Breast Cancer Recurrence Assay (MammaPrint )

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1 Harmony Behavioral Health, Inc. Harmony Behavioral Health of Florida, Inc. Harmony Health Plan of Illinois, Inc. HealthEase of Florida, Inc. Ohana Health Plan, a plan offered by WellCare Health Insurance of Arizona, Inc. WellCare Health Insurance of Illinois, Inc. WellCare Health Insurance of New York, Inc. WellCare Health Plans of New Jersey, Inc. WellCare of Florida, Inc. WellCare of Connecticut, Inc. WellCare of Georgia, Inc. WellCare of Kentucky, Inc. WellCare of Louisiana, Inc. WellCare of New York, Inc. WellCare of Ohio, Inc. WellCare of Texas, Inc. WellCare Prescription Insurance, Inc. Breast Cancer Recurrence Assay (MammaPrint ) Policy Number: Original Effective Date: 12/1/2011 Revised Date(s): N/A DISCLAIMER The Clinical Coverage Guideline is intended to supplement certain standard WellCare benefit plans. The terms of a member s particular Benefit Plan, Evidence of Coverage, Certificate of Coverage, etc., may differ significantly from this Coverage Position. For example, a member s benefit plan may contain specific exclusions related to the topic addressed in this Clinical Coverage Guideline. When a conflict exists between the two documents, the Member s Benefit Plan always supersedes the information contained in the Clinical Coverage Guideline. Additionally, Clinical Coverage Guidelines relate exclusively to the administration of health benefit plans and are NOT recommendations for treatment, nor should they be used as treatment guidelines. The application of the Clinical Coverage Guideline is subject to the benefit determinations set forth by the Centers for Medicare and Medicaid Services (CMS) National and Local Coverage Determinations and state-specific Medicaid mandates, if any. APPLICATION STATEMENT The application of the Clinical Coverage Guideline is subject to the benefit determinations set forth by the Centers for Medicare and Medicaid Services (CMS) National and Local Coverage Determinations and state-specific Medicaid mandates, if any.

2 BACKGROUND In 2010, over 207,000 new cases of breast cancer among women in the United States while 39,840 died from the disease (NCI, 2011a). With early detection, the 5-year survival rate for women with breast cancer is 98.6%; if the cancer spreads to the lymph nodes the 5-year survival drops to 83.8% and decreases drastically to 23.4% when the cancer metastasizes (NCI, 2011b). Due to the high rate of early detection prior to metastasis (93%), the overall 5-year survival rate is 89.1%; the number is 12% lower among black women (NCI, 2011b). MammaPrint (Agendia, BV, Amsterdam, Holland; also referred to as the "Amsterdam signature"), in 2010 became the only FDA-approved test for stage 1 and 2 breast cancer patients of all ages and is a predictor of disease outcome, especially in early stage breast cancer. The test identifies patients with early metastasis risk which is likely within 5 years following surgery; MammaPrint provides practitioners with a clear rationale to assess the benefit of chemotherapy in addition to other clinical information and pathology tests. ( FDA Expands Approval for MammaPrint Test, 2010). A benefit of Mammaprint is the ability to influence the usage, or non-usage, of chemotherapy. The test measures the activity of 70 genes, providing information about the likelihood that cancer will recur. It measures each of these genes in a sample of a woman's breast-cancer tumor and then uses a specific formula to produce a score that determines if the patient is deemed low-risk or high-risk for metastasis. In clinical trials, 1 in 4 women found to be at high risk by Mammaprint had recurrence of their cancer within 5 years. However, there are questions regarding the accuracy of this test. The positive predictive values at 5 and 10 years were 23% and 29%, respectively, while the corresponding negative predictive values were 95% and 90%, respectively. Mammaprint was tested on 307 patients under the age of 61 years who underwent surgery for stage I or stage II breast cancer, and who have tumor size equal to or less than 5 cm, and lymph node-negative. The study found that Mammaprint more than doubled physicians' ability to predict breast cancer recurrence. Furthermore, a major clinical study is now underway to determine the tests efficacy in helping patients avoid needless chemotherapy; the European study will recruit 6,000 patients with early-stage breast cancer. POSITION STATEMENT Use of the Breast Cancer Recurrent Assay (MammaPrint ) is considered experimental and investigational and is not a covered benefit. Centers for Medicare and Medicaid Services (CMS) Patients with high risk of relapse need to be identified and treated with a systematic adjuvant therapy. However, while adjuvant therapies, such as chemotherapy and hormonal therapy, can reduce the risk of distant metastases by approximately one-third, it is estimated that many patients receiving chemotherapy may have survived without it and also avoided often unpleasant side-effects. MammaPrint, in addition to other tests and clinical factors, helps to classify the tumors into high and low risk for recurrence. Chemotherapy itself has inherent risk of morbidity, particularly in patients with comorbid conditions. When physicians make treatment decisions that chemotherapy can be safely avoided and alternative therapy (hormonal manipulation, radiation therapy) used, there can be patient benefit. Indications and Limitations of Coverage Based on analysis of peer-reviewed publications, FDA approval, local guidance by practicing oncologists, review by knowledgeable pathologists, and guidance from our Contractor Advisory Committee oncologists, Palmetto GBA has determined that the MammaPrint genetic expression profiling test is considered safe and effective and reasonable Clinical Coverage Guideline page 2

3 and necessary to contribute to breast cancer prognoses with the following limitations: 1. Characteristics of the Disease The MammaPrint test is covered for patients with breast cancer with the following criteria: Tumor size <5.0 cm Lymph node negative Stage 1 and Stage 2 invasive breast cancer ER+ or ER- Tamoxifen independent Nodal micrometastases (< 2.0 mm) No more than three positive lymph nodes 2. Medical Necessity of the Test Medical tests are covered only when ordered by the treating physician, when necessary for diagnosis or treatment decisions, and when used in patient care. Documentation on file with the treating physician should indicate that results of the MammaPrint test are expected to play a significant role (along with other clinical findings) in the prognosis of the patient. For example, a patient with a large, high grade stage 3 invasive carcinoma who in agreement with the oncologist and patient, has decided to have adjuvant chemotherapy regardless of the results of the test would not be an appropriate candidate for this test. 3. Timeliness of the Test MammaPrint is FDA approved for assisting in the prognosis of patients with breast cancer of non-metastatic or stage 1 and 2 invasive breast carcinoma. In addition, more recent clinical data supports its use for micrometastases and for 1-3 positive lymph nodes. Usual chemotherapies have been studied for effectiveness based on initiation within 3 months of diagnosis. MammaPrint test is not considered reasonable and necessary for care when more than six months have elapsed since diagnosis, or if chemotherapy has been initiated, since the value of the test for highly delayed chemotherapy is not established. NOTE: Applies to claims payable by Medicare Part B. HAYES RATING FOR GENETIC TEST A rating of C was given by Hayes for the MammaPrint assay for prediction of risk of breast cancer recurrence in women with primary breast cancer. POSITION AND POLICY STATEMENTS National Comprehensive Cancer Network (NCCN) The NCCN guidelines for systemic adjuvant treatment for invasive breast cancer discussed the availability and some of the clinical data behind the MammaPrint assay, but declined to include the assay in its clinical guidelines. In contrast, the Oncotype Dx 21-gene assay was included as an option for some patients to aid in estimating the likelihood of cancer recurrence and potential benefit from chemotherapy (NCCN, 2011). Clinical Coverage Guideline page 3

4 Evaluation of Genomic Applications in Practice (EGAPP) Working Group In January 2009, the EGAPP Working Group published a report on the ability of tumor gene expression profiling to improve the outcomes of patients with breast cancer (EGAPP Working Group, 2009). This report was based on an earlier systematic review of the literature (Marchionni, Wilson, Wolff, & et al., 2008). The MammaPrint assay was included in the review and the conclusions were as follows (EGAPP Working Group, 2009): Analytical Validity: Some data were available for the MammaPrint assay, although estimates of analytical sensitivity and specificity could not be made. Overall, there was inadequate evidence of the analytical validity for the MammaPrint assay. Clinical Validity: Data were found to be adequate that characterized the association of MammaPrint with future metastases, but inadequate evidence was identified to assess the added value to standard risk stratification, and finally, the population to which the test applied could not be determined. Clinical Utility: No evidence was found with regards to the clinical utility of the MammaPrint assay. Overall, although use of the MammaPrint assay could plausibly improve patient outcomes, there was insufficient evidence to assess the balance of risks and harms (EGAPP Working Group, 2009). American Society of Clinical Oncology (ASCO) In 2007, ASCO published an update to the recommendations of the use of tumor markers in the treatment and management of breast cancer. The recommendation for the MammaPrint assay was that the precise clinical utility and appropriate application remain to be determined and are under investigation (Harris, Fritsche, Mennel, & et al., 2007). CLINICAL EVIDENCE In a study by Deck, Sinha, Kerlin, Barone, Rivera, Garcia, & et al. (2011), MammaPrint was measured in a prospective U.S. breast cancer patient cohort to determine how it compares to treatment advice according to National Comprehensive Cancer Network (NCCN) consensus guidelines. MammaPrint results were evaluated in fresh tumor samples from 111 breast cancer patients (median age 62) in 7 U.S. hospitals, collected by core needle biopsy or from a surgical specimen between July 2008 and November According to NCCN treatment recommendations, 6 patients should receive adjuvant endocrine therapy: 5 of these patients were classified as High Risk by NCCN guidelines and 1 as Low Risk by MP. For another 5 patients, NCCN recommendations could not be determined due to a missing clinical parameter (all high risk by MP). For the remaining 100 patients, NCCN guidelines recommends (n=46) or suggests to consider (n=54) adjuvant chemotherapy: 24 of these patients were classified as MammaPrint low risk and the remaining as MammaPrint high risk. For the 100 (94%) out of 111 patients, NCCN guidelines either recommended or suggested considering adjuvant chemotherapy. In contrast, MammaPrint indicated a low risk of recurrence in 24 of these cases. Integration of MammaPrint into clinical risk assessment could improve the management of early-stage breast cancer and avoid unnecessary chemotherapy for low risk patients. Knauer, Cardoso, Wesseling, Bedard, Linn, Rutgers, & et al. (2010) investigated whether the 70-gene MammaPrint signature identifies HER-2-positive patients with favorable outcome. In the group of 89 chemotherapy-naive patients, after a median follow-up of 7.4 years, 35 (39%) distant recurrences and 29 (33%) breast cancer-specific deaths occurred. The 70-gene signature classified 20 (22%) patients as good prognosis, with 10-year distant disease-free survival (DDFS) of 84%, compared with 69 (78%) poor prognosis patients with 10-year DDFS of 55%. Clinical Coverage Guideline page 4

5 The 70-gene prognosis signature is an independent prognostic indicator that identifies a subgroup of HER-2- positive early breast cancer with a favorable long-term outcome. Kunz (2011) studied the adaptation of MammaPrint into clinical work-up procedures through an investigation of 56 patients with an average age of 45 years treated at a general hospital in Germany between 2004 and To assess MammaPrint s accuracy, a meta-analysis was performed on a subgroup from previously described retrospective studies ( n = 689). Retrospectively validated data revealed that the MammaPrint helped to identify young breast cancer patients with clinicopathologic low risk disease who might be spared chemotherapy. Kunz also found that MammaPrint has a very high negative predictive value for distant disease following adjuvant treatment in older women with breast cancer. The principal outcome of our study is the observation that gene expression analysis separated patients with an intermediate clinical risk for distant disease into distinct low- and high-risk groups. Thus, in 34 women with an intermediate risk according to the St. Gallen guidelines, MammaPrint classified 11 as high and 23 as low risk. While this prospective study has no long-term follow-up of the patients, it has to be suggested that our findings corroborate recent analyses that the 70-gene signature has high clinical relevance regarding the stratification of younger women with early breast cancer disease. Gene expression analysis provides a prognostic tool serving to separate breast cancer patients with an intermediate clinical risk into distinctive good and poor prognosis risk groups and thus may provide an important tool helping to select appropriate adjuvant therapy. Two studies have evaluated the use of the MammaPrint test in subjects with node-negative disease (Bueno-de- Mesquita, van Harten, Retel, & et al., 2007; Bueno-de-Mesquita, Linn, Keijzer, & et al., 2009). MammaPrint prognostic index results were compared to other commonly used clinicopathologic risk indexes, and both reported favorable results. None of these studies has evaluated the impact of the MammaPrint test on overall survival, nor on the avoidance of unnecessary treatment with chemotherapy. Knauer, Mook, Rutgers, & et al. (2010) reported the results of a quasi meta-analysis study involving the data from previous studies. The data set included data from 541 subjects who had received either breast conserving surgery or mastectomy with sentinel node biopsy or axillary lymph node dissection followed by radiotherapy. For this study, data for all subjects who received endocrine therapy (ET) alone or ET plus adjuvant chemotherapy (ET+CT) was reanalyzed for benefit of adjuvant CT using groups classified as good or poor prognosis based upon MammaPrint testing as a framework. Additionally, time-to-event data was gathered and analyzed from the pooled data. The authors reported that BCSS and distant disease-free survival (DDFS) were significantly better in subjects classified as having a good prognosis compared to those classified as poor prognosis (p < 0.01). Furthermore, the data showed that subjects in the poor prognosis group who had received ET+CT had a significantly longer BCSS and DDFS when compared to those in the good prognosis group (BCSS 94% vs. 81%, p < 0.01; DDFS 88% vs. 76%, p < 0.01). No differences between the ET and EC+CT groups were found in relation to the benefit of CT in the good prognosis group. In a systematic review on gene expression profiling assays in early-stage breast cancer, Marchionni, Wilson, Wolff, & et al. (2008) summarized evidence on the validity and utility of 3 gene expression-based prognostic breast cancer tests: Oncotype Dx, MammaPrint, and H/I. The authors concluded that gene expression technologies show great promise to improve predictions of prognosis and treatment benefit for women with early-stage breast cancer. However, more information is needed on the extent of improvement in prediction, characteristics of women in whom the tests should be used, and how best to incorporate test results into decision making about breast cancer treatment. Harris, Fritsche, Mennel, & et al. (2007) state: "The precise clinical utility and appropriate application for other multiparameter assays, such as the MammaPrint assay, the "Rotterdam Signature," and the Breast Cancer Gene Expression Ratio are under investigation." Clinical Coverage Guideline page 5

6 The AHRQ technology assessment (2008) states: "The evidence for clinical implications of using MammaPrint was not as clear as with Oncotype DX, and the ability to predict chemotherapy benefit does not yet exist. The H/I ratio test requires further validation. For all tests, the relationship of predicted to observed risk in different populations still needs further study, as does their incremental contribution, optimal implementation, and relevance to patients on current therapies." EVIDENCE-BASED PROJECTIONS A weakness of the MammaPrint in the United States is the requirement that a fresh frozen tissue specimen is needed for the test to be possible because of the degradation of RNA in FFPE samples. A recent study has examined the possibility of using FFPE samples to perform microarray analysis using a complementary DNA (cdna)-mediated annealing, selection, extension, and ligation (DASL) assay. Twenty matched FFPE and fresh frozen samples were analyzed using the new DASL assay and the MammaPrint test, and a high level of concordance was found (Mittempergher et al., 2011). If a new version of the MammaPrint assay can be developed that can accept FFPE specimens for analysis, this would greatly enhance the practicality and acceptability of this assay. The MINDACT study, which is investigating the clinical utility of the MammaPrint assay, is currently ongoing, but results will not be available for several more years. Until the results of this study are available, the clinical utility of the MammaPrint assay remains undefined. CODING CPT * Code Unlisted Chemistry Procedure when billed for MammaPrint ICD-9-CM Procedure Codes No applicable codes HCPCS Level II Code S3854* Gene expression profiling panel for use in the management of breast cancer treatment *S- Codes are NON COVERED FOR MEDICARE ICD-9-CM Diagnosis Codes Covered when ALL of the above criteria are met Malignant neoplasm of female breast, nipple and areola Malignant neoplasm of female breast, central portion Malignant neoplasm of female breast, upper-inner quadrant Malignant neoplasm of female breast, lower-inner quadrant Malignant neoplasm of female breast, upper-outer quadrant Malignant neoplasm of female breast, lower-outer quadrant Malignant neoplasm of female breast, axillary tail Malignant neoplasm of female breast, other specified site(s) Malignant neoplasm of female breast, unspecified site(s) Malignant Neoplas of Other and Unspecified Sites of Male Breast V86.0 Estrogen Receptor Positive Status (ER+) V86.1 Estrogen Receptor Negative Status (ER-) *Current Procedural Terminology (CPT ) 2011 American Medical Association: Chicago, IL. Clinical Coverage Guideline page 6

7 REFERENCES Peer Reviewed 1. Bueno-de-Mesquita, J.M., Linn, S.C., Keijzer, R., & et al. (2009). Validation of 70-gene prognosis signature in node-negative breast cancer. Breast Cancer Research and Treatment, 117(3), Bueno-de-Mesquita, J.M., van Harten, W.H., Retel, V.P., et al. (2007). Use of 70-gene signature to predict prognosis of patients with node-negative breast cancer: a prospective community-based feasibility study (RASTER). Lancet Oncolology, 8(12), Deck, K.B., Sinha, R., Kerlin, D., Barone, J., Rivera, E., Garcia, A.A., & et al. (2011). Comparison of MammaPrint and TargetPrint with clinical parameters in patients with breast cancer: Findings from a prospective U.S. cohort. Journal of Clinical Oncology, 29: Harris, L., Fritsche, H., Mennel, R., & et al. (2007). American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. Journal of Clinical Oncology, 25(33), Hayes Directory. (2011, June 6). MammaPrint. Retrieved from 6. Knauer, M., Cardoso, F., Wesseling, J., Bedard, P.L., Linn, S.C., Rutgers, E.J.T., & et al. (2010). Identification of a low-risk subgroup of HER-2-positive breast cancer by the 70-gene prognosis signature. British Journal of Cancer, 103(12), Knauer, M., Mook, S., Rutgers, E.J., & et al. (2010). The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Research and Treatment, 120(3), Kunz, G. (2011). Use of a genomic test (MammaPrint ) in daily clinical practice to assist in risk stratification of young breast cancer patients. Archives of Gynecology & Obstetrics, 283(3), Marchionni, L., Wilson, R.F., Wolff, A.C., & et al. (2008). Systematic review: gene expression profiling assays in early-stage breast cancer. Annals of Internal Medicine, 148(5): Mittempergher, L., de Ronde, J.J., Nieuwland, M., & et al. (2011). Gene expression profiles from formalin fixed paraffin embedded breast cancer tissue are largely comparable to fresh frozen matched tissue. PLoS ONE, 6(2): e Government Agencies, Professional and Medical Organizations 1. Agency for Healthcare Research and Quality (AHRQ). (2008). Technology assessment number 160: impact of gene expression profiling tests on breast cancer outcomes. Retrieved from 2. Agendia. (2011). MammaPrint. Retrieved from 3. Centers for Medicare and Medicaid Services. (2011, September). Local coverage determination for MammaPrint breast cancer prognosis (L30376). Retrieved from 4. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. (2009). Recommendations from the EGAPP working group: can tumor gene expression profiling improve outcomes in patients with breast cancer? Genetic Medicine, 11(1), National Cancer Institute (NCI). (2011b). Breast cancer treatment (PDQ ): sage information for breast cancer. Retrieved from 6. United States Food and Drug Administration. (2010). 510(k) substantial equivalence determination decision summary. Retrieved from HISTORY AND REVISIONS Date Action 12/1/2011 Approved by MPC. New guideline. New template design approved by MPC. Clinical Coverage Guideline page 7

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