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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 milk 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 gold 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, radiation therapy, and hormonal therapy (for hormone receptor-positive tumors) in women with node-negative disease. 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).
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.
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®.
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.
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 breast cancer meeting 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.
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
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.
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.