Genetic Assays of Tumor Tissue to Predict Prognosis of Breast Cancer* Printer-Friendly Version   

Medical Policy: 02.04.09 
Original Effective Date: December 2005 
Reviewed: January 2008 
Revised: July 2008 

This policy applies to all products unless specific contract limitations, exclusions or exceptions apply. Please refer to the member's coverage manual for benefit availability. Managed care guidelines related to referral authorization, and precertification of inpatient hospitalization, home health, home infusion and hospice services apply.

Description: 

For women with early stage breast cancer, 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 physician.

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. Three gene expression tests are commercially available in the United States: OncoType DX™, MammaPrint®, and the Breast Cancer Gene Expression Ratio. If these panels are more accurate then 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™ (Genomic Health, Inc.) is available only from the CLIA-licensed Genomic Health laboratory as a laboratory-developed service. This test has not been approved by the FDA; to date, FDA approval is not required, although this may change if and when the FDA draft, In Vitro Diagnostic Multivariate Index Assay (IVDMIA) guidelines are finalized and published. Genomic Health indications for the test are newly diagnosed breast cancer patients with stage I or II disease that is node-negative and estrogen receptor-positive, and who will be treated with tamoxifen.

OncoType DX™ 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 the primary breast cancer. The levels of expression are manipulated by an empirically derived, prospectively defined mathematical algorithm to calculate a recurrence score (RS) of 0 to 100, which is then used to assign a patient to 1 of 3 groups by estimated risk of distant recurrence: low risk (< 18), intermediate risk (18 to 30), and high risk (> 30). Genomic Health recommends that physicians use the score on a continuous scale, because the likelihood of distant recurrence at 10 years increases continuously as the risk score increases. Tissue sampling, rather then technical performance of the assay is likely to be the greatest source of variability in results. The OncoType DX™ assay was validated in studies using archived tumor samples from subsets of patients enrolled in already-completed randomized controlled trials of early breast cancer treatment.

For hormone receptor-positive, HER2-negative early breast cancer patients the 2008 National Comprehensive Cancer Network (NCCN) guidelines indicate that OncoType DX™ may be considered in patients whose tumors are node-negative, hormone-receptor-positive, HER2-negative, and 0.6-1.0 cm in size with moderate/poor differentiation or unfavorable features OR > 1 cm in size. NCCN does not suggest OncoType DX™ for HER2-positive tumors.

The 2007 American Society of Clinical Oncology (ASCO) guidelines indicate that “In newly diagnosed patients with node-negative, estrogen-receptor positive breast cancer, the OncoType DX™ assay can be used to predict the risk of recurrence in patients treated with tamoxifen.” In contrast, the St. Gallen expert consensus panel did not accept the molecularly based tools such as OncoType DX™ as sufficiently established to define risk categories.

Limitations of the current evidence, such as confirmation of optimal RS cutoff values for tamoxifen-treated and separately for aromatase inhibitor-treated patients and recommendations for patients with intermediate (11-25) RS values, may be answered by the results of the ongoing Trial Assigning IndividuaLized Options for Treatment (Rx), also known as TAILORx.  . TAILORx was launched in April 2006 and is designed to determine the best individual therapy for women with node-negative, estrogen receptor-positive breast cancer by using OncoType DX™ , and whether hormonal therapy alone or hormone therapy together with combination chemotherapy is better for women who have an OncoType DX™ RS of 11-25. Primary outcome measures for TAILORx include, disease-free survival, distant recurrence-free interval, recurrence-free interval, and overall survival. Results of TAILORx will not be available for at least 10 years.

MammaPrint® (Agendia) is a gene profiling assay that uses a customized RNA expression profile to measure the expression of a panel of 70 genes in breast cancer tumor tissue samples. Agendia sought FDA marketing clearance by classifying MammaPrint® as a Class II medical device and submitted a de novo 510(k) in September 2006, ahead of the FDA’s publication of the draft In Vitro Diagnostic Multivariate Index Assay (IVDMIA) guidelines. In February 2007, FDA granted marketing clearance for MammaPrint® as the first IVDMIA approved under the 510(k) premarket clearance process. The intended indication states that MammaPrint® is a qualitative in vitro diagnostic test, performed in a single laboratory, using the gene expression profile of fresh, frozen breast cancer tissue samples to assess an individual patient’s risk for distant metastases. The test is indicated for use in women who are less than 61 years of age, have stage I or stage II breast cancer with tumor size ≤ 5.0 cm, and who are lymph node-negative.

MammaPrint® is currently being studied in the MINDACT trial. MINDACT is a phase III trial underway in 250 hospitals in 30 European countries and is comparing the effectiveness of the MammaPrint® assay to standard clinical-pathologic criteria in determining the need for chemotherapy. MINDACT assumes MammaPrint® has been validated to predict the likelihood of breast cancer recurrence. Trial participants are evaluated and assigned a risk category according to the result of genomic testing and clinical evaluation. The 2 genomic categories are genomic high-risk (GHR) and genomic low risk (GLR). The 2 clinical categories are clinical high-risk (CHR) and clinical low-risk (CLR). Based on these scores women will be assigned to a treatment group: women with both CHR and GHR will receive chemotherapy; women with both CLR and GLR will not receive chemotherapy; and women with discordant risk between the 2 tools will be randomly assigned to receive chemotherapy or no chemotherapy. MINDACT was launched in December 2006. Trial participants will be followed annually for 15 years.

Breast Cancer Gene Expression Ratio is a quantitative assay that measures the ratio of the HOXB13 and IL17BR genes and is marketed as Aviara H/I^SM, a marker of recurrence risk in untreated breast cancer that is ER-positive and node-negative. No analyses show whether the Breast Cancer Gene Expression Ratio better classifies conventionally classified high-risk patients according to recurrence outcomes. There are no published studies retrospectively evaluating the ability of the Breast Cancer Gene Expression Ratio to predict chemotherapy benefit in comparison with conventional criteria. Another molecular biomarker, marketed as Aviara MGI^SM (Molecular Grade Index) is intended to improve the accuracy of tumor grading. In a paper published in May 2008, the combination of the Aviara MGI^SM and Aviara H/I ^SM enhances risk stratification pertaining to endocrine therapy benefit and treatment outcome. The combination of these two biomarkers is commercially available as the Aviara Breast Cancer Index^SM.

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Policy: 

The use of OncoType DX™ to predict recurrence risk for deciding whether or not to undergo adjuvant chemotherapy may be considered medically necessary in women newly diagnosed with breast cancer meeting all of the following characteristics:

• Unilateral, non-fixed tumor;
• Node-negative (lymph nodes with micrometastases are not considered positive for purposes of treatment recommendations);
• Hormone-receptor-positive (ER-positive or PR-positive);
• HER2-negative;
• Tumor size 0.6 to 1.0 cm with moderate/poor differentiation or unfavorable features, OR tumor size > 1 cm;

AND

• Who will be treated with hormonal or aromatase inhibitor therapy.

OncoType DX™ should only be ordered after surgery and subsequent pathology examination of the tumor has been completed. The test should be ordered in the context of a physician-patient discussion regarding risk preferences and when the test result will aid the patient in making decisions regarding chemotherapy.

All other indications for OncoType DX™ are considered investigational.

The use of MammaPrint® for any indication is considered investigational because there is insufficient evidence to determine whether it is better than conventional risk assessment tools in predicting recurrence.

The use of the Breast Cancer Gene Expression Ratio or Aviara H/I^SM, the Aviara MGI^SM, and the Aviara Breast Cancer Index ^SM  for any indication is considered investigational because there is insufficient evidence to determine whether any of these biomarkers alone or in combination is better than conventional risk assessment tools in predicting recurrence.

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Procedure Codes and Billing Guidelines: 

• To report provider services, use appropriate CPT** codes, Alpha Numeric (HCPCS) level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes.
• HCPCS code S3854, Gene expression profiling panel for use in the management of breast cancer treatment 

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Selected References: 

• A review of medical literature and recommendations from Wellmark's Medical Policy Advisory Council (MPAC), a council of practicing physicians who advise and assist Wellmark in the development and implementation of medical policies. The council is comprised of primary care and specialty physicians from Iowa and South Dakota.
• Esteva FJ, Sahin AA, Cristofanilli M et al. Prognostic role of a multigene reverse transcriptase-PCR assay in patients with Node-negative breast cancer not receiving adjuvant systemic therapy. Clin Cancer Res. 2005; 11(9):3315-3319.
• Paik S, Shak S. Tang G et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004; 351(27):2817-2826.
• Wang Y, Klijn JGM, Zhang Y et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 2005; 365:671-79.
• Gianni L, Zambetti M, Clark K et al. Gene expression profiles of paraffin-embedded core biopsy tissue predict response to chemotherapy in patients with locally advanced breast cancer. J Clin Oncol. 2004; 22 (14 Suppl):501 [Abstract].
• Hannemann J, Oosterkanp HM, Bosch CA et al. Changes in gene expression profiling due to primary chemotherapy in patients with locally advanced breast cancer. J Clin Oncol. 2004; 22(14 Suppl):502 [Abstract].
• Van de Vijver MJ, He YD, Van 't Veer LJ et al. A gene-expression signature as a predicator of survival in breast cancer. N Engl J Med. 2002; 347(25):1999-2009.
• Habel LA, Quesenberry CP, Jacobs M et al. Gene expression and breast cancer mortality in Northern California Kaiser Permanente patients; a large population-based case control study. Proceedings from the 41st Annual Meeting of the American Society of Clinical Oncology. May 13-17, 2005. Orlando, FL. Abstract #603.
• ECRI. Oncotype DX^TM Assay to Predict Recurrence in Breast Cancer. Plymouth Meeting (PA): ECRI Health Technology Information Service; 2005. (ECRI Hotline Response).
• Blue Cross Blue Shield Association Technology Evaluation Center. Gene Expression Profiling for Managing Breast Cancer Treatment. Assessment Program 2005; 20(3).
• Hayes Inc. Gene Expression Profiling of Tumor Tissue to Predict Breast Cancer Recurrence. Hayes Alert. September 2005; VIII(9).
• National Comprehensive Cancer Network. Clinical Practice Guidelines. Breast Cancer. v.2.2006. (http://nccn.org/professional/physician_gls/PdF/breast.pdf)
• Paik S, Tang G, Shak S et al. gene Expression and benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor-Positive Breast Cancer. J Clin Oncol. 2006 Aug 10;24(23):3717-8.
• TARGET [database online]. Plymouth Meeting (PA): ECRI; 2006 Aug. Gene expression assay for predicting recurrence of breast cancer.
• Goldhirsch A, Wood W, Gelber R et al.Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 2007;18(7):1133-44.
• Mina L, Soule SE, Badve S et al. Predicting response to primary chemotherapy: gene expression profiling of paraffin-embedded core biopsy tissue. Breast Caner Res treat 2007;103(2):197-208.
• Glas AM, Floore A, Delahaye LJ et al. Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genomics 2006; 7:278.
• Reid JF, Lusa L, De Cecco L et al. Limits of predictive models using microarray data for breast cancer clinical treatment outcome. J Natl Cancer Inst 2005;97(12):927-30.
• Harris L, Fritsche H, Mennel R et al. American Society of Clinical Oncology 2007 Update of recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol. 2007 Nov 20;25(33). Published ahead of print on October 22, 2007 as 10.1200/JCO.2007.14.2364.
• Emerging Technology (TARGET) Evidence Report. Plymouth Meeting (PA): ECRI Institute; January 2008. Gene expression profiling of breast cancer to predict the likelihood of recurrence.
• Ma X-J, Salunga R, Dahiya S et al. A Five-Gene Molecular Grade Index and HOXB13:IL17BR Are Complementary Prognostic Factors in Early Stage Breast Cancer. Clin Cancer Res 2008;14(9):2601-2608.
• Jerevall PL, Brommesson S, Strand C et al. Exploring the two-gene ration in breast cancer-independent roles for HOXB13 and IL17BR in prediction of clinical outcome.  Breast Cancer Res Treat. 2008 Jan;107(2):225-34. E-pub 2007 Apr 24.
• Jansen MP, Sieuwerts AM, Look MP et al. HOXB13-to-IL17BR expression ratio is related with tumor aggressiveness and response to tamoxifen of recurrent breast cancer: a retrospective study. J Clin Oncol. 2007 Feb 20;25(6):662-8. 

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Wellmark Blue Cross and Blue Shield
Medical Policy Analyst
Station 304
636 Grand Ave
Des Moines, Iowa 50309

*Prior Approval is recommended for this policy.

**Current Procedural Terminology © 2008 American Medical Association. All Rights Reserved.

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.