Clinical Policy Title: Gene expression profile testing for breast cancer

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1 Clinical Policy Title: Gene expression profile testing for breast cancer Clinical Policy Number: Effective Date: December 1, 2013 Initial Review Date: July 17, 2013 Most Recent Review Date: February 18, 2015 Next Review Date: February 2016 Policy contains: Gene expression profile/test. Breast cancer. Oncotype Dx. MammaPrint. ABOUT THIS POLICY: Keystone First has developed clinical policies to assist with making coverage determinations. Keystone First 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 Keystone First 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. Keystone First 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. Keystone First clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Keystone First will update its clinical policies as necessary. Keystone First clinical policies are not guarantees of payment. Coverage policy Keystone First considers the use of gene expression profile testing in breast cancer to be investigational and, therefore, not medically necessary. Background 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 disease. Assisting in treatment decisions: in the case of breast cancer, decisions about adding chemotherapy (adjuvant) to the primary treatment (surgical removal of the tumor). Predicting future disease. Identifying carriers of disease. Prenatal testing. Evaluating molecular genetic tests in the absence of a gold standard: Marchionni et al. (AHRQ 2008) point out that the field of gene expression testing lacks the gold standard (outside the tests under evaluation 1

2 themselves; microarrays and reverse transcriptase polymerase chain reaction [RT-PCR]) traditionally used to evaluate diagnostic test accuracy or operating characteristics (sensitivity, specificity, positive and negative predictive values), making definitive evaluation of analytic validity, i.e., accuracy, for gene expression tests difficult and evidence for operational characteristics partial. Knowledge of these characteristics is essential to rational use of tests for any purposes: screening, diagnosis, choosing therapy or monitoring its effectiveness. AHRQ cites a single 2007 study providing adequately detailed information to suggest fairly good performance for some components of the assays with laboratory procedures and specimen quality substantially impacting reliability. AHRQ also notes the publication of economic analyses for gene expression tests in breast cancer, one of which (Cosler 2009) is listed in Table 1, and for which AHRQ reports only moderate confidence in the analysis due to limitations: the study was sponsored by the test manufacturer and was incompletely reported. In other words, translating information about newer gene expression tests into commonly understood measures of diagnostic test performance was not feasible with information available at the time AHRQ finalized searches in Breast cancer is the most commonly diagnosed malignancy and the second leading cause of cancerrelated death in women in the United States (for 2007: 178,000 new cases and 40,000 deaths). Treatment usually includes surgery to remove the tumor and involves lymph nodes. At least 75 percent of patients are expected to survive, with a multimodal approach following surgery by radiation (in cases of breast conservation, large tumors or many involved nodes), endocrine therapy (for essentially all women with tumors expressing the estrogen receptor), and/or chemotherapy (poor risk factors such as large tumors, involved lymph node, or inflammatory cancer). Gene expression profiling is an attempt to more precisely define risks and thus treatment, avoiding unnecessary chemotherapy with its adverse effects or using it where it might not have been deemed necessary by traditional, less precise risk estimators, such as clinical and microscopic pathology factors. Men can also suffer breast cancer, with pathology similar to females although with a much lower incidence. Prognostic factors for men include tumor size and lymph node involvement. Methods Searches (January February, 2015): Keystone First searched PubMed and the databases of: UK National Health Services Centre 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. Searches were conducted on February 10, 2015, using the terms gene expression test and breast cancer. Included were: 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. 2

3 Findings: The TAILORx trial anticipated by Marchionni (AHRQ2008 [Table 1]) has yet to publish results. TAILORx (Trial Assigning Individualized Options for Treatment [Rx]) will test whether genes associated with increased risk of recurrence in early stage breast cancer can be used to assign patients to the most appropriate and effective treatment. TAILORx is particularly important as the first randomized controlled trial to examine a method for personalizing cancer treatment. It was initiated in 2006 and will randomize 7,000 women with breast cancer at 900 treatment centers (National Cancer institute 2010). As of February 10, 2015, lists TAILORx as open; no longer recruiting. A retrospective cross-sectional study incorporating Oncotype (McVeigh 2014) has published but relies on surrogate/intermediate outcomes (changes in chemotherapy use), rather than survival. Its retrospective design and reliance on intermediate outcomes do little to change the investigational status of Oncotype DX for the purposes of this policy. Alternate means of estimating Oncotype DX/TAILORx risk categories are also under investigation (Ingoldsby 2013). Citation Mislick (2014) Content/methods/recommendations Cost-effectiveness:Oncotype vs. Mammostrat: Mammostrat saved $2,268 over 10 years, attributable to differences in test cost. NICE (provisional guidance; 2013) Gene expression profiling and expanded immunohistochemistry tests to guide the use of adjuvant chemotherapy in early breast cancer management: Citation Content/methods/recommendations Marchionni (2008; below) updated through Oncotype DX recommended for: o Estrogen receptor-positive lymph node negative and human epidermal growth factor receptor 2 (HER-2) negative to guide chemotherapy decisions. The person is assessed as intermediate risk. The decision to prescribe chemotherapy remains unclear (information on biological features of disease is likely to help predict course of disease). The manufacturer provides the test at a price making its use costeffective from the provider organization perspective. 3

4 Cosler (2009) Economic analysis Gene expression profile data to guide adjuvant treatment in early breast cancer: Costs and outcomes of using 21-gene expression profile data to guide treatment decisions for women with early stage breast cancer. Three strategies: tamoxifen alone, chemotherapy followed by tamoxifen, gene expression profile (abstract does not specify name of test) to guide choice (tamoxifen for low risk followed by chemo for intermediate and high risk). Gene expression data gained 2.2 years vs. tamoxifen alone but NS difference for combination. Supported by test manufacturer and incompletely reported (see Background discussion). NICE (2009) Early and locally advanced breast cancer Diagnosis and treatment: Diagnostic and evaluation interventions/practices considered do not include gene expression tests. Marchionni (AHRQ; 2008) Impact of gene expression profiling tests on breast cancer outcomes: Four key questions, originally focused on Oncotype DX (Genomic Health Inc.) and MammaPrint (Agendia); a third added during review (H/I ratio based on two-gene signature AviaraDx [Quest Diagnostics]) : studies using prognostic test as primary intervention (therapeutic decisionmaking) and reporting outcomes (morbidity, mortality QoL). No direct evidence for impact on outcomes. No RCTs but some studies did use previous RCTs (prospectively gathered samples which increased value as evidence). Ongoing RCTs: TAILORx (Oncotype) and MNDACT (MammmaPrint) expected to provide results allowing almost direct inference about impact on outcomes. Hayes (2007) MammaPrint: 4

5 Citation Content/methods/recommendations Peer-reviewed studies comparing MammaPrint to standard clinical criteria prognosis, Three studies (N = 19,307): potential conflict of interest by one investigator, all using archived tissue samples, lack of blinding to MammaPrint results. Further studies needed. 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 role in prognosis well documented. FISH (Fluorescence in situ hybridization) A molecular genetic test used to identify presence, absence or rearrangement of specific DNA sequences characteristic of some genetic conditions. Hematoxylin and eosin (H&E) A widely-used staining method in histology (the microscopic examination of tissues). It produces the characteristic pink and blue-violet colors familiar to students of the pre-clinical basic sciences and which distinguish cellular substructures, such as nuclei from other intra- or extracellular material. HER-2 receptor Human epidermal growth factor receptor 2 is a protein that in humans is coded by the ERBB2 gene. Amplification or over-expression of this gene has been shown to play a role in the pathogenesis and progression of certain aggressive types of breast cancer. Immunohistochemistry A laboratory process exploiting the binding of antigens to specific antibodies in order to visualize the bound aggregates microscopically by color or fluorescence. Gold standard (for diagnostic tests) The criterion standard for diagnosis; hypothetically the test with 100 percent sensitivity, or that which correctly identifies all individuals with a disease. In many cases, this has been and remains light microscope histopathology, which is not an option for genes. Medically Necessary- A service or benefit is Medically Necessary if it is compensable under the MA Program and if it meets any one of the following standards: The service or benefit will, or is reasonably expected to, prevent the onset of an illness, condition or disability. The service or benefit will, or is reasonably expected to, reduce or ameliorate the physical, mental or developmental effects of an illness, condition, injury or disability. The service or benefit will assist the Member to achieve or maintain maximum functional capacity in performing daily activities, taking into account both the functional capacity of the Member and those functional capacities that are appropriate for Members of the same age Related policies: Keystone First Utilization Management program description. 5

6 References Professional associations/other: National Cancer Institute. The TAILORx breast cancer trial. Posted May 23, 2006; reviewed 10/22/ Accessed July 20, (NICE) National Institute for Health and Clinical Excellence. 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 (NICE). National Collaborating Center for Cancer. Early and locally advanced breast cancer: diagnosis and treatment. London (UK): National Institute for Health and Clinical Excellence (NICE). Clinical guideline no Palmetto GBA (contractor #01192; MAC-part B). LCD for Oncotype DX test-breast cancer prognosis (L28287). Effective 9/2/2008. 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): Hayes, Inc. MammaPrint (Agendia BV) Genetic assay for breast cancer. Health Technology Brief. May 15, 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): Marchionni L, Wilson RF, Marinopoulos SS, Wolff AC, Parmigiani G, Bass EB, Goodman SN. Impact of gene expression profiling tests on breast cancer outcomes. Evidence report/technology assessment Number 160. AHRQ Publication No. 08-E002. January 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) 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: Centers for Medicare & Medicaid Services (CMS) national coverage determination: No NCD 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. 6

7 CPT Codes Description Comparative analysis using short tandem repeat markers: patient and comparative specimen Unlisted molecular pathology procedure (MammaPrint) 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 9 Codes Description Nipple and areola, female breast Central portion Upper-inner quadrant Lower-inner quadrant Upper-outer quadrant Lower-outer quadrant Axillary tail Other specified sites of female breast Breast (female) unspecified Nipple and areola, male breast Other and unspecified sites of male breast ICD-10 Code Description C Malignant neoplasm of nipple and areola, right female breast C Malignant neoplasm of nipple and areola, left female breast C Malignant neoplasm of nipple and areola, unspecified female breast C Malignant neoplasm of nipple and areola, right male breast C Malignant neoplasm of nipple and areola, left male breast C Malignant neoplasm of nipple and areola, unspecified male breast C Malignant neoplasm of central portion of right female breast C Malignant neoplasm of central portion of left female breast C Malignant neoplasm of central portion of unspecified female breast C Malignant neoplasm of central portion of right male breast C Malignant neoplasm of central portion of left male breast C Malignant neoplasm of central portion of unspecified male breast C Malignant neoplasm of upper-inner quadrant of right female breast C Malignant neoplasm of upper-inner quadrant of left female breast C Malignant neoplasm of upper-inner quadrant of unspecified female breast C Malignant neoplasm of upper-inner quadrant of right male breast C Malignant neoplasm of upper-inner quadrant of left male breast C Malignant neoplasm of upper-inner quadrant of unspecified male breast C Malignant neoplasm of lower-inner quadrant of right female breast C Malignant neoplasm of lower-inner quadrant of left female breast C Malignant neoplasm of lower-inner quadrant of unspecified female breast C Malignant neoplasm of lower-inner quadrant of right male breast C Malignant neoplasm of lower-inner quadrant of left male breast 7

8 C Malignant neoplasm of lower-inner quadrant of unspecified male breast C Malignant neoplasm of upper-outer quadrant of right female breast C Malignant neoplasm of upper-outer quadrant of left female breast C Malignant neoplasm of upper-outer quadrant of unspecified female breast C Malignant neoplasm of upper-outer quadrant of right male breast C Malignant neoplasm of upper-outer quadrant of left male breast C Malignant neoplasm of upper-outer quadrant of unspecified male breast C Malignant neoplasm of lower-outer quadrant of right female breast C Malignant neoplasm of lower-outer quadrant of left female breast C Malignant neoplasm of lower-outer quadrant of unspecified female breast C Malignant neoplasm of lower-outer quadrant of right male breast C Malignant neoplasm of lower-outer quadrant of left male breast C Malignant neoplasm of lower-outer quadrant of unspecified male breast C Malignant neoplasm of axillary tail of right female breast C Malignant neoplasm of axillary tail of left female breast C Malignant neoplasm of axillary tail of unspecified female breast C Malignant neoplasm of axillary tail of right male breast C Malignant neoplasm of axillary tail of left male breast C Malignant neoplasm of axillary tail of unspecified male breast C Malignant neoplasm of overlapping sites of right female breast C Malignant neoplasm of overlapping sites of left female breast C Malignant neoplasm of overlapping sites of unspecified female breast C Malignant neoplasm of overlapping sites of right male breast C Malignant neoplasm of overlapping sites of left male breast C Malignant neoplasm of overlapping sites of unspecified male breast C Malignant neoplasm of unspecified site of right female breast C Malignant neoplasm of unspecified site of left female breast C Malignant neoplasm of unspecified site of unspecified female breast C Malignant neoplasm of unspecified site of right male breast C Malignant neoplasm of unspecified site of left male breast C Malignant neoplasm of unspecified site of unspecified male breast HCPCS Codes S3854 Description Gene expression profiling panel for use in the management of breast cancer treatment 8