Biomarkers for Oncology

Jurisdiction: JL MAC Part B. States: Delaware, District of Columbia, Maryland, New Jersey, Pennsylvania. Type: Active LCD

Compliance with the provisions in this policy may be monitored and addressed through post payment data analysis and subsequent medical review audits. History/Background and/or General Information The emergence of personalized laboratory medicine has been characterized by a multitude of testing options which can more precisely pinpoint management needs of individual patients. As a result, the growing compendium of products described as biomarkers requires careful evaluation by both clinicians and laboratorians as to what testing configurations are reasonable and necessary under the Medicare Act. There are a plethora of burgeoning tools, including both gene-based (genomic) and protein-based (proteomic) assay formats, in tandem with more conventional (longstanding) flow cytometric, cytogenetic, etc. biomarkers. Classified somewhat differently, there are highly diverse approaches ranging from single mutation biomarkers to multiple biomarker platforms, the latter of which often depend upon sophisticated biomathematical interpretative algorithms. The term “biomarker” refers to a broad subcategory of medical signs (i.e., objective indications of medical state observed from outside the patient) which can be measured accurately and reproducibly. Medical signs stand in contrast to medical symptoms, which are limited to indications of health or illness perceived by the patient. In 1998, the National Institute of Health (NIH) defined a biomarker as: "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes pathogenic processes, or pharmacologic response to a therapeutic intervention." 1 This current LCD focuses upon selected testing in oncology, with some emphasis upon applying the revised 2016 CPT molecular coding format. The LCD primarily applies to molecular biomarker testing but does involve some other types of related biomarker testing, such as proteomics. There are separate Local Coverage Determinations (LCDs) that address other biomarkers, which include a multitude of assays which are not specifically discussed below. (Please refer to the Novitas website for a complete listing of LCDs.) Local Medicare coverage of such biomarkers must be predicated upon four fundamental principles: First, the biomarkers must have proven clinical validity/utility (CVU). Second, to support the medical necessity of the service, there must be acceptance/uptake of specific testing into patient management. It is essential that physicians be familiar enough with all specific biomarkers, of which they order, such that all test results may become clinically actionable. Providers managing oncological conditions must demonstrate that the use of biomarkers will be used to assist in the management/treatment of the beneficiary. Peer-reviewed full manuscript evidence is required to support combination panels for multiple biomarkers, particularly regarding their alleged composite clinical validity/utility. For example, such potential billing for multiple, diverse biomarkers (e.g., diagnostic/monitoring/prognostic/predictive) can only achieve medical necessity when it is evident how each requested biomarker can be individually contributory. It is useful to categorize oncology biomarkers into functional clusters which reflect both (1) The predominant intent of testing (with the caveat that individual assays may cross over into more than one category) and (2) the relative evidentiary expectations: Oncology Biomarkers Used for Diagnosis/Classification/Monitoring/Surveillance: These types of assays are supportable by case-control sensitivity/specificity studies, with appropriate designs in place to minimize the extent of bias and confounding. Oncology Biomarkers Used for Prognosis/Prediction: Oncology biomarkers used for prognosis/prediction (i.e., a predictive biomarker is associated with response [benefit] or lack of response to a particular therapy, relative to other available therapy, whereas a prognostic biomarker provides information on the likely outcome of the disease in an untreated individual). There is a complex and diverse set of study methods which can drive the robust formulation of evidence for such esoteric testing. This is well-summarized by Deverka et al 2 at the Center for Medical Technology Policy, but there are currently NO standardized thresholds or benchmarks for evaluating the CVU/medical necessity of emerging biomarkers. However, the following sources (although not exhaustive and complete) may help support CVU when requesting reconsideration for coverage of biomarkers that are not included in this LCD: FDA labeling documentation. National Comprehensive Cancer Network (NCCN) Biomarkers Compendium recommendations, particularly where Category 1 evidence is noted. Findings from well-established, independent technology assessments (e.g., Evaluation of Genomic Applications in Practice and Prevention [EGAPP], Agency for Healthcare Research and Quality [AHRQ], Blue Cross and Blue Shield Association Technology Evaluation Center [BCBSA TEC] and the Cochrane Collaboration). Other independent, objective evaluations or systematic literature reviews, which can substantively contribute to the evidence base, including, but not restricted to, emerging National Institutes of Health (National Cancer Institute) guidelines for the accrual of genomics/proteomics clinical validity/utility evidence. Although there is not a prescriptive format for such systematic reviews, the documentation submitted for reconsideration purposes should include the following three elements: Some type of recurring/periodic Committee structure, which is comprised of at least qualified biomathematicians/methodologists, molecular pathology laboratory specialists and relevant clinicians (e.g., oncologists). Evidence of active sharing of the critical evaluations in a manner that enables sufficiently broad input into this process, and a feasibly wide acceptance of this process by representative molecular pathology stakeholders. There is no preference between such a Committee being based at a single site, or even rotating among several sites. Transparency of the biomarker evaluations via minutes (or a summary of minutes). Covered Indications MOLECULAR TESTS Covered clinical types of application(s) are identified below as diagnostic (DX), prognostic (PROG), or predictive (PRED). 1. Colorectal Cancer KRAS (12/13) - PRED of resistance to an anti-EGFR agent KRAS codon 61 - PRED of resistance to an anti-EGFR agent KRAS codon 146 - PRED of resistance to an anti-EGFR agent NRAS - PRED of resistance to an anti-EGFR agent BRAF - PRED of resistance to an anti-EGFR agent + DX (sporadic vs. Lynch syndrome) PIK3CA - PRED of resistance to an anti-EGFR agent + PROG for local recurrence MSI by PCR - PRED of 5-FU resistance + DX MLH1 promoter hypermethylation - PRED of 5-FU resistance + DX mRNA (oncotype-Colon) – PRED for the recurrence risk for patients with Stage II colon cancer Hereditary colon cancer disorders Sept9 ColonSeq This testing provides information to the patient and provider regarding potential treatment options and implications for RAS and BRAF mutations. Please refer to DA52986-Billing and Coding: Biomarkers for Oncology regarding coding and billing information. 2. Non-Small Cell Lung Cancer (NSCLC) EGFR- PRED of anti-EGFR response KRAS (12/13) - PRED of anti-EGFR resistance KRAS codon 61 - PRED of anti-EGFR resistance KRAS codon 146 - PRED of anti-EGFR resistance BRAF - PROG + PRED for anti-RAF inhibitor ThermoFisher Oncomine DX Target Test for Non-Small Cell Lung Cancer (NSCLC) is a 23 gene panel including a 3 gene target test (companion test) approved by the FDA in June 2017 for NSCLC from tissue specimens. It can simultaneously identify the three gene variants that are a key to targeted therapy selection: BRAF and ROS1, and EGFR. The targeted therapies are dabrafenib (Tafinlar) in combination with trametinib (Mekinist), crizotinib (Xalkori), and gefitinib (Iressa), respectively. These three drugs are approved therapies for NSCLC patients with the above gene variants. Oncomine DX Target Test is the only FDA approved companion test that detects ROS1 fusions and that detects BRAF V600E, but it does not detect ALK fusions. Coverage is limited as specified in NCD 90.2, Next Generation Sequencing (NGS) for Patients with Advanced Cancer. Please refer to the NCD for full coverage details. LungSeq Testing for genetic alteration in these genes can determine targeted therapy options that have the potential to decrease tumor burden, decrease symptoms, increase survival, and dramatically improve the quality of life for patients with specific genetic alterations. Please refer to A52986, Billing and Coding: Biomarkers for Oncology regarding coding and billing information. 3. Melanoma BRAF - PRED of response to Vemurafenib KIT - PRED of response to Imatinib (TKI) NRAS - PROG + PRED for anti-MEK inhibitor 4. Uveal Melanoma GNAQ – PROG GNA11 - PROG 5. Brain BRAF - PRED EGFR - PRED MGMT - PRED IDH1 - DX + PROG IDH2 - DX + PROG PIK3CA - PRED PTEN - PRED CIMP - PRED TERT - DX 6. Thyroid BRAF - DX + PRED KRAS - PRED for Selumetinib HRAS - PRED for Selumetinib NRAS - PRED for Selumetinib PIK3CA - PRED RET - DX PAX8/PPARG- DX ThyraMIR Thyroid miRNA classifier (aPCR based microRNA gene expression classifier) (PRED) evaluates the expression levels of 10miRNA genes within an FNA biopsy: miR-29b-1-5p, miR-31-5p, miR-138-1-3p, miR-139-5p, miR-146b-5p, miR-155, miR-204-5p, miR-222-3p, miR-375, and miR-551b-3p. Oncology Thyroid, provides gene expression analysis of 142 genes utilizing fine needle aspirate, algorithm reported as a categorical result (Afirma - PRED). ThyraMIR is used as a companion test to ThyGeNEXT when ThyGeNEXT results are inconclusive. ThyraMIR, ThyGeNEXT and Afirma services will be considered reasonable and necessary for patients with any of the following conditions: An indeterminate pathology on fine needle aspiration Patients with one or more thyroid nodules with a history or characteristics suggesting malignancy such as: Nodule growth over time Family history of thyroid cancer Hoarseness, difficulty swallowing or breathing History of exposure to ionizing radiation Hard nodule compared with rest of gland consistency Presence of cervical adenopathy RosettaGX Reveal thyroid MicroRNA test, an assay used for the classification of indeterminate thyroid nodules, will be considered reasonable and necessary when the conditions outlined above for ThyraMIR, ThyGeNEXT and Afirma are met. ThyroSeq is a test utilized to better define the need for thyroid surgery and the type of such surgery. ThyroSeq will be considered reasonable and necessary when the conditions outlined above for ThyraMir, ThyGeNEXT, and Afirma are met. 7. Ovary/Fallopian Tube/Peritoneum AKT1 - PRED for PI3K/AKT/mTOR inhibitors BRAF - DX + PROG KRAS - DX + PROG MLH1 promoter hypermethylation - DX MSI by PCR - DX PIK3CA - PRED for PI3K/AKT/mTOR inhibitors PTEN - PRED for PI3K/AKT/mTOR inhibitors TP53 - DX + PROG 8. Uterus AKT1 - PRED for PI3K/AKT/mTOR inhibitors BRAF - PRED KRAS - PRED MLH1 promoter hypermethylation - DX MSI by PCR - DX PIK3CA - PRED for PI3K/AKT/mTOR inhibitors PTEN - PRED for PI3K/AKT/mTOR inhibitors + DX + PROG TP53 - DX + PROG 9. Urinary Tract FGFR3 - PROG MSI by PCR - DX MLH1 promoter hypermethylation - DX 10. Prostate The PROGENSA PCA3 Assay (PRED) is an FDA-approved, automated molecular test (assay) that helps physicians determine the need for repeat prostate biopsies in men who have had a previous negative biopsy. PTEN – PROG and THER RB1 – DX and PROG TP53 - PROG 11. Gastrointestinal Stomal Tumor KIT - PRED for Sumatinib + DX PDGFRA - PRED for Sumatinib + DX 12. Cancer of Unknown Primary (CUP) Molecular testing, using the Rosetta Cancer Origin Test(PROG), is considered reasonable and necessary in the pathologic diagnoses of CUP when a conventional surgical pathology/imaging work-up is unable to identify a primary neoplastic site. Other applications of this technology are considered not reasonable and necessary and are considered investigational in the use of diagnosis of specific tumor types such as NSCLC and renal cancers. TUO CTID (Cancer Type ID) (DX) is considered reasonable and necessary in the pathologic diagnoses of CUP when a conventional surgical pathology/imaging work-up is unable to identify a primary neoplastic site. Other applications of this technology are considered not reasonable and necessary and are considered investigational in the use of diagnosis of specific tumor types such as NSCLC and renal cancers. 13. Leukemias and Lymphomas Acute lymphoid leukemia (ALL) JAK1 JAK2 BCR/ABL1 - DX ABL1 (kinase domain) - PROG IGH - DX TCRB - DX TCRG - DX TP53 - PROG MLL/AF4 - DX E2A/PBX1 - DX ETV6/RUNX1 - DX KRAS NRAS NOTCH1 FBXW7 Acute myeloid leukemia (AML, and including acute promyelocytic leukemia): All PROG, except as noted below. TP53 PML/RARA - DX RUNX1/RUNX1T1 - DX CBFB/MYH11 - DX FLT3 ITD FLT3 D835 NPM1 KRAS NRAS KIT CEBPA IDH1 IDH2 DNMT3A JAK2 (p.V617F) JAK2 (exon 12) MPL DEK/CAN - DX ASXL1 EZH2 TET2 PML/RARalpha U2AF1 SRSF2 ZRSR2 Hairy cell leukemia BRAF IGH somatic hypermutation - PROG IGH - DX Aplastic anemia TCRB - DX TCRG - DX Burkitt’s lymphoma IGH - DX TP53 - PROG Myeloproliferative diseases (MPD - essential thrombocytosis [ET], myelofibrosis & polycythemia vera [PV]) KIT TP53 BCR/ABL1 - DX JAK2 (p.V617F) - DX JAK2 (exon 12) - DX MPL - DX CALR - DX CSF3R - DX ASXL1 - PROG TET2 - PROG EZH2 - PROG Calr (exon 9) Chronic myeloid leukemia (CML) and chronic myelomonocytic leukemia (CMML) ABL1 T3151 – CML only KRAS - PROG NRAS - PROG BCR/ABL1 - DX ABL1 (kinase domain) - PRED for Imatinib FLT3 ITD - PROG FLT3 D835 - PROG KIT - PROG JAK2 (p.V617F) - PROG JAK2 (exon 12) - PROG Chronic lymphoid leukemia (CLL) IGH - DX IGH somatic hypermutation - PROG TP53 - PROG IGH direct probe method BTK PLCG2 BIRC3 BTK NOTCH1 SF3B1 Follicular lymphoma IGH/BCL2 - DX Hypereosinophilia Syndrome (HES) KIT (including p.D816V) - PROG + DX FIP1L1/PDGFRA Fusion - DX Mantle cell lymphoma CCND1/IGH - DX Mastocytosis KIT (including p.D816V) - PROG + DX FIP1L1/PDGFRA Fusion - DX TCRG - DX T-cell prolymphocytic leukemia JAK1 JAK3 TCRB - DX TCRG - DX T-cell large granular lymphocytic leukemia(TLGLL) STAT3 STAT5B Myelodysplastic syndrome (MDS): All below biomarkers are PROG. FLT3 ITD FLT3 D835 NPM1 KRAS NRAS KIT CEBPA IDH1 IDH2 DNMT3A JAK2 (p.V617F) JAK2 (exon 12) MPL ASXL1 EZH2 TET2 Cytogenomic microarray analysis, or alternatively, a single nucleotide polymorphism (SNP) array for the same testing, is covered for the identification of various mutations. These tests are used in the diagnosis/prognosis of various hematological malignancies. Waldenstrom's Lymphoplasmacytic Lymphoma MYD88 14. Myeloma Gene Expression Profile (MyPRS) (PROG) isolates plasma cells from myeloma patients, extracts DNA, which is then subjected to MicroArray testing and application of validated software programs to identifying patterns of genetic abnormalities. Seventy highly predictive genes have been identified and correlated to myeloma early relapse. MyPRS gives a predictive risk signature as high-risk or low risk at this time. A high-risk score predicts a less than 20% three-year complete remission whereas a low risk predicts a five-year complete remission of greater than 60%. The predictive value for the stratification of therapeutic interventions allows these patients to be treated in a more personalized manner based on their own genetic profile. This test is considered reasonable and necessary only after the initial diagnosis of multiple myeloma has been made and will be available to be used in the stratification of therapeutic interventions. It would be inappropriate to use this test as a diagnostic tool or as a monitoring device of ongoing therapy. Other testing is available for this function. The coverage is set to include only two clinical settings: Once after initial diagnosis is made. In the event MyPRS was not tested at diagnosis of myeloma and there is ongoing initial therapy with persistent disease, MyPRS can be done still as an initial test. OR If relapse has occurred and a change in the therapeutic modalities is contemplated. Please refer to the limitations section of this policy for frequency limitations. 15. Hereditary neuroendocrine tumor disorders - Must include 6 genes with genomic sequence analysis NEX GEN including: MAX SDHB SDHC SDHD TMEM127 VHL Please refer to the limitations section of this policy for frequency limitations. 16. Hereditary neuroendocrine tumor disorders; duplication/deletion analysis panel - must include analysis for: SDHB SDHC SDHD VHL 17. Neuroendocrine Tumors MGMT - PROG PTEN – PROG and THER RB1 – DX and PROG TP53 – DX and PROG TSC2 - PROG 18. Prosigna breast cancer gene signature assay (PROG) Background Women with early breast cancer and up to 3 locally positive lymph nodes whose tumor is estrogen-receptor positive will usually receive anti-hormonal therapy such as tamoxifen or aromatase inhibitors. U.S. (NCCN 3 ) and international (St. Gallen 4 ) guidelines predicate the decision for adjuvant chemotherapy on the size and grade of the breast cancer and other factors including genomic assays that provide additional information on risk of recurrence. 5 According to a 2014 review, “Prognostic factors provide an indication of whether a patient needs subsequent therapy.” 5 Similarly, another 2014 review article states, “Efforts should be focused on reducing chemotherapy in patients unlikely to benefit.” 7 The PAM50 breast cancer gene signature test was developed in the late 1990s and initial studies showed a strong correlation with breast cancer recurrence and with complete pathologic response to neoadjuvant chemotherapy. 8 While test results are reported on a scale of 1-100 as a Risk of Recurrence (ROR) score, the underlying algorithm is also able to classify cases into the luminal A and B, Her2neu, and triple-negative subtype classifications. The Nanostring nCounter nucleic acid analysis system replicates the PAM50 algorithm, as an FDA cleared kit, the Prosigna Breast Cancer Gene Signature Assay. 9 The Prosigna package insert was updated in January 2015 reflecting additional studies. 10 Notably, the Prosigna platform and the original PAM50 platform have a 0.997 correlation. 11 For the FDA, the Prosigna test was validated in a large population of post-menopausal, estrogen-receptor positive women based on 1,017 cases of the TransATAC study. 11 The study showed a strong correlation with long-term breast cancer recurrence and added substantial additional prognostic information over a clinical treatment score based on standard clinical variables. This study was replicated in an independent population, also on the Prosigna test, using 1,620 samples from the ABCSG8 trial. 12 A separate analysis of these trials validated prediction of distant recurrence in years 5-10 after initial diagnosis 10 and has been incorporated in the FDA labeling. 9 The Prosigna test is issued as separate reports, consistent with FDA review and labeling, for node-negative and node-positive (1-3 node) populations. Analytic performance, precision, reproducibility, and analysis of the clinical validations are provided in the FDA labeling. 9 Clinical utility of this breast cancer gene signature has also been assessed. The study of Martin et al 13 showed a 20% decision impact on decisions for or against adjuvant chemotherapy in an all-comers population of 200 new cases of incident breast cancer, when Prosigna test information became available after all other clinical information had been considered. The net rates of selecting adjuvant chemotherapy for low, intermediate, and high-risk cases were similar to those observed in a meta-analysis of Oncotype DX decision data. 14 Additional support for the use of these test results in treatment decisions comes from Parker et al 8 , in which there was a strong association with neoadjuvant chemotherapy response. Low-scoring cases have a very low chance of complete pathological response to neoadjuvant chemotherapy, while high-scoring cases approach a 50% chance of complete pathological response. The same findings have been observed for other breast cancer gene signatures based on prognostic algorithms. 15 The Prosigna test is reasonable and necessary when performed according to the FDA label. 9 19. Desmoid Fibromatosi CTNNB1 – DX and PROG 20. Hepatic Adenoma CTNNB1 – DX and PROG 21. Bladder CDKN2A – PROG FGFR1 – PROG FGFR3 – PROG MTOR – PROG PIK3CA – DX and PROG PTEN – PROG RB1 – PROG TP53 - PROG NON-MOLECULAR ASSAYS The VeriStrat assay is a mass spectrophotometric, serum-based predictive proteomics assay for NSCLC patients, where “first line” EGFR mutation testing is either wild-type or not able to be tested (e.g., if tissue might not be available). This test is a driver of therapy, most notably EGFR inhibitors such as erlotinib, and it has been validated by randomized controlled studies (Carbone et al 16 and Stinchecomb et al 17 ) and physician uptake data (Akerley et al 18 ) to support this coverage niche. This LCD does not address ALK and ROS1 FISH assays, which are indicated as predictive biomarkers for Crizotinib therapy, since they are currently covered assays. However, it is expected that non-molecular testing for these two biomarkers should provide adequate predictive information. FISH tests for bladder cancer are complex tests based on precision reagents, controls, and mathematical algorithms, all of which must be validated in clinical trials in order to support cutoff points for critical patient care decisions. Therefore, in each local physician’s office or laboratory, this category of testing is not easily replicated by miscellaneous research use or ASR reagents. Novitas will consider the coverage of FISH test kits based on peer-reviewed literature and approved manufacturer claims. The OVA1 proteomic assay (PROG) will be considered reasonable and necessary when performed according to the FDA label. 19 The Risk of Ovarian Malignancy Algorithm (ROMA is a qualitative serum test (PROG) that combines the results of HE4 EIA, ARCHITECT CA 125 II and menopausal status into a numerical score. ROMA is intended (per FDA clearance) to aid in assessing whether a premenopausal or postmenopausal woman who presents with an ovarian adnexal mass is at high or low likelihood of finding malignancy at surgery. ROMA™ will be considered reasonable and necessary for women who meet the FDA labeling criteria. 20 Limitations Note: Please refer to the indications for any restrictions specific to the various assays. Please see NCD 90.2 for coverage details related to Next Generation Sequencing (NGS) for Patients with Advanced Cancer. Most genomic testing should be a once in a lifetime test. Documentation in the medical record should clearly support the need for repeat testing to include the following: recurrence of disease, change in behavior of disease, etc. The following tests will all be covered once per lifetime per beneficiary: Brain Molecular Biomarkers Hereditary neuroendocrine tumor disorders Hereditary neuroendocrine tumor disorders; duplication/deletion analysis: ThyraMIR, Afirma, ThyGeNEXT, RosettaGX Reveal and ThyroSeq tests Should the unlikely situation of a second, unrelated thyroid nodule with indeterminate pathology occur, coverage may be considered upon appeal with supporting documentation. TUO CTID (Cancer TYPE ID) While some biomarkers have utility for testing once per lifetime, there are tumor specific scenarios where repeat testing would be needed for assessment of response to therapy or to identify basis of disease progression. In cases with metastatic or recurrent tumors, repeat testing may be useful in determining further clinical management. Also, biomarkers such as BCR-ABL1 fusion, PML-RARA fusion are useful in monitoring response to therapy and predict a response up to four times per annum. Notice: Services performed for any given diagnosis must meet all of the indications and limitations stated in this policy, the general requirements for medical necessity as stated in CMS payment policy manuals, any and all existing CMS national coverage determinations, and all Medicare payment rules.