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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. Five gene expression tests are commercially available in the U.S.: Oncotype DX™ (a 21-gene reverse transcriptase-polymerase chain reaction [RT-PCR] assay; Genomic Health), the 70-gene signature MammaPrint® (Agendia), Mammostrat® Breast Cancer Test (Clarient Diagnostic Services), the Breast Cancer IndexSM, a combination of the Molecular Grade Index (MGI) and the HOXB13:IL17BR Index (bioTheranostics), the BreastOncPx™ (Breast Cancer Prognosis Gene Expression Assay; LabCorp), NexCourse® Breast IHC4 (Geneoptix), and the PAM50 Breast Cancer Intrinsic Classifier (ARUP National Reference Laboratory).  If these panels are more accurate than current conventional classifiers, they could be used to aid chemotherapy decision-making, where current guidelines do not strongly advocate its use, without negatively affecting disease free and overall survival outcomes.

Oncotype DX, using a slightly different algorithm to calculate results, is also marketed for patients with noninvasive, ductal carcinoma in situ (DCIS) to predict the 10-year risk of local recurrence (DCIS or invasive carcinoma). The stated purpose is to help guide treatment decision making in women with DCIS treated by local excision, with or without adjuvant tamoxifen therapy.

All tests except MammaPrint are provided as laboratory-developed tests (LDTs) in Clinical Laboratory Improvement Act (CLIA)-licensed laboratories operated by each company. These LDTs have not been cleared by the U.S. Food and Drug Administration (FDA); to date, FDA clearance is not required.

MammaPrint has received 510(k) clearance for marketing by the FDA. All U.S. tests are performed at the CLIA-licensed Agendia clinical laboratory.

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 (e.g., MammaPrint 70-gene signature, Mammostrat Breast Cancer Test, the Breast Cancer Index, the BreastOncPx, NexCourse Breast IHC4, or PAM50 Breast Cancer Intrinsic Classifier) for any indication is considered investigational.

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.

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 DX^TM 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 DX^TM 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.

The code(s) listed below are ONLY covered if the procedure is performed according to the "Policy" section of this document.

Covered Codes