clinical outcomes such as survival or recurrence.

 

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. However, evidence for clinical validity has shown that EndoPredict is able to identify women who can safely forgo adjuvant chemotherapy and thereby avoid negative effects of the therapy.

 

Summary

For individuals who have early-stage node-negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with EndoPredict, the evidence includes 3 prospective-retrospective studies and observational studies. The studies revealed that a low score was associated with a low absolute risk of 10-year distant recurrence (average risk at 10 years for the 2 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

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

In 2013, Sgori et. al. reported on a prospective comparison study using archival tumor blocks from the TransATAC tissue bank from all postmenopausal patients with estrogen-receptor-positive breast cancer from whom the 21-gene recurrence score and IHC4 values had already been derived. Breast cancer index (BCI) analysis was performed in matched samples with sufficient residual RNA using two BCI models-cubic (BCI-C) and linear (BCI-L)-using previously validated cutoffs. They assessed prognostic ability of BCI for distant recurrence over 10 years (the primary endpoint) and compared it with that of the 21-gene recurrence score and IHC4. We also tested the ability of the assays to predict early (0-5 years) and late (5-10 years) distant recurrence. To assess the ability of the biomarkers to predict recurrence beyond standard clinicopathological variables, we calculated the change in the likelihood-ratio χ(2) (LR-χ(2)) from Cox proportional hazards models. Suitable tissue was available from 665 patients with estrogen-receptor-positive, N0 breast cancer for BCI analysis. The primary analysis showed significant differences in risk of distant recurrence over 10 years in the categorical BCI-C risk groups (p<0·0001) with 6·8% (95% CI 4·4-10·0) of patients in the low-risk group, 17·3% (12·0-24·7) in the intermediate group, and 22·2% (15·3-31·5) in the high-risk group having distant recurrence. The secondary analysis showed that BCI-L was a much stronger predictor for overall (0-10 year) distant recurrence compared with BCI-C (interquartile HR 2·30 [95% CI 1·62-3·27]; LR-χ(2)=22·69; p<0·0001). When compared with BCI-L, the 21-gene recurrence score was less predictive (HR 1·48 [95% CI 1·22-1·78]; LR-χ(2)=13·68; p=0·0002) and IHC4 was similar (HR 1·69 [95% CI 1·51-2·56]; LR-χ(2)=22·83; p<0·0001). All further analyses were done with the BCI-L model. In a multivariable analysis, all assays had significant prognostic ability for early distant recurrence (BCI-L HR 2·77 [95% CI 1·63-4·70], LR-χ(2)=15·42, p<0·0001; 21-gene recurrence score HR 1·80 [1·42-2·29], LR-χ(2)=18·48, p<0·0001; IHC4 HR 2·90 [2·01-4·18], LR-χ(2)=29·14, p<0·0001); however, only BCI-L was significant for late distant recurrence (BCI-L HR 1·95 [95% CI 1·22-3·14], LR-χ(2)=7·97, p=0·0048; 21-gene recurrence score HR 1·13 [0·82-1·56], LR-χ(2)=0·48, p=0·47; IHC4 HR 1·30 [0·88-1·94], LR-χ(2)=1·59, p=0·20).  The authors concluded BCI-L was the only significant prognostic test for risk of both early and late distant recurrence and identified two risk population for each timeframe. It could help to identify patients at high risk for late distant recurrence who might benefit from extended endocrine or other therapy.

 

Zhang et. al. (2013) examined the prognostic performance of an optimized model of Breast Cancer Index (BCI), an algorithmic gene expression-based signature, for prediction of early (0-5 years) and late (>5 years) risk of distant recurrence in patients with estrogen receptor-positive (ER(+)), lymph node-negative (LN(-)) tumors. The BCI model was validated by retrospective analyses of tumor samples from tamoxifen-treated patients from a randomized prospective trial (Stockholm TAM, n = 317) and a multi-institutional cohort (n = 358). Within the Stockholm TAM cohort, BCI risk groups stratified the majority (65%) of patients as low risk with less than 3% distant recurrence rate for 0 to 5 years and 5 to 10 years. In the multi-institutional cohort, which had larger tumors, 55% of patients were classified as BCI low risk with less than 5% distant recurrence rate for 0 to 5 years and 5 to 10 years. For both cohorts, continuous BCI was the most significant prognostic factor beyond standard clinicopathologic factors for 0 to 5 years and more than five years. The authors concluded, the prognostic sustainability of BCI to assees early and late distant recurrence risk at diagnosis has clinical use for decisions of chemothrapy at diagnosis and for decisions for extended adjuvant endocrine therapy beyond five year.

 

Sestak et. al. (2018) see information above under EndoPredict. 

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because there are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

 

No decision impact studies were identified that report clinical outcomes such as survival or recurrence.

 

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. However, evidence for clinical validity has shown that BCI is able to identify women who can safely forgo adjuvant chemotherapy and thereby avoid negative effects of the therapy.

 

Summary

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 2 prospective-retrospective studies and a registry-based observational study. The findings from the 2 prospective-retrospective studies showed that a low-risk Breast Cancer Index score is associated with low 10-year distant recurrence rates (average risk at 10 years, 5%-7%; upper bound of the 95% CI, 8% to 10%). The findings from the registry-based observational study also showed low 10- 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)

Clinically Valid

A test must detect the presence of absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Bueno-de-Mesquita et. al. (2011), the 70 gene prognosis signature has strong prognostic value in node-negative breast cancer, independent of established prognostic factors, and is unclear whether all node-negative patients should receive a signature result. They evaluated its additional prognostic information to a combination of established prognostic guidelines. Seven hundred and one (701) patients were evaluated in whom signature results were available. Clinical risk was on the basis of Adjuvant! Online (AO), St Gallen guidelines (St G) and Nottingham Prognostic Index (NPI). Overall survival (OS) analyses were carried out in patients treated at the Netherlands Cancer Institute (Amsterdam) who did not receive adjuvant systemic treatment (AST). Only 6% (10 of 156) of estrogen receptor (ER)-negative tumors had a good prognosis signature. The signature was not useful for ER-positive tumors and concordant high AO, high St G and/or high NPI clinical risks (N = 139). The 10-year OS estimate for good signature tumors with these characteristics was <80% and AST would therefore be appropriate irrespective of the signature result. In contrast, for patients with a concordant low AO, low St G and/or low NPI risk and in discordant clinical risk patients, the signature identified low-risk patients in whom AST could be safely withheld (10-year OS > 90%).The authors concluded, the 70-gene prognosis signature provides additional prognostic information especially in ER-positive lymph node-negative breast cancer patients with a predominant low or discordant clinical risk on the basis of AO, St G and/or NPI. 

 

In 2017, van ‘t Veer et. al., their study analyses was conducted on the Stockholm tamoxifen (STO-3) trial which randomized postmenopausal node-negative patients to 2-year tamoxifen (followed by an optional randomization for an additional 3-year tamoxifen versus nil), versus no adjuvant treatment, provides a unique opportunity to evaluate long-term 20-year benefit of endocrine therapy within prognostic risk classes of the 70-gene prognosis signature that was developed on adjuvantly untreated patients. Assessed by Kaplan-Meier analysis 20-year breast cancer-specific survival (BCSS) and 10-year distant metastasis-free survival (DMFS) for 538 estrogen receptor (ER)-positive, STO-3 trial patients with retrospectively ascertained 70-gene prognosis classification. Multivariable analysis of long-term (20 years) BCSS by STO-3 trial arm in the 70-gene high-risk and low-risk subgroups was performed using Cox proportional hazard modeling adjusting for classical patient and tumor characteristics. Tamoxifen-treated, 70-gene low- and high-risk patients had 20-year BCSS of 90 and 83%, as compared to 80 and 65% for untreated patients, respectively (log-rank p < 0.0001). Notably, there is equivalent tamoxifen benefit in both high (HR 0.42 (0.21-0.86), p = 0.018) and low (HR 0.46 (0.25-0.85), p = 0.013) 70-gene risk categories even after adjusting for clinicopathological factors for BCSS. Limited tamoxifen exposure as given in the STO-3 trial provides persistent benefit for 10-15 years after diagnosis in a time-varying analysis. 10-year DMFS was 93 and 85% for low- and high-risk tamoxifen-treated, versus 83 and 70% for low- and high-risk untreated patients, respectively (log-rank p < 0.0001). The authors concluded, patients with ER-positive breast cancer, regardless of high or low 70-gene risk classification, receive significant survival benefit lasting over 10 years from adjuvant tamoxifen therapy, even when given for a relatively short duration.

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avid unnecessary therapy, or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because there are intervention studies, the preferred evidence would be from the randomized controlled trials (RCTs).

 

The MIDACT trail (Cardosa et. al. 2016) an international, prospective, randomized, phase 3 study sought to provide evidence on clinical utility of the addition of the 70-gene signature to standard clinical-pathologic criteria in selecting patients for adjuvant chemotherapy. They reported five year outcomes and the results of the treatment randomization for groups with discordance in risk. From 2007 and 2011 patients were enrolled at 112 institutions in nine European countries. Eligible patients were women between the ages of 18 and 70 years with histologically confirmed primary invasive breast cancer (stage T1 or T2 or operable T3). In the initial study design all patients had to have lymph-node negative disease as described in the protocol. In August 2009, the protocol was revised to allow the enrollment of women with up to three positive axillary nodes. The study design called for following all the patients according to local standards for at least 10 years; those receiving endocrine therapy will be followed for a minimum of 15 years. The study enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher. A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease. The authors concluded, in a large group of patients at high clinical risk for breast cancer recurrence, the addition of the 70-gene signature to the traditional clinical and pathological factors provided valuable information for considering which patients might benefit from adjuvant chemotherapy. Chemotherapy with its attendant toxic effects could be avoided in these patients at high clinical risk but low genomic risk at a cost of a risk of distant metastasis at 5 years that is 1.5 percentage points higher. Follow-up is ongoing to determine whether these conclusions remain valid for longer-term outcome.

 

Indirect evidence on clinical utility rests on clinical validity, if the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. However, evidence for clinical validity has shown that MammaPrint is able to identify women who can safely forgo adjunt chemotherapy and thereby avoid effects of the therapy.

 

Summary

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 10-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 10-year distant recurrence, the source is not considered high quality. The RCT (MINDACT) showed 5-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

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

In 2013, Dowsett et. al. compared PAM50 risk of recurrence score with Oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. mRNA from 1,017 patients with ER-positive primary breast cancer treated with anastrozole or tamoxifen in the ATAC trial was assessed for risk of recurrence (ROR) using the NanoString nCounter. Likelihood ratio (LR) tests and concordance indices (c indices) were used to assess the prognostic information provided beyond that of a clinical treatment score (CTS) by RS (recurrence score), ROR (risk of recurrence), or IHC4, an index of DR (distant recurrence) risk derived from immunohistochemical assessment of ER, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and Ki67. ROR added significant prognostic information beyond CTS in all patients (LR-χ(2) = 33.9; P < .001) and in all four subgroups: node negative, node positive, HER2 negative, and HER2 negative/node negative; more information was added by ROR than by RS. C indices in the HER2-negative/node-negative subgroup were 0.73, 0.76, and 0.78 for CTS, CTS plus RS, and CTS plus ROR, respectively. More patients were scored as high risk and fewer as intermediate risk by ROR than by RS. Relatively similar prognostic information was added by ROR and IHC4 in all patients but more by ROR in the HER2-negative/node-negative group. The authors concluded, ROR provides more prognostic information to endocrine treated patients with ER positive, node-negative disease than RS, with better differentiation of intermediate and higher risk groups.

 

Gnant et. al. (2014) reported on 1478 postmenopausal women with estrogen receptor (ER) positive early breast cancer (EBC) treated with tamoxifen or tamoxifen followed by anastrozole from the prospective randomized ABCSG-8 trial were entered into this study. Patients did not receive adjuvant chemotherapy. RNA was extracted from paraffin blocks and analyzed using the PAM50 test. Both intrinsic subtype (luminal A/B, HER2-enriched, basal-like) and risk of recurrence (ROR) score were calculated. The primary analysis was designed to test whether the continuous ROR score adds prognostic value in predicting distant recurrence (DR) over and above standard clinical variables. In all tested subgroups, ROR score significantly adds prognostic information to the clinical predictor (P<0.0001). PAM50 assigns an intrinsic subtype to all cases, and the luminal A cohort had a significantly lower ROR at 10 years compared with Luminal B (P<0.0001). Significant and clinically relevant discrimination between low- and high-risk groups occurred also within all tested subgroups. The authors concluded, the results of the primary analysis, in combination with recently published results from the ATAC trial, constitute Level 1 evidence for clinical validity of the PAM50 test for predicting the risk of DR in postmenopausal women with ER positive EBC. A 10-year metastasis risk of <3.5% in the ROR low category makes it unlikely that additional chemotherapy would improve this outcome-this finding could help to avoid unwarranted overtreatment.

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary treating.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

 

No decision impact studies were identified that report clinical outcomes such as survival or recurrence.

 

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. However, evidence for clinical validity has shown that assay is able to identify women who can safely forgo adjuvant chemotherapy and thereby avoid negative effects of therapy.

 

Summary

For individuals who have early-stage node-negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with Prosigna, the evidence includes 2 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 10 years, 3%-5%; upper bound 95% 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 Considering Adjuvant Chemotherapy

Oncotype DX Breast (21 Gene Assay)

Clinically valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Albain et. al. (2010 ) performed a retrospective analysis on the prognostic and predictive value of the 21 gene recurrence score assay in postmenopausal women with node-positive, estrogen-receptor positive breast cancer on chemotherapy. The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, estrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumor banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, they assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes. There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0.006; hazard ratio [HR] 2.64, 95% CI 1.33-5.27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; log-rank p=0.97; HR 1.02, 0.54-1.93), but an improvement in disease-free survival for those with a high recurrence score (score > or =31; log-rank p=0.033; HR 0.59, 0.35-1.01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival. The authors concluded, the recurrence score using the 21-gene recurrence score assay is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumors with a high recurrence score. A low recurrence identifies women who might not benefit from anthracyline-based chemotherapy, despite positive nodes.

 

Dowsett et. al. (2010) examined a sample of node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen to predict the risk of distant recurrence using the 21-gene recurrence score from the TransATAC study (tamoxifen alone or in combination).  RNA was extracted from 1,372 tumor blocks from postmenopausal patients with hormone receptor-positive primary breast cancer in the monotherapy arms of ATAC. Twenty-one genes were assessed by quantitative reverse transcriptase polymerase chain reaction, and the RS was calculated. Cox proportional hazards models assessed the value of adding RS (recurrence score) to a model with clinical variables (age, tumor size, grade, and treatment) in node-negative (N0) and node-positive (N+) women. Reportable scores were available from 1,231 evaluable patients (N0, n = 872; N+, n = 306; and node status unknown, n = 53); 72, 74, and six DRs (distant recurrence) occurred in N0, N+, and node status unknown patients, respectively. For both N0 and N+ patients, RS was significantly associated with time to DR in multivariate analyses (P < .001 for N0 and P = .002 for N+). RS also showed significant prognostic value beyond that provided by Adjuvant! Online (P < .001). Nine-year DR rates in low (RS < 18), intermediate (RS = 18 to 30), and high RS (RS > or = 31) groups were 4%, 12%, and 25%, respectively, in N0 patients and 17%, 28%, and 49%, respectively, in N+ patients. The prognostic value of RS was similar in anastrozole- and tamoxifen-treated patients. The authors concluded, this study confirmed the performance of RS (recurrence score) in postmenopausal HR positive patients treated with tamoxifen in a large contemporary population and demonstrated that RS is an independent predictor of DRA in No and N + (positive) hormone receptor positive patients treated with anastrozole, adding value to estimates with standard clinicopathologic features.

 

In 2017, Nitz et. al. a prospective randomized phase 3 PlanB trial used the Oncotype DX Recurrence Score (RS) to define a genomically low-risk subset of clinically high-risk pN0-1 early breast cancer (EBC) patients for treatment with adjuvant endocrine therapy (ET) alone.  They reported on five-year data evaluating the prognostic value of RS, Ki-67, and other traditional clinicopathological parameters. A central tumor bank was prospectively established within PlanB. Following an early amendment, hormone receptor (HR)+ , pN0-1 RS ≤ 11 patients were recommended to omit chemotherapy. Patients with RS ≥ 12, pN2-3, or HR-negative/HER2-negative disease were randomized to anthracycline-containing or anthracycline-free chemotherapy. Primary endpoint: disease-free survival (DFS). From 2009 to 2011, PlanB enrolled 3198 patients (central tumor bank, n = 3073) with the median age of 56 years, 41.1% pN+, and 32.5% grade 3 EBC. Chemotherapy was omitted in 348/404 (86.1%) eligible RS ≤ 11 patients. After 55 months of median follow-up, five-year DFS in ET-treated RS ≤ 11 patients was 94% (in both pN0 and pN1) versus 94% (RS 12-25) and 84% (RS > 25) in chemotherapy-treated patients (p < 0.001); five-year overall survival (OS) was 99 versus 97% and 93%, respectively (p < 0.001). Nodal status, central/local grade, tumor size, continuous Ki-67, progesterone receptor (PR), IHC4, and RS were univariate prognostic factors for DFS. In a multivariate analysis including all univariate prognostic markers, only pN2-3, central and local grade 3, tumor size >2 cm, and RS, but not IHC4 or Ki-67 were independent adverse factors. If RS was excluded, IHC4 or both Ki-67 and PR entered the model. The impact of RS was particularly pronounced in patients with intermediate Ki-67 (>10%, <40%) tumors. The authors concluded, the excellent five-year outcomes in clinically high-risk, genomically low-risk (RS ≤ 11) pN0-1 patients without adjuvant chemotherapy support using RS with standardized pathology for treatment decisions in HR-positive HER2-negative EBC. Ki-67 has the potential to support patient selection for genomic testing

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

 

No decision impact studies were identified that report clinical outcomes such as survival and recurrence. The ongoing RxPonder trial is randomizing patients with early stage estrogen receptor-positive, HER2-negative breast cancer and 1 to 3 positive nodes, stratified by RS (recurrence score) (0 to 13, 14 to 25) to adjuvant chemotherapy or no adjuvant chemotherapy. Results of the trial will most likely define utility of the RS in node-positive patients.

 

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. However, evidence for clinical validity has shown that assay is able to identify women who can safely forgo adjuvant chemotherapy and thereby avoid negative effects of therapy in node positive (1 to 3) patients.

 

Summary

Results from prospective and retrospective studies have suggested using Oncotype DX recurrence risk score for treatment decisions in early stage node positive breast cancer may identify those women who can safely forgo adjuvant chemotherapy and thereby avoid negative effects of therapy. NCCN 2018 (version 3.2018) Breast Cancer guideline for invasive breast cancer states for axillary node positive tumors, states the following: Patients with lymph node-positive disease are most often candidates for chemotherapy and, if the tumor is hormone receptor-positive, for the addition of endocrine therapy (category 1). When HER2 is amplified or over-expressed, HER2 targeted therapy should be incorporated into the adjuvant chemotherapy. The NCCN panel noted in a foot note that the 21- gene recurrence score can be considered in select patient with 1 to 3 involved ipsilateral axillary lymph nodes (ALNs) to guide the addition of combination chemotherapy to standard hormone therapy based on the restrospective study by Albain et. al (2010, see above). The ongoing RxPonder trial is randomizing patients with early stage estrogen receptor-positive, HER2-negative breast cancer and 1 to 3 positive nodes, stratified by RS (recurrence score) (0 to 13, 14 to 25) to adjuvant chemotherapy or no adjuvant chemotherapy. Results of the trial will most likely define utility of the RS in node-positive patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

 

EndoPredict

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

In 2011, Filipits et. al. evaluated the potential prognostic value of EndoPredict EP and EPclin risk scores among node-positive patients in a combined analysis of ABCSG-6 and ABCSG-8 trial samples. Of the 537 node-positive patients, 85% had a single positive node, 240 were classified as EP low risk and 297 were classified as EP high risk. The 10 year absence of distant recurrence for node-positive patients was shown in a Kaplan-Meier curve. The 10 year absence of distant recurrence estimate for node-positive patients appears to be about 85% in EP low risk and 73% in high risk patients. CIs were not provided. The 10 year absence of distance recurrence estimates for the EPclin low risk group and EPclin high risk group were 94.9% (95% CI, 90.8% to 99.0%) and 72.2% (95% CI, 65.6% and 78.8%), respectively.

 

Buus et. al. (2016) reported on the prognostic value of EndoPredict among node-positive patietns from ATAC trial. Of the 248 node-positive patients, 80% had a single positive node, 94 were classified as EP low risk, and 154 were classified as EP high risk; 47 were classified as EPclin low risk and 201 were classified as EPclin high risk. The 10 year distant recurrence-free survival for EP low and high risk were 21.3% (95% CI, 13.9% to 31.9%) and 36.4% (95% CI, 28.9% to 45.2%), respectively. The 10 year distant recurrence-free rate for EPclin low and high risk were 5.0% (95% CI, 1.2% to 18.9%) and 36.9% (95% CI, 30.2% to 44.5%), respectively.

 

Clinically Useful

A test is clinically useful if the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

 

No decision impact studies were identified that report clinical outcomes such as survival or recurrence.

 

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. One of the two studies provided evidence for clinical validity, which would allow for the identification of women who can safely forgo adjuvant chemotherapy. The second study also reported low point estimate,  however, the wide CIs exceeded 10%. 

 

Summary

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 2 prospective-retrospective analyses. In 1 study, the 10-year distant recurrence rate in low-risk EPclin score patients was estimated to be 5% (95% CI, 1% to 9%). In the other study, 10-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.

 

Breast Cancer Index (BCI)

No studies were identified that met inclusion criteria in node-positive study populations for the Breast Cancer Index (BCI) test. The evidence is insufficient to determine the effects of the technology on health outcomes

 

MammaPrint (70 Gene Signature)

The previously described MINDACT study (Cardosa et. al. 2016) initially enrolled only patients with node-negative disease but began including women with 1 to 3 positive nodes in 2009. Subgroup results were reported from the randomized MINDACT comparison of adjuvant chemotherapy with no chemotherapy in node-positive patients who are classified as high risk based on clinical criteria and low risk based on genetic risk with MammaPrint. Overall, the study included 1404 node-positive patients; 296 (16%) with 1 positive node; 114 (6%) with 2 positive nodes; 65 (4%) with 3 positive nodes, and 2 (0.1%) with 4 or more positive nodes. In the high clinical risk and low genetic risk group, 353 node positive patients were randomized to chemotherapy, and 356 node positive patients were randomized to no chemotherapy. The 5 year distant recurrence was 3.7 (95% CI, 1.9% to 6.9%) in the chemotherapy group and 4.4% (95% CI, 2.6% to 7.3%) in the no chemotherapy group (HR=0.88; 95% CI, 0.42 to 1.82; p=0.72).

 

Summary

Based on the MINDACT study 5 year distant recurrence rates for treated and untreated women are similar, which would indicate that the low risk patients can safely forgo adjuvant chemotherapy. Based on American Society of Clinical Oncology (ASCO) focused update on the use of biomarkers to guide decisions on adjuvant systemic therapy for women with early stage invasive breast cancer in 2017 MammaPrint recommendations were updated to the following regarding node positive breast cancer:

  • If a patient has ER/PgR–positive, HER2-negative, node positive, breast cancer, the MammaPrint assay may be used in patients with one to three positive nodes and at high clinical risk per MINDACT categorization to inform decisions on withholding adjuvant systemic chemotherapy due to its ability to identify a good prognosis population with potentially limited chemotherapy benefit. However, such patients should be informed that a benefit of chemotherapy cannot be excluded, particularly in patients with greater than one involved lymph node (Type: evidence based; Evidence quality: high; Strength of recommendation: moderate).
  • If a patient has ER/PgR–positive, HER2-negative, node positive, breast cancer, the MammaPrint assay should not be used in patients with one to three positive nodes and at low clinical risk per MINDACT categorization to inform decisions on withholding adjuvant systemic chemotherapy. There are insufficient data on the clinical utility of MammaPrint in this specific patient population (Type: informal consensus; Evidence quality: low; Strength of recommendation: moderate).

 

MINDACT categorization: is based on age, tumor size, tumor grade, lymph node status, hormone receptor status, HER2 status and clinical pathologic subtype. 

 

NCCN Guideline for Breast Cancer (Version 3.2018) multigene assays for consideration of addition of adjuvant systemic chemotherapy to adjuvant endocrine therapy, has the following recommendation regarding MammaPrint (70 gene signature) for node negative and 1-3 positive nodes:

  • Prognostic; NCCN Category of Evidence and Consensus 1 (based upon high level evidence, there is uniform NCCN consensus that the intervention is appropriate):
    • With a median follow-up of 5 years, among patients at high clinical risk and low genomic risk, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5% to 96.2%) among those who did not receive adjuvant chemotherapy. Among patients with 1-3 positive nodes, the rates of survival without distant metastases were 96.3% (95% CI, 93.1 to 98.1) in those who received adjuvant chemotherapy versus 95.6 (95% CI, 92.7 to 97.4) in those who did not receive adjuvant chemotherapy. Therefore, the additional benefit of adjuvant chemotherapy may be small in this group.   

 

The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

 

Prosigna

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

Grant et. al. (2015) examined the potential prognostic value of the PAM50 ROR (risk of recurrence) score, including clinical predictors, among node-positive patients in a combined analysis of the ABCSG-8 and ATAC trial samples. Samples from 543 patients treated with endocrine therapy alone were included, and 10 year distant recurrence (the primary end point) analyzed. Among patients with a single positive node and a low risk score, a 10 year distant recurrence occurred in 6.6% (95% CI, 3.3% to 12.8%). In all other risk categories or with 2 or 3 positive nodes, distant recurrence rates were considerably higher with upper bounds for the 95% CIs of 25% or more. Overall survival (OS) was not included in the report.

 

Clinically Useful

A test is clinically useful if the use of the result informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy or avoid unnecessary therapy, or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferered evidence would be from randomized controlled trials.

 

No decision impact studies were identified that provide clinical outcomes such as survival and recurrence.

 

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility. One study provided evidence for clinical validity. The point estimate for the 10 year distant recurrence rate was 7%, however, the CI as large and did not meet the threshold benefit of less than 10%.

 

Summary

For individuals who have early-stage node-positive invasive breast cancer who are considering adjuvant chemotherapy who receive gene expression profiling with the Prosigna risk of recurrence (ROR) score, the evidence includes a single prospective-retrospective study. The 10-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 10-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.

 

Additional Gene Expression Assays in Breast Cancer

BluePrint and TargetPrint

Gene expression patterns have led to the identification of molecular subtypes of breast cancer, which have different prognoses and responses to treatment regimens. These molecular subtypes are largely distinguished by differential expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) in the tumor, and are classified as luminal basal, or HER2 type. Luminal type breast cancers are ER-positive; basal type breast cancers correlate best with ER-, PR- and HER2- negative (triple negative) tumors, and HER2 type, with high expression of HER2.

 

At present, methodology for molecular subtyping is not standardized, and breast cancer subtyping is routinely assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).

 

BluePrint is an 80 gene expression assay that classifies breast cancer into basal type, luminal type, or HER2 type. The test is marketed as an additional stratifier into a molecular subtype after risk assessment with MammaPrint. This assists the physician in determining a patient’s individual risk for metastasis and/or recurrence and which patients can safely forego chemotherapy.

 

TargetPrint is a microarray based gene expression test that offers a quantitative assessment of ER, PR and HER2 overexpression in breast cancer. The test is marketed to be used in conjunction with MammaPrint and BluePrint. This assists the physician in determining a patient’s individual risk for metastasis and/or recurrence and which patients can safely forego chemotherapy. 

 

Summary

The 80-gene expression assay BluePrint discriminates among three breast cancer molecular subtypes, and TargetPrint is a method to measure ER, PR, and HER2 as an alternative to immunohistochemistry and FISH. Clinical utility of BluePrint is unknown, as it is unclear how this test will add to treatment decision making using currently available, accepted methods (e.g. clinical and pathologic parameters). The incremental benefit of using TargetPrint as an alternative to current standard methods of measuring ER, PR and HER2 has not been demonstrated, nor is it included in recommendations for testing issued by the American Society of Clinical Oncology (ASCO). The evidence is insufficient to determine the effects of this testing on net health outcomes.

 

Mammostrat

Patients with early stage breast cancer, treated with endocrine therapy, have approximately 90% 5 year disease free survival. However, some postmenopausal patients with hormone sensitive early breast cancer remain at high risk of relapse despite endocrine therapy and, in addition, might benefit from adjuvant chemotherapy. The challenge is to prospectively identify such patients. The Mammostrat test uses five immunohistochemical markers (SLC7A5, HTF9C, P53, NDRG1 and CEACAM5) to stratify patients regarding recurrence risk and may inform treatment decisions. The Mammostrat test measures the levels of the five immunohistochemical markers into a risk index score and the individual is assigned to a risk category high, moderate or low.

 

Summary

The existing studies include a single validation study and randomized clinical trials. In 2012, Bartlett and others published the results of a study evaluating the efficacy of Mammostrat in a multinational randomized open label phase III trial (TEAM trial) in postmenopausal women with hormone receptor positive early breast cancer testing the efficacy of 5 years of exemestane (25 mg once per day) versus tamoxifen (20 mg once per day for 2.5 to 3 years) followed by exemestane (for another 2.5 to 2 years). The authors tested 4598 pathology blocks from TEAM participants, who were node positive in 47% of subjects and in whom 36% were treated with adjuvant chemotherapy, and reported on 3837 that were successfully scored.  In the 1226 (31.9%) subjects that were both node negative and did not receive chemotherapy, the Mammostrat test was a significant prognostic factor for distant relapse-free survival (p=0.004).  Subjects with moderate or high scores were reported to be 58% and 159% more likely to experience distant relapse that those with low Mammostrat scores.  Similarly, Mammostrat results were an independent factor in multivariate analysis for disease-free survival in these populations (p=0.038).  In the sample of subjects treated without chemotherapy (n=2559), multivariate analysis found that Mammostrat score remained an independent predictor of distant relapse-free survival risk (p<0.001), with a 45% and 75% increase in recurrence risk for medium and high-risk scores, respectively, compared with subjects with low-risk scores.  However, for disease-free survival, no significant benefit from Mammostrat was seen (p=0.085).  When a multivariate analysis was conducted in the total study population, analyses adjusted for conventional prognostic factors (i.e., nodal status, grade, size, age, treatment, HER2, and quantitative PR and ER), the Mammostrat score remained an independent predictor of distant relapse-free survival risk (P for trend <0.001) with a 50% and 91% increase in risk of recurrence for medium and high-risk scores, respectively compared with subjects with low-risk scores.  In a similar analysis for disease-free survival, significant additional prognostic value of the Mammostrat score alongside conventional markers was found (P for trend <0.001).  The results from this trial are promising, but this is only an initial report of the use of the Mammostrat test.  Further studies seeking evidence addressing the clinical utility of this test are warranted. Additionally, per the American Society of Clinical Oncology guidelines (see below) Mammostrat is not recommended to guide decisions in adjuvant systemic chemotherapy in patients with breast cancer. The evidence is insufficient to determine the effects of this testing on net health outcomes.

 

Ductal Carcinoma In Situ (DCIS) Considering Radiation Therapy (RT)

DCIS is breast cancer located in the lining of the mammary ducts that has not yet invaded nearby tissues. It may progress to invasive cancer if untreated. The incidence of DCIS diagnosis in the United States has increased in tandem with the widespread use of screening mammography, account for about 20% of all newly diagnosed invasive plus noninvasive breast tumors. Recommended treatment is lumpectomy or mastectomy with or without radiation treatment; postsurgical tamoxifen treatment is recommended for estrogen receptor (ER)-positive DCIS, especially if excision alone is used. Because the overall rate of ipsilateral tumor recurrence (DCIS or invasive carcinoma) is approximately 25% at 10 years, it is believed many genotypical women are over-treated with radiotherapy. Thus, accurate prediction of recurrence risk may identify those women who may safely avoid radiation.

 

The Oncotype DX DCIS test uses information from 12 (7 cancer related and 5 reference genes) of the 21 genes assayed in the standard Oncotype DX breast test (21-gene expression profile) for early breast cancer to predict 10 year risk of local recurrence (DCIS or invasive carcinoma). The stated purpose is help guide treatment-decision making in  women with DCIS treated by local excision, with or without adjuvant tamoxifen therapy.

 

The DCIS Score is obtained by performing the Oncotype DX breast cancer assay, using a distinct DCIS algorithm and coefficients that was pre-specified because of its ability to predict recurrence in patients with DCIS regardless of whether adjuvant tamoxifen therapy was given. The development of the DCIS Score algorithm was based on published results for the Oncotype DX Breast Cancer Assay showing similarity in the expression profiles of the Recurrence Score genes between DCIS and invasive breast cancer (IBC) when both are present within the same patient tumor. The DCIS Score algorithm was developed based on published data obtained from Kaiser Permanente and NSABP B-14 studies in which the proliferation gene group, PR and GSTM1 were found to predict distant recurrence regardless of whether adjuvant tamoxifen therapy was given. This DCIS score was subsequently validated as a predictor of local recurrent in patients from ECOG E5194 study.

 

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

 

In 2013, Solin et. al. in a retrospective analysis of data and samples from patients in the prospective Eastern Cooperative Oncology Group E5194 study, they compared the Oncotype DX Breast DCIS Score with 10 year local recurrence risk in a subset of DCIS patients (N=327) treated only with surgery or with tamoxifen. The continuous Oncotype DX Breast DCIS Score was significantly associated with developing either a local recurrence or invasive carcinoma (HR=2.31; 95% CI, 1.15 to 4.49; p=0.02) whether or not patients were treated with tamoxifen. However, whether women are better categorized as to their local recurrence risk by Oncotype DX Breast DCIS Score compared with standard clinical indicators of risk was not addressed.

 

In 2015, Rakovitch et. al. in a retrospective analysis evaluated 571 tumor specimens with negative margins from a convenience cohort of patients with DCIS treated by breast-conserving surgery (lumpectomy) alone. Patients were drawn from a registry of 5752 women in Ontario Canada, who were diagnosed with DCIS between 1994 and 2003 with validation of treatment and outcomes. Central pathology assessment excluded cases with invasive cancer, DCIS < 2 mm or positive margins. Cox model was used to determine the relationship between independent covariates, the DS (DCIS Score) (hazard ratio (HR)/50 Cp units (U)) and LR (local recurrence). Tumor blocks were collected for 828 patients. Final evaluable population includes 718 cases, of whom 571 had negative margins. Median follow-up was 9.6 years. 100 cases developed LR following BCS (breast conserving surgery) alone (DCIS, N = 44; invasive, N = 57). In the primary pre-specified analysis, the DS was associated with any LR (DCIS or invasive) in ER postive patients (HR 2.26; P < 0.001) and in all patients regardless of ER status (HR 2.15; P < 0.001). DCIS Score provided independent information on LR risk beyond clinical and pathologic variables including size, age, grade, necrosis, multifocality, and subtype (adjusted HR 1.68; P = 0.02). DCIS was associated with invasive LR (HR 1.78; P = 0.04) and DCIS LR (HR 2.43; P = 0.005). This study had several limitations: patients were not randomized and were selected for treatment by BCS alone based on clinic-pathologic features and patient preference; during the time interval of this study many pathology reports lacked tumor size and resection margin width information, therefore, margin width and tumor size data were incomplete; in addition data on clinical presentation or family history of breast cancer which may predict LR were not available; tamoxifen utilization during the time period of this study was limited and 95% of cases treated with BCS alone had ER-positive DCIS and therefore slightly lower event rates might be expected with tamoxifen administration.

    

Rakovitch et. al. (2018) combined the population from the 2 studies described above in Solin (2013) and Rakovitch (2015) and calculated 10-year local recurrence (LR) rates by DCIS category (low, intermediate and high), age, tumor size, and year of diagnosis. The combined cohort included 773 patients. The DS and age at diagnosis, tumor size and year of diagnosis provided independent prognostic information on the 10-year LR risk (p ≤ 0.009). Hazard ratios from E5194 and ODC cohorts were similar for the DS (2.48, 1.95 per 50 units), tumor size ≤ 1 versus  > 1-2.5 cm (1.45, 1.47), age ≥ 50 versus < 50 year (0.61, 0.84) and year ≥ 2000 (0.67, 0.49). Utilization of DS combined with tumor size and age at diagnosis predicted more women with very low (≤ 8%) or higher (> 15%) 10-year LR risk after BCS alone compared to utilization of DS alone or clinicopathological factors alone. This analysis has several limitations: the study population includes few women (N=37) with tumors > 2.5 cm treated by breast conserving surgery (BCS) alone (6% of Ontario cohort); therefore risk estimates in women with DCIS lesions > 2.5 cm should be interpreted with caution; and the analysis does not account for the impact of tamoxifen. Approximately one-third of the E5194 and 17% of those > 65 years in Ontario cohort received tamoxifen. Tamoxifen was used more frequency by patients diagnosed in 2000 or later (48.9%) than patients diagnosed before 2000 (15.0%). A sensitivity analysis E5194 data was conducted to assess the effect of tamoxifen regression parameter estimates. The values of the HRs (hazard rations) are similar to those in the main analysis, indicating that tamoxifen use did not greatly influence the estimates in this study.

 

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy or avoid unnecessary testing.

 

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

 

No direct impact studies were identified that provide clinical outcomes such as survival or recurrence.

 

Summary

Based on review of the available evidence for Oncotype DX Breast DCIS Score of low risk of recurrence, it is unclear whether estimated recurrence risks for this group are low enough or estimated with sufficient precision (most of the post estimates and CIs included the threshold of 10%), except for estimates for 2 subgroups:

  1. patients aged ≥ 50 with tumors ≤ 1 cm and
  2. patients with tumors ≤ 2.5 cm. Conclusions are limited because there are no comparison recurrence rate estimates for women based on standard of care (risk predictions based on clinical algorithms)

 

No studies were identified evaluating the EndoPredict, Breast Cancer Index, MammaPrint or Prosigna for patients with DCIS.

 

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 Adjuvant Endocrine Therapy Beyond Five Years

In the absence of direct evidence that gene expression profiling tests improve outcomes in women considering extended endocrine therapy, the following need to be considered:

  • the expected absolute benefit and certainty of benefit from extended endocrine therapy;
  • whether a test accurately discriminates good from poor outcomes (i.e. prognostic value for recurrences) at those thresholds; and
  • whether the test provides incremental improvement over clinical risk prediction algorithms or tools.

 

Multiple randomized controlled trials have demonstrated improvements in overall and breast cancer specific survival (BCSS) outcomes with 5 to 10 years of tamoxifen for estrogen receptor-positive tumors. Results from trials using aromatase inhibitors following 5 years of endocrine therapy have reported inconsistent benefits in BCSS and duration of aromatase inhibitor use is uncertain. In addition, extended adjuvant endocrine therapy may be associated with serious adverse events, including pulmonary embolism, endometrial cancer, osteoporosis, and fractures. Common side effects such as hot flashes, sexual dysfunction, and musculoskeletal symptoms often lead to poor compliance with as many as 40% of patients discontinuing treatment after 3 years. Accurately identifying low-risk patients who might obtain little benefit from extended endocrine therapy could allow patients to make treatment decisions consistent with how they value the potential benefits and harms.

 

Currently physicians and patients use clinicopathologic parameters such as tumor size and nodal status to estimate risk of breast cancer while deciding on extended endocrine therapy. A clinical tool has been developed and validated in 2018 (Clinical Treatment Score post-5 years [CTS5]). While this tool did not exist when the studies providing evidence for extended therapy had been conducted, the tool is simple, and utilizes clinical parameters (tumor size, tumor grade, age, and number of nodes) that physicians and patients currently use when considering extended endocrine therapy. CTS5 identified 42% of women with < 1% risk of distant recurrence, who may be advised of the limited potential value of extended endocrine therapy (Dowsett et. al. 2018).

 

Summary

At least 3 randomized controlled trials (RCTs) have demonstrated survival improvements with extended tamoxifen. Results from trials using aromatase inhibitors following 5 years of endocrine therapy have reported inconsistent benefits in breast cancer specific survival (BCSS) and duration of aromatase inhibitor use is uncertain. Recent trials comparing the use of aromatase inhibitors for different durations (2.5 years compared with 5 years and 3 years compared with 6 years) found that were not significant improvements in breast cancer specific mortality or overall mortality among the different duration groups. American Society of Clinical Oncology (ASCO) 2017 focused update on use of biomarkers to guide decisions on adjuvant systemic therapy for women with early stage invasive breast cancer includes the following recommendation regarding extended endocrine therapy: If a patient has ER/PgR positive, HER2-negative (node negative) breast cancer and has had 5 years of endocrine therapy without evidence of recurrence, the clinician should not use multi-parameter gene expression or protein assays (Oncotype DX, EndoPredict, PAM50 (Prosigna  Breast Cancer Prognostic Gene Signature Assay), Breast Cancer Index, or IHC4) to guide decisions on extended endocrine therapy. (Type: evidence based; Evidence quality: intermediate; Strength of recommendation: moderate).

 

In the absence of direct evidence demonstrating clinical utility, the following need to be considered:

  • Expected absolute benefit and certainty of benefit from extended endocrine therapy: Extended tamoxifen therapy provides an absolute reduction in breast cancer mortality of 2.8% between years 5 and 14, with no difference in overall mortality. Despite credible studies, there are conflicting reports and uncertainty around aromatase inhibitors (AI). Additional sources of uncertainty for extended endocrine therapy are optimal combinations of tamoxifen and AIs, the optimal duration of extended therapy (Davies et. al. 2013).
  •  

    Adverse events are significant. The ATLAS trial reports a cumulative risk of endometrial cancer of 3.1% in years 5 to 14 with tamoxifen treatment. Relative risk for pulmonary embolus was 1.9 (CI 1.1 to 3.1) in the same follow-up period. AIs have increased cardiovascular and musculoskeletal adverse effects compared to tamoxifen.

     

    In addition, rates of noncompliance in women taking endocrine therapy are as high as 30% (Burstein et. al. 2010).

     

  • Prognostic value of the test: All molecular tests (Oncotype DX, EndoPredict, Breast Cancer Index, MammaPrint and Prosigna) have conducted nonconcurrent prospective studies and reported low distant recurrence rates (ranging from 1.4 to 4.8) and confidence intervals (ranging from 0 to 7.9).
  •  

  • Incremental improvement of the test over clinical risk prediction algorithms: Currently, physicians and patients use clincopathologic parameters such as tumor size and nodal status to estimate risk of breast cancer recurrence while deciding on extended endocrine therapy. A clinical tool has been developed and validated in 2018 (Clinical Treatment Score post 5 years [CTS5]). CTS5 is simple, and utilizes clinical parameters (tumor size, tumor grade, age, and number of nodes) that physicians and patients currently use when considering extended endocrine therapy. CTS5 identified 42% of women with < 1% risk of distant recurrence, who may be advised to safely forgo extended endocrine therapy.
  •  

    Guidelines recommend that women and their physicians consider extended endocrine therapy, but do not categorically recommend extended endocrine therapy. Individual risk of adverse events will weigh heavily in women’s decisions. Considerations are the magnitude of benefit expected from extended endocrine therapy, the assessment of individual risk of adverse events, tolerability of therapy and the prognostic information available from existing clinical risk assessment tools. Thus it is unclear whether gene expression classification of risk, especially for low risk categories, adds sufficient incremental information to alter the calculation of risk and benefits of extended endocrine therapy.

     

    The ability of the test to reclassify patients assessed with a clinical prediction tool was not reported. Reclassification of patients initially considered high risk by clinical criteria to a lower risk would allow avoidance of overtreatment of patients with significant side effects. However, it is unclear whether there is consistent improved reclassification of patients to lower risk categories. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Test Comparison Studies

Hornberger et. al. (2012) conducted a systematic review on the clinical validity, clinical utility, change in clinical practice, and economic implications of early stage breast cancer stratifiers. Fifty-six articles published original evidence addressing the Oncotype DX RS (recurrence score) (n=31), MammsPrint (n=14), Adjuvant! Online (n=12), 5-antibody immunohistochemical (IHC) panel (Mammostart n=3), and a 14 gene signature (BreastOncPx n=1). Oncotype DX RS satisfied level 1 evidence for estimating distant recurrence risk, OS (overall survival) and response to adjuvant chemotherapy, and level 2 evidence for estimating local recurrence risk. Mammostrat and MammaPrint satisfied level 2 evidence for estimating distant recurrence risk and OS. Adjuvant! Online satisfied level 2 evidence for estimating distant recurrence risk, OS and chemotherapy response. BreastOncPx satisfied level 3 evidence for predicting distant recurrence risk and OS. Ten studies reported changes in clinical practice patterns using Oncotype DX overall, Oncotype DX was associated with change in treatment recommendations and/or decisions in 21% to 74% of cases.

 

Sgroi et. al. (2013) compared with Breast Cancer Index (BCI) with Oncotype DX Breast in 665 lymph node-negative women receiving endocrine therapy but not chemotherapy in the ATAC trial. The distribution of patients across risk groups was similar. For patients receiving tamoxifen alone or in combination with anastrozole, 10 year distant recurrence risk estimates for the 2 tests were similar within risk groups. In the anastrozole group, the BCI was a better predictor of risk: 5% of the BCI low risk patients had distant recurrence compared with 9% of Oncotype DX Breast low risk patients, and 22% of the BCI high risk patients had distant recurrence compared with 13% of Oncotype DX Breast high risk patients. These values were reported without 95% CIs; it is therefore not possible to assess the degree of overlap between risk groups.

 

Dowsett et. al. (2013) compared the PAM50 ROR (risk of recurrence) score with the Oncotype DX 21 Gene RS (recurrence score) and IHC4 breast cancer algorithm. Patients had estrogen receptor-positive, primary breast disease treated with anastrozole or tamoxifen in the ATAC trial (a double-blinded, phase 3 clinical trial designed to compare the ability of anastrozole, tramoxfen, and the 2 drugs in combination to prevent breast cancer recurrence in postmenopausal women with hormone-receptor positive tumors). Lymph node-negative and positive patients were included. Messenger RNA from 1017 patients was assessed for ROR, and likelihood ratio tests and concordance indices were used to assess the prognostic information provided beyond that of CTS (clinical treatment score). Statistical testing of these parameters was significant and favored the ROR score over the RS. More patients were classified as high risk and fewer as intermediate risk by the ROR than by RS. Prognostic information provided by the ROR score and IHC4 was similar.

 

Sestak et.al. (2016) examined cross stratification between the Breast Cancer Index (BCI) and Oncotype DX RS (recurrence score)l using the same data as Sgroi et. a. (2013). Patients from the ATAC trial (N=665) who are postmenopausal, hormone receptor-positive, and node-negative were included. Medial follow-up was 10 years. Gene expression analyses for both scores were conducted, and risk categories were determined based on prespecified cutoff points (RS: < 18=low risk, 18-31=intermediate risk, > 31=high risk; BCI: <5.0825=low risk, 5.0825-6.5025=intermediate risk, >6.5025=high risk). Each gene expression score was combined with the CTS (clinical treatment score) an algorithm of nodal status, tumor size, grade, age, and treatment. In a multivariate analysis, when the BCI was added to RS plus CTS, there was a significant effect on prognostic information. When RS was added to the BCI plus CTS, no additional prognostic information was added.

 

Bosl et. al. (2017) compared MammaPrint with EndoPredict (EP) in 48 tumor samples, 29 were node- negative, and 19 were node-positive. For the MammaPrint test, RNA quality was low for 3 samples. Of the 45 tested by MammaPrint, 17 (38%) were classified as low risk, and 28 (62%) were classified as high risk for recurrence. Four samples were excluded from the EndoPredict analysis because the tumors were estrogen-receptor positive or HER2-positive, which are not part of the inclusion criteria for the test. Based on EP molecular score, 8 (18%) samples were classified as low risk, and 36 (82%) samples were classified as high risk. Based on the EPclin score, 17 (39%) samples were considered low risk, and 27 (61%) samples were considered high risk. There was no statistically significant agreement between MammaPrint and molecular EP (overall concordance 63%) or between MammaPrint and EPclin (overall concordance 66%).

 

In 2018, Sestak et. al. compared Breast Cancer Index (BCI), Oncotype DX, Prosigna, and EPclin using samples from the TransATAC RCT. Distance recurrence rates for each of these tests appear above in the respective categories for node-negative adjuvant chemotherapy, node-positive chemotherapy, and extended endocrine therapy, in which the low risk categories of all 4 tests exhibited both low overall 10 year distant recurrence rates and low 5 to 10 distant recurrence rates (within the threshold of < 10%). Comparatively, among those who are considering adjuvant chemotherapy (N-591), EPclin classified the most women as low risk (N=429) compared with the other 3 tests which classified 318 to 365 women as low risk. Among those who are considering extended endocrine therapy (n=535), EPclin classified the most women as low risk (N=393) compared with the other 3 tests which classified 292 to 351 women as low risk.

 

Additional Applications

Based on study published in May 2008 (Badve et. al.) that compared Oncotype DX estrogen (ER) and progesterone (PR) receptor results with traditional IHC (immunohistochemistry) results. Genomic Health includes quantitative estrogen (ER) and progesterone (PR) component results in Oncotype DX 21-gene profile reports. The study reported 90% or better concordance between the 2 assays, but quantitative estrogen (ER) receptor by Oncotype Dx was more strongly associated with disease recurrence than IHC results. However, estrogen (ER) and progestrone (PR) receptor analysis is traditionally conducted during pathology examination of all breast cancer biopsies, whereas Oncotype DX Breast is indicated only for known estrogen receptor-positive tumors, after the pathology examination is complete, the patient meets specific criteria, and patient and physician are considering preferences for risk and chemotherapy. Thus, Oncotype DX Breast should not be ordered as a substitute for estrogen (ER) and progesterone (PR) receptor IHC. Additionally, accepted guidelines for estrogen (ER) and progesterone (PR) receptor testing outline standards for high-quality IHC testing and do not recommend confirmatory testing; thus the 21-gene RS (recurrence score [Oncotype DX Breast]) should not be ordered to confirm estrogen (ER) and progesterone (PR) IHC results. A subsequent study by Khoury et. al. (2015) reported better correlation (for overall data) between the IHC and Oncotype DX for progesterone receptor status (Spearman p=0.91) than for estrogen receptor status (Spearman p=0.65), but worse concordance (at various cut points) for progesterone receptor status (99%) than for estrogen receptor status (88%).

 

Practice Guidelines and Position Statements

American Society of Clinical Oncology (ASCO)

In 2017, the American Society of Clinical Oncology (ASCO) issued an update on the use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer which included the following recommendation:

 

Oncotype DX
  • If a patient has ER/PgR positive, HER2 negative (node-negative) breast cancer, the clinician may use the 21-gene recurrence score (RS; Oncotype DX; Genomic Health) to guide decisions on adjuvant systemic chemotherapy.
    • Type: evidence based
    • Evidence quality: high
    • Strength of recommendation: strong
  • If a patient has ER/PgR positive, HER2 negative (node-positive) breast cancer, the clinician should not use the 21 gene RS (Oncotype DX; Genomic Health) to guide decisions on adjuvant systemic chemotherapy.
    • Type: evidence based
    • Evidence quality: intermediate
    • Strength of recommendation: moderate
  • If a patient has HER2-positive breast cancer or triple negative (TN) breast cancer, the clinician should not use the 21-gene RS (Oncotype DX; Genomic Health) to guide decisions on adjuvant systemic therapy.
    • Type: informal consensus
    • Evidence quality: insufficient
    • Strength of recommendation: strong

 

EndoPredict
  • If a patient has ER/PgR positive, HER2-negative (node negative) breast cancer, the clinician may use the 12-gene risk score (EndoPredict) to guide decisions on adjuvant systemic chemotherapy.
    • Type: evidence based
    • Evidence quality: intermediate
    • Strength of recommendation: moderate
  • If a patient has ER/PgR positive, HER2-negative (node positive) breast cancer, the clinician should not use the 12-gene risk score (EndoPredict) to guide decisions on adjuvant systemic chemotherapy.
    • Type: evidence based
    • Evidence quality: insufficient
    • Strength of recommendation: moderate
  • If a patient has HER-2 positive breast cancer or triple negative (TN) breast cancer, the clinician should not use the 12-gene risk score (EndoPredict) to guide decisions on adjuvant systemic therapy.
    • Type: informal consensus
    • Evidence quality: insufficient
    • Strength of recommendation: strong

 

MammaPrint
  • If a patient has ER/PgR positive, HER-2 negative node-negative breast cancer, the MammaPrint assay may be used in those with high clinical risk per MINDACT categorization to inform decisions on withholding adjuvant systemic chemotherapy due to its ability to identify a good-prognosis population with potentially limited chemotherapy benefit.
    • Type: evidence based
    • Evidence quality: high
    • Strength of recommendation: strong
  • If a patient has ER/PgR positive, HER2-negative, node negative, breast cancer, the MammaPrint assay should not be used in those with low clinical risk per MINDACT categorization to inform decisions on withholding adjuvant systemic chemotherapy, because women in low clinical risk category had excellent outcomes and did not appear to benefit from chemotherapy even with genomic high-risk cancer.
    • Type: evidence based
    • Evidence quality: high
    • Strength of recommendation: strong
  • If a patient has ER/PgR positive, HER2-negative, node-postive, breast cancer, the MammaPrint assay may be used in patients with one to three positive nodes and at high clinical risk per MINDACT categorization to inform decisions on withholding adjuvant systemic chemotherapy due to its ability to identify a good-prognosis population with potentially limited chemotherapy benefit. However, such patients should be informed that a benefit of chemotherapy cannot be excluded, particularly in patients with greater than one involved lymph node.
    • Type: evidence based
    • Evidence quality: high
    • Strength of recommendation: strong
  • If a patient has ER/PgR positive, HER2-negative, node positive, breast cancer, the MammaPrint assay should not be used in patients with one to three positive nodes and at low clinical risk per MINDACT categorization to inform decisions on withholding adjuvant systemic chemotherapy. There are insufficient data on the clinical utility of MammaPrint in this specific patient population.
    • Type: evidence based
    • Evidence quality: high
    • Strength of recommendation: moderate
  • If patient has HER-2 positive breast cancer, the clinician should not use the MammaPrint assay to guide decisions on adjuvant systemic therapy. Additional studies are required to address the role of MammaPrint in patients with this tumor subtype who are also receiving HER-2 targeted therapy.
    • Type: informal consensus
    • Evidence quality: low
    • Strength of recommendation: moderate
  • If a patient has ER-PgR negative and HER2-negative breast cancer, triple negative (TN), the clinician should not use the MammaPrint assay to guide decisions on adjuvant systemic chemotherapy.
    • Type: informal consensus
    • Evidence quality: insufficient
    • Strength of recommendation: strong

 

Note: MINDACT categorization is based on age, tumor size, tumor grade, lymph node status, hormone receptor status, HER2 status and clinical pathologic subtype).

 

Prosigna (PAM50) Risk of Recurrence Score
  • If a patient has ER/PgR-positive, HER-2 negative (node negative) breast cancer, the clinician may use the PAM50 risk of recurrence (ROR) score (Prosigna Breast Cancer Prognostic Gene Signature Assay), in conjunction with other clinicopathologic variables, to guide decisions on adjuvant systemic therapy.
    • Type: evidence based
    • Evidence quality: high
    • Strength of recommendation: strong
  • If a patient has ER/PgR positive, HER-2 negative (node positive) breast cancer, the clinician should not use the PAM50-ROR score (Prosigna Breast Cancer Prognostic Gene Signature Assay) to guide decisions on adjuvant systemic therapy.
    • Type: evidence based
    • Evidence quality: intermediate
    • Strength of recommendation: moderate
  • If a patient has HER-2 positive breast cancer, the clinician should not use the PAM50-ROR score (Prosigna Breast Cancer Prognostic Gene Signature Assay) to guide decisions on adjuvant systemic therapy.
    • Type: informal consensus
    • Evidence quality: insufficient
    • Strength of recommendation: strong
  • If a patient has triple negative (TN) breast cancer, the clinician should not use the PAM50-ROR score (Prosigna Breast Cancer Prognostic Gene Signature Assay) to guide decisions on adjuvant systemic therapy.
    • Type: informal consensus
    • Evidence quality: insufficient
    • Strength of recommendation: strong

 

Breast Cancer Index
  • If a patient has ER/PgR positive, HER2-negative, node negative breast cancer, the clinician may use the Breast Cancer Index to guide decisions on adjuvant systemic therapy.
    • Type: evidence based
      Evidence quality: intermediate
      Strength of recommendation: moderate
  • If a patient has ER/PgR positive, HER2-negative, node positive breast cancer, the clinician should not use the Breast Cancer Index to guide decisions on adjuvant systemic therapy.
    • Type: informal consensus
    • Evidence quality: insufficient
    • Strength of recommendation: strong
  • If a patient has HER2-positive breast cancer or triple negative (TN) breast cancer, the clinician should not use the Breast Cancer Index to guide decisions on adjuvant systemic therapy.
    • Type: informal consensus
    • Evidence quality: insufficient
    • Strength of recommendation: strong

 

Mammostrat
  • If a patient has ER/PgR-positive, HER2-negative (node-positive or node negative) breast cancer, the clinician should not use the five-protein assay Mammostrat to guide decisions on adjuvant systemic therapy.
    • Type: evidence based
    • Evidence quality: intermediate
    • Strength of recommendation: moderate
  • If a patient has HER-2 positive breast cancer or triple negative (TN) breast cancer, the clinician should not use the five protein assay Mammostrat to guide decisions on adjuvant systemic therapy.
    • Type: informal consensus
    • Evidence quality: insufficient
    • Strength of recommendation: strong

 

Immunohistochemistry 4 (IHC-4)
  • If a patient has ER/PgR positive, HER2-negative (node positive or node negative) breast cancer, the clinician should not use immunohistochemistry 4 (IHC-4) to guide decisions on adjuvant systemic chemotherapy.
    • Type: evidence based
    • Evidence quality: intermediate
    • Strength of recommendation: moderate
  • If a patient has HER2-positive breast cancer or triple negative (TN) breast cancer, the clinician should not use IHC-4 to guide decisions on adjuvant systemic therapy.
    • Type: informal consensus
    • Evidence quality: insufficient
    • Strength of recommendation: strong

 

Extended Endocrine Therapy
  • If a patient has ER/PgR positive, HER2-negative (node negative) breast cancer and has had 5 years of endocrine therapy without evidence of recurrence, the clinician should not use multi-parameter gene expression or protein assays (Oncotype DX, EndoPredict, PAM50 (Prosigna Breast Cancer Prognostic Gene Signature Assay), Breast Cancer Index, or IHC4) to guide decisions on extended endocrine therapy.
    • Type: evidence based
    • Evidence quality: intermediate
    • Strength of recommendation: moderate

 

National Comprehensive Cancer Network (NCCN)

Breast Cancer Version 3.2018 (Invasive Breast Cancer)
Estimating Risk of Relapse or Death and Benefits of Systemic Treatment

There are many gene based assays to predict prognosis such as distant recurrence, local recurrence, or survival.

 

The 21 gene assay using reverse transcription polymerase chain reaction (RT-PCR) on RNA isolated from paraffin embedded breast cancer tissue is among the best-validated prognostic assays, and there are data showing that it can predict who is most likely to respond to systemic chemotherapy.

 

Studies have shown that the 21 gene assay recurrence score obtained is predictive of locoregional and distant recurrence for postmenopausal women treated with tamoxifen or those treated with an aromatase inhibitor. Studies have also demonstrated the ability of the recurrence score to independently predict response to adjuvant chemotherapy.  Unplanned, retrospective subset analysis from a single randomized clinical trial in post-menopausal, ALN-positive, ER positive breast cancer found that the 21-gene RT-PCR assay may provide predictive information for chemotherapy benefit in addition to tamoxifen. Patients with a high score in the study benefits from chemotherapy, whereas patients with a low score did not appear to benefit from the addition of chemotherapy regardless of the number of positive lymph nodes. Many other multi-gene or multi-gene expression assay systems have been developed.

 

The 70 gene signature assay uses microarray technology to analyze gene expression profile from breast tumor tissue (formalin fixed, paraffin embedded fresh or frozen breast tumor tissue) to help identify patients with early stage breast cancer likely to develop distant metastases. This assay is approved by the FDA to assist in assignment of women with ER positive or ER negative breast cancer into a high versus low risk for recurrence, but not for predicting benefit for adjuvant systemic therapy. The prospective RASTER study reported that breast cancer patients classified by the 70 gene signature as low risk (of whom 85% did not receive adjuvant chemotherapy) had an overall 97% distant recurrence free interval at five years.

 

Another assay with 50 genes identifies intrinsic breast cancer subtypes (luminal A, luminal B, HER2 enriched and basal-like) in addition to generating a risk of recurrence (ROR) score that can be used to predict prognosis among postmenopausal women with hormone-positive breast cancer.  In a retrospective analysis of the ATAC trial, the ROR score obtained using the 50 gene assay in postmenopausal patients treated with adjuvant tamoxifen or anastrozole was seen to have a continuous relationship with the risk of distant recurrence at 10 years in node negative and node positive disease. The retrospective analysis also compared the ROR score obtained using the 50-gene assay with recurrence score obtained using the 21-gene assay. Both assays identified similar percentage of low risk patients (hormone receptor-positive, node-negative) with similar risk of recurrence. The ABCSG-8 trial showed that the ROR score providers prognostic information and predicts the risk of distant recurrence in post-menopausal women with ER-positive early stage breast cancer. A recent combined analysis of the ATAC and ABCSG-8 trials reported ROR score as a strong predictor of late distant recurrence (greater than 5 years) for patients with hormone receptor-positive, node-negative disease. The NCCN panel members acknowledge that many assays have been clinically validated for prediction of prognosis. However, based on the currently available data, the panel believes that the 21 gene assay has been best validated for its use as prognostic test as well as in predicting who is most likely to respond to systemic chemotherapy.

 

Axillary Lymph Node Negative Tumors

For those with lymph node negative hormone receptor positive breast cancer tumors greater than 0.5 cm, the panel recommends endocrine therapy (category 1) with the consideration of chemotherapy. Incremental benefit of combination chemotherapy in patients with lymph node negative, hormone receptor positive breast cancer may be relatively small. However, chemotherapy should not be withheld from these patients solely based on ER positive tumor status. The panel considers the 21 gene RT-PCR assay an option for these patients to help estimate the likelihood of recurrence and benefit from chemotherapy. The panel emphasizes that the recurrence score should be used for decision making only in the context of other elements of risk stratification for an individual patient.

 

Axillary Lymph Node Positive Tumors

Patients with lymph node positive disease are most often candidates for chemotherapy and, if the tumor is hormone receptor positive, for the addition of endocrine therapy (category 1). When HER2 is amplified for over-expressed, HER2 targeted therapy should be incorporated into the adjuvant chemotherapy. The NCCN Panel has noted in a footnote that the 21 gene RT PCR assay recurrence score can be considered in select patients with 1 to 3 involved ipsilateral ALNs to guide the addition of combination chemotherapy to standard hormone therapy based on the retrospective study at Albain et. al.

 

Guideline for Systemic Adjuvant Treatment – Hormone Receptor Positive – HER2 Negative Disease

Footnotes
  • The 21 gene RT-PCR assay recurrence score can be considered in select patients with 1-3 involved ipsilateral axillary lymph nodes to guide the addition of combination chemotherapy to standard hormone therapy. A retrospective analysis of a prospective randomized trial suggests that the test is predictive in this group similar to its performance in node negative disease.
  • Other prognostic multigene assays may be considered to help assess risk of recurrence but not have been validated to predict response to chemotherapy.

 

Multigene Assays for Consideration of Addition of Adjuvant Systemic Chemotherapy to Adjuvant Endocrine Therapya
AssayPredictivePrognosticNCCN Category of Evidence and ConsensusRecurrence Risk and Treatment Implications
21 gene (Oncotype DX) (for pN0 or node negative)

Yes

Yes

1 (based upon high level evidence, there is uniform NCCN consensus that the intervention is appropriate)

< 26 (recurrence risk): Patient with T 1 b/c and T2, hormone receptor positive, HER2 negative and lymph node negative tumors, with risk scores (RS) between 0-10 have a high risk of distant recurrence of less than 4% and those with RS 11-25, derived no benefit from the addition of chemotherapy to endocrine therapy in the prospective TAILORx study. In women 50 years of age or younger, with RS 16-25 addition of chemotherapy to endocrine therapy was associated with a lower rate of distance recurrence compared with endocrine monotherapy. Consideration should be given for the addition of chemotherapy to endocrine therapy in this group.

 

26-30 (recurrence risk): In patients with T1 and T2 hormone receptor positive, HER2 negative and lymph node negative tumors and RS of 26-30, the omission of chemotherapy has not been studied prospectively. Clinicians should consider additional clinical and pathological factors with regard to the addition of chemotherapy to endocrine therapy in decision making.

 

31(recurrence risk): For patients with T b/c and T2 hormone receptor positive, HER2-negative and lymph node negative tumor RS ≥ 31, the addition of chemotherapy to endocrine therapy is recommended.

21 gene (Oncotype DX) (for pN+ or node positive)

Awaiting results of Rxponder study

Yes

2A (Based upon lower level evidence, there is uniform NCCN consensus that the intervention is appropriate)

Low < 18 (recurrence risk): The RS (recurrence score) in women with hormone receptor positive, lymph node positive tumors receiving endocrine monotherapy. A secondary analysis of a prospective registry of women with hormone receptor-positive, HER2 negative, lymph node positive tumors demonstrated a 5 year risk of distant recurrence of 2.7% in patients with a RS of < 18 treated with endocrine monotherapy. In the West German Plan B study 110 women with hormone receptor positive, HER2 negative, lymph node positive tumors and a RS of < 11 showed a 5 year disease free survival of 94.4% when treated with endocrine monotherapy. For hormone receptor positive, HER2 negative lymph node positive tumors, clinicians should be aware that the optimal RS cut off (<11 versus <18) is still unknown both for prognosis (risk of recurrence) as well as prediction of chemotherapy benefit.

 

Intermediate (18-30) or High (≥ 31) (recurrence risk): In a secondary analysis of the SWOG 8814 trial of women with hormone receptor positive, lymph node positive tumors high RS (≥ 31) was predictive of chemotherapy benefit. Because of a higher risk of distant recurrence, patients with hormone receptor positive 1-3 positive lymph nodes and RS of ≥ 18 should be considered for adjuvant chemotherapy in addition to endocrine therapy.

 

 

 

70 gene (MammaPrint) (for node negative and 1-3 positive nodes)

Not determined

Yes

1 based upon high level evidence, there is uniform NCCN consensus that the intervention is appropriate)

Low and high (recurrence risk): With a median follow-up, among patients at high clinical risk and low genomic risk, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval (CI), 92.5% to 96.2%) among those who did not receive adjuvant chemotherapy. Among patients with 1-3 positive nodes, the rates of survival without distant metastases were 96.3% (95% CI, 93.1 to 98.1) in those who received adjuvant chemotherapy versus 95.6% (95% CI, 92.7 to 97.4) in those who did not receive adjuvant chemotherapy. Therefore, the additional benefit of adjuvant chemotherapy may be small in this group.  

PAM50 (Prosigna) (for node negative and 1-3 positive nodes)

Not determined

Yes

2A (Based upon lower level evidence, there is uniform NCCN consensus that the intervention is appropriate)

Node negative low (0-40); Node negative intermediate (41-60); Node negative high (61-100) (recurrence risk): For patients with T1 and T2 hormone receptor positive, HER2 negative, lymph node negative tumors, a risk of recurrence score in the low range regardless of T size places the tumor into the same prognostic category as T1a-T1b, N0, M0.

 

Node positive low (0-40); Node positive high (41-100) (recurrence risk): In patients with hormone receptor positive, HER2 negative, 1-3 positive lymph nodes with low risk of recurrence score, treated with endocrine therapy alone, the distant recurrence risk was less than 3.5% at 10 years and no distant recurrence was seen at 10 years in TransATAC study in similar group.     

12 gene (EndoPredict) (node negative and 1-3 nodes)

Not determined

Yes

2A (Based upon lower level evidence, there is uniform NCCN consensus that the intervention is appropriate)

Low (<3.3287; High (>3.3287) (recurrence risk): For patients with T1 and T2 hormone receptor positive, HER2 negative and lymph node negative tumors, a 12 gene low risk score regardless of T size places the tumor into the same prognostic category as T1a-T1b, N0, M0. In ABCSG 6/8 patients in low risk group has risk of distant recurrence of 4% at 10 years and in the TransATAC study, patients with 1-3 positive nodes in the low risk group had a 5.6% risk of distance recurrence at 10 years.

Breast Cancer Index (BCI)

Not determined

Yes

2A (Based upon lower level evidence, there is uniform NCCN consensus that the intervention is appropriate)

Low risk of late occurrence (0-5); High risk of late occurrence (5.1 – 10) (recurrence risk): For patients with T1 and T2 hormone receptor positive, HER2 negative and lymph node negative tumors, a BCI in the low risk range regardless of T size places the tumor into the same prognostic category as T1a-T1b, N0, M0. There are limited data as to the role of BCI in hormone receptor positive, HER2 negative and lymph node positive breast cancer.

 

aMultigene assays provide prognostic and therapy predictive information that complements T,N,M and biomarker information. Use of these Assays is not required for staging. The 21-gene assay (Oncotype DX) is preferred by the NCCN Breast Cancer Panel for node negative breast cancer. Other prognostic multigene assays can provide additional prognostic information in patients with 1-3 positive lymph nodes but are unknown if predictive if chemotherapy benefit in 1-3 positive lymph nodes.

 

Regulatory Status

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 Breast and other tests listed 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.

 

February 2007, MammaPrint (Agendia) was cleared for marketing by the FDA through the 501(k) process for the prediction of breast cancer metastasis. In January 2015, MammPrint was cleared for marketing by the FDA thorugh the 510(k) process for use in fresh-frozen, paraffin-embedded breast cancer tissue.

 

September 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.

 

Currently the Breast Cancer Index (Biotheranostics) and EndoPredict (distributed by Myriad) are not FDA approved.

 

Prior Approval:

Not applicable

 

Policy:

Medically Necessary

The use of OncoType DX Breast test (21-gene expression profile) to predict recurrence risk for deciding whether or not to undergo adjuvant chemotherapy may be considered medically necessary for an individual with primary breast cancer meeting ALL of the following criteria:

  • Unilateral tumor; AND 
  • Node-negative (lymph nodes with micrometastases not greater than 2 mm are considered negative for purposes of this policy statement) OR with 1-3 involved ipsilateral axillary positive lymph nodes; AND
  • Breast tumor is hormone-receptor-positive (estrogen-receptor positive (ER-positive) or progesterone-receptor positive (PR-positive)); AND
  • Breast tumor is human epidermal growth factor receptor 2 (HER2)-negative; AND
  • Tumor size 0.6 to 1.0 cm with moderate/poor differentiation or unfavorable features, OR tumor size > 1 cm; AND
  • Adjuvant chemotherapy is not precluded due to any other factor (e.g. advanced age and/or significant co-morbidities); AND
  • The patient and the physician (prior to the testing) have discussed the potential results of the test and agree to use the results to guide therapy (i.e. the member will forgo adjuvant chemotherapy if Oncotype DX score is low) the test result will aid the patient in making the decision regarding adjuvant chemotherapy; AND
  • When ordered within six months following diagnosis, since the value of the test for making decisionsgarding delayed chemotherapy is unknown

 

For patients who otherwise meet the above criteria but who have multiple ipsilateral primary tumors, use of Oncotype DX Breast test (21-gene expression profile) may be considered medically necessary for the tumor with the most aggressive histologic characteristics. It is not necessary to conduct testing on each tumor, treatment is based on the most aggressive lesion.

 

The OncoType DX Breast test (21-gene expression profile) 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 adjuvant chemotherapy.

 

The use of OncoType DX Breast test (21-gene expression profile) if ordered as a substitute for standard estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) testing would be considered not medically necessary.

 

The ER and PR analysis is traditionally conducted during pathology examination of all breast cancer biopsies, whereas Oncotype DX Breast is indicated after the pathology examination is complete, the patient meets specific criteria, and patient and physician are considering preferences for risk and chemotherapy. Thus, Oncotype DX Breast cancer test (21-gene profile) should not be ordered as a substitute for ER and PR IHC. Additionally, accepted guidelines for ER and PR testing outline standards for high-quality IHC testing and do not recommend confirmatory testing; thus the 21-gene RS (Oncotype DX Breast) should not be ordered to confirm ER/PR IHC results and would be considered not medically necessary.

 

EndoPredict, Breast Cancer Index or Prosigna Assays

The use of EndoPredict, the Breast Cancer Index, or Prosigna assays to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy therapy may be considered medically necessary for an individual with primary breast cancer meeting ALL of the following criteria:

  • Unilateral tumor; AND

  • Node-negative (lymph nodes with micrometastases not greater than 2 mm are considered negative for purposes of this policy statement); AND

  • Breast tumor is hormone-receptor-positive (estrogen-receptor positive (ER-positive) or progesterone-receptor positive (PR-positive)); AND

  • Breast tumor is human epidermal growth factor receptor 2 (HER2)-negative; AND

  • Tumor size 0.6 to 1.0 cm with moderate/poor differentiation or unfavorable features, OR tumor size > 1 cm; AND

  • Adjuvant chemotherapy is not precluded due to any other factor (e.g. advanced age and/or significant co-morbidities); AND

  • The patient and the physician (prior to the testing) have discussed the potential results of the test and agree to use the results to guide therapythe test result will aid the patient in making the decision regarding adjuvant chemotherapy; AND

  • When ordered within six months following diagnosis, since the value of the test for making decisions regarding delayed chemotherapy is unknown

 

For patients who otherwise meet the above criteria but who have multiple ipsilateral primary tumors, use of EndoPredict, Breast Cancer Index or Prosigna assays may be considered medically necessary for the tumor with the most aggressive histologic characteristics. It is not necessary to conduct testing on each tumor, treatment is based on the most aggressive lesion.

 

The EndoPredict, Breast Cancer Index or Prosigna assays 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 adjuvant chemotherapy.

 

MammaPrint

The use of MammaPrint to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy therapy may be considered medically necessary for an individual with primary breast cancer meeting ALL of the following criteria:

  • Breast cancer is nonmetastatic node negative or with 1-3 positive ipsilateral axillary lymph nodes; AND
  • Breast tumor is estrogen receptor positive or progesterone receptor positive; AND
  • Breast tumor is HER2 (human epidermal growth factor receptor 2) negative; AND
  • The member is determined to be at high clinical risk of recurrence (based on age, tumor size, tumor grade, lymph node status, hormone receptor status, HER2status and clinical pathologic subtype. Physician may also utilize on line clinical tools   to incorporate this information to obtain as score to determine high risk for recurrence); AND
  • Adjuvant chemotherapy is not precluded due to any factor (e.g. advanced age and/or significant co-morbidities; AND
  • The patient and the physician (prior to the testing) have discussed the potential results of the test and agree to use the results to guide therapy (the test result will aid the patient in making the decision regarding adjuvant chemotherapy); AND
  • When ordered within six months following diagnosis, since the value of the test for making decisions regarding delayed chemotherapy is unknown.

 

Investigational

Oncotype DX Breast (21 Gene Expression Profile)

All other indications for OncoType DX Breast test (21-gene expression profile), including but not limited to the following are considered investigational, because the

evidence is insufficient to determine the effects of the technology on net health outcomes by review of the available published peer-reviewed medical literature:

  • Patients with bilateral disease; or
  • To consider length of treatment with tamoxifen

 

EndoPredict, Breast Cancer Index and Prosigna

All other indications for EndoPredict, the Breast Cancer Index, or Prosigna assays, including but not limited to the following are considered investigational, because the evidence is insufficient to determine the effects of the technology on net health outcomes by review of the available published peer reviewed medical literature:

  • Determination of recurrence risk in breast cancer patients with positive lymph nodes
  • Patients with bilateral disease; or
  • To consider length of treatment with tamoxifen

 

MammaPrint

All other indications for MammaPrint not meeting the above criteria to include considering the length of treatment with tamoxifen is considered investigational, because the evidence is insufficient to determine the effects of the technology on net health outcomes by review of available published peer-reviewed medical literature.

 

Oncotype DX Breast DCIS Score

Use of subsets of genes from the 21 gene expression profile for predicting recurrence risk in patients with ductal carcinoma in situ (DCIS) i.e. Oncotype DX Breast DCIS Score to inform treatment planning after excisional surgery is considered investigational as there is insufficient evidence to support a conclusion concerning net health outcomes by review of the available published peer-reviewed medical literature.

 

Mammostrat, TargetPrint and BluePrint

  • All other gene expression assays for any indication to include breast cancer prognosis or to predict breast cancer will respond to specific treatment (predictive factor) are considered investigational including but not limited to the following:
    • Mammostrat
  • The use of gene expression assays for quantitative assessment of ER, PR and HER2 overexpression (e.g. TargetPrint) is considered investigational.
  • The use of gene expression assays to molecularly subclassify breast cancer (e.g. BluePrint) is considered investigational.

 

Based on the peer-reviewed medical literature further studies seeking evidence addressing clinical utility of these tests are warranted. Additionally society guidelinesdo not include or indicate the use of these tests to guide decisions regarding adjuvant therapy.  The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Definitions

Adjuvant Chemotherapy: Adjuvant means additional. Adjuvant chemotherapy is given to patients after primary treatment (e.g. chemotherapy and radiation, or chemotherapy and surgery), when the doctor thinks there is a high risk the cancer will return. Adjuvant chemotherapy aims to destroy hidden cancer cells that remain but are undetectable.

 

Neoadjuvant Chemotherapy: Is the administration of chemotherapeutic agents before surgery or radiation therapy. The reduction in the size of larger tumors, or to prevent metastatic cancer from spreading is the goal of neoadjuvant chemotherapy.

 

Ipsilateral: On the same side.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 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 likeligood of benefit from extended endocrine therapy
  • 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 (Oncotype DX)
  • 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 (Prosigna Breast Cancer Prognostic Gene Signature Assay)
  • 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 (MammaPrint)
  • 81479 Unlisted molecular pathology procedure (may be used to represent Mammostrat, Breast Cancer Index (BCI), BluePrint, TargetPrint)
  • 81599 Unlisted multianalyte assay with algorithmic analysis (may be used to represent EndoPridict, Mammostrat, Breast Cancer Index (BCI), BluePrint, TargetPrint)
  • 84999 Unlisted chemistry procedure (may be used to represent Mammostrat, Breast Cancer Index (BCI), BluePrint, TargetPrint)
  • 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 (Prosigna Breast Cancer Prognostic Gene Signature Assay)
  • 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 (OncoTypeDX Breast DCIS Score Test)
  • S3854 Gene expression profiling panel for use in the management of breast cancer treatment (may be used to represent Mammostrat, BluePrint, TargetPrint)

 

Selected References:

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  • Oncotype DX Breast DCIS Score
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  • Schroeder B, Zhang Y, Stal O, et al. Risk stratification with Breast Cancer Index for late distant recurrence in patients with clinically low-risk (T1N0) estrogen receptor-positive breast cancer. NPJ Breast Cancer. 2017;3:28. PMID 28795152
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Policy History:

  • December 2018 - Interim Review, Policy Revised
  • August 2018 - Annual Review, Policy Revised
  • August 2017 - Annual Review, Policy Revised
  • March 2017 - Interim Review, Policy Revised
  • August 2016 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.