Wednesday, November 13, 2019

CPT 81225, 81226, 81227 - Genotype-Guided Tamoxifen Treatment

Code Description CPT

81225 CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *8, *17) 

81226 CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN) 

81227 CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6) 

81479 Unlisted molecular pathology procedure

81599 Unlisted multianalyte assay with algorithmic analysis

Genotype-Guided Tamoxifen Treatment


Certain types of breast cancer are affected by hormones. Cancer cells that are said to be estrogen receptor positive (ER-positive) have receptors that attach to estrogen. Once attached, estrogen then acts like a fertilizer to help the cancer grow. Hormone therapy is used to prevent estrogen from connecting to the receptors. Tamoxifen is a type of hormone therapy that can be used for ER-positive breast cancer to prevent it from coming back and to treat breast cancer that’s already spread to other parts of the body. It’s also used for ER-positive ductal carcinoma in situ (DCIS). To process tamoxifen into its more active form, the body uses a specific, important enzyme (CYP2D6) that’s made by a particular gene. A small percentage of people (about 10%) have a form of the gene that doesn’t make as much of this important enzyme as most other people make. A genetic test has been developed to try to see if a person has the gene form that makes a smaller amount of the needed enzyme. This genetic test is investigational (unproven). Large, well-designed medical studies don’t show a strong link between this gene and tamoxifen’s effectiveness. More studies are needed. 

Note:  The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.

Policy Coverage Criteria  Test Investigational  Cytochrome P450 2D6 (CYP2D6) testing 


Genotyping to determine cytochrome P450 2D6 (CYP2D6) variants is considered investigational for the purpose of managing treatment with tamoxifen for women at high risk for or with breast cancer.

Related Information 

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1).

The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology*“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”*to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA 

Previous  Updated  Definition
Mutation Disease-associated variant
Disease-associated change in the DNA sequence
Variant Change in the DNA sequence 
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence 
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology. 


Tamoxifen is prescribed as a component of adjuvant endocrine therapy to prevent endocrine receptor-positive breast cancer recurrence, to treat metastatic breast cancer, and to prevent disease in high-risk populations and in women with ductal carcinoma in situ. Tamoxifen is a prodrug that undergoes extensive metabolism to yield its active form: 4-hydroxy tamoxifen and endoxifen (primary active form) via the CYP2D6 enzyme. Variants in the CYP2D6 gene are associated with significant alterations in endoxifen concentrations leading to the hypothesis that CYP2D6 variation may affect the clinical outcomes of women treated with tamoxifen but not with drugs not metabolized by CYP2D6, such as anastrozole. Gene Expression-Based Assays for Cancers of Unknown Primary

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