Corporate Medical Policy Pharmacogenetics Testing AHS – M2021 File Name: pharmacogenetics_testing Origination: 01/2019 Last CAP Review: 07/2020 Next CAP Review: 07/2021 Last Review: 04/2021 Description of Procedure or Service Description Pharmacogenetics aims to study the influence of genetic variation on drug response and drug toxicity, which allows physicians to select a more targeted therapeutic strategy to suit each patient’s genetic profile (Aka et al., 2017). Genetic variations in human proteins, such as, cytochrome P450 enzymes, Thiopurine methyltransferase (TPMT), Dihydropyrimidine dehydrogenase (DPD), and cell surface proteins, highlights the clinical importance of pharmacogenetic testing. Cytochrome (CYP) P450 enzymes are a class of enzymes essential in the synthesis and breakdown metabolism of various molecules and chemicals. Found primarily in the liver, these enzymes are also essential for the metabolism of many medications. CYP P450 enzymes, approximately 58 CYP human genes, are essential to produce many biochemical building blocks, such as cholesterol, fatty acids, and bile acids. Additional cytochrome P450 are involved in the metabolism of drugs, carcinogens, and internal substances, such as toxins formed within cells. Mutations in CYP P450 genes can result in the inability to properly metabolize medications and other substances, leading to increased levels of toxic substances in the body (Bains, 2013; Tantisira & Weiss, 2020). Thiopurine methyltransferase (TPMT) is an enzyme that methylates azathioprine, mercaptopurine and thioguanine into active thioguanine nucleotide metabolites. Azathioprine and mercaptopurine are used for treatment of nonmalignant immunologic disorders; mercaptopurine is used for treatment of lymphoid malignancies; and thioguanine is used for treatment of myeloid leukemias (Relling et al., 2011). Dihydropyrimidine dehydrogenase (DPD), encoded by the gene DPYD, is a rate-limiting enzyme responsible for fluoropyrimidine catabolism. The fluoropyrimidines (5-fluorouracil and capecitabine) are drugs used in the treatment of solid tumors, such as colorectal, breast, and aerodigestive tract tumors (Amstutz et al., 2018). A variety of cell surface proteins, such as antigen-presenting molecules and other proteins, are encoded by the human leukocyte antigen genes (HLAs). HLAs are also known as major histocompatibility complex (MHC) (Viatte, 2019). Related Policies In Vitro Chemoresistance and Chemosensitivity Assays AHS – G2100 Metabolite Markers of Thiopurines Testing AHS – G2155 Testing for Targeted Therapy of Non-Small-Cell Lung Cancer AHS – M2030 Therapeutic Drug Monitoring for 5-Fluorouracil AHS – M2067 Genetic Testing for Lipoprotein A Variant(s) as a Decision Aid for Aspirin Treatment and/or CVD Risk Assessment AHS – M2082 Page 1 of 48 An Independent Licensee of the Blue Cross and Blue Shield Association Pharmacogenetics Testing AHS – M2021 Molecular Panel Testing of Cancers for Diagnosis, Prognosis, and Identification of Targeted Therapy AHS – M2109 ***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician. Policy BCBSNC will provide coverage for pharmacogenetics testing when it is determined the medical criteria or reimbursement guidelines below are met. Benefits Application This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy. When Pharmacogenetics Testing is covered 1. Testing for the CYP2D6 genotype once per lifetime is considered medically necessary for individuals being considered for therapy with any of the medication listed below, or who are in their course of therapy with a medication listed below, to aid in therapy selection and/or dosing. • Eliglustat • Tetrabenazine (for doses over 50 mg) 2. Testing for the TPMT and NUDT15 genotype once per lifetime is considered medically necessary for individuals being considered for therapy with the below medication, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing. • Azathioprine • Mercaptopurine • Thioguanine 3. Testing for the following Human Leukocyte Antigens (HLAs) genotypes once per lifetime is considered medically necessary for individuals being considered for therapy with the below medication, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing: • HLA-B*57:01 before treatment with Abacavir • HLA-B*15:02 for treatment with Carbamazepine limited to patients of Asian descent 4. Testing for the following genotypes once per lifetime is considered medically necessary for individuals being considered for therapy with the below medication, or who are in their course of therapy with a medication listed below, to aid in therapy selection and/or dosing. • CFTR for treatment with Ivacaftor • G6PD for treatment with Rasburicase, Primaquine, Chloroquine, Dapsone, Pegloticase, Primaquine, and Tafenoquine. 5. Testing for the CYP2C9, CYP4F2, VKORC1, and rs12777823 genotype once per lifetime is considered medically necessary for individuals being considered for Warfarin therapy. 6. Testing for CYP2C9 genotype once per lifetime is considered medically necessary for individuals considered for therapy with Siponimod. Page 2 of 48 An Independent Licensee of the Blue Cross and Blue Shield Association Pharmacogenetics Testing AHS – M2021 7. Testing for CYP2C19 genotype once per lifetime is considered medically necessary for individuals considered for therapy with clopidogrel. When Pharmacogenetics Testing is not covered 1. Genetic testing for the presence of variants in the SLCO1B1 gene for the purpose of identifying patients at risk of statin-induced myopathy is considered not medically necessary. 2. Reimbursement is not allowed for the following pharmacogenetics testing: a. Genotyping for any medication therapy more than once per lifetime (see policy guideline). * b. Testing for the specific genotype for individuals on medications not listed as meeting coverage criteria for testing. c. Testing for all other genotypes including, but not limited to, use of other medication therapy not listed as meeting coverage criteria. d. Genotyping the general population. e. Pharmacogenetic panel testing for mental health disorders including, but not limited to, Genecept (Genomind) Assay and GeneSight Psychotropic panel. 3. Reimbursement is not allowed for all other single nucleotide polymorphism (SNP) testing, either as individual SNPs or as a panel of SNPs, for all indications. The list of SNPs includes, but is not limited to the following: • 5HT2C (serotonin receptor) • 5HT2A (serotonin receptor) • SLC6A4 (serotonin transporter) • DRD1 (dopamine receptor) • DRD2 (dopamine receptor) • DRD4 (dopamine receptor) • DAT1 or SLC6A3 (dopamine transporter) • DBH (dopamine beta-hydroxylase) • COMT (catechol-O-methyl-transferase) • MTHFR (methylenetetrahydrofolate reductase) • γ-Aminobutyric acid (GABA) A receptor • OPRM1 (µ-opioid receptor) • OPRK1 (κ-opioid receptor) • UGT2B15 (uridine diphosphate glycosyltransferase 2 family, member 15) 4. Proprietary Lab tests, including panel tests for any of the genotypes listed in this policy are considered investigational. The following single nucleotide polymorphism (SNP) testing, either as individual SNPs or as a panel of SNPs, is considered investigational for all indications: Cytochrome P450 genes: CYP3A4, CYP2B6, CYP1A2. *Policy Guideline: Genotyping once per lifetime Any gene should be tested once per lifetime regardless the indication (exception would be for HLA where a specific variant is testing for the medication). Policy Guidelines Page 3 of 48 An Independent Licensee of the Blue Cross and Blue Shield Association Pharmacogenetics Testing AHS – M2021 Background Genetic variations play a potentially large role in an individual’s response to medications. However, drug metabolism and responses are affected by many other factors, including age, sex, interactions with other drugs, and disease states (Tantisira & Weiss, 2020). Nonetheless, inherited differences in the metabolism and disposition of drugs and genetic polymorphisms in the targets of drug therapy can have a significant influence on the efficacy and toxicity of medications potentially even more so than clinical variables such as age and organ function (Kapur, Lala, & Shaw, 2014; Ting & Schug, 2016). Genetic variation can influence pharmacodynamic factors through variations affecting drug target receptors and downstream signal transduction, or pharmacokinetic factors, affecting drug metabolism and/or elimination (Tantisira & Weiss, 2020). The Cytochrome P450 (CYP 450) system is a group of enzymes responsible for the metabolism of many endogenous and exogenous substances, including many pharmaceutical agents. This system may serve to “activate” an inactive form of a drug, as well as inactivate and/or clear a drug from circulation. The CYP 450 enzymes are responsible for the clearance of over half of all drugs, and their activity can be affected by diet, age, and other medications. The genes encoding for the CYP 450 enzymes are highly variable with multiple alleles that confer various levels of metabolic activity for specific substrates. In some cases, alleles can be highly correlated