Coverage Policy Manual
Policy #: 2009003
Category: Laboratory
Initiated: February 2009
Last Review: October 2023
  Genetic Test: Tamoxifen Treatment (CYP2D6)
Description:
Tamoxifen 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). 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.
 
Background
 
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) (Goetz, 2008). 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 cytochrome P450 2D6 (CYP2D6) enzyme. Plasma concentrations of endoxifen exhibit high inter-individual variability, as described in breast cancer patients (Stearns, 2003). 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 responses 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 CYP2D6 genotype, phenotype, and clinical implications with use of Tamoxifen are summarized below:
 
    • A genotype with 3 or more copies of functional alleles and a phenotype of ultra-rapid metabolizer has no potential clinical implications with use of Tamoxifen.
    • A genotype with 1 active allele and 1 inactive allele, 2 decreased activity alleles, or 1 decreased activity allele and 1 inactive allele with a phenotype of intermediate metabolizer has the following clinical implications with use of Tamoxifen: increased risk for relapse of breast cancer, avoid concomitant use of CYP2D6 inhibitors, and consider aromatase inhibitor for postmenopausal women
    • A genotype with 2 inactive allele and a phenotype of poor metabolizer has a potential clinical implication of increased risk for relapse of breast cancer and aromatase inhibitor should be considered for postmenopausal women.
 
The prevalence of CYP2D6 poor metabolizers is approximately 7% to 10% in White individuals of Northern European descent, 1.9% to 7.3% in Black individuals, and 1% or less in most Asian populations studied. The poor metabolizers phenotype in White individuals is largely accounted for by CYP2D6*3 and *4 nonfunctional variants, and in Black and Asian populations by the *5 non-functional 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 Black, Asian, and White individuals, respectively. Few studies have investigated the frequency of CYP2D6 variant alleles or poor metabolizers in the Hispanic population (Bernard, 2006).
  
Endocrine Therapy Regimens
Tamoxifen has several prescribing indications (Drugs.com, 2023): 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 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.
 
For postmenopausal 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 the reduction in "risk of invasive breast cancer in postmenopausal women with osteoporosis" or those at "high risk for invasive breast cancer" (Eli Lilly, 2023).
 
Pharmacologic Inhibitors of Metabolic Enzymes
CYP2D6 activity may be affected not only by genotype but also by co-administration of drugs that block or induce CYP2D6 function. Studies of selective serotonin reuptake inhibitors (SSRIs), in particular, have shown that fluoxetine and paroxetine, but not sertraline, fluvoxamine, or venlafaxine, are potent CYP2D6 inhibitors (Alfaro, 1999; Alfaro, 2000; Lam, 2002). Some individuals treated with fluoxetine or paroxetine changed from an extensive metabolizer phenotype to a poor metabolizer (Alfaro, 1999). The degree of inhibition may depend upon the SSRI 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.
 
Regulatory Status
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 (CLIA). CYP2D6 genotyping assays are available under the auspices of CLIA. Laboratories that offer laboratory-developed tests must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) 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 (FDA product code: NTI) are summarized below:
 
    • xTAG CYP2D6 Kit V3, manufactured by Luminex Molecular Diagnostics, was approved in 2017
    • xTAG CYP2C19 Kit V3, manufactured by Luminex Molecular Diagnostics, was approved in 2013
    • Spartan RX CYP2C19 Test System, manufactured by Spartan Bioscience, was approved in 2013
    • xTAG CYP2D6 Kit V3 (including TDAS CYP2D6), manufactured by Luminex Molecular Diagnostics, was approved in 2013
    • Verigene CYP2C19 Nucleic Acid Test (CYP2C19), manufactured by Nanosphere, was approved in 2012
    • Infiniti CYP2C19 Assay, manufactured by AutoGenomics, was approved in 2010
    • xTAG CYP2D6 Kit V3, Model I030C0300, manufactured by Luminex Molecular Diagnostics, was approved in 2010
    • Invader UGT1A1 Molecular Assay, manufactured by Third Wave Technologies, was approved in 2005  
    • Roche AmpliChip CYP450 Test, manufactured by Roche Molecular Systems, was approved in 2005  
Policy/
Coverage:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing for CYP2D6 or any other gene to predict effectiveness of Tamoxifen therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, genetic testing for CYP2D6 or any other gene to predict effectiveness of Tamoxifen therapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
Potential indications for CYP2D6 pharmacogenomic testing include patients who are to be treated with TAM (alone or prior to treatment with an aromatase inhibitor) for prevention of breast cancer in high risk women or women with DCIS, for adjuvant treatment to prevent breast cancer recurrence, or for treatment of metastatic disease, and who have no contraindications to treatment with aromatase inhibitors (for treatment of existing disease) or raloxifene (for prevention of disease). Post-menopausal patients determined to be CYP2D6 poor metabolizers could avoid TAM therapy and be treated with aromatase inhibitors alone. Pre-menopausal patients might consider ovarian ablation. For any indication, co-administration of drugs that inhibit CYP2D6 activity should be taken into account.
 
Mayo Clinic investigators, Goetz et al., determined CYP2D6 genotype from archived tumor samples and buccal cells from living tamoxifen-treated patients enrolled into a prospective, randomized phase III breast cancer trial conducted by the North Central Cancer Treatment Group.   The authors reported that the CYP2D6*4 variant allele was an independent predictor of higher risk for breast cancer relapse (Goetz et al. 2005).
 
In 2007, the same investigators conducted a follow-up study using the same population of patients.  It was concluded that, CYP2D6 inhibiting medications taken concomitantly are an independent predictor of outcomes in postmenopausal women receiving tamoxifen therapy.
 
Two studies conducted by Wegman et al reported contrasting conclusions in comparison to the above two studies.   CYP2D6 was studied in 226 patients with breast cancer patients in a trial receiving tamoxifen 40 mgs over a 2 year period.  The investigators found that patients with at least one CYP2D6*4 variant allele had better outcomes than those not treated with tamoxifen (Wegman et al. 2005).  Limitations to this study include the following: tissue samples were available for only 33% of originally enrolled patients; only 47 patients carried a *4 allele; tamoxifen dose was 40 mg/day instead of the standard 20 mg/day and was only administered for 2 years instead of the standard 5 years. In another retrospective study with a larger cohort and dosing of tamoxifen 20 mg or 40 mg over 5 years, estrogen receptor-positive patients who were homozygous for CYP2D6*4 showed improved survival outcomes compared to patients with the wild-type genotype (Wegman et al. 2007).
 
This finding was again supported in a retrospective trial conducted on archived DNA samples and data from pathology reports and hospital tumor registry data from 162 patients receiving tamoxifen and 175 patients not receiving tamoxifen. (Nowell et al. 2005) The authors report a trend toward better overall survival in patients with CYP2D6*4 treated with tamoxifen alone or in combination with chemotherapy and radiation.  
 
“Because patients underwent varying lengths of treatment or may have undergone additional therapies, and because hormone receptor status was not centrally tested, comparing these and the Mayo study is difficult. As a possible explanation of the seemingly contradictory results, it is helpful to note that in the Mayo Trial, the outcomes of women who were likely to have intermediate concentrations of endoxifen (heterozygous CYP2D6*4) were no different from those women carrying 2 wild-type alleles.  (Higgins et al. 2009)”.
 
Schroth et al (2007) conducted a non-randomized retrospective cohort analysis of patients diagnosed with primary invasive breast cancer.    DNA from 206 patients receiving adjuvant tamoxifen monotherapy and from 280 patients not receiving tamoxifen therapy was isolated from archived samples and genotyped for numerous polymorphisms of CYP2D6, CYP2C19, CYP2B6, CYP2C9 and CYP3A5.  The results from this trial are similar to those of the Mayo Trial.  Improved outcomes were seen in women treated with tamoxifen who were carriers of a variant allele, compared to those with functional alleles (Higgins et al., 2009).
 
“Although most select studies suggest that poor metabolizers of CYP2D6 have a worse outcome than wild-type patients when treated with tamoxifen in either the preventive, adjuvant or advanced disease settings, not all studies have provided consistent results, and at least 2 suggest the opposite.”(Higgins et al., 2009)
 
Conflicting data on the clinical outcomes of CYP2D6 genotyping and variability of results of clinical trials suggest that CYP2D6 is not the only determining factor in tamoxifen activity.  The effectiveness of genetic testing to predict response to tamoxifen therapy is the subject of continuing debate and is presently being studied in randomized clinical trials to determine if genetic testing results in improved outcomes.
 
2012 Update
A literature search was conducted using the MEDLINE database through March 2012.  There was no new literature identified that would prompt a change in the coverage statement.
 
Two professional guidelines were noted to support the coverage statement. Regarding the use of CYP2D6 genetic testing prior to prescribing tamoxifen, the National Comprehensive Cancer Network (NCCN) breast cancer guidelines state “At this time, based on current data the panel recommends against CYP2D6 testing for women being considered for tamoxifen therapy. Co-administration of strong inhibitors of CYP2D6 should be used with caution” (NCCN V.1.2012).  
 
The American Society of Clinical Oncology’s (ASCO) 2010 guideline update states: “The Update Committee recommends against using CYP2D6 genotype to select adjuvant endocrine therapy. The Update Committee encourages caution with concurrent use of CYP2D6 inhibitors” (Burstein, 2010).
 
2013 Update
A literature search was conducted using the MEDLINE database through April 2013.  There was no new literature identified that would prompt a change in the coverage statement. The key identified literature is summarized as follows:
Tumor tissues and isolated DNA samples were obtained from 4861 women enrolled in the randomized Breast International Group (BIG) 1-98 trial (Regan, 2012).  Extracted DNA was used for CYP2D6 genotyping. Genotype combinations were used to categorize CYP2D6 phenotypes as poor, intermediate and extensive metabolizers. Associations between CYP2D6 metabolism phenotypes and breast cancer-free intervals were assessed. The study results showed no association between CYP2D6 metabolism phenotypes and breast cancer-free interval. The authors concluded that the results of this study do not support the use of CYP2D6 genotyping in deciding whether or not to treat postmenopausal breast cancer patients with tamoxifen (Regan, 2012).
 
The literature to date does not clearly support a significant association between CYP2D6 genotype and tamoxifen treatment outcome. Therefore, the coverage intent is unchanged.
 
Ongoing Clinical Trials
A search of the clinicaltrials.gov website identified the following ongoing clinical trials designed to assess the relationship between CYP2D6 and tamoxifen treatment in women with breast cancer.
 
NCT01124695- This phase II open-label trial sponsored by the Eastern Cooperative Oncology Group in collaboration with the National Cancer Institute is assessing the correlation between CYP2D6 and progression free survival in patients with metastatic breast cancer treated with tamoxifen. The study has an estimated enrollment of 240 patients. Estimated study completion date is July 2016.
 
NCT00764322- The UNC Lineberger Comprehensive Cancer Center in collaboration with the National Cancer Institute is sponsoring this trial which will study blood samples taken from women with breast cancer or ductal carcinoma in situ who are receiving tamoxifen therapy. The change in endoxifen levels will be evaluated after an increase in tamoxifen dose in patients with intermediate-metabolizing CYP2D6 genotypes. This study is ongoing but not recruiting patients. Estimated study completion date is August 2015.
 
NCT00973037-This prospective, observational study assessing the impact of CYP2D6 genotype on the clinical effects of tamoxifen in the treatment of breast cancer is sponsored by the Korean University Anam Hospital in collaboration with the National Cancer Center, Korea. The estimated study completion date is April 2016.
 
NCT01357772-This is a randomized, placebo-controlled, phase 3 study of low dose tamoxifen in women with breast intraepithelial neoplasia. CYP2D6 genotyping will be performed. The estimated study completion date is November 2017.
 
NCT00963209- This study is a phase 3, open-label study examining different plasma concentrations of tamoxifen and its metabolites with different daily schedules of drug. The relationship between clinical symptoms and CYP2D6 genotype will be assessed.
 
Practice Guidelines and Position Statements
The current National Comprehensive Cancer Network (NCCN) breast cancer guidelines recommend against testing for women with breast cancer being considered for tamoxifen treatment (NCCN, V3.2013).
  
2014 Update
A literature search conducted through April 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
The published literature on the association of CYP2D6 genotype with the effectiveness of tamoxifen therapy in the treatment of non-metastatic breast cancer has produced inconsistent results. A 2012 review tried to identify factors that may have led to the discrepant findings in published studies (Hertz, 2012).  The review included a total of 17 independent published studies, and selected 6 factors to compare across 11 negative and 6 positive studies. The comparison of the factors across different studies suggested that tamoxifen combination therapy (defined as any additional therapy, including radiation), genotyping comprehensiveness (how many and which alleles were tested) and CYP2D6 inhibitor coadministration may account for some of the contradictory results. The review found that studies that enrolled patients on tamoxifen monotherapy, genotyped the CYP2D6 gene more comprehensively, and accounted for CYP2D6 inhibitor coadministration were more likely to have positive findings.
 
2015 Update
A literature search was conducted using the MEDLINE database through April 2014. Several new prospective studies were identified (Saladores, 2015; Martinez, 2014;Martins, 2014). 69) but do not provide any direct evidence of clinical utility. Review of the available literature does not prompt a change in the coverage statement.
 
2016 Update
A literature search conducted through September 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In a 2016 study, Hertz and colleagues increased tamoxifen dose from 20 mg/day to 40 mg/day based on genotype (Hertz, 2016). Endoxifen concentrations in IM were similar to those of EM, but endoxifen levels in PM were not. The dose escalation did not increase toxicity or reduce quality of life, raising the possibility that more effective doses of tamoxifen might be given. A beneficial effect on survival with this increase in tamoxifen dose would be needed to demonstrate clinical utility.
 
Ongoing and Unpublished Clinical Trials
A search of the clinical trials database through September 2016 did not reveal any new trials that might influence this review.
 
2017 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.  
 
Rationale:
 
2018 Update
A literature search was conducted through September 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Prospective Cohort Studies
Multiple retrospective and prospective cohort studies have investigated the association between CYP2D6 genotype and tamoxifen effectiveness and reported contradictory results with relative risks ranging from 0.08 to 13.1 for the association between variant CYP2D6 genotypes and breast cancer recurrence or mortality (Ahern, 2017). The contradictory results may be due to differences in the types of additional therapies patients received, how many and which CYP2D6 alleles were tested, tissue type examined (tumor or germline DNA), and co-administration with CYP2D6 inhibitors. Many of these studies have also been summarized in multiple systematic reviews and meta-analyses with inconsistent results. Data in most of these studies derived from a convenient sample, which was further limited by relatively small numbers of patients, lack of comprehensive genotype data and patient data (eg, concomitant medications), and detailed clinical outcomes data. Among the most influential studies of the association between CYP2D6 genotype and tamoxifen effectiveness are 3 non-concurrent prospective studies nested within large prospective, randomized double-blind trials that compared tamoxifen with anastrozole, letrozole, or combination tamoxifen and anastrozole in postmenopausal women with hormone receptor–positive early stage breast cancer (Rae, 2012; Regan, 2012; Goetz, 2013). In the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial and Breast International Group 1-98 (BIG 1-98) trial, a subset of patients who received tamoxifen and were genotyped for CYP2D6 variants (n=588 and n=1243, respectively) did not show any statistically significant associations between phenotype (patients classified as poor, intermediate, or extensive metabolizer) and breast cancer recurrence. In the Austrian Breast and Colorectal Cancer Study Group trial, a case-control study was done using a subset of patients where cases were defined as those with disease recurrence, contralateral breast cancer, second non-breast cancer, or died and controls were identified from the same treatment arm of similar age, surgery/radiation, and stage (Goetz, 2013). Results showed that patients with 2 poor metabolizer alleles had higher likelihood of recurrence than women with 2 extensive metabolizer alleles. Concerns about the substantial departure from Hardy-Weinberg equilibrium for the CYP2D6 allele, *4 and analyses not meeting the Simon-Paik-Hayes criteria for non-concurrent prospective studies have been raised to explain the lack of effect in the ATAC and BIG 1-98 trials.
American Society of Clinical Oncology
The 2016 guidelines from the American Society of Clinical Oncology on the use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer stated the following for CYP2D6 variants to guide adjuvant endocrine therapy selection:
 
    • “The clinician should not use CYP2D6 polymorphisms to guide adjuvant endocrine therapy selection (Type: Evidence based; Evidence quality: Intermediate; Strength of recommendation:  Moderate).
    • The ability of polymorphisms in CYP2D6 to predict tamoxifen benefit has been extensively studied. The results of these pharmacogenomics studies have been controversial, with more recent studies being negative. At this point, data do not support the use of this marker to select patients who may or may not benefit from tamoxifen therapy” (Harris, 2016).
 
2019 Update
A literature search was conducted through September 2019.  There was no new information identified that would prompt a change in the coverage statement.  
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
One trial of genotype-directed dosing that assessed outcomes of breast cancer recurrence was identified (TARGET-1: CYP2D6 Genotype-Guided Tamoxifen Dosing in Hormone Receptor-Positive Metastatic Breast Cancer trial). The RCT is a phase II, proof-of-concept study performed at multiple centers in Japan. A total of 184 patients were included in this study, of which 136 had at least 1 CYP2D6 variant-type allele. Only 1 patient classified as a poor metabolizer with 2 null alleles was included in this trial. The results of this trial did not find a significant difference in outcomes between increased tamoxifen dosing and standard dosing in patients with CYP2D6 genotypic variants (Tamura, 2020).
 
The TARGET-1 trial has limited generalizability to all patients, due to its single-country design and small sample size (Tamura, 2020). No significant difference was seen in progression free survival with genotype-guided dosing, even though the trial detected significant differences in tamoxifen metabolite concentrations between tamoxifen doses and allelic variations. Because the trial was a proof-of-concept, phase II design, the median follow-up for clinical outcomes was only 22.9 months. The study did not address outcomes of OS or recurrence. Additionally, the primary analysis comparing progression free survival only included patients with variant alleles, and patients with 2 wild-type alleles were not included in reported analyses.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A more recent prospective cohort study assigned treatment doses according to CYP2D6 metabolizer status and compared outcomes using propensity score matching (Blancas, 2023)., This study by Blancas et al took place in a single center in Spain between 2000 – 2010. Participants included Women with HR-positive breast cancer planned for adjuvant tamoxifen for 5 or more years. Participants (N=220) underwent CYP2D6 genotyping and were assigned metabolizer status (Poor Metabolizer [PM], n=13; Intermediate Metabolizer [IM], n=84; Normal Metabolizer [NM], n=119; Ultra Metabolizer [UM], n=4) according to CPIC guidelines. Treatment consisted of PM: Tamoxifen 20 mg/d for 4 months, then 40 mg/d for 4 months, then 60 mg/d for 4 months, then 20 mg/d for remainder of 5 years. All others: Tamoxifen 20 mg/d for 5 years. The study results include IM and PM (rapid) vs NM and UM (slow), HR (95% CI); Overall survival: Overall cohort: 0.77 (0.34 to 1.76) Propensity-matched: 0.85 (0.28 to 2.52); Disease free survival: Overall cohort: 1.27 (0.67 to 2.42) Propensity-matched: 1.37 (0.62 to 3.03). Poor metabolizers constituted less than 10% of the overall cohort in the study by Blancas et al, suggesting that the study may have been underpowered to detect any differences in survival outcomes driven by genotype-guided tamoxifen regimen differences.
 
A 2022 update to the American Society of Clinical Oncology (ASCO) guideline stated that the recommendation against use of CYP2D6 polymorphisms to guide adjuvant endocrine therapy had been archived (Andre, 2022).
 
Regarding the use of CYP2D6 genotyping before prescribing tamoxifen, the National Comprehensive Cancer Network breast cancer guidelines (v.4.2023) state: "CYP2D6 genotype testing is not recommended for patients considering tamoxifen" (NCCN, 2023).
CPT/HCPCS:
81226CYP2D6 (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)
81418Drug metabolism genomic sequence panel, must include testing of at least 6 genes, including CYP2C19, CYP2D6, and CYP2D6
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Ahern TP, Hertz DL, Damkier P, et al.(2017) Cytochrome P-450 2D6 (CYP2D6) genotype and breast cancer recurrence in tamoxifen-treated patients: evaluating the importance of loss of heterozygosity. Am J Epidemiol. Jan 15 2017;185(2):75-85. PMID 27988492

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