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DESCRIPTIONLaboratory tests have been developed that detect the expression, via messenger RNA (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 patients decide whether to include adjuvant chemotherapy in post-surgical management.
For women with early-stage, invasive breast cancer (i.e. cancer extends 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 positive, and lymph node-negative. These women have an approximately 15% baseline risk of recurrence; approximately 85% of these patients 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 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 patients 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 physicians.
Recently, several groups have identified panels of gene expression markers (“signatures”) that appear to predict the baseline risk of breast cancer recurrence after surgery, radiotherapy, and endocrine therapy (for hormone receptor-positive tumors). Several gene expression tests commercially available in the U.S. are listed in the table below. 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).
Gene Expression Tests for Breast Cancer Commercially Available in the United States
ER: estrogen receptor; HER2: human epidermal growth factor receptor 2; IHC: immunohistochemistry; Ki-67: a marker of tumor proliferation; MGI: Molecular Grade Index; PAM50: prediction analysis of microarray 50 gene set; PR: progesterone receptor; RT-PCR: real-time reverse transcriptase-polymerase chain reaction.
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.
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®.
MammaPrint® was U.S. Food and Drug Association (FDA)-approved on February 6, 2007. MammaPrint® is performed in Agendia laboratories in the Netherlands and in California. On January 23, 2015, MammaPrint® received FDA 510(k) marketing clearance for use in fresh-frozen, paraffin-embedded breast cancer tissue.
Prosigna™ received 510(k) clearance from FDA based on substantial equivalence to MammaPrint® on September 6, 2013.
Other tests mentioned in this policy are offered as laboratory-developed tests under Clinical Laboratory Improvement Amendments (CLIA)‒licensed laboratories. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratories offering such tests as a clinical service must meet general regulatory standards of CLIA and must be licensed by CLIA for high-complexity testing.
POLICYThe use of the 21-gene RT-PCR assay (i.e.,Oncotype DX®) to determine recurrence risk for deciding whether or not to undergo adjuvant chemotherapy may be considered medically necessary in women with primary, invasive breast cancer meeting all of the following characteristics:
The 21-gene RT-PCR assay Oncotype DX® should only be ordered on a tissue specimen obtained during surgical removal of the tumor and after subsequent pathology examination of the tumor has been completed and determined to meet the above criteria (i.e., the test should not be ordered on a preliminary core biopsy). The test should be ordered in the context of a physician-patient discussion regarding risk preferences when the test result will aid in making decisions regarding chemotherapy.
For patients who otherwise meet the above characteristics but who have multiple ipsilateral primary 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.
All other indications for the 21-gene RT-PCR assay (i.e., Oncotype DX®), including determination of recurrence risk in invasive breast cancer patients with positive lymph nodes or patients with bilateral disease, are considered investigational.
Use of a subset of genes from the 21-gene RT-PCR assay for predicting recurrence risk in patients with noninvasive ductal carcinoma in situ (i.e., Oncotype DX® DCIS) to inform treatment planning following excisional surgery is considered investigational.
The use of other gene expression assays, MammaPrint® 70-gene signature, Mammostrat® Breast Cancer Test, the Breast Cancer IndexSM, BreastOncPx™, NexCourse® Breast IHC4, Prosigna®, BreastPRS™, and EndoPredict® for any indication is considered investigational.
The use of gene expression assays in men with breast cancer is considered investigational.
The use of gene expression assays to molecularly subclassify breast cancer (eg, BluePrint®) is considered investigational.
The use of gene expression assays for quantitative assessment of ER, PR, and HER2 overexpression (eg, TargetPrint®) is considered investigational.
POLICY GUIDELINESUnfavorable features that may prompt testing in tumors from 0.6 to 1 cm in size include the following: angiolymphatic invasion, high histologic grade, or high nuclear grade.
The 21-gene reverse transcriptase-polymerase chain reaction (RT-PCR) assay Oncotype DX® should not be ordered as a substitute for standard estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 (HER2) testing.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY3/31/2005: Approved by Medical Policy Advisory Committee (MPAC)
6/6/2005: Code Reference section completed
3/15/2006: Policy reviewed, no changes
3/21/2006: Coding updated. HCPCS 2006 revision added to policy
1/21/2008: Oncotype DXTM added to policy statement
1/23/2008: CPT 89240 added to covered codes. Non-covered codes table changed to covered codes table for the Oncotype DXTM as outlined in the POLICY section. Description section updated
3/27/2008: Reviewed and approved by the Medical Policy Advisory Committee (MPAC)
10/7/2008: Policy statement rewritten and clarified.
04/20/2010: Policy description updated. Policy statements revised to add more detail; specific statements added regarding testing of multiple ipsilateral primaries and timing of Oncotype DX testing (i.e., within 6 months following diagnosis). Outdated references deleted from the Sources section.
08/02/2011: Policy reviewed; no changes.
03/13/2013: Policy description revised regarding available assays. The investigational policy statement for Oncotype DX was revised to include ibreast cancer patients with positive lymph nodes and patients with bilateral disease. Added the following policy statement: Use of a subset of genes from the 21-gene RT-PCR assay for predicting recurrence risk in patients with noninvasive ductal carcinoma in situ (i.e., Oncotype DX DCIS) to inform treatment planning following excisional surgery is considered investigational. The investigational policy statement regarding the use of other gene expression assays for any indication was expanded to add the following tests: MammaPrint 70-gene signature, Mammostrat Breast Cancer Test, the Breast Cancer Index, the BreastOncPx, NexCourse Breast IHC4, or PAM50 Breast Cancer Intrinsic Classifier.
09/22/2014: Policy description updated regarding available assays. Added the following tests to the investigational policy statement: Prosigna™ BreastPRS™, and EndoPredict™. Added the following policy statements: 1) The use of gene expression assays in men with breast cancer is considered investigational. 2) The use of gene expression assays to molecularly subclassify breast cancer (eg, BluePrint®) is considered investigational. 3) The use of gene expression assays for quantitative assessment of ER, PR, and HER2 overexpression (eg, TargetPrint®) is considered investigational.
04/27/2015: Added CPT code 81519 to the Code Reference section.
07/06/2015: Code Reference section updated for ICD-10.
12/31/2015: Policy guidelines updated to add medically necessary and investigative definitions.
02/02/2016: Policy description updated regarding gene expression tests for breast cancer. Medically necessary policy statement updated to make the following changes: "women with breast cancer" changed to "women with primary, invasive breast cancer" and "unilateral, non-fixed tumor" changed to "unilateral tumor."
06/06/2016: Policy number added.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.36
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.