Clinical Policy Title: Gene expression profile testing for breast cancer

Clinical Policy Title: Gene expression profile testing for breast cancer Clinical Policy Number: 02.01.14 Effective Date: December 1, 2013 Initial Review Date: July 17, 2013 Most Recent Review Date: April 27, 2016 Next Review Date: April 2017 Related policies: Policy contains: Gene expression profile/assay/test. Breast cancer. Oncotype DX. MammaPrint. OpenArray RealTime PCR CP# 02.01.02 CP# 17.01.03 Genetic testing for breast and ovarian cancer Breast cancer screening in women ABOUT THIS POLICY: Select Health of South Carolina has developed clinical policies to assist with making coverage determinations. Select Health of South Carolina s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Select Health of South Carolina when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Select Health of South Carolina s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Select Health of South Carolina s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Select Health of South Carolina will update its clinical policies as necessary. Select Health of South Carolina s clinical policies are not guarantees of payment. Coverage policy Select Health of South Carolina considers the use of 21-gene expression profile testing (i.e., Oncotype DX ) in early-stage breast cancer to be clinically proven and, therefore, medically necessary where the following criteria are met: Breast cancer is nonmetastatic, or with 1 3 involved ipsilateral axillary lymph nodes; AND Breast tumor is estrogen receptor positive; AND Breast tumor is HER-2 receptor negative or breast tumor is HER2 receptor positive and less than 1 cm in diameter; AND Adjuvant chemotherapy is not contraindicated due to any other factor (e.g., advanced age and/or significant co-morbidities); AND Member and physician (prior to testing) have discussed the potential results of the test and agree to use the results to guide therapy. 1

Limitations: All other uses of gene expression testing for breast cancer are not medically necessary. Note: The following CPT/HCPCS codes are not listed in the South Carolina Medicaid fee schedule: 81519 - Oncology (breast), mrna, gene expression profiling by real-time RT-PCR of 21 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as recurrence score (Oncotype Dx) Alternative Covered Services: None. Background Breast cancer is the most common cancer among women worldwide and the leading cause of premature mortality among women in the United States. In 2015, the American Cancer Society estimated that 231,840 women were diagnosed with breast cancer and 40,290 women died in the United States of the disease. Genetic testing or gene expression testing includes a variety of laboratory tests (analysis of deoxyribonucleic acid [DNA], ribonucleic acid [RNA], genes or gene products) for the purposes of: Diagnosing breast cancer and other diseases. Assisting in treatment decisions (e.g., adding adjuvant chemotherapy to the radical surgical treatment of breast cancer). Predicting future breast disease (e.g., cancer in the contralateral breast). Identifying carriers of disease to prevent generational occurrence of breast cancer. The results of a contemporary large multicenter, multinational trial have given support to the validity of molecular genetic testing for breast cancer. Although only one genetic assay, the Oncotype DX 21-gene expression test, made by Genomic Health Inc., was endorsed by the results of the TAILORx study released in November 2015, it is likely that others will emerge in the future and that the management of cancers other than breast cancer will eventually be impacted. The MammaPrint test, made by Agendia, is a genomic test that analyzes the activity of certain genes in early-stage breast cancer. The European Organization for Research and Treatment of Cancer is currently studying MammaPrint as part of its microarray in node-negative and 1 3 positive lymph node disease may avoid chemotherapy (MINDACT) project, which is a prospective randomized study comparing the 70-gene expression profile with the common clinical-pathological criteria in selecting patients with 0 3 positive nodes for adjuvant chemotherapy in breast cancer. Early results suggest the MammaPrint test may eventually be widely used to help make treatment decisions based on the risk of recurrence of breast cancer within 10 years after diagnosis. OpenArray Real-Time polymerase chain reaction (PCR) is a new approach to nucleic acid detection and quantification, which is a different method of absolute quantification and rare allele detection relative to conventional PCR. It works by partitioning a sample into many individual real-time PCR reactions; some portion of these reactions contain the target molecule (positive), while others do not (negative). Following PCR analysis, the fraction negative answers generates an absolute answer for the exact number of target molecules in the sample, without reference to standards or endogenous controls. 2

Searches Select Health of South Carolina searched PubMed and the databases of: UK National Health Services Center for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on March 1, 2016. Searched terms were: " breast cancer (MeSH)," and "gene expression test (MeSH)." We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings The American Society of Clinical Oncology (ASCO) has promulgated clinical practice guidelines to provide recommendations on the appropriate use of breast tumor biomarker assays for guiding decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer (Harris, 2016). A literature search from 2006 through 2014 identified 50 relevant studies with medical evidence of clinical utility for the Oncotype DX biomarker assay. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP 2015) working group found that the available medical evidence supports the clinical validity of Oncotype DX in predicting risk of distant metastases in women with hormone receptor-positive (HR+), early-stage breast cancer that is either node-negative or node-positive. However, no direct evidence was found that use of Oncotype DX tumor gene expression profiling to guide treatment decisions improves clinical outcomes in women with early breast cancer. Finally, the group noted that there is indirect evidence, from retrospective studies on archived tissue samples from randomized controlled trials (RCTs), that the Oncotype DX test can predict benefit from chemotherapy. They also affirmed that Oncotype DX testing has been reported, based on economic modeling studies, to be cost-effective in several different health care systems and to save costs in the U.S. health care setting; however, these studies were based on assumptions regarding the clinical utility of the test that require confirmation by clinical trial results. Dreyfus (2015) found the 21-gene assay Oncotype DX assay may be used to estimate the risk of recurrence and to predict the benefit of adjuvant chemotherapy at an early stage of endocrine responsive breast cancers, without human epidermal growth factor receptor 2 (HER-2) overexpression or amplification. The Oncotype DX test correlates positively with recurrence score (RS), classifying patients into three groups of low, intermediate or high risk. Between August 2013, and May 2015, the Oncotype DX assay was applied to patients with indication for adjuvant 3

chemotherapy for HR+ and HER-2 negative cancers. Twenty-six (66.7 percent) of 39 women were identified as having unlikely material indication for chemotherapy. The economy obtained through the use of the test was estimated at 173,000 euros. The authors concluded using Oncotype DX reduced the indications for adjuvant chemotherapy, and generated significant beneficial medical and economic impact. An analysis of a subset of results of the TAILORx trial, published in the New England Journal of Medicine (Sparano, 2015), showed that a majority of women with early-stage breast cancer who receive a low-risk score from a 21-gene expression assay (Oncotype DX test) remain disease-free after five years of hormonal therapy alone, without added chemotherapy. TAILORx enrolled 10,273 patients across 1,182 sites in six countries, including the United States and Canada. The clinical trial enrolled women ages 18 75 with estrogen receptor (ER) positive, HER-2/neu negative, nodenegative invasive breast cancers either >1cm or 0.6 1 cm in size with intermediate- to highhistologic grade. Every patient in the trial was tested with the assay, which divides women based on an analysis of the expression of 21 genes, into one of three risk categories: low, intermediate and high. In the trial, women with an Oncotype DX RS of 10 received hormonal therapy alone; women with an RS >25 were treated with hormonal therapy plus chemotherapy; while women with a midrange RS from 11 25 the primary study group were randomized to receive hormonal therapy with or without chemotherapy. The RS 10 women (n=1,629) demonstrated an impressive rate of invasive disease-free survival of 93.8 percent, and freedom from recurrence of breast cancer at a distant site was 99.3percent. Freedom from recurrence was 98.7percent and overall survival was 98 percent in this cohort. Multivariate analysis did not reveal an effect of age, tumor size or type of surgery on rate of recurrence or survival. Histologic grade showed an association with risk of recurrence. The study provides prospective validation for the use of OncotypeDX RS to spare patients from chemotherapy who would otherwise be recommended to receive it. The study was sponsored by the National Cancer Institute (NCI). On the downside, only 16 percent of women tested with Oncotype DX fell into the low RS group; and although these results (at five years of follow up) are impressive, late recurrence of invasive breast cancer after five years typically accounts for nearly half of all distant recurrences from breast cancer. The National Institute for Health and Clinical Excellence (NICE) of the United Kingdom published provisional guidelines in 2013 and endorsed the use of the 21-gene expression profile assay in the management of early breast cancer. Oncotype DX was recommended for estrogen receptor-positive lymph node negative and HER-2 negative breast cancer to guide chemotherapy decisions. 4

Summary of clinical evidence: Citation Harris (2016) EGAPP (2015) Content, Methods, Recommendations ASCO recommendations on appropriate use of breast tumor biomarker assay results to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer. A literature search and prospectively defined study selection sought systematic reviews, meta-analyses, RCTs, prospective and retrospective studies, and prospective comparative observational studies published from 2006 through 2014. Outcomes of interest included overall survival and disease-free or recurrence-free survival. Expert panel members used informal consensus to develop evidence-based guideline recommendations. The literature search identified 50 relevant studies. One RCT and 18 retrospective studies were found to have evaluated the clinical utility, as defined by the guideline, of specific biomarkers for guiding decisions on the need for adjuvant systemic therapy. No studies that met guideline criteria for clinical utility were found to guide choice of specific treatments or regimens. In addition to estrogen and progesterone receptors and HER-2, the panel found sufficient evidence of clinical utility for the biomarker assays Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and urokinase plasminogen activator and plasminogen activator inhibitor type 1 in specific subgroups of breast cancer. No biomarker except for estrogen receptor, progesterone receptor and HER-2 was found to guide choices of specific treatment regimens. Treatment decisions should also consider disease stage, comorbidities and patient preferences. In women with early-stage invasive breast cancer, gene expression profiling is increasingly being used as an aid to estimate the likely benefit from chemotherapy treatment. EGAPP found adequate evidence for clinical validity of Oncotype DX in the population of women with lymph node-positive disease, using evidence from recent systematic reviews and other sources. EGAPP found that new evidence supports the clinical validity of Oncotype DX in predicting risk of distant metastases in women with hormone receptor-positive, early-stage breast cancer that is either node-negative or node-positive. No direct evidence was found that use of Oncotype DX tumor gene expression profiling to guide treatment decisions improves clinical outcomes in women with early breast cancer. There is indirect evidence, from prospective retrospective studies on archived tissue samples from RCTs, that the Oncotype DX test can predict benefit from chemotherapy. Although Oncotype DX testing has been reported, on the basis of economic modeling studies, to be cost-effective in several different health-care systems and to save costs in the United States health-care setting, studies were based on assumptions regarding the clinical utility of the test that require confirmation by clinical trial results. 5

Dreyfus (2015) Sparano (2015) The 21-gene assay (Oncotype DX ) test corresponds to an RS, classifying patients into three groups (low, intermediate or high risk). Thirty-nine patients had the test, 26 (66.7%) of them demonstrating diminished indication regarding chemotherapy. The economy obtained through the use of the test was estimated around 173,000 euros. The RS provided an additional decision value compared to other common decision criteria. Use of Oncotype DX reduced the need of adjuvant chemotherapy and the medical and economic impact could be significant. RCT inclusive of 10,253 patients diagnosed with invasive breast cancer included a cohort of 1,626 women (15.9%) who had a recurrence score of 0 10 on 21-gene expression assay (i.e., OncotypeDX ). Patients with hormone-receptor positive, HER2-negative, axillary node negative breast cancers that had a favorable gene-expression profile had very low rates of recurrence at five years with endocrine therapy alone. NICE (2013) Cosler (2009) Guidelines for use of gene expression profiling and expanded immunohistochemistry tests to guide the use of adjuvant chemotherapy in early breast cancer management: Oncotype DX recommended for estrogen receptor-positive lymph node negative and HER-2 negative breast cancer to guide chemotherapy decisions. Prospective study of costs and outcomes of using 21-gene expression profile data to guide treatment decisions for women with early stage breast cancer. Gene expression profiling was associated with a survival gain of 2.2 years. Bias was implied as the study was supported by test manufacturer and incompletely reported. Marchionni (2008) Retrospective study focused on Oncotype DX and MammaPrint gene expression profiling tests on breast cancer outcomes. Found no direct evidence for impact on outcomes. Glossary Estrogen receptor (ER) A group of intracellular proteins used to predict prognosis and select treatment in breast cancer patients. The precise mechanisms of action are incompletely understood but their role in anticipating prognosis is well documented. Genetic testing (also known as gene expression assay and gene expression profiling) A type of test used to determine the presence or absence of a specific gene or set of genes to help diagnose a disease, screen for specific health conditions and for other purposes. Hormone receptor (HR) Breast cancer that is responsive to hormones (implying that hormone receptors are present on the cells of the cancer) is referred to as HR-positive or HR+; thus, the tumor can be treated with therapies that block the hormones from the cancer cells. 6

Human epidermal growth factor 2 receptor (HER-2) Her-2 is a protein coded by the ERBB2 gene. Amplification or overexpression of this gene has been shown to play a role in the pathogenesis and progression of aggressive types of breast cancer; however, there are treatments that specifically target the Her-2 receptor and offer effective treatment of the cancer. References Professional associations/other: Agency for Healthcare Research and Quality (AHRQ). Impact of gene expression profiling tests on breast cancer outcomes. Evidence report/technology assessment Number 160. AHRQ Publication No. 08-E002. January 2008. Hayes Inc., Hayes Medical Technology Brief. MammaPrint (Agendia BV) Genetic assay for breast cancer. Lansdale, Pa. Hayes Inc.; May, 2007. Harris LN, Ismaila N, McShane LM, et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016; 8. pii: JCO652289. National Institute for Health and Clinical Excellence (NICE) Early and locally advanced breast cancer: diagnosis and treatment. London (UK): National Institute for Health and Clinical Excellence (NICE). Clinical guideline no.80.2009. National Institute for Health and Clinical Excellence (NICE). Gene expression profiling and expanded immunohistochemistry tests to guide the use of adjuvant chemotherapy in early breast cancer management MammaPrint, Oncotype Dx, IHC4, and Mammostrat. Diagnostics consultation document 3. 2013. Peer-reviewed references: Cosler LE, Lyman GH. Economic analysis of gene expression profile data to guide adjuvant treatment in women with early-stage breast cancer. Cancer Investigation.2009;27(10):953-9. de Groot S, Charehbili A, van Laarhoven H, et al. Insulin-like growth factor 1 receptor expression and IGF1R 3129G > T polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01). Breast Cancer Res. 2016; 18: 3. Dreyfus C, Ballester M, Gligorov J, et al. Impact of the 21-gene assay in decision-making during multidisciplinary breast meeting: A French experience. Gynecol Obstet Fertil. 2015;43(12):780-5. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: does the use of Oncotype DX tumor gene expression profiling to guide treatment decisions improve outcomes in patients with breast cancer? Genet Med. 2015; 17. Ingoldsby H, Webber M, Wall D, Scarrott C, Newell J, Callagy G. Prediction of Oncotype DX and TAILORx risk categories using histopathological and immunohistochemical markers by classification and regression tree (CART) analysis. Breast. 2013;10(1016):89-91. 7

McVeigh TP, Hughes LM, et al. The impact of Oncotype Dx testing on breast cancer management and chemotherapy prescribing patterns in a tertiary referral center. European journal of Cancer.2014;50(16)2763-70. Mislick K, Schonfeld W, et al. Cost-effectiveness of Mammostrat compared with Oncotype DX to inform the management of breast cancer. Clinico-economics and Outcomes Research. 2014;6:37-47. Sparano J, Gray R, Makower D, et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2015; 373:2005-2014. Clinical trials: Searched clinicaltrials.gov on March 7, 2016, using terms gene expression profile testing for breast cancer Open Studies. Twenty-nine studies were found, four were relevant. ECOG-ACRIN Cancer Research Group and National Cancer Institute (NCI). MRI and Gene Expression in Diagnosing Patients With Ductal Breast Cancer In Situ. ClinicalTrials.gov website. http://clinicaltrials.gov/show/nct02352883. Published January, 2015. Updated September 2015. Accessed March 7, 2016. Case Comprehensive Cancer Center. Assessment of Candidate Protein Expression in Breast Cancer Specimens. ClinicalTrials.govwebsite. http://clinicaltrials.gov/show/nct00918892. Published June, 2009. Updated September 2015. Accessed March 7, 2016. Haukeland University Hospital. PErsonalized TREatment of High-risk MAmmary Cancer - the PETREMAC Trial (PETREMAC). ClinicalTrials.gov website. http://clinicaltrials.gov/show/nct02624973. Published November, 2015. Updated December 2015. Accessed March 7, 2016. Hospital General Universitario Gregorio Marañon. Predictors of Response to Neoadjuvant Docetaxel- Carboplatin Chemotherapy for Patients With Stage II and III Triple Negative Breast Cancer. ClinicalTrials.gov Web site. http://clinicaltrials.gov/show/nct01560663. Published March, 2012. Updated February 2016. Accessed March 7, 2016. CMS National Coverage Determination (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill in accordance with those manuals. 8

CPT Codes Description 81265 Comparative analysis using short tandem repeat markers: patient and comparative specimen 81479 Unlisted molecular pathology procedure (MammaPrint) 81519 Oncology (breast), mrna, gene expression profiling by real-time RT-PCR of 21 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as recurrence score (Oncotype Dx) ICD-10 Code Description C50.011 Malignant neoplasm of nipple and areola, right female breast C50.012 Malignant neoplasm of nipple and areola, left female breast C50.019 Malignant neoplasm of nipple and areola, unspecified female breast C50.021 Malignant neoplasm of nipple and areola, right male breast C50.022 Malignant neoplasm of nipple and areola, left male breast C50.029 Malignant neoplasm of nipple and areola, unspecified male breast C50.111 Malignant neoplasm of central portion of right female breast C50.112 Malignant neoplasm of central portion of left female breast C50.119 Malignant neoplasm of central portion of unspecified female breast C50.121 Malignant neoplasm of central portion of right male breast C50.122 Malignant neoplasm of central portion of left male breast C50.129 Malignant neoplasm of central portion of unspecified male breast C50.211 Malignant neoplasm of upper-inner quadrant of right female breast C50.212 Malignant neoplasm of upper-inner quadrant of left female breast C50.219 Malignant neoplasm of upper-inner quadrant of unspecified female breast C50.221 Malignant neoplasm of upper-inner quadrant of right male breast C50.222 Malignant neoplasm of upper-inner quadrant of left male breast C50.229 Malignant neoplasm of upper-inner quadrant of unspecified male breast C50.311 Malignant neoplasm of lower-inner quadrant of right female breast C50.312 Malignant neoplasm of lower-inner quadrant of left female breast C50.319 Malignant neoplasm of lower-inner quadrant of unspecified female breast C50.321 Malignant neoplasm of lower-inner quadrant of right male breast C50.322 Malignant neoplasm of lower-inner quadrant of left male breast C50.329 Malignant neoplasm of lower-inner quadrant of unspecified male breast C50.411 Malignant neoplasm of upper-outer quadrant of right female breast C50.412 Malignant neoplasm of upper-outer quadrant of left female breast C50.419 Malignant neoplasm of upper-outer quadrant of unspecified female breast C50.421 Malignant neoplasm of upper-outer quadrant of right male breast C50.422 Malignant neoplasm of upper-outer quadrant of left male breast C50.429 Malignant neoplasm of upper-outer quadrant of unspecified male breast C50.511 Malignant neoplasm of lower-outer quadrant of right female breast C50.512 Malignant neoplasm of lower-outer quadrant of left female breast C50.519 Malignant neoplasm of lower-outer quadrant of unspecified female breast C50.521 Malignant neoplasm of lower-outer quadrant of right male breast C50.522 Malignant neoplasm of lower-outer quadrant of left male breast C50.529 Malignant neoplasm of lower-outer quadrant of unspecified male breast C50.611 Malignant neoplasm of axillary tail of right female breast C50.612 Malignant neoplasm of axillary tail of left female breast C50.619 Malignant neoplasm of axillary tail of unspecified female breast C50.621 Malignant neoplasm of axillary tail of right male breast C50.622 Malignant neoplasm of axillary tail of left male breast C50.629 Malignant neoplasm of axillary tail of unspecified male breast C50.811 Malignant neoplasm of overlapping sites of right female breast C50.812 Malignant neoplasm of overlapping sites of left female breast C50.819 Malignant neoplasm of overlapping sites of unspecified female breast C50.821 Malignant neoplasm of overlapping sites of right male breast C50.822 Malignant neoplasm of overlapping sites of left male breast 9

C50.829 Malignant neoplasm of overlapping sites of unspecified male breast C50.911 Malignant neoplasm of unspecified site of right female breast C50.912 Malignant neoplasm of unspecified site of left female breast C50.919 Malignant neoplasm of unspecified site of unspecified female breast C50.921 Malignant neoplasm of unspecified site of right male breast C50.922 Malignant neoplasm of unspecified site of left male breast C50.929 Malignant neoplasm of unspecified site of unspecified male breast HCPCS Codes N/A Description 10