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Assays of Genetic Expression in Tumor Tissue for Breast Cancer Prognosis (Independence Administrators)
06.02.27n

Policy


This policy only applies to members for whom Independence Administrators serves as the claims administrator and whose group has not enrolled in the UM vendor program.  For those groups who have been given the option to enroll in the UM vendor program, this policy is no longer applicable upon their renewal effective date. Individual member benefits must be verified before/prior to providing services.​

The intent of this policy is to communicate the coverage positions for assays of genetic expression in tumor tissue for breast cancer prognosis.

For information on policies related to this topic, refer to the Cross References section in this policy.

MEDICALLY NECESSARY

The Oncotype DX® or MammaPrint® test is considered medically necessary and, therefore, covered for individuals with primary, invasive stage I or stage II breast cancer when the test is ordered within six months of a primary breast cancer diagnosis, test results are expected to have significant clinical value by helping the individual decide for or against chemotherapy, clinical documentation indicates that the test results are expected to play a significant clinical role in the evaluation of the individual's prognosis, AND all of the criteria for the specific test are met:

ONCOTYPE DX®
  • The individual is a candidate for possible adjuvant chemotherapy such as tamoxifen or aromatase inhibitors (ie, chemotherapy is not precluded due to other factors such as advanced age and/or significant comorbidities ), and testing is being done specifically to guide the decision as to whether or not adjuvant chemotherapy will be used.
  • The breast cancer is nonmetastatic (node negative) or with 1-3 involved ipsilateral axillary lymph nodes.
  • The breast tumor is unilateral and non-fixed (ie, tumor does not adhere to the chest wall).
  • The breast tumor is hormone receptor--positive, (ie, estrogen-receptor positive or progesterone-receptor positive).
  • The breast tumor is human epidermal growth factor--receptor 2 (HER2) negative.
  • The breast tumor size is 0.6 to 1 cm with moderate/poor differentiation or unfavorable features OR tumor size is larger than 1 cm.
  • The breast tumor is sentinel lymph node--negative by hematoxylin and eosin (H&E) staining, even if immunoassay is positive for sentinel lymph node; OR the breast tumor has axillary node micrometastasis, which is no greater than 2.0 millimeters (mm) in size.
Use of EndoPredict, the Breast Cancer Index, MammaPrint, and Prosigna to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy is considered medically necessary and, therefore, covered in women with primary, invasive breast cancer with the same characteristics as considered medically necessary for Oncotype DX. (Medical necessiy for breast cancer with 1-3 involved ipsilateral axillary lymph nodes applies only to Oncotype DX and MammaPrint). 

MAMMAPRINT®
  • Chemotherapy has not been initiated.
  • The individual is Tamoxifen independent (ie, the individual has not received Tamoxifen therapy) at the time of MammaPrint® testing, but the individual is a candidate for possible adjuvant chemotherapy (ie, chemotherapy is not precluded due to other factors advanced age and/or significant comorbidities ),
  • The breast cancer is nonmetastatic.
  • The tumor size is less than or equal to 5.0 centimeters (cm).
  • The breast tumor is sentinel lymph node--negative and/or any nodal micrometastases are no greater than 2.0 millimeters (mm) in size.

  • Cancer stage is T1 or T2 or operable T3 at high clinical risk.

In cases where there are multiple primary breast tumors, MammaPrint® may be medically necessary and, therefore, covered if each primary breast tumor separately meets the criteria listed above. If multiple breast tumors meet the eligibility criteria, the Recurrence Score (RS) from one tumor must be determined before subsequent testing of another tumor.

The Oncotype DX, EndoPredict, the Breast Cancer Index, MammaPrint, and Prosigna assays must 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 (ie, the test should not be ordered on a preliminary core biopsy). The test should be ordered in the context of a physician-patient discussion regarding risk preferences when the test result will aid in making decisions regarding chemotherapy.

For indiviudals who otherwise meet the above characteristics but who have multiple ipsilateral primary tumors, a specimen from the tumor with the most aggressive histologic characteristics must be submitted for testing. It is not necessary to test each tumor; treatment is based on the most aggressive lesion.


EXPERIMENTAL/INVESTIGATIONAL

All other indications for the 21-gene RT-PCR assay (i.e., Oncotype DX®), the 70-Gene Signature assay (i.e., MammaPrint®), EndoPredict, the Breast Cancer Index, and PROSIGNA™ breast cancer prognostic gene signature assay / PAM50 Breast Cancer Intrinsic Subtype Classifier, including determination of recurrence risk in individuals with invasive breast cancer with positive lymph nodes or individuals with bilateral disease, are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

Use of a subset of genes from the 70-Gene Signature (i.e., MammaPrint®), or the 21-gene RT-PCR assay for predicting recurrence risk in individuals with noninvasive ductal carcinoma in situ (i.e., Oncotype DX® DCIS) to inform treatment planning after excisional surgery are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

All other gene expression assays for breast cancer prognosis (e.g., Mammostrat® Breast Cancer Test,  Insight TNBCtype, BreastOncPx™, NexCourse® Breast IHC4, BreastPRS™, Insight® DX Breast Cancer Profile, and MapQuant Dx™) for any indication are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

The use of gene expression assays in men with breast cancer is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

The use of gene expression assays to molecularly subclassify breast cancer (eg, BluePrint®) either in conjunction with MammaPrint or alone is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

The use of gene expression assays for quantitative assessment of ER, PR, and HER2 overexpression (eg, TargetPrint®) is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

PreludeDx™'s DCISionRT® Test is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

The laboratory and/or the ordering health care professional's documentation should indicate that the individual has cancer of the breast that is hormone receptor--positive and node-negative among meeting other clinical criteria for medically necessary testing. In addition, prior to ordering the test, the ordering health care professional's documentation should indicate that the intention to treat or not treat with adjuvant chemotherapy would be contingent, at least in part, on the results of the test for the individual in question and would play a significant role in management of the individual. For example, an individual with a large, high-grade cancer who, in agreement with the oncologist, has decided to have adjuvant chemotherapy, regardless of the results of the test, would not be an appropriate candidate for this test.​

Guidelines

​BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, a number of assays of genetic expression in tumor tissue detailed and specified in the MEDICALLY NECESSARY section of this medical policy bulletin are covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

However, services that are identified in this policy as experimental/investigational are not eligible for coverage or reimbursement by the Company.

The Company’s laboratory network has extensive genetic testing capabilities; therefore, providers should refer members only to participating laboratories for covered services. In the unusual circumstance that a specific covered test and related services are not available through a participating laboratory, providers must contact the Company to obtain preapproval.

Members who have out-of-network benefits may choose to use a non-participating laboratory for a medically necessary service, but they will have greater out-of-pocket costs associated with that service. In addition, the member will be financially responsible for the entire cost of any service that is non-covered (e.g., a service that is considered experimental/investigational).

Description

​According to the American Cancer Society (ACS), breast cancer is the most common cancer among women (other than skin cancer) and is the second leading cause of cancer death in women, after lung cancer. Early detection of the disease by mammography is especially valuable because it increases treatment options and saves lives. Factors that increase the risk of breast cancer include personal or family history of breast cancer, biopsy-confirmed atypical hyperplasia, significant mammographic breast density, an irregular menstrual history, recent use of oral contraceptives, giving birth for the first time after 30 years of age, never giving birth, obesity after menopause, postmenopausal hormone therapy, or consumption of one or more alcoholic beverages per day.


Taking into account the medical circumstances and an individual's preference, treatment options may involve a lumpectomy (local removal of the tumor) or mastectomy (surgical removal of the breast). Treatment may also include the removal of axillary lymph nodes if the cancer has spread to these nodes. Radiation therapy, chemotherapy, and hormone therapy are adjuvant post-surgical treatment options that are used to prevent recurrence of the cancer and/or progression of the disease. Typically, two or more of these methods are used.

Prognosis in breast cancer is currently based on an individual's age, tumor size, histology, status of the axillary lymph nodes, histologic type, and hormone receptor status. The subset of women with breast cancer who would benefit from adjuvant chemotherapy, radiation therapy, or hormone therapy after surgery is unclear. Individuals with the same set of risk factors can have markedly different prognoses. For example, not all women with positive axillary lymph nodes are destined to progress to metastatic disease, yet adjuvant chemotherapy is routinely recommended in these cases. According to the ACS, providers generally recommend adjuvant therapy for women with a tumor larger than 1 cm or if the cancer has spread to the lymph nodes. Currently, there are no exclusive risk factors that would improve individual selection criteria for adjuvant therapy or other breast cancer treatments.

Laboratory tests have been developed that detect the expression, via messenger ribonucleic acid (mRNA) or protein, of many different genes in breast tumor tissue and combine the results into a prediction of distant recurrence risk for women with early stage breast cancer. Test results may help providers and individuals decide whether to include adjuvant chemotherapy in postsurgical management.

For women with early-stage, invasive breast cancer (ie, cancer extending beyond the basement membrane of the mammary ducts into adjacent tissue), adjuvant chemotherapy provides the same proportional benefit regardless of prognosis. However, the absolute benefit of chemotherapy depends on the baseline risk of recurrence. For example, women with the best prognosis have small tumors, are estrogen receptor (ER)--positive, and lymph node--negative. These women have an approximately 15% baseline risk of recurrence; approximately 85% of these individuals would be disease-free at 10 years with tamoxifen treatment alone and could avoid the toxicity of chemotherapy, if they could be accurately identified. Conventional risk classifiers (eg, Adjuvant! Online) estimate recurrence risk by considering criteria such as tumor size, type, grade, and histologic characteristics; hormone receptor status; and lymph node status. 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, more individuals are treated with chemotherapy than can benefit. Better predictors of baseline risk could help women, who prefer to avoid chemotherapy if assured that their risk is low, make better treatment decisions in consultation with their healthcare providers.

GENE EXPRESSION TESTS FOR BREAST CANCER PROGNOSIS

Several manufacturers 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 U.S. include 21-Gene Recurrence Score (Oncotype DX®), 70-Gene Signature (MammaPrint®), Breast Cancer IndexTM, Mammostrat® Breast Cancer Test, BreastOncPx™, NexCourse® Breast IHC4, Prosigna™/ PAM50 Breast Cancer Intrinsic Subtype Classifier, BreastPRS™, and EndoPredict™. If these panels are more accurate risk predictors than current conventional classifiers, they could be used to aid chemotherapy decision making when current guidelines do not strongly advocate chemotherapy, without negatively affecting disease-free and overall survival (OS).

These laboratory tests have been developed to detect the expression, via messenger RNA, of different genes in breast tumor tissue and combine the results to determine prognosis in patients with breast cancer. Test results may help providers and individuals decide whether to include adjuvant chemotherapy in the postsurgical management of breast cancer, to alter treatment in individuals with ductal carcinoma in situ or triple-negative (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) breast cancer (TNBC), or to recommend extended endocrine therapy in individuals who are recurrence-free at 5 years. 


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


Early-Stage Node-Negative Invasive Breast Cancer

For the evaluation of breast cancer-related gene expression profiling tests for the management of all early-stage breast cancer populations, study populations considered had positive hormone receptor status, and negative human epidermal growth factor receptor 2 status. Studies retrospectively collecting tumor samples from prospective trials that provide at least 5-year distant recurrence rates or at least 5-year survival rates in node-negative women were included in this part of the evidence review.


Oncotype DX (21-Gene Assay)

For individuals who have early-stage node-negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with Oncotype DX (21-gene assay), the evidence includes multiple prospective clinical trials and prospective-retrospective studies. Individuals 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 been demonstrated with stronger study designs for evaluating biomarkers.


EndoPredict

For individuals who have early-stage node-negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with EndoPredict, the evidence includes 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 the individuals in these studies were classified as low-risk.


Breast Cancer Index

For individuals who have early-stage node-negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with the Breast Cancer Index, the evidence includes findings from 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%).


MammaPrint (70-Gene Signature)

For individuals who have early-stage node-negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with MammaPrint (70-gene signature), the evidence includes a prospective-retrospective study and a randomized controlled trial 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%-96%), but not as high survival for the low-risk group not treated with tamoxifen (83%, 95% CI, 76%-88%). The randomized controlled trial Microarray In Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy showed 5 year distance recurrence rates below the 10% threshold among individuals identified as low-risk.


Prosigna

For individuals who have early-stage node-negative invasive breast cancer considering adjuvant chemotherapy who receive gene expression profiling with Prosigna, the evidence includes 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%). 


Early-Stage Node-Positive (1 to 3 Nodes) Invasive Breast Cancer

For decisions on the management of early-stage node-positive disease, Oncotype DX, EndoPredict, MammaPrint, and Prosigna were evaluated. Only studies presenting a minimum of 5 year distant recurrence rates or 5 year survival rates were included in this part of the evidence review.


Oncotype DX (21-Gene Assay)

For individuals who have early-stage node-positive invasive breast cancer who are considering adjuvant chemotherapy who receive gene expression profiling with Oncotype DX (21-gene assay), the evidence includes 3 prospective-retrospective studies. The prospective-retrospective studies showed that Oncotype DX stratifies node-positive individuals into high- and low-risk for distant recurrence-free survival. The studies have proposed different cutoffs for low-risk. One of the studies with a recurrence score cutoff for low-risk of 18 reported CIs for estimates and those are very wide. The analysis from the Plan B study included patients with node-negative and node-positive breast cancer. The authors reported that subgroup analyses of individuals with node-positive breast cancer who were classified as low-risk (recurrence score <=11) experienced higher rates of survival than individuals classified as high-risk, though no rates were provided. Five-year DFS in individuals with 1 to 3 positive nodes or pN1 disease and recurrence score <=11 treated with endocrine therapy alone (n=110) was 94.4% (95% CI, 89.5 to 99.3%). There is a wide range of survival improvements over which individuals would elect or refuse adjuvant chemotherapy but consensus on cutoffs and accurate risk estimates are needed to inform patient decisions.


EndoPredict

For individuals who have early-stage node-positive invasive breast cancer who are considering adjuvant chemotherapy who receive gene expression profiling with EndoPredict, the evidence includes 2 prospective-retrospective analyses. In 1 study, the 10-year distant recurrence rate in low-risk EndoPredict score individuals was estimated to be 5% (95% CI, 1% to 9%). In the other study, the 10-year distant recurrence rate in low-risk EndoPredict score individuals was estimated to be 5% but the upper bound of the 95% CI was close to 20%. To establish that the test has the 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.


MammaPrint (70-Gene Signature)

For individuals who have early-stage node-positive invasive breast cancer who are considering adjuvant chemotherapy who receive gene expression profiling with MammaPrint (70-gene signature), the evidence includes a clinical utility study. The randomized controlled trial Microarray In Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy showed 5-year distance recurrence rates below the 10% threshold among node-positive (1 to 3 nodes) individuals identified as low-risk.


Prosigna

For individuals who have early-stage node-positive invasive breast cancer who are considering adjuvant chemotherapy who receive gene expression profiling with the Prosigna risk of recurrence (ROR) score, the evidence includes a single prospective-retrospective study. The 10 year distant recurrence rate in low-risk Prosigna ROR individuals with a single positive node is roughly twofold the rate in low-risk ROR score node-negative individuals. However, in the single available study, the upper bound of the 95% CI for 10-year distant recurrence in node-positive individuals classified as ROR score low-risk was about 13%, which approaches the range judged clinically informative in node-negative individuals. The predicted recurrence rates require replication. To establish that the test has the 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.


Ductal Carcinoma In Situ

The Oncotype DX Breast DCIS Score is the only assay investigated for patients with DCIS.


Oncotype DX Breast DCIS Score

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


Extended Endocrine Therapy

For this indication, Oncotype DX, EndoPredict, Breast Cancer Index, MammaPrint, and Prosigna were evaluated. Studies retrospectively collecting tumor samples from prospective trials that provided 10 year distant recurrence rates or 10 year survival rates were included in this part of the evidence review. Studies comparing genetic assays with clinical risk prediction tools were also included.

Oncotype DX (21-Gene Assay)

For individuals who have early-stage node-negative invasive breast cancer who are distant recurrence-free at 5 years who are considering extending endocrine treatment who receive gene expression profiling with Oncotype DX (21-gene assay), the evidence includes 2 studies using data from the same previously conducted clinical trial. One analysis did not provide CIs and the other study reported a distant recurrence rate of 4.8% (95% CI, 2.9% to 7.9%) for the low-risk group. The ability of the test to reclassify individuals assessed with a clinical prediction tool was not reported.


EndoPredict

For individuals who have early-stage node-negative invasive breast cancer who are distant recurrence-free at 5 years who are considering extending endocrine treatment who receive gene expression profiling with EndoPredict, the evidence includes 2 analyses of archived tissue samples from 2 previously conducted clinical trials. The studies showed low distant recurrence rates in individuals classified as low-risk with EndoPredict. However, in 1 of the analyses, the lower-bound of the 95% CI for the distant recurrence rate in the high-risk group falls within a range that may be clinically meaningful for decision-making about avoiding extended endocrine treatment both at 5 to 10 years (5.9%; 95% CI, 2.2% to 9.5%) and at 5 to 15 years (15.1%; 95% CI, 4.0% to 24.9%). The ability of the test to reclassify individuals assessed with a clinical prediction tool was not reported although one publication reported that EPclin was prognostic after controlling for a clinical prediction tool. Additional prospective trials or retrospective-prospective studies of archived samples are needed to confirm risk of disease recurrence with sufficient precision in both low- and high-risk groups. More importantly, clarity is needed about how the test would inform clinical practice.


Breast Cancer Index

For individuals who have early-stage node-negative invasive breast cancer who are distant recurrence-free at 5 years who are considering extending tamoxifen treatment who receive gene expression profiling with the Breast Cancer Index, the evidence includes 3 analyses of archived tissue samples from 2 previously conducted clinical trials and a retrospective cohort study. The analyses showed low distant recurrence rates and high distant recurrence-free survival rates in individuals classified as low-risk with the test. Two studies suggested that, in addition to having a more favorable prognosis, low-risk individuals may receive less benefit from extended endocrine therapy. The ability of the test to reclassify individuals assessed with a clinical prediction tool was not reported. Clarity about how the test would inform clinical practice is needed. 


For individuals who have early-stage node-positive invasive breast cancer who are distant recurrence-free at 5 years who are considering extending endocrine treatment who receive gene expression profiling with the Breast Cancer Index, the evidence includes 4 analyses of archived tissue samples from previously conducted clinical trials. The analyses showed low distant recurrence rates and high distant recurrence-free survival rates in individuals classified as low-risk with the test. The studies suggested that, in addition to having a more favorable prognosis, low-risk individuals may receive less benefit from extended endocrine therapy. The ability of the test to reclassify individuals assessed with a clinical prediction tool was not reported. Clarity about how the test would inform clinical practice is needed.


MammaPrint (70-Gene Signature)

For individuals who have early-stage node-negative invasive breast cancer who are distant recurrence-free at 5 years who are considering extending tamoxifen treatment who receive gene expression profiling with MammaPrint (70-gene signature), the evidence includes a retrospective-prospective study. Analyses on individuals classified as ultralow-risk (a subgroup of the low-risk group) showed that this ultralow-risk group experienced high 10- and 20-year breast cancer-specific survival rates. Additional studies are needed to confirm the results of this single study. The ability of the test to reclassify individuals assessed with a clinical prediction tool was not reported. Clarity about how the test would inform clinical practice is needed.


Prosigna

For individuals who have early-stage node-negative invasive breast cancer who are distant recurrence-free at 5 years who are considering extending tamoxifen treatment who receive gene expression profiling with Prosigna, the evidence includes several studies from previously conducted clinical trials examined in 3 publications. The studies showed low distant recurrence rates in individuals classified as low-risk with the test. A reclassification result suggested that the test may offer little improvement over clinical predictors alone. Clarity about how the test would inform clinical practice is needed. 


Triple-Negative Breast Cancer

The Insight TNBCtype Test is the only assay investigated for individuals with TNBC.


Insight TNBCtype Test

For individuals who have TNBC considering neoadjuvant chemotherapy who receive gene expression profiling with the Insight TNBCtype test, the evidence includes retrospective cohort studies. Although the studies have shown that TNBC subtypes may differ in their response to neoadjuvant chemotherapy, as the studies were not prospectively designed or powered to specifically address the TNBC population or their specific therapeutic questions, conclusions cannot be drawn based on these findings. Additional Simon et al (2009) category A or B studies are required. Additionally, further clarity about how the test would inform clinical practice is still needed.​


MAMMOSTRAT® BREAST CANCER TEST, BREASTONCPX™, NEXCOURSE® Breast IHC4, BREASTPRS™

Evidence supporting these tests comprises clinical validity data showing that these tests are independently and significantly associated with distant recurrence and that the tests can identify a lower risk population of women with early, invasive breast cancer who may not need chemotherapy. In almost all cases, these tests are not added to and compared with a standard clinicopathologic classifier such as Adjuvant! Online. The BreastOncPx™ validation study included a receiver operating characteristic (ROC) curves analysis comparing the test with Adjuvant! Online, but no clear evidence supporting clinical utility was available. NexCourse® Breast IHC4 (immunohistochemical markers) was compared with standard clinicopathological prognostic classifiers in a reclassification analysis and was shown to accurately reclassify significant numbers of individuals from high and intermediate risk to low risk, but sample size was small and insufficient for conclusions.

No published literature on the use of gene expression profiling in men with breast cancer was identified.

OTHER TESTS (INCLUDING 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®.

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®.

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 (eg, 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) and the College of American Pathologists.

All other tests/assays in these testing spaces lack, at least, reliable evidence regarding their clinical utilities.

References

Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. Jan 2010; 11(1): 55-65. 


Amir E, Seruga B, Niraula S, et al. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst. Sep 07 2011; 103(17): 1299-309. 


Andre F, Ismaila N, Henry NL, et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Update-Integration of Results From TAILORx. J Clin Oncol. Aug 01 2019; 37(22): 1956-1964. 


Badve SS, Baehner FL, Gray RP, et al. Estrogen- and progesterone-receptor status in ECOG 2197: comparison of immunohistochemistry by local and central laboratories and quantitative reverse transcription polymerase chain reaction by central laboratory. J Clin Oncol. May 20 2008; 26(15): 2473-81. 


Bartlett JMS, Sgroi DC, Treuner K, et al. Breast Cancer Index and prediction of benefit from extended endocrine therapy in breast cancer patients treated in the Adjuvant Tamoxifen-To Offer More? (aTTom) trial. Ann Oncol. Nov 01 2019; 30(11): 1776-1783. 


Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg E, et al. Optimal Duration of Extended Adjuvant Endocrine Therapy for Early Breast Cancer; Results of the IDEAL Trial (BOOG 2006-05). J Natl Cancer Inst. Jan 01 2018; 110(1). 


Bosl A, Spitzmuller A, Jasarevic Z, et al. MammaPrint versus EndoPredict: Poor correlation in disease recurrence risk classification of hormone receptor positive breast cancer. PLoS One. 2017; 12(8): e0183458. 


Bueno-de-Mesquita JM, Sonke GS, van de Vijver MJ, et al. Additional value and potential use of the 70-gene prognosis signature in node-negative breast cancer in daily clinical practice. Ann Oncol. Sep 2011; 22(9): 2021-2030. 


Burstein HJ, Curigliano G, Loibl S, et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. Ann Oncol. Oct 01 2019; 30(10): 1541-1557. 


Burstein HJ, Griggs JJ, Prestrud AA, et al. American society of clinical oncology clinical practice guideline update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Oncol Pract. Sep 2010; 6(5): 243-6. 


Burstein HJ, Lacchetti C, Anderson H, et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update. J Clin Oncol. Feb 10 2019; 37(5): 423-438. 


Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. Aug 10 2010; 28(23): 3784-96. 


Burstein HJ, Temin S, Anderson H, et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J Clin Oncol. Jul 20 2014; 32(21): 2255-69.


Buus R, Sestak I, Kronenwett R, et al. Comparison of EndoPredict and EPclin With Oncotype DX Recurrence Score for Prediction of Risk of Distant Recurrence After Endocrine Therapy. J Natl Cancer Inst. Nov 2016; 108(11). 


Cardoso F, van't Veer LJ, Bogaerts J, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med. Aug 25 2016; 375(8): 717-29. 


Colleoni M, Sun Z, Price KN, et al. Annual Hazard Rates of Recurrence for Breast Cancer During 24 Years of Follow-Up: Results From the International Breast Cancer Study Group Trials I to V. J Clin Oncol. Mar 20 2016; 34(9): 927-35.


Curigliano G, Burstein HJ, Winer EP, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. Aug 01 2017; 28(8): 1700-1712. 


Davies C, Godwin J, Gray R, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. Aug 27 2011; 378(9793): 771-84. 


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Coding

CPT Procedure Code Number(s)

MEDICALLY NECESSARY


THE FOLLOWING CODE IS USED TO REPRESENT BREAST CANCER INDEX™


81518


THE FOLLOWING CODE IS USED TO REPRESENT ONCOTYPE DX® BREAST (21-GENE RECURRENCE SCORE)


81519


THE FOLLOWING CODES ARE USED TO REPRESENT MAMMAPRINT® (70-GENE SIGNATURE)


81521, 81523


THE FOLLOWING CODE IS USED TO REPRESENT PROSIGNA™/ PAM50 BREAST CANCER INTRINSIC SUBTYPE CLASSIFIER


81520


THE FOLLOWING CODE IS USED TO REPRESENT ENDOPREDICT™


81522


THE FOLLOWING CODE IS USED TO REPRESENT GENETIC COUNSELING BEFORE AND AFTER GENETIC TESTING


96040


EXPERIMENTAL/INVESTIGATIONAL


THE FOLLOWING CODE IS USED TO REPRESENT ONCOTYPE DX® BREAST DCIS


0045U


THE FOLLOWING CODE IS USED TO REPRESENT INSIGHT TNBCTYPE™


0153U


THE FOLLOWING CODE IS USED TO REPRESENT PreludeDx™'s DCISionRT® Test


0295U


THE FOLLOWING CODE IS USED TO REPRESENT MAMMOSTRAT® BREAST CANCER TEST, BREASTONCPX™, NEXCOURSE® BREAST IHC4, BREASTPRS™, BLUEPRINT®, AND TARGETPRINT® INSIGHT DX BREAST CANCER®, MAPQUANT DX™


81479

ICD - 10 Procedure Code Number(s)
N/A
ICD - 10 Diagnosis Code Number(s)

​N/A

HCPCS Level II Code Number(s)

MEDICALLY NECESSARY

THE FOLLOWING CODE IS USED TO REPRESENT INTERPRETATION AND REPORT

G0452 Molecular pathology procedure; physician interpretation and report

THE FOLLOWING CODE IS USED TO REPRESENT GENETIC COUNSELING BEFORE AND AFTER GENETIC TESTING

S0265 Genetic counseling, under physician supervision, each 15 minutes

EXPERIMENTAL/INVESTIGATIONAL

THE FOLLOWING CODE IS USED TO REPRESENT MAMMOSTRAT® BREAST CANCER TEST, BREASTONCPX™, NEXCOURSE® BREAST IHC4, BREASTPRS™, BLUEPRINT®, AND TARGETPRINT® INSIGHT DX BREAST CANCER®, MAPQUANT DX​™​

S3854 Gene expression profiling panel for use in the management of breast cancer treatment​

Revenue Code Number(s)
N/A


Coding and Billing Requirements

Policy History

6/6/2022
6/6/2022
8/9/2023
06.02.27
Medical Policy Bulletin
Commercial
No
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