Tuesday, January 8, 2019

CPT 81225, 81226, 81227, 81599 - Genotype-Guided Tamoxifen Treatment

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.

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 

Unlisted multianalyte assay with algorithmic analysis 

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. 

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.

Background  Tamoxifen Metabolism 

Tamoxifen is a pro-drug that undergoes extensive metabolism to yield its active form: 4hydroxytamoxifen (4-OH tamoxifen) and 4-hydroxy-N-desmethyltamoxifen (endoxifen).

Among these 2 metabolites, endoxifen is thought to be the major metabolite that exerts the pharmacodynamic effect of tamoxifen. The metabolism of tamoxifen into 4-OH tamoxifen is catalyzed by multiple enzymes, while endoxifen is formed predominantly by the CYP2D6 enzyme. Plasma concentrations of endoxifen exhibit high interindividual variability, as described in breast cancer patients.

Because CYP2D6 enzyme activity is known to vary across individuals, variants in the CYP2D6 gene are of great interest for understanding tamoxifen metabolism variability and variation in levels of circulating active metabolites. Moreover, known variability in endoxifen levels has been hypothesized to result in variable response to tamoxifen treatment.

Metabolic Enzyme Genotypes 

The CYP2D6 gene exhibits a high degree of polymorphism, with more than 100 allelic variants identified. The relations among genotype, phenotype, and clinical implications are summarized in Table 3.

The prevalence of CYP2D6 poor metabolizers is approximately 7% to 10% in whites of Northern European descent, 1.9% to 7.3% in blacks, and 1% or less in most Asian populations studied. The poor metabolizer phenotype in whites is largely accounted for by CYP2D6*3 and *4 nonfunctional variants, and in black and Asian populations, by the *5 nonfunctional variant. Some poor metabolizers may have 1 nonfunctional allele and 1 reduced-function allele. Among reduced function variants, CYP2D6*17, *10, and *8 are the most important in blacks, Asians, and whites, respectively. Few studies have investigated the frequency of CYP2D6-variant alleles or of poor metabolizers in the Hispanic population.

Endocrine Therapy Regimens 

Tamoxifen has several labelled indications

* Chemoprevention of invasive breast cancer in high-risk women without current disease or with ductal carcinoma in situ
* Adjuvant treatment of primary breast cancer
* Treatment of metastatic disease

In women with breast cancer, endocrine receptor-positive disease predicts a likely benefit from tamoxifen treatment. Tamoxifen is currently the most commonly prescribed adjuvant treatment to prevent recurrence of endocrine receptor-positive breast cancer in premenopausal or perimenopausal women. 

For post-menopausal women with osteoporosis or at high risk for invasive breast cancer, raloxifene is an alternative treatment for invasive cancer risk reduction. Currently, raloxifene is indicated for treatment of reduction in the “risk of invasive breast cancer in postmenopausal women with osteoporosis” or those at “high risk for invasive breast cancer.”

Pharmacologic Inhibitors of Metabolic Enzymes 

CYP2D6 activity may be affected not only by genotype but also by co-administered drugs that block or induce CYP2D6 function. Studies of selective serotonin reuptake inhibitors, in particular, have shown that fluoxetine and paroxetine, but not sertraline, fluvoxamine, or venlafaxine, are potent CYP2D6 inhibitors.

Some individuals treated with fluoxetine or paroxetine have changed from extensive metabolizer phenotype to poor metabolizer.

The degree of inhibition may depend on selective serotonin reuptake inhibitors dose.
Thus, CYP2D6 inhibitor use must be considered in assigning CYP2D6 functional status, and potent CYP2D6 inhibitors may need to be avoided when tamoxifen is administered.

Summary of Evidence

For individuals who are treated with tamoxifen for breast cancer or are high risk for breast cancer who receive CYP2D6 genotype-guided tamoxifen treatment, the evidence includes multiple retrospective cohort studies and nonconcurrent prospective studies. Relevant outcomes include overall survival, disease-specific survival, medication use, and treatment-related morbidity. Data in most of these studies derived from a convenient sample, which was further limited by relatively small numbers of patients and lack of comprehensive genotype data, patient data (eg, concomitant medications), and detailed clinical outcomes data. Three influential nonconcurrent prospective studies nested within large prospective, randomized double-blind clinical trials in postmenopausal women with hormone receptor–positive earlystage breast cancer also reported contradictory results. Two larger studies failed to show statistically significant associations between phenotype (patients classified as poor, intermediate, or extensive metabolizer) and recurrence of breast cancer. No trials of genotype-directed dosing or drug choice that compared health outcomes for patients managed with and without the test were identified. It is not known whether CYP2D6 genotype-guided tamoxifen treatment results in the selection of a treatment strategy that would reduce the rate of  breast cancer recurrence, improve disease-free survival or overall survival, or reduce adverse events. The evidence is insufficient to determine the effects of the  technology on health outcomes.

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