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MP 2.04.51 Genetic Testing for Tamoxifen Treatment

Section
Medicine 
Original Policy Date
3/2008
Last Review Status/Date
Reviewed with Literature Search/5:2014
Issue
5:2014
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

 


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). 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.

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 tamoxifen may have poorer outcomes than patients with relatively normal CYP2D6 activity. Some have recommended that patients who are to be prescribed tamoxifen be genotyped for CYP2D6, and patients who are poor metabolizers (PMs) be treated with alternative therapy, if possible.

Background

Tamoxifen Metabolism

Tamoxifen undergoes extensive primary and secondary metabolism, and the plasma concentrations of tamoxifen and its metabolites vary widely. 4-hydroxytamoxifen (4-OH tamoxifen) has demonstrated 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent in vitro cell proliferation when compared with the parent drug (summarized in (1). Another metabolite, 4-hydroxy-N-desmethyl tamoxifen (endoxifen), has identical properties and potency compared with 4-OH tamoxifen. (2-5) Because 4-OH tamoxifen represents less than 20% of the product of tamoxifen primary metabolism and steady-state plasma endoxifen concentrations are on average 5- to 10-fold higher than 4-OH tamoxifen, it has been assumed that endoxifen is the major active metabolite of tamoxifen.

The metabolism of tamoxifen to 4-OH tamoxifen 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. (5) The CYP2D6 enzyme has known inter-individual variability in activity and therefore has been of great interest in investigating tamoxifen metabolism and variation in circulating active metabolite levels. Moreover, the 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 is 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. (6) Lash et al. modeled the effect of CYP2D6 variant alleles on estrogen receptor binding by tamoxifen and metabolites and found negligible effect. (7) As the authors note, however, modeling cannot account for many metabolic complexities, and mechanistic data would be needed to show how the decrease in high-affinity metabolites associated with CYP2D6 variants reduces the protection against recurrence conferred by tamoxifen therapy.

Metabolic Enzyme Genotypes

The CYP2D6 gene exhibits a high degree of polymorphism, with more than 75 allelic variants identified. While the most prevalent CYP2D6 *1 and *2 alleles (both termed “wild-type” for this Policy) produce an enzyme with normal activity, there are several variant (V) alleles that result in enzymes with no activity or reduced activity. Because individuals have two CYP2D6 alleles, various combinations of the possible alleles result in a spectrum of CYP2D6 function; these have been categorized as extensive metabolizers (EM or “normal”), intermediate metabolizers (IM), and poor metabolizers (PM). An additional, rare category of ultra-rapid metabolizers (UM) is defined by possession of three or more functional alleles due to gene duplication.

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 nonfunctional variants and by the *5 non-functional variant in African-American and Asian populations. Some PMs may reflect the combination of a nonfunctional 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. (8)

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 regarding the effect of variant alleles for these enzymes is in earlier stages of discovery.

Endocrine Therapy Regimens

Tamoxifen has several labelled indications(9):

  • chemoprevention of invasive breast cancer in high-risk women without current disease or with DCIS;
  • 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 the only adjuvant treatment approved for preventing breast cancer in women with DCIS (approximately 20% of all new breast cancers)(10) and for preventing disease in pre- or perimenopausal women at high risk. Thus, pharmacogenomic evaluation would not change treatment in these women.

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 an effective treatment compared with no adjuvant therapy but may be accompanied by acute and chronic adverse effects, eg, 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 analogs in pre- or perimenopausal women with hormone receptor-positive tumors confers benefits comparable with chemotherapy. 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 withsystemic disease.(11)

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.(12)

Pharmacogenomics of tamoxifen have been most often studied in postmenopausal women who have endocrine receptor-positive tumors and require endocrine therapy to prevent recurrence. For this population, breast cancer guidelines from NCCN make no preferential treatment recommendations among the following choices(11):

  • aromatase inhibitors (AI) for 5 years
  • tamoxifen for 2-3 years, followed by AI to complete 5 years or longer
  • tamoxifen for 4.5-6 years, followed by AI for 5 years
  • tamoxifen for 5 years in women with contraindications to AI treatment, who decline AI treatment, or who are intolerant to AI treatment.

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 premenopausal 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
CYP2D6 activity may be affected not only by genotype but also by coadministered drugs that block 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.(14-16) Some individuals treated with fluoxetine or paroxetine changed from EM phenotype to PM.(12) The degree of inhibition may depend upon 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
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.


Policy

 

Genotyping to determine cytochrome p450 2D6 (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 Guidelines

 

 

Coding

Effective in 2012, there is a specific CPT code for this testing:

 

81226: CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN). 


Benefit Application
BlueCard/National Account Issues

 

State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.


Rationale

 

Literature Review

This policy was created in 2008 and has been updated regularly, with the most recent literature search through May 26, 2014.

This policy is based on a 2011 TEC Assessment,(17) which was updated in 2013.(18) Additional details about the studies described in this section are available in the Assessments.

Potential indications for CYP2D6 pharmacogenomic testing include tamoxifen treatment of breast cancer in the adjuvant setting to prevent recurrence (alone or preceding aromatase inhibitor [AI] therapy) or for metastatic disease; prevention of breast cancer in high-risk women or women with ductal carcinoma in situ (DCIS); and absence of contraindications to AIs (for treatment) or raloxifene (for disease prevention).
If evidence indicated poorer outcomes with tamoxifen treatment in CYP2D6-poor metabolizers (PMs), postmenopausal patients determined to be CYP2D6 PMs could avoid tamoxifen therapy and receive AIs alone. Premenopausal patients might consider ovarian ablation. For any indication, coadministration of drugs that inhibit CYP2D6 activity should be taken into account.

Analytic Validity (technical performance of the assay)
The Roche AmpliChip CYP450 Test for detecting variants in CYP2D6 has been fully validated for analytic validity; a summary of results submitted for clearance by the U.S. Food and Drug Administration (FDA) is provided in FDA’s decision summary.(19)

Although comparable information on the analytic validity of laboratory-developed tests usually is not available, in an experienced laboratory and with validation of in-house results compared with either sequencing or AmpliChip, accurate and reliable performance should be achievable as demonstrated by Heller et al.(20)

Clinical Validity (association of genetic marker with intermediate or clinical outcomes)
Four studies evaluated CYP2D6 genotype as a prognostic marker in patients not treated with tamoxifen to ensure that a prognostic association would not confound the effect of genotype on tamoxifen outcomes.(21-24) Although there were limitations in study quality or reporting, none of the studies found that outcome varied by CYP2D6 genotype in untreated patients.

Indirect Association of Genotype with Clinical Outcomes
Fifteen prospective cohort studies of adjuvant tamoxifen treatment provided consistent evidence that CYP2D6 nonfunctional variant alleles are associated with significantly reduced plasma endoxifen levels.(5,24-37) However, endoxifen levels overlap across all genotypes, suggesting that CYP2D6 genetic variability does not explain all variation in endoxifen levels; in a 2013 study of 224 Asian women, 10% of the variance in endoxifen levels was explained by CYP2D6 genotype.(37) Seven of 8 studies reported significant associations of low CYP2D6 function with reduced plasma 4-hydroxytamoxifen (4-OH tamoxifen) levels.(24,25,27,28,31-33,35) Coadministration of potent CYP2D6 inhibitors to CYP2D6 homozygous wild-type patients (extensive metabolizers, EMs) was associated with endoxifen levels near those of patients who are PMs; thus, use of CYP2D6 inhibitors should be taken into account in assigning metabolizer status in clinical studies.

Two studies reported on the relationship between CYP2D6 genotype and active tamoxifen metabolites and between genotype and clinical outcomes in the same patient population.(24,28) Both studies enrolled breast cancer patients from Asian populations, focusing almost exclusively on the reduced (but not absent) function CYP2D6*10 variant. Both studies reported reduced endoxifen and/or 4-OH tamoxifen
concentrations in conjunction with 1 or 2 variant alleles and also reported decreasing disease- or recurrence-free survival. Both studies were small and had study design flaws likely resulting in selection bias. In 2011, Madlensky et al reported on the association of tamoxifen metabolite levels with breast cancer outcomes in 1370 samples from the Women’s Healthy Eating and Living (WHEL) study.(32) WHEL enrolled 3088 women with early stage breast cancer who were diagnosed from 1991 to early 2000 and received tamoxifen.(38) Endoxifen and 4-OH tamoxifen levels were strongly associated with CYP2D6 phenotype but were not linearly associated with breast cancer outcome. A threshold effect was identified with endoxifen, such that patients with endoxifen levels greater than 6 ng/mL had a 30% lower risk of additional breast cancer events (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.52 to 0.94). Notably, 24% of PM patients had endoxifen levels above this threshold.

Three prospective studies in 2011 and 2012 increased tamoxifen dose for patients who were already taking tamoxifen and were genotyped as intermediate metabolizers (IMs) or PMs (and not administered CYP2D6 inhibitors).(29-31) Tamoxifen metabolite levels were measured at baseline and after 2 to 4 months and compared with those of EM patients who had no dose change. In general, tamoxifen metabolite concentrations increased with increasing dose; IM patient levels reached those of EM patients, and PM patient levels remained somewhat lower. However, these results were not related to breast cancer outcomes. Moreover, metabolite levels were highly variable across individuals, and in one study, low plasma endoxifen concentrations were found in all CYP2D6 genotypes.(30) Thus, it is likely that CYP2D6 accounts for only part of the variability in endoxifen levels.(39) The influence of other gene variants on tamoxifen treatment outcomes has been reported.(40,41)

Direct Association of Genotype with Clinical Outcomes
An ideal study would compare tamoxifen-treated women versus those not receiving tamoxifen, with stratification by CYP2D6 genotype to see if PMs derive less benefit from tamoxifen than EMs. One group conducted such a study retrospectively, on archived samples from a randomized controlled trial (RCT) of tamoxifen treatment.(23) Paradoxically, they found that EMs treated with tamoxifen received no statistically significant clinical benefit compared with EMs not treated with tamoxifen and that carriers of a CYP2D6*4 nonfunctional variant allele obtained significant benefit from tamoxifen treatment. There were several limitations to this study.

Twenty-four other studies evaluated the association between CYP2D6 genotype and clinical outcomes in women treated with tamoxifen.

Nine small studies (N range, 21-282) in Asian populations focused on the CYP2D6*10 reduced function allele,(24,27,28,41-46) and 6 reported significant results for the association of CYP2D6 genotype with outcomes of tamoxifen treatment.(24,27,28,45,46) However, some of these studies may be affected in unpredictable ways by different types of bias, for example, by selecting among survivors at a time distant from diagnosis and surgery to draw whole blood for CYP2D6 genotyping (survivor selection bias). Two studies that reported no association may have had less potential for bias.(42,43) One larger study (N=716) of Korean patients with breast cancer who received tamoxifen adjuvant therapy (most with adjuvant chemotherapy) found no CYP2D6 genotype-associated significant difference in recurrence-free survival (RFS) regardless of treatment or prognostic subgroup.(33)

Thirteen studies evaluated samples from primarily white patients administered tamoxifen for adjuvant treatment of invasive breast cancer or, in 1 study, for metastatic breast cancer.(21,22,47-58) Of the 5 largest studies, 4 reported no significant association for time to recurrence.(47,49-51) Two of the negative studies were retrospective analyses of clinical trial samples,(49,50) and a third was a case-control study nested in a population-based cancer registry.(47) All 3 were designed to minimize potential for bias; their size (N range, 588-991) allowed comparison of homozygous nonfunctional CYP2D6 genotypes with fully functional wild-type genotypes, ie, the most extreme comparison and most likely to reveal a true association. The largest of the 5 studies (N=1345) reported significant results; however, this study combined samples from different sources, some of which had already been analyzed for this hypothesis.(48) In addition, it is unclear from the report whether nearly half of the samples were obtained from patients who had survived and were available at a time distant from their diagnosis and surgery, a type of selection bias that can unpredictably affect results. The remaining 8 small studies reported a variety of significant and nonsignificant results; no pattern of bias, genotyping or group scheme, or accounting for CYP2D6 inhibitor use (among possibilities) explained the differences in results. The heterogeneity of results across all studies and clear results of no genotype-tamoxifen treatment outcome
in 3 large studies with the least apparent potential for bias strongly suggests lack of support for clinical validity in postmenopausal patients treated with adjuvant tamoxifen for breast cancer.

Two nested matched case-control studies examined patients who were originally enrolled in chemoprevention trials using tamoxifen. (59, 60) In neither the larger (591 cases, 1126 controls) nor the smaller study (47 cases, 135 controls) was CYP2D6 genotype associated with the risk of developing breast cancer. A 2013 matched case-control study from the Women’s Environment Cancer and Radiation Epidemiology (WECARE) study sample reported no association of CYP2D6 variants and risk for contralateral breast cancer in tamoxifen-treated women (139 cases, 338 controls).(61) WECARE participants (998 cases [women with contralateral breast cancer] and 2112 controls [women without contralateral breast cancer]) comprised women from 4 U.S. cancer registries and 1 Danish registry who were diagnosed with localized invasive breast cancer before age 55.

Published literature on the association of CYP2D6 genotype with tamoxifen therapy effectiveness for treatment of nonmetastatic breast cancer has yielded inconsistent results. A 2012 review tried to identify factors that may have led to discrepant findings.(62) The authors selected 6 factors to compare across 11 negative and 6 positive studies and identified 3 factors that may account for contradictory results: tamoxifen combination therapy (defined as any additional therapy, including radiation); genotyping comprehensiveness (how many and which alleles were tested); and CYP2D6 inhibitor coadministration. 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.

Subsequent studies in white patients have reported discrepant results. Two large studies from Scandinavia (total N=1365) reported no association between CYP2D6 genotype and disease recurrence in tamoxifen-treated women with early breast cancer.(63,64) In contrast, a 2013 German study of 94 women with advanced breast cancer reported significantly shorter progression-free survival (PFS) and overall survival (OS) in patients without any fully functional CYP2D6 allele (IM/IM [intermediate metabolizers], IM/PM, PM/PM) compared with those who had at least 1 functional allele (EM/EM, EM/IM, EM/PM) (HR for PFS, 2.19 [95% CI, 1.15 to 4.18], p=0.017; HR for OS, 2.79 [95% CI, 1.12 to 6.99],
p=0.028).(65) Some authors have suggested that CYP2D6 genotyping is clinically relevant in premenopausal women(66) and others in postmenopausal women.(67)

Several meta-analyses in 2013 and 2014 published inconsistent results. None of the studies included concomitant use of CYP2D6-inhibiting drugs in their analyses. Taken together, these analyses may be considered exploratory because the authors varied inclusion criteria, outcome definitions, and comparisons of interest.

  • An International Tamoxifen Pharmacogenomics Consortium pooled retrospective data from 12 participating sites. (68) Results from 1996 postmenopausal women with estrogen receptor-positive breast cancer who were prescribed tamoxifen 20 mg daily for 5 years (40% of the total sample) reported a significant association of CYP2D6 PM status with both reduced invasive disease-free survival (DFS) (HR for invasive disease or death, 1.25 [95% CI, 1.06 to 1.47], p=0.009) and reduced breast cancer-free interval (HR for recurrence, 1.27 [95% CI, 1.01 to 1.61], p=0.041), presumably in comparison with EMs. (The comparison group was not explicitly defined.) Statistical heterogeneity was nonsignificant (Cochran’s Q, p>0.05) for both outcomes. For analyses using less stringent inclusion criteria (eg, pre- and postmenopausal women combined), associations between CYP2D6 metabolizer status and survival outcomes were not statistically significant. A critique of this study is that adjustment for multiple comparisons was not performed, and the statistically significant association may no longer be statistically significant had adjustment for multiple comparisons been reported.(69)
  • Lum et al conducted a systematic review to January 29, 2012 and pooled results from 22 retrospective studies (total N=4936).(70) For the outcome of all-cause mortality, relative risk (RR) (incorporating odds ratio, HRs, and rate ratio) for CYP2D6 PMs or IMs compared with EMs or ultrarapid metabolizers (Ums) was not statistically significant (RR=1.11 [95% CI, 0.94 to 1.31], p=0.237). Statistical heterogeneity was low (I2=20%). When outcomes were expanded to include PFS (RR=1.27 [95% CI, 1.11 to 1.45], p<0.001) and recurrence (RR=1.19 [95% CI, 1.07 to 1.33], p=0.002), relative risks were statistically significant, but statistical heterogeneity was moderate to substantial (I2=56% and 53%, respectively).
  • Zeng et al conducted a systematic review to February 21, 2013, and pooled 20 retrospective studies (total N=11,701).(71) Among several comparisons (PM vs EM, IM vs EM, PM/IM vs EM, PM vs IM/EM), the association of CYP2D6 metabolizer status with both DFS and OS was statistically significant only for the comparison of any variant allele versus wild-type EM (HR for DFS, 1.37 [95% CI, 1.12 to 1.69], p=0.002; HR for OS, 1.24 [95% CI, 1.03 to 1.50], p=0.021). Statistical heterogeneity was substantial for the analysis of DFS (I2=67%) but minimal for OS (I2=0%). There was evidence of publication bias for the outcome of DFS.
  • Jung and Lim pooled results from 10 retrospective studies (total N=5183) and found an increased risk of recurrence among carriers of CYP2D6 variant alleles compared with wild-type EMs (pooled HR=1.64 [95% CI, 1.07 to 2.79]).(72) However, this result is questionable due to the inclusion of 4 small studies (N range, 18-282) with unstable risk estimates (HRs >3 with large CIs).

Clinical Utility (impact of using the test on medical decision making and health outcomes)
There is no direct evidence of clinical utility. Ruddy et al (2013) implemented a tamoxifen adjustment algorithm for 99 patients treated at the Dana Farber Cancer Institute.(73) Recommendations to modify tamoxifen therapy were made for 18 patients (18%), all of whom had low endoxifen levels (<6 ng/mL), and 2 of whom also were identified as CYP2D6 PMs. Survival outcomes were not reported.

Two indirect chains of evidence can be constructed. One depends on demonstrating a significant association between in vivo endoxifen levels and clinical outcomes; this evidence is insufficient. The other depends on the association of genotype with clinical outcomes, summarized in the section on clinical validity. There are several limitations to the overall body of evidence, but the largest, most well-designed studies do not support a significant association. As a result, this indirect chain of evidence fails, and therefore the evidence does not support clinical utility.

Ongoing Clinical Trials
A search of online site ClinicalTrials.gov identified 3 phase 3 trials determining CYP2D6 genotyping in patients receiving tamoxifen for breast cancer:

  • A RCT is examining clinical outcomes of tamoxifen-treated male breast cancer patients and the influence of CYP2D6 activity (NCT01638247).
  • An RCT is enrolling women with breast intraepithelial neoplasia to determine risk of progression to invasive disease (NCT01357772).
  • A cohort study is examining different plasma concentrations of tamoxifen and its metabolites with different daily schedules of drug (NCT00963209).

The Eastern Cooperative Oncology Group is conducting a Phase 2 prospective study to assess the correlation between CYP2D6 genotype and PFS in patients with metastatic or recurrent breast cancer treated with single-agent tamoxifen (NCT01124695). Estimated enrollment is 240 patients, and completion is expected in July 2016.

Summary
Published data on the association between CYP2D6 genotype and tamoxifen treatment outcome have yielded inconsistent results. Some inconsistencies in the literature may be due to differences across studies in the types of additional therapies patients received, how many and which CYP2D6 alleles were tested, and coadministered CYP2D6 inhibitors. The largest, most well-designed studies do not support a significant association. Thus, because the impact of testing on net health outcome is unknown, genotyping to manage tamoxifen therapy is considered investigational.

Practice Guidelines and Position Statements
National Comprehensive Cancer Network
Regarding the use of CYP2D6 genetic testing before prescribing tamoxifen, 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.”(11)

The American Society of Clinical Oncology
A 2010 guideline update from ASCO 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.” (74)

A 2013 guideline update from ASCO states, “Data from the NSABP-P1 and STAR trials do not support the use of CYP2D6 testing to identify women not likely to benefit from tamoxifen therapy for breast cancer prevention.”(75)

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

References:

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  3. Lim YC, Li L, Desta Z et al. Endoxifen, a secondary metabolite of tamoxifen, and 4-OH-tamoxifen induce similar changes in global gene expression patterns in MCF-7 breast cancer cells. J Pharmacol Exp Ther 2006; 318(2):503-12.
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Codes

Number

Description

CPT  81226 CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6)(e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)
ICD-9 Diagnosis   Investigational for all codes
ICD-10-CM (effective 10/1/15)    Investigational for all codes
   C50.011 – C50.929 Malignant neoplasm of nipple and breast, code range
   C79.81 Secondary malignant neoplasm of breast
   D05.01 – D05.99 Carcinoma in situ of breast; code range
   D07.30 – D07.39 Carcinoma in situ of other and unspecified female genital organs; code range
  Z13.71-Z13.79 Encounter for screening for genetic and chromosomal anomalies code range
  Z85.3 Personal history of malignant neoplasm of breast, female or male
  Z80.3 Family history of malignant neoplasm of breast
ICD-10-PCS (effective 10/1/15)    Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.


Index
Tamoxifen, Genetic Testing


Policy History

Date Action Reason
03/13/08 Add policy to Medicine section, Pathology/ Laboratory subsection New Policy
07/09/09 Replace policy Policy updated with literature search; references 22-26 added. Policy statements unchanged
4/14/11 Replace policy Policy updated with literature search and TEC Assessment; references 6, 7, 15, 16, 21, 22, 24, 25, 27, 29-33, 36, 38-40 added; references 9 and 10 updated. No change to policy statement
04/12/12 Replace policy Policy updated with literature search. References 25-32, 38,39, 48-50 added. No change to policy statement.
6/13/13 Replace policy Policy updated with literature search through May 13, 2013. Reference 51 added. Reference 10 updated. No change to policy statement.
5/22/14 Replace policy Policy updated with literature review through March 26, 2014; references 9, 12, 18-19, 34-38, 46, 63-73, and 75 added; references 10-11 updated. No change to policy statement.