Medical Policy

Policy Num:      11.003.095
Policy Name:    Genotype-Guided Tamoxifen Treatment
Policy ID:          [11.003.095]  [Ac / B / M- / P-]  [2.04.51]

Last Review:       September 13, 2024
Next Review:       September 20, 2025
 

Related Policies:

11.003.38 - Cytochrome P450 Genotype-Guided Treatment Strategy

 Genotype-Guided Tamoxifen Treatment

Summary

Tamoxifen 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. Tamoxifen is a pro-drug that undergoes extensive metabolism to yield its active form: 4-hydroxytamoxifen and endoxifen (primary active form) via the 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.

Summary of Evidence

For individuals who are treated with tamoxifen for breast cancer or are high-risk for breast cancer who receive CYP2D6 genotype-guided tamoxifen treatment, the evidence includes multiple retrospective and prospective cohort studies and nonconcurrent prospective studies. The relevant outcomes include overall survival, disease-specific survival, medication use, and treatment-related morbidity. Published data on the association between CYP2D6 genotype and tamoxifen treatment outcomes have yielded inconsistent results. Data in most of these studies derived from a convenient sample, which was further limited by relatively small numbers of patients and lack of comprehensive genotype data, patient data (eg, concomitant medications), and detailed clinical outcomes data. Three influential nonconcurrent prospective studies nested within large prospective, randomized double-blind clinical trials in postmenopausal women with hormone receptor-positive early stage breast cancer also reported contradictory results, with two larger studies failing to show statistically significant associations between phenotype (patients classified as poor, intermediate, or extensive metabolizer) and recurrence of breast cancer. No trials of genotype-directed dosing or drug choice that compared health outcomes for patients managed with and without the test were identified. It is not known whether CYP2D6 genotype-guided tamoxifen treatment results in the selection of a treatment strategy that would reduce the rate of breast cancer recurrence, improve disease-free survival or overall survival, or reduce adverse events. The evidence is insufficient to determine the effects of the technology on health outcomes.

Objective

The objective of this evidence review is to determine whether genotype-guided tamoxifen treatment improves the net health outcome in patients with breast cancer or those who are at high-risk of developing breast cancer.

Policy Statements

Genotyping to determine cytochrome P450 2D6 (CYP2D6) variants is considered investigational for the purpose of managing treatment with tamoxifen for women at high risk for or with breast cancer.

Policy Guidelines

Coding

Please see the codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

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).^1, Among these two 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 CYP2D6 enzyme. Plasma concentrations of endoxifen exhibit high interindividual variability, as described in breast cancer patients.^2, 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 response 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 genotype, phenotype, and clinical implications are summarized in Table 1.

Table 1. Relation Among the CYP2D6 Genotype, Phenotype, and Clinical Implications

Adapted from Swen et al (2011).^3,

The prevalence of CYP2D6 poor metabolizers is approximately 7% to 10% in whites of Northern European descent, 1.9% to 7.3% in blacks, and 1% or less in most Asian populations studied. The poor metabolizer phenotype in whites is largely accounted for by CYP2D6*3 and *4 nonfunctional variants, and in black and Asian populations, by the *5 nonfunctional variant. Some poor metabolizers may have one nonfunctional allele and onereduced-function allele. Among reduced-function variants, CYP2D6*17, *10, and *8 are the most important in blacks, Asians, and whites, respectively. Few studies have investigated the frequency of CYP2D6-variant alleles or poor metabolizers in the Hispanic population.^4,

Endocrine Therapy Regimens

Tamoxifen has several labeled indications^5,:

• 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 a likely benefit from tamoxifen treatment. Tamoxifen is currently the most commonly prescribed adjuvant treatment to prevent recurrence of the endocrinereceptor-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 treatment of reduction in the "risk of invasive breast cancer in postmenopausal women with osteoporosis" or those at "high risk for invasive breast cancer."^6,

Pharmacologic Inhibitors of Metabolic Enzymes

CYP2D6 activity may be affected not only by genotype but also by co-administered drugs that block or induce CYP2D6 function. Studies of selective serotonin reuptake inhibitors, in particular, have shown that fluoxetine and paroxetine, but not sertraline, fluvoxamine, or venlafaxine, are potent CYP2D6 inhibitors.^7,8,9, Some individuals treated with fluoxetine or paroxetine have changed from extensive metabolizer phenotype to poor metabolizer.^7, The degree of inhibition may depend on selective serotonin reuptake inhibitors 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. CYP2D6 genotyping assays are available under the auspices of Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by Clinical Laboratory Improvement Amendments 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 in Table 2.

Table 2. Testing Kits for CYP450 Genotyping Cleared for Marketing by the FDA

FDA: Food and Drug Administration.

Several manufacturers market diagnostic genotyping panel tests for CYP450 genes, such as the YouScript Panel (Genelex Corp.), which includes CYP2D6, CYP2C19, CYP2C9, VKORC1, CYP3A4, and CYP3A5. Other panel tests include both CYP450 and other non-CYP450 genes involved in drug metabolism, such as the GeneSight Psychotropic panel (Assurex Health) and PersonaGene Genetic Panels (AIBioTech). These panel tests are beyond the scope of this evidence review.

Rationale

This evidence review was created in March 2008 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through June 21, 2024 .

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

The primary goal of pharmacogenomics testing and personalized medicine is to achieve better clinical outcomes compared with the standard of care. Drug response varies greatly between individuals, and genetic factors are known to play a role. However, in most cases, the genetic variation only explains a modest portion of the variance in the individual response because clinical outcomes are also affected by a wide variety of factors including alternate pathways of metabolism and patient- and disease-related factors that may affect absorption, distribution, and elimination of the drug. Therefore, assessment of clinical utility cannot be made by a chain of evidence from clinical validity data alone. In such cases, evidence evaluation requires studies that directly demonstrate that the pharmacogenomic test alters clinical outcomes; it is not sufficient to demonstrate that the test predicts a disorder or a phenotype.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Genotype-Guided Tamoxifen Treatment

Clinical Context and Therapy Purpose

The purpose of genotype-guided tamoxifen treatment is to tailor drug selection (eg, tamoxifen or an aromatase inhibitor) or dose selection (eg, tamoxifen 40 mg/d instead of the standard 20 mg/d dose) or strategy (eg, ovarian ablation in premenopausal women) while minimizing treatment failures or toxicities based on a patient's genotype.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients receiving or being considered for tamoxifen therapy:

• Treatment of breast cancer in the adjuvant setting to prevent recurrence (alone or preceding aromatase inhibitor therapy) or for metastatic disease.

• Prevention of breast cancer in high-risk women or women with ductal carcinoma in situ; and absence of contraindications to aromatase inhibitors (for treatment) or raloxifene (for disease prevention).

Interventions

The therapy being considered is cytochrome P450 2D6 (CYP2D6) genotype-guided tamoxifen treatment. Commercial tests for individual genes or gene panels are available and listed in the Regulatory Status section.

Comparators

The following practice is currently being used: clinically guided tamoxifen treatment.

Outcomes

The general outcomes of interest are overall survival (OS), disease-specific survival, medication use, and treatment-related morbidity. The potential beneficial outcomes of primary interest would be a reduction in the rate of recurrence and improvement in disease-free survival or OS. Specific outcomes are listed in Table 3. The follow-up to determine whether genotype-guided tamoxifen treatment reduces adverse events or avoids treatment failure is during the first 10 years after treatment initiation.

Table 3. Outcomes of Interest for Individuals With or at High-Risk for Breast Cancer

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Meta-Analyses and Systematic Reviews

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.^10, Many of these studies have been summarized in multiple systematic reviews and meta-analyses with inconsistent results.^10,11, 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. A comparison of the studies included in 2 recent reviews is in Table 4. These reviews analyzed a total of 45 studies published between 2005 and 2017. Characteristics and results of these reviews are summarized in Tables 5 and 6.

Table 4. Comparison of Studies Included in Genotype-Guided Tamoxifen Treatment Systematic Reviews and Meta- Analyses

*Schroth et al. 2007 and Goetz et al 2005 include the same sample as Schroth et al. 2009.

Table 5. Systematic Reviews & Meta-Analyses of Genotype-Guided Tamoxifen Treatment: Characteristics

NR=not reported.

Table 6. Systematic Reviews & Meta-Analyses of Genotype-Guided Tamoxifen Treatment: Results

1. Adjusted for bias due to tissue sampling.CI=confidence interval; NA=not applicable; RR=relative risk.

Drögemöller et al (2019) conducted a systematic review of the association between CYP2D6 genetic variation and survival outcomes after tamoxifen treatment.^11, Included studies showed conflicting conclusions. In multivariate analyses, there was no significant relationship between survival outcomes and the confounders of sample size (p=.83), ethnicity (p=.33), or source of DNA (p=.14). Comprehensive genotyping panels were more likely to report a significant association with CYP2D6-survival outcome: 11 of 13 studies that used comprehensive genotyping found a significant association between CYP2D6 and survival outcomes. Limitations of the studies identified by the review authors included differences in survival outcome definitions, differences in metabolizer group classifications, low consent rates, and not controlling for CYP2D6 inhibitor use. Data in most of these studies were derived from a convenience 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.

Randomized Controlled Trial

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.^57,

Table 7. Summary of TARGET-1 Characteristics

HR=hormone receptor; V/V=variant/variant; wt/V=wild type/variant; wt/wt=wild type/wild type.

Table 8. Summary of Key TARGET-1 Results

¥ Median follow-up = 22.9 months.* Comparison between tamoxifen 40 mg and 20 mg groups with wt/V or V/V genotypes.CI=confidence interval; HR=hazard ratio; NR=not reported; NS=not significant; PFS=progression free survival; V/V=variant/variant; wt/V=wild type/variant; wt/wt=wild type/wild type.

The TARGET-1 trial has limited generalizability to all patients, due to its single-country design and small sample size.^57, 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.

Table 9. Study Relevance Limitations of TARGET-1

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Population key: 1. Intended use population unclear; 2. Clinical context for treatment is unclear; 3. Study population unclear; 4. Study population not representative of intended use; 5. Study population is subpopulation of intended useb Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparatorc Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectivelyd Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Not CONSORT reporting of harms; 4. Not established and validated measurements; 5. Clinically significant difference not presented; 6. Clinically significant difference not supportede Follow-up key: 1. Not sufficient duration for benefits; 2. Not sufficient duration for harms

Table 10. Study Design and Conduct Limitations of TARGET-1

CI=confidence interval; PFS=progression free survival.The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocations concealment unclear; 4. Inadequate control for selection biasb Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physicianc Selective Reporting key: 1. Not registered; 2. Evidence of selective reported; 3. Evidence of selective publicationd Follow-up key: 1. High loss to follow up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials)e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important differencef Statistical key: 1. Test is not appropriate for outcome type: a) continuous; b) binary; c) time to event; 2. Test is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p-values not reported; 4. Comparative treatment effects not calculated

No trials examining genotype-directed drug or strategy choice were identified. Ruddy et al (2013) implemented a tamoxifen adjustment algorithm for 99 patients treated at a cancer treatment institute.^58, Recommendations to modify tamoxifen therapy were made for 18 (18%) patients, all of whom had low endoxifen levels (<6 ng/mL), and 2 of whom also were identified as CYP2D6 poor metabolizers. Breast cancer recurrence or survival outcomes were not reported.

Observational Studies

Among the most influential studies of the association between CYP2D6 genotype and tamoxifen effectiveness are 3 nonconcurrent 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.^43,44,21, A more recent prospective cohort study assigned treatment doses according to CYP2D6 metabolizer status and compared outcomes using propensity score matching.^59,

Table 11. Summary of Key Observational Comparative Genotype-Guided Tamoxifen Treatment Study Characteristics

ABCSG=Austrian Breast and Colorectal Cancer Study Group; ATAC=Arimidex, Tamoxifen, Alone or in Combination trial; BIG=Breast International Group; ER=estrogen receptor; HR=hormone receptor; NA=not applicable; RCT=randomized controlled trial.

Table 12. Summary of Key Observational Comparative Genotype-Guided Tamoxifen Treatment Study Results

CI: confidence interval; EM: extensive metabolizer; HR: hazard ratio; IM: intermediate metabolizer; NA: not applicable; NM: normal metabolizer; NR: not reported; NS: not significant; OR: odds ratio; PM: poor metabolizer; UM: ultra metabolizer.¥ Number and percentage of cases and controls with each phenotype not reported.

In the Arimidex, Tamoxifen, Alone or in Combination trial^43, and Breast International Group 1-98 trial,^44, 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.^21, Results showed that patients with 2 poor metabolizer alleles had a 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 nonconcurrent prospective studies have been raised to explain the lack of effect in the Arimidex, Tamoxifen, Alone or in Combination trial and Breast International Group 1-98 trials.^60,Poor metabolizers constituted less than 10% of the overall cohort in the study by Blancas et al (2023), suggesting that the study may have been underpowered to detect any differences in survival outcomes driven by genotype-guided tamoxifen regimen differences.^59,

For individuals who are treated with tamoxifen for breast cancer or are at high-risk for breast cancer who receive CYP2D6 genotype-guided tamoxifen treatment, the evidence includes a single randomized controlled trial (RCT), several meta-analyses and systematic reviews, multiple retrospective and prospective cohort studies, and nonconcurrent prospective studies. Relevant outcomes include overall survival (OS), disease-specific survival, medication use, and treatment-related morbidity. Published data on the association between CYP2D6 genotype and tamoxifen treatment outcomes have yielded inconsistent results. Data in most of these studies were derived from a convenience sample, which was further limited by relatively small numbers of patients and lack of comprehensive genotype data, patient data (eg, concomitant medications), and detailed clinical outcomes data. Three influential nonconcurrent prospective studies nested within large prospective, randomized, double-blind clinical trials in postmenopausal women with hormone receptor-positive early-stage breast cancer also reported contradictory results, with 2 larger studies failing to show statistically significant associations between phenotype (patients classified as poor, intermediate, or extensive metabolizers) and recurrence of breast cancer. The RCT examining genotype-directed dosing found no difference in progression-free survival between a standard dose and increased dose; however, this trial was limited by its proof of concept design. No trials of genotype-directed drug choice that compared health outcomes for patients managed with and without the test were identified. It is not known whether CYP2D6 genotype-guided tamoxifen treatment results in the selection of a treatment strategy that would reduce the rate of breast cancer recurrence, improve disease-free survival or OS, or reduce adverse events. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Society of Clinical Oncology

In 2016, the guidelines published by the American Society of Clinical Oncology (ASCO) 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."^61,

A 2022 update to the ASCO guideline stated that the recommendation against use of CYP2D6 polymorphisms to guide adjuvant endocrine therapy had been archived.^62,

Clinical Pharmacogenetics Implementation Consortium

In 2018, the Clinical Pharmacogenetics Implementation Consortium issued therapeutic recommendations for tamoxifen prescribing based on CYP2D6 genotype/metabolic phenotype.^63, For the clinical endpoints of recurrence and event-free survival, the evidence was graded as moderate for the statements that CYP2D6 poor metabolizers have a higher risk of breast cancer recurrence or worse event-free survival. However, for the comparison of other metabolizer groups and other clinical endpoints, the evidence was considered weak regarding an association between CYP2D6 metabolizer groups and clinical outcomes.

National Comprehensive Cancer Network

Regarding the use of CYP2D6 genotyping before prescribing tamoxifen, the National Comprehensive Cancer Network breast cancer guidelines (v.4.2024 4.2023) state: "CYP2D6 genotype testing is not recommended for patients considering tamoxifen."^64,

U.S. Preventive Services Task Fo

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 12.

Table 12. Summary of Key Trials

NCT: national clinical trial.

References

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