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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 for metastatic breast cancer, and to prevent disease in high-risk populations and in women with ductal carcinoma in situ (DCIS). The cytochrome P450 (CYP450) 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 have been hypothesized to have a negative 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. Because CYP2D6 enzyme activity is known to vary across individuals, CYP2D6 is 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.
Alternatively and more recently, it has been estimated that at doses used for adjuvant treatment, which are intended to saturate the estrogen receptor, more than 99% of estrogen receptors are bound by low-affinity tamoxifen and both low- and high-affinity metabolites. Lash and colleagues modeled the effect of CYP2D6 variant alleles on estrogen receptor binding by tamoxifen and metabolites and found negligible effect. As the authors note, however, modeling cannot account for many metabolic complexities, and mechanistic data would be needed to show how a decrease in high-affinity metabolites associated with CYP2D6 variants reduces the protection against recurrence conferred by tamoxifen therapy.
Metabolic Enzyme Genotypes
The prevalence of CYP2D6 PMs is approximately 7–10% in Caucasians of Northern European descent, 1.9–7.3% in African Americans, and 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 have one non-functional allele and one 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.
Other enzymes metabolize 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 in earlier stages of discovery.
Endocrine Therapy Regimens
In women with breast cancer, endocrine-receptor-positive disease predicts likely benefit from TAM treatment.
TAM is the only adjuvant treatment approved for preventing breast cancer in women with ductal carcinoma in situ (about 20% of all new breast cancers), 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. 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 pre- or perimenopausal 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 postmenopausal women with osteoporosis or at high-risk for invasive breast cancer, raloxifene is an alternative treatment for invasive cancer risk reduction; efficacy equals that of tamoxifen, and risk of endometrial hyperplasia is markedly reduced. 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 include the following category 1 and category 2 recommendations for adjuvant endocrine therapy:
In clinical practice, AIs may eventually replace TAM because of fewer adverse effects and equal or better efficacy. However, there is no evidence as yet to support AI use in pre-menopausal women. TAM also is important in the treatment of metastatic cancer, where either TAM or AI resistance may develop. Therefore the use of pharmacogenomics to increase 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.
The Roche AmpliChip CYP450 Test (Model 04381866190) is cleared by the U.S. Food and Drug Administration (FDA) and can be used to identify a patient's CYP2D6 genotype.
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.
Although FDA has considered updating the label for tamoxifen (brand and generics) with information or recommendations regarding CYP2D6 genotyping and impact on tamoxifen efficacy, and has held an Advisory Committee meeting to answer specific questions regarding the evidence and recommendations, no label update has yet been issued.
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 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.
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.
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 added.
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.