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DESCRIPTIONTamoxifen (TAM) is prescribed as a component of adjuvant endocrine therapy to prevent endocrine receptor-positive breast cancer recurrence, as treatment of metastatic breast cancer, and to prevent disease in high-risk populations and in women with ductal carcinoma in situ (DCIS). The cytochrome P450 (CYP) metabolic enzyme CYP2D6 has a major role in tamoxifen metabolism. The CYP2D6 gene is polymorphic; variant DNA gene sequences resulting in proteins with reduced or absent enzyme function may be associated with lower plasma levels of active tamoxifen metabolites, which could have an impact on TAM treatment efficacy.
Because a small, but significant, proportion of most ethnic populations have markedly reduced CYP2D6 metabolic capacity, there is concern that similar proportions of patients treated with TAM may have poorer outcomes than patients with relatively normal CYP2D6 activity. Some have recommended that patients who are to be prescribed TAM be genotyped for CYP2D6, and patients who are poor metabolizers (PMs) be treated with alternative therapy, if possible.
The metabolism of tamoxifen to 4-OH TAM is catalyzed by multiple enzymes. However, endoxifen is formed predominantly by CYP2D6. The plasma concentration of endoxifen exhibits high inter-individual variability, as described in breast cancer patients. The CYP2D6 enzyme has known inter-individual variability in activity and therefore has been of great interest in investigating TAM metabolism and variation in circulating active metabolite levels.
Metabolic Enzyme Genotypes
Griese et al studied the correlation of CYP2D6 functional categories with genotypes in 195 Caucasian individuals in Germany. While all poor metabolizers were “unambiguously identified as carriers of two nonfunctional alleles the most frequent functional genotypes extensively overlapped.” Thus, fully functional homozygous wild-type genotypes are consistently assigned to the EM category and homozygous inactive variant genotypes are consistently assigned to the PM category in pharmacogenomic studies. However, assignment of other genotypes with function in between these two is inconsistent among authors making it difficult to compare results across studies.
The prevalence of CYP2D6 PMs is approximately 7–10% in Caucasians of Northern European descent, 1.9–7.3% in African Americans, and about 1% or less in most Asian populations studied. The PM phenotype in whites is largely accounted for by CYP2D6 *3 and *4 non-functional variants, and by the *5 non-functional variant in African-American and Asian populations. Some PMs may reflect the combination of a non-functional and a reduced function allele. Among reduced function variants, *17, *10 and *8 are the most important in African-Americans, Asians, and Caucasians, respectively. Few studies have investigated the frequency of CYP2D6 variant alleles or of PMs in the Hispanic population.
Several other enzymes are involved in the metabolism of tamoxifen to the active metabolite 4-OH TAM. Polymorphisms in the genes for these enzymes could have an effect on overall TAM efficacy. Research regarding the effect of variant alleles for these enzymes is currently in the discovery stage and will not be further discussed in this policy.
Endocrine Therapy Regimens
TAM is the only adjuvant treatment approved for preventing breast cancer in women with ductal carcinoma in situ (about 20% of all new breast cancer), and for preventing disease in pre- or perimenopausal women at high risk. Thus, pharmacogenomic evaluation would not change treatment in these women.
TAM is currently the most commonly prescribed adjuvant treatment to prevent recurrence of endocrine-receptor-positive breast cancer in pre- or perimenopausal women. Pharmacogenomic evaluation could direct consideration of ovarian ablation or suppression in those found to be CYP2D6 PMs. (Note: In pre- or perimenopausal women with hormone receptor positive tumors, ovarian ablation is an effective treatment compared to no adjuvant therapy, but may be accompanied by acute and chronic side effects, e.g., hot flushes, sweats, and sleep disturbance. Ovarian ablation does not appear to add benefit to adjuvant chemotherapy. Similarly, functional ovarian suppression with gonadotropin releasing factor analogues in women with hormone receptor positive tumors confers benefits comparable to chemotherapy. The National Comprehensive Cancer Network (NCCN) guidelines indicate ovarian ablation/suppression is an option in combination with endocrine therapy for premenopausal women who have invasive or recurrent disease, and is recommended for premenopausal women with systemic disease.)
For prevention of cancer in postmenopausal women, who make up the majority of patients with breast cancer, raloxifene is an alternative treatment option, with equal efficacy and markedly reduced risk of endometrial hyperplasia. Raloxifene is currently not indicated for the treatment of invasive breast cancer, reduction of the risk of recurrence of breast cancer, or reduction of risk of noninvasive breast cancer (see full prescribing information at http://pi.lilly.com/us/evista-pi.pdf ).
The pharmacogenomics of TAM have been most often studied in post-menopausal women with endocrine receptor-positive tumors who require endocrine therapy to prevent recurrence. For this population, the NCCN breast cancer guidelines make no preferential treatment recommendations among the following choices:
In clinical practice, AIs may eventually replace TAM because of fewer adverse effects and equal or better efficacy. However, it is not yet clear that AI treatment alone maintains or improves long-term outcomes compared to sequential use of TAM and AI. Nor is there evidence as yet to support AI use in pre-menopausal women. Finally, TAM is important in the treatment of metastatic cancer, where either TAM or AI resistance may develop. Therefore the use of pharmacogenomics to improve the likelihood of tamoxifen benefit is of current interest.
Pharmacologic Inhibitors of Metabolic Enzymes
Thus, CYP2D6 inhibitor use must be considered in assigning CYP2D6 functional status, and potent CYP2D6 inhibitors may need to be avoided when TAM is administered.
CYP2D6 genotyping assays are also available as non-FDA-cleared laboratory-developed services; laboratories offering such tests as a clinical service must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA) and must be licensed by CLIA for high-complexity testing.
POLICYGenotyping to determine cytochrome p450 (CYP2D6) genetic polymorphisms is considered investigational for the purpose of managing treatment with tamoxifen for women at high risk for or with breast cancer.
POLICY EXCEPTIONSFederal 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 GUIDELINESInvestigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY3/27/2008: 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.
SOURCE(S)Blue Cross and Blue Shield Association Policy # 2.04.51
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.