Medical Policy: 02.04.59
Original Effective Date: August 2016
Reviewed: August 2018
Revised: August 2018
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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.
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 patients 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.
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.
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 5 to 10 years following initial diagnosis has support in national guidelines. However, the regimens available and the evidence to support them vary.
Randomized controlled trials published recently have shown that extended endocrine therapy decreases the risk of recurrence. The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines were informed primarily of the ATLAS trial, which compared 5 and 10 years of tamoxifen and the subsequent aTTom trial (reported in abstract form). In both trials, in women who were hormone receptor-positive and had completed 5 years of tamoxifen, 5 years of extended tamoxifen was associated with improvements in breast cancer specific mortality; ATLAS showed improvements in overall survival.
Overall, the available trial evidence would suggest that 10 years of tamoxifen in pre or postmenopausal women can be linked with improved survival while trials of extended aromatase inhibitors in different populations of hormone receptor-positive patients have had mixed results.
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 appears 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 conventional 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.
|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||Genomic Health (Redwood City, CA)||21 gene reverse transcriptase polymerase chain reaction identifies 3 groups as low, intermediate and high risk for distant recurrence|
|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.
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.
The main outcome of interest is 10 year 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. For extended endocrine indications the main outcome of interest is 10 year distant recurrence-free survival conditional on recurrence-free survival for 5 years.
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 and harms determines the thresholds that inform decisions. Most geno typical women will accept substantial adverse effects for even modest benefit.
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.
Outcomes of interest for all assays are disease specific survival and change in disease status.
In 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.
The assays would be performed following the diagnosis of early stage node negative or node positive invasive breast cancer, because patients are considering adjuvant chemotherapy.
The assays would be performed following the diagnosis of DCIS, because patients are considering radiotherapy (RT).
The assays would be performed after 5 years of no recurrence of early stage node negative invasive breast cancer because patients are considering extended endocrine therapy.
Oncotype DX Breast cancer test (21- gene expression profile) 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 genotypical 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).
Invasive breast cancer is defined as having spread beyond the tissue in which it developed and into surrounding normal tissue. It is also called infiltrating breast cancer. Invasive breast cancer is designated as stage I or II (often designated as IA, IB, IIA, or IIB) when the tumor is 5 cm or less in diameter with 3 or fewer positive lymph nodes or greater than 5 cm in diameter with no positive nodes.
To date, research studies on Oncotype DX Breast have generally tested only one tumor per patient. When Oncotype DX Breast testing is planned for two or more tumors from the same patient during the same breast cancer episode, it is important to determine whether the tumors are multifocal (arising from the same primary tumor) or multicentric (distinctly separate tumors). When the tumors appear to be very close in proximity, they can often be assumed to be different parts of the same tumor. A patient that has multiple tumors, a specimen from the tumor with the most aggressive histological characteristics should be submitted for testing. It is not necessary to conduct testing on each tumor, treatment is based on the most aggressive lesion. In most cases, the tumor indicating the highest risk is readily apparent based on size, or can be identified based on grade or human epidermal growth factor receptor 2 (HER2) testing.
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:
Based on a study of analytic validity, tissue sampling rather than technical performance of the assay is likely to be the greatest source of variability in results. The 21-gene expression profile was validated in studies using archived tumor samples from subsets of patients enrolled in already completed randomized controlled trials of early breast cancer treatment. Patients enrolled in the trial arms from which specimens were obtained had primary, unilateral breast cancer with no history of prior cancer and were treated with tamoxifen; tumors were ER-positive, most were HER2-negative, and in the case of at least 1 trial multifocal tumors were excluded.
The Oncotype DX Breast cancer test (21-gene expression profile) is supported by strong evidence of clinical validity, i.e. that the Recurrence Score (RS) is associated with risk of distant recurrence in genotypical women with invasive breast cancer that is positive for hormone receptors, negative for human epidermal grown factor receptor 2 (HER2) amplification and without lymph node involvement. Limited but sufficient evidence supports analytic validity and clinical utility in this population. Oncotype DX Breast adds additional risk information to conventional clinical classification of individual high risk patients and identifies a subset of patients who would otherwise be recommended for chemotherapy but who are actually at lower risk of recurrence (average risk at 10 years 7%-9%; upper bound of the 95% confidence intervals, 11% to 15%). The available evidence is therefore sufficient to determine that Oncotype DX breast improves the net health outcome for genotypical women with hormone receptor positive, HER2-negative, lymph node-negative invasive breast cancer. A genotypical woman who prefers to avoid the toxicity and inconvenience of chemotherapy and whose Oncotype DX RS value show that she is at low risk of recurrence might decide to decline chemotherapy.
In 2014, a Blue Cross Blue Shield Association TEC assessment addressed gene expression profiling in women with lymph-node negative breast cancer to select adjuvant chemotherapy, specifically use of Oncotype DX, MammoPrint, the Breast Cancer Index, and Prosigna/PAM50 gene expression assay. The assessment concluded that use of Oncotype DX to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy in women with unilateral, hormone receptor-positive, lymph node – negative breast cancer who will receive hormonal therapy meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria; and that use of MammaPrint, the Breast Cancer Index, and Prosigna to determine recurrence risk in women with unilateral, hormone receptor – positive, lymph node-negative breast cancer who will receive hormonal therapy does not meet TEC criteria.
For individuals who have early stage node negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with Oncotype DX Breast (21-gene assay), the evidence includes multiple prospective clinical trials and prospective-retrospective studies. Patients classified as low risk with Oncotype DX Breast 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%-10%). These results have been demonstrated with stronger study designs for evaluating biomarkers. The evidence is sufficient to determine that the technology results in a meaningful improvement in net health outcomes.
In women who are node-positive, Oncotype DX Breast has also been proposed for use in women with hormone receptor positive, HER2 negative disease, node positive breast cancer to guide the addition of combination chemotherapy to standard hormone therapy. A retrospective analysis of a prospective randomized trial suggests that Oncotype DX Breast is predictive in this group similar to its performance in node-negative disease. Although the evidence is not robust regarding the test’s prognostic ability for this population, however, the clinical usefulness has been validated by the National Comprehensive Cancer Network (NCCN) as a category 2A level of evidence and the recommendation is a uniform consensus that the intervention is appropriate to consider this testing in patients with 1-3 involved ipsilateral axillary lymph nodes.
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 (mastectomy is also an option) with or without radiation treatment; postsurgical tamoxifen treatment is recommended for 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 genotypical 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.
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.
For individuals who have ductal carcinoma in situ (DCIS), considering radiotherapy who receive gene expression profiling with the Oncotype DX Breast DCIS Score test, the evidence includes prospective-retrospective studies and prospective trials. Although 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 an Oncotype DX Breast DCIS Score is low enough to consider changing the management of DCIS. The evidence is insufficient
to determine the effects of this testing on net health outcomes.Therefore, Oncotype DX Breast DCIS Score test for predicting recurrence risk in patients with noninvasive ductal carcinoma in situ (DCIS) to inform treatment planning after excisional surgery is considered investigational.
Oncotype DX Breast cancer testing has been studied and validated based on samples from genotypical women with breast cancer. Breast cancer is rare in genotypical men, which makes it difficult to conduct adequate trials in genotypical males, so experts have traditionally agreed that interventions based on research with genotypical women can also be applied to genotypical men. However, recent studies have demonstrated important differences in the biology of breast cancer between genotypical males and genotypical females. Therefore, it can no longer be presumed that the results of research in genotypical women with breast cancer can be applied to genotypical men.
Based on review of the peer reviewed medical literature, no published literature on the use of gene expression profiling in genotypical men with breast cancer has been identified. Therefore, the use of gene expression profiling i.e. Oncotype DX Breast testing (21-gene expression profile) is considered investigational because the safety and effectiveness of this service cannot be established.
Based on study published in May 2008 that compared Oncotype DX ER and PR results with traditional IHC results, Genomic Health is now including quantitative ER and PR component results in Oncotype DX Breast cancer test (21-gene profile) reports. The study reported 90% or better concordance between the 2 assays, but quantitative ER by Oncotype Dx Breast was more strongly associated with disease recurrence than IHC results. However, 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.
In early stage, estrogen receptor (ER) positive, HER-2 negative breast cancer, the decision to administer chemotherapy is largely based on prognostic criteria since large sub-set of women do not derive benefit from the addition of chemotherapy to endocrine therapy. 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.
The EndoPredict gene signature was developed in a training cohort of 964 hormone receptor-positive and HER-2 negative tumor samples. Eight genes (BIRC5, UBE2C, DHCR7, RBBP8, IL6ST, ASGP1, MGP and STC2) were selected as relevant for therapeutic decision making; they include proliferation-associated genes as well as estrogen receptor signaling-associated genes. The signature also included three RNA normalization genes (CALM2, OAZ1 and RPL37A) and one DNA reference gene (HBB). The EndoPredict (EP) score is calculated using a mathematical formula that combines the activity levels of 12 genes. The EP score is then combined with tumor size and lymph node status to produce the EPclin score. EndoPredict is uniquely distinguished from other breast cancer gene expression tests because it has been validated with the incorporation of these well-established prognostic factors of tumor size and lymph node status. Patients with an EPclin score of 3.3 or less are classified as low risk of distant recurrence and those with a score greater than 3.3 are classified as high risk. For patients in the low risk group, the absolute benefit of adjuvant chemotherapy is unlikely to outweigh the risks. There is sufficient discrimination of the two risk groups so that there is no intermediate risk group.
The reliance on a molecular prognostic tool for women with early, ER positive, HER2-negative breast cancer is well-established, as this group has high survival rates; yet is heterogenous, with not all women receiving the same benefit from chemotherapy. EndoPredict combines a 12-gene expression signature with tumor size and nodal status to identify certain breast cancer patient with sufficiently low risk of distant recurrence that they can safely forgo chemotherapy. The evidence includes 3 prospective-retrospective studies and observational studies. The studies showed that a low score was associated with a low absolute risk of 10 year distant recurrence. Over half of patients in the studies were classified at low risk. Additionally, EndoPredict has been incorporated into clinical guidelines for optimal therapeutic decision-making. The evidence is sufficient to determine that this testing results in a meaningful improvement in net health outcome.
The 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.
For individuals who have early stage node negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with the Breast Cancer Index (BCI), the evidence includes findings from 2 prospective-retrospective studies and 1 registry-based observational study. The findings from the 2 prospective-retrospective studies showed that a low risk BCI score is associated with low 10 year distant recurrence rates. The findings from the registry based observational study also showed low 10 year distant recurrence rates. Additionally, Breast Cancer Index (BCI) has been incorporated into clinical guidelines for optimal therapeutic decision-making. The evidence is sufficient to determine that this testing results in a meaningful improvement in net health outcome.
The Prosigna Breast Cancer Prognostic Gene Signature Assay 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 genotypical women with hormone receptor positive and lymph node negative invasive breast cancer.
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. Additionally, Prosigna Breast Cancer Prognostic Gene Signature Assay (PAM50) has been incorporated into clinical guidelines for optimal therapeutic decision-making. The evidence is sufficient to determine that this testing results in a meaningful improvement in net health outcome.
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. MammaPrint is indicated for breast cancer patients that fulfill the following criteria:
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.
For individuals who have early stage node negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with the 70-gene signature MammaPrint, the evidence includes a prospective-retrospective and a study using cancer registry cohort. The prospective-retrospective study reported a high 10 year distant metastases-free survival for the low risk group treated with tamoxifen (93%; 95% CI, 88% to 96%), but not has 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. A recently reported study of clinical utility only reported 5 year results and may not identify a group with sufficiently low risk. NCCN guidelines state “other prognostic multigene assays have not been validated to predict response to chemotherapy,” this statement would include the MammaPrint (70 gene signature) assay. Further studies are needed in regards to clinical utility and the use of MammaPrint assay for individuals who have early stage breast cancer considering adjuvant chemotherapy. The evidence is insufficient to determine the effects of this testing on net health outcomes.
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.
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.
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.
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.
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:
Note: MINDACT categorization is based on age, tumor size, tumor grade, lymph node status, hormone receptor status, HER2 status and clinical pathologic subtype).
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.
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.
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 uses as prognostic test as well as in predicting who is most likely to respond to systemic chemotherapy.
Patients with high recurrence score obtained using the 21 gene assay clearly benefit from chemotherapy, whereas patients with low score do not appear to benefit from the addition of chemotherapy regardless of the number of positive lymph nodes. The results from the prospective TAILORx study support the use of the 21-gene assay to spare the use of chemotherapy in patients with low risk score. In patients with a low-risk score (< 10) at 5 years, the risk of the recurrence of breast cancer at a distant site was less than 1% and the risk of any recurrence was less than 2%.
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.
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.
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.
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 in genotypical women with primary breast cancer meeting ALL of the following criteria:
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.
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 in genotypical women with primary breast cancer meeting ALL of the following criteria:
Node-negative (lymph nodes with micrometastases not greater than 2 mm are considered negative for purposes of this policy statement)
Hormone-receptor-positive (estrogen-receptor positive (ER-positive) or progesterone-receptor positive (PR-positive))
Human epidermal growth factor receptor 2 (HER2)-negative
Tumor size 0.6 to 1.0 cm with moderate/poor differentiation or unfavorable features, OR tumor size > 1 cm
who will be treated with adjuvant endocrine therapy, e.g., tamoxifen or aromatase inhibitors
when the test result will aid the patient in making the decision regarding adjuvant chemotherapy (i.e., when chemotherapy is a therapeutic option) 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.
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.
To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.
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Centers for Medicare & Medicaid Services. Local Coverage Determination (LCD): MolDX: Breast Cancer IndexSM Genetic Assay (L35631). 2015;
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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.
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