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DESCRIPTIONTamoxifen 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 (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 tamoxifen treatment efficacy. Some have recommended that patients who are to be prescribed tamoxifen be genotyped for CYP2D6, and patients who are poor metabolizers be treated with alternative therapy, if possible.
The metabolism of tamoxifen to 4-OH tamoxifen is catalyzed by multiple enzymes. However, endoxifen is formed predominantly by CYP2D6. Plasma concentrations 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, CYP2D6*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 tamoxifen. Polymorphisms in the genes for these enzymes could have an effect on overall tamoxifen efficacy. Research on 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 tamoxifen treatment.
Tamoxifen 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 more effective treatment than no adjuvant therapy, but may be accompanied by acute and chronic side effects (e.g., hot flushes, sweats, and sleep disturbance). Similarly, functional ovarian suppression with gonadotropin-releasing factor analogues in pre- or perimenopausal women with hormone receptor-positive tumors confers benefits comparable to chemotherapy. National Comprehensive Cancer Network (NCCN) guidelines indicate ovarian ablation or suppression are options in combination with endocrine therapy for premenopausal women who have invasive or recurrent disease and are 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. Currently, raloxifene is not indicated for treatment of invasive breast cancer; reduction of breast cancer recurrence risk; or noninvasive breast cancer risk reduction (see full prescribing information at http://pi.lilly.com/us/evista-pi.pdf).
Pharmacogenomics of tamoxifen have been most often studied in post-menopausal women who have endocrine receptor-positive tumors who require endocrine therapy to prevent recurrence. For this population, 2016 breast cancer guidelines from NCCN include the following category 1 and 2 recommendations for tamoxifen therapy:
In clinical practice, AIs may eventually replace tamoxifen 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. Tamoxifen also is important for treatment of metastatic cancer, where either tamoxifen 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 tamoxifen is administered.
The Roche AmpliChip CYP450 Test (Model 04381866190) is cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process and can be used to identify CYP2D6 genotype.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). CYP2D6 genotyping assays are also available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Although FDA has considered updating the label for tamoxifen (brand and generics) with information or recommendations on CYP2D6 genotyping and impact on tamoxifen efficacy, and held an advisory committee meeting to answer specific questions on 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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
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 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.
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.
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.