Genotype-Guided Tamoxifen Treatment

POLICY NUMBER

L.2.04.464

DESCRIPTION

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 pro-drug that undergoes extensive metabolism to yield its active form: 4-hydroxytamoxifen and endoxifen (primary active form) via the cytochrome P450 2D6 (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.

Tamoxifen Metabolism

Tamoxifen is a pro-drug that undergoes extensive metabolism to yield its active form: 4-hydroxytamoxifen (4-OH tamoxifen) and 4-hydroxy-N-desmethyltamoxifen (endoxifen). Among these two 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 cytochrome P450 2D6 (CYP2D6) enzyme. Plasma concentrations of endoxifen exhibit high inter-individual 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 GenotypesThe CYP2D6 gene exhibits a high degree of polymorphism, with more than 100 allelic variants identified. Each allele is associated with either normal, decreased, or absent enzyme function. Each allele can be assigned an activity score from 0 to 1 which then determines the phenotype. The relations among activity score based on genotype and phenotype are summarized in the table below. Intermediate and poor metabolizers have lower plasma endoxifen concentrations compared with normal metabolizers; however, the impact on treatment outcomes is unclear.

Relation Among the CYP2D6 Genotype and Phenotype

Endocrine Therapy RegimensTamoxifen has several labeled 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; and

• 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 pre- or peri-menopausal women. For postmenopausal women, an aromatase inhibitor is often the preferred adjuvant.

Pharmacologic Inhibitors of Metabolic EnzymesCYP2D6 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 a poor metabolizer. The degree of inhibition may depend on the selective serotonin reuptake inhibitor 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.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. CYP2D6 genotyping assays are also available under the auspices of Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Several testing kits for CYP450 genotyping cleared for marketing by the FDA through the 510(k) process are summarized in the table below.

Testing Kits for CYP450 Genotyping Cleared for Marketing by the FDA

Several manufacturers market diagnostic genotyping panel tests for CYP450 genes, such as the YouScript Panel (Genelex Corp.), which includes CYP2D6, CYP2C19, CYP2C9, VKORC1, CYP3A4, and CYP3A5. Other panel tests include both CYP450 and other non-CYP450 genes involved in drug metabolism, such as the GeneSight Psychotropic panel (Assurex Health). These panel tests are beyond the scope of this policy.

POLICY

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

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

3/27/2008: Policy added.

7/17/2008: Reviewed and approved by the Medical Policy Advisory Committee (MPAC).

12/24/2008: Coding reference section updated per 2009 CPT/HCPCS revisions.

06/21/2011: Policy description and statement unchanged. Added FEP verbiage to the Policy Exceptions section.

05/09/2012: Policy reviewed; no changes.

01/10/2013: Added CPT code 81226 to the Code Reference section.

10/15/2013: Policy reviewed; no changes.

07/01/2014: Policy reviewed; description updated regarding tamoxifen metabolism. Policy statement unchanged. Removed deleted CPT codes 83890, 83891, 83892, 83893, 83894, 83896, 83897, 83898, 83900, 83901, 83902, 83903, 83904, 83905, 83906, 83907, 83908, 83909, 83912, 83913, 83914, 88384, 88385, and 88386 from the Code Reference section.

07/30/2015: Code Reference section updated for ICD-10.

09/18/2015: Policy description updated regarding the NCCN breast cancer guidelines for adjuvant endocrine therapy. Policy statement unchanged. Investigative definition updated in the Policy Guidelines section.

06/06/2016: Policy number A.2.04.51 added.

08/19/2016: Policy description updated regarding breast cancer guidelines from the NCCN for tamoxifen therapy. Policy statement unchanged. Policy Guidelines updated to add genetic counseling information.

07/17/2017: Policy description updated regarding the NCCN's guidelines for adjuvant endocrine therapy for postmenopausal women with breast cancer. Policy statement updated to change "genetic polymorphisms" to "variants." Policy Guidelines updated regarding standard terminology for variant classification.

08/07/2018: Policy title changed from "Genetic Testing for Tamoxifen Treatment" to "Genotype-Guided Tamoxifen Treatment." Policy description updated regarding metabolic enzyme genotypes and devices. Policy statement unchanged. Policy Guidelines updated regarding genetics nomenclature and to remove genetic counseling information.

10/01/2018: Code Reference section updated to add new CPT codes 0070U, 0071U, 0072U, 0073U, 0074U, 0075U, and 0076U.

08/12/2019: Policy reviewed; no changes.

08/17/2020: Policy reviewed. Policy statement unchanged. Policy Guidelines updated to remove genetics nomenclature information.

08/27/2021: Policy description updated regarding tests. Policy statement unchanged.

08/09/2022: Policy reviewed. Policy statement updated to change "women" to "individuals."

08/08/2023: Policy description updated. Policy statement unchanged.

09/12/2024: Policy description updated. Policy statement unchanged.

10/09/2025: Policy number changed from "A.2.04.51" to "L.2.04.464." Policy description updated regarding metabolic enzyme genotypes, endocrine therapy regimens, and devices. Policy statement unchanged.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.51

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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