Background

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 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 CYP2D6 enzyme. Plasma concentrations of endoxifen exhibit high inter-individual 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

Genotype	Phenotype	Potential Clinical Implications With Use of Tamoxifen
≥3 copies of functional alleles	Ultrarapid metabolizer	None
Any one of the following scenarios: 1 active allele and 1 inactive allele 2 decreased activity alleles 1 decreased activity allele and 1 inactive allele	Intermediate metabolizer	Increased risk for relapse of breast cancer Avoid concomitant use of CYP2D6 inhibitors Consider aromatase inhibitor for postmenopausal women
2 inactive alleles	Poor metabolizer	Increased risk for relapse of breast cancer Consider aromatase inhibitor for postmenopausal women

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 1 nonfunctional allele and 1 reduced-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.

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."^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 inhibitor 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 in Table 2.

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

Device Name	Manufacturer	Approval Date
xTAG CYP2D6 Kit V3	Luminex Molecular Diagnostics	2017
xTAG CYP2C19 Kit V3	Luminex Molecular Diagnostics	2013
Spartan RX CYP2C19 Test System	Spartan Bioscience	2013
xTAG CYP2D6 Kit V3 (including TDAS CYP2D6)	Luminex Molecular Diagnostics	2013
Verigene CYP2C19 Nucleic Acid Test (CYP2C19)	Nanosphere	2012
Infiniti CYP2C19 Assay	AutoGenomics	2010
xTAG CYP2D6 Kit V3, Model I030C0300	Luminex Molecular Diagnostics	2010
Invader UGT1A1 Molecular Assay	Third Wave Technologies	2005
Roche AmpliChip CYP450 Test	Roche Molecular Systems	2005

FDA: U.S. 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.

Related Policies

• Cytochrome P450 Genotype-Guided Treatment Strategy (Policy #033 in the Medicine Section)

For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)

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: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical policy updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Previous	Updated	Definition
Mutation	Disease-associated variant	Disease-associated change in the DNA sequence
	Variant	Change in the DNA sequence
	Familial variant	Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

Variant Classification	Definition
Pathogenic	Disease-causing change in the DNA sequence
Likely pathogenic	Likely disease-causing change in the DNA sequence
Variant of uncertain significance	Change in DNA sequence with uncertain effects on disease
Likely benign	Likely benign change in the DNA sequence
Benign	Benign change in the DNA sequence

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.


Medicare 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. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has determined that this service is not covered. For additional information, please refer to Novitas Solutions Inc, LCD Biomarkers Overview (L35062). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46

Local Coverage Article: Billing and Coding: Biomarkers Overview (A56541). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/pagebyid?contentId=00024370.

Medicaid Coverage:

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was originally created in 2009 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through May 20, 2020.

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.

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.

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 question addressed in this evidence review is: Does a genotype-guided treatment strategy change patient management in a way that it improves net health outcome?

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

Patients

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 test being considered is 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 managed 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

Outcomes	Details
Medication use	Change to alternative treatment (aromatase inhibitor) or strategy (ovarian ablation in premenopausal women)
Treatment-related morbidity	Reduction in adverse events

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 are included 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 SR & M-A

Study	Ahern et al. (2016)10,	Drögemöller et al. (2019)11,
Abraham et al. (2010)12,	⚫	⚫
Abreu et al. (2015)13,		⚫
Bijl et al. (2009)14,	⚫	⚫
Brooks et al. (2013)15,		⚫
Chamnanphon et al. (2013)16,	⚫	⚫
Damodaran et al. (2012)17,	⚫	⚫
De Ameida Melo et al. (2016)18,		⚫
Dezentje et al. (2013)19,	⚫
Goetz et a. (2005)20,*	⚫
Goetz et al. (2013)21,	⚫	⚫
Gor et al. (2010)22,	⚫
Gunaldi et al. (2014)23,		⚫
Hertz et al. (2017)24,		⚫
Johansson et al. (2016)25,		⚫
Karle et al (2013)26,		⚫
Kiyotani et al. (2010)27,	⚫	⚫
Kiyotani et al. (2010)28,		⚫
Lammers et al. (2010)29,		⚫
Lash et al. (2011)30,	⚫	⚫
Lei et al. (2016)31,		⚫
Margolin et al. (2013)32,		⚫
Markkula et al. (2014)33,	⚫
Martins et al. (2014)34,		⚫
Morrow et al. (2012)35,		⚫
Mwinyi et al. (2014)36,	⚫
Newman et al. (2008)37,		⚫
Nowell et al. (2005)38,		⚫
Okishiro et al. (2009)39,	⚫	⚫
Park et al. (2011)40,	⚫	⚫
Park et al. (2012)41,		⚫
Province et al. (2014)42,		⚫
Rae et al. (2012)43,	⚫	⚫
Regan et al. (2012)44,	⚫	⚫
Schroth et al. (2007)45,*	⚫
Schroth et al. (2009)46,*		⚫
Sirachainan et al. (2012)47,	⚫	⚫
Stingl et al. (2010)48,		⚫
Sukasem et al. (2012)49,	⚫	⚫
Teh et al. (2012)50,	⚫	⚫
Thompson et al. (2011)51,		⚫
Toyama et al. (2009)52,		⚫
Wegman et al. (2005)53,		⚫
Wegman et al. (2007)54,		⚫
Xu et al (2008)55,	⚫	⚫
Yazdi et al. (2015)56,		⚫

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

Table 5. SR & M-A of Genotype-Guided Tamoxifen Treatment Characteristics

Study (Year)	Dates	Trials	Participants	N (Range)	Design	Duration
Ahern et al. (2016)10,	2005-2014	31 total (21 included in analysis)	Women treated with tamoxifen for breast cancer treated who had underwent CYP2D6 genotyping	NR (NR)	Observational	NR
Drögemöller et al. (2019)11,	2005-2016	48 total (representing 38 unique study populations)	Women treated with tamoxifen for breast cancer treated who had underwent CYP2D6 genotyping	20,054 (39-4973)	Observational	NR

NR=not reported

Table 6. SR & M-A of Genotype-Guided Tamoxifen Treatment Results

Study (Year)	Overall survival	Rate of Recurrence	Disease free survival	Adverse events	Change to alternative treatment or strategy
Ahern et al. (2016)10,	Composite of mortality or recurrence		NA	NA	NA
RR (95% CI)	1.71 (1.24 to 2.36)
P for homogeneity	<0.001
Adjusted RR (95% CI)1	1.80 (1.28 to 2.54)
Drögemöller et al. (2019)11,	Association between CYP2D6 and tamoxifen survival outcomes	NA	NA	NA	NA
Studies reporting at least 1 statistically significant association, n/N (%)	20/38 (52.6%)
Studies reporting no statistically significant association, n/N (%)	18/38 (47.4%)

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=0.83), ethnicity (P=0.33), or source of DNA (P=0.14). 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

Author (Year); Study	Countries	Sites	Dates	Participants	Active	Comparator
Tamura et al. (2020); TARGET-157,	Japan	54	2012-2016	Patients with HR-positive metastatic breast cancer, without visceral spread, needing first-line tamoxifen therapy	Tamoxifen 40 mg daily (n=70 patients with CYP2D6 genotype wt/V or V/V)	Tamoxifen 20 mg daily (n=66 patients with CYP2D6 genotype wt/V or V/V; n=48 patients with CYP2D6 genotype wt/wt)

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

Study (Year)	Disease free survival		Adverse events
Tamura et al. (2020)57,	PFS rate at 6 months, %	Median PFS (months)¥	Tamoxifen related, any grade, n (%)
N	180	132	183
Tamoxifen 40 mg daily (wt/V or V/V)	67.6%	14.4	49 (70.0%)
Tamoxifen 20 mg daily (wt/V or V/V)	66.7%	11.8	43 (66.2%)
Tamoxifen 20 mg daily (wt/wt)	63.0%	NR	29 (60.4%)
HR (95% CI)*	NS/NR	0.75 (0.50 to 1.14)	NS/NR

¥ 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; NA=not applicable; 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

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-upe
Tamura et al. (2020)57,	5 - Study population from Japan				1,2 - Less than 10 years

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 use
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively
^d 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 supported
^e Follow-up key: 1. Not sufficient duration for benefits; 2. Not sufficient duration for harms

Study	Allocationa	Blindingb	Selective Reportingc	Follow-upd	Powere	Statisticalf
Tamura et al. (2020)57,		1,2 - Open-label study 3 - Outcome assessed locally; central blinded review used to randomly validate outcomes in approximately 28% of patients		6 - 1 patient with progressive disease and 2 patients with inadequate images excluded from final analysis		3 - CI/p-value not reported for PFS at 6 months

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocations concealment unclear; 4. Inadequate control for selection bias
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reported; 3. Evidence of selective publication
^d 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 difference
^f 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
CI=confidence interval; PFS=progression free survival

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,

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

Author (Year)	Study Type	Country/Institution	Dates	Participants	Treatment1	Treatment2	Follow-up
Rae et al. 2012; ATAC43,	Observational cohort	381 centers in 81 countries Patients from United Kingdom included in genetic study; all other countries were used as comparators in certain analyses	1996-2000	Postmenopausal women with non-metastatic, invasive breast cancer Eligible to receive adjuvant hormonal therapy Had underwent CYP2D6 genotyping during prospective RCT period N=588	Treated with tamoxifen	NA	10 years
Regan et al. 2012; BIG 1-9844,	Observational cohort	International, multicenter	1998-2003	Postmenopausal women with HR-positive breast cancer, previously enrolled in RCT Had a tissue sample available for CYP2D6 analysis from original RCT period N=4393	Treated with tamoxifen	NA	Median: 76 months
Goetz et al. 2013; ABCSG21,	Matched case-control	Multicenter Genetic substudy occurred in Austria and United States	1996-2009	Postmenopausal women with ER-positive breast cancer, previously enrolled in RCT Had a tissue sample available for CYP2D6 analysis from original RCT period Cases were identified by disease recurrence, contralateral breast cancer, second non-breast cancer, or death n=319 cases and 557 controls	Arm A: Treated with tamoxifen for 5 years Arm B: Treated with tamoxifen for 2 years followed by anastrozole for 3 years	NA	5 years

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

Study (Year)	Overall survival	Disease free survival	Recurrence		Adverse events
Rae et al. 201243,	NA	NA	Distant recurrence in 10 years	Any recurrence in 10 years	NA	NA
N			588	588
All, n (%)¥			89 (15.1%)	115 (19.6%)
PM vs. IM [score 0.5], HR (95% CI)			2.8 (0.93 to 8.46)	2.15 (0.85 to 5.40)
PM vs. IM [score 1.0], HR (95% CI)			1.31 (0.49 to 3.48)	0.94 (0.43 to 2.08)
PM vs. IM [score 1.5], HR (95% CI)			0.76 (0.20 to 2.84)	0.68 (0.23 to 1.96)
PM vs. EM, HR (95% CI)			1.25 (0.50 to 3.15)	0.99 (0.48 to 2.08)
Regan et al. 201244,	NA	NA	Any Recurrece		Treatment induced hot flashes within 2 years
			WITHOUT previous chemotherapy	WITH previous chemotherapy	WITHOUT previous chemotherapy	WITH previous chemotherapy
N			973	270	487	1706
EM, n (%)			75 (12.3%)	37 (22.2%)	42%	38%
IM, n (%)			40 (14.4%)	12 (15.6%)	49%	39%
IM vs. EM, HR (95% CI)			0.95 (0.50 to 1.40)	0.57 (0.29 to 1.10)	1.23 (1.05 to 1.43)	NR/NS
PM, n (%)			8 (9.3%)	3 (11.5%)	48%	30%
PM vs. EM, HR (95% CI)			0.58 (0.28 to 1.21)	0.76 (0.23 to 2.48)	1.24 (0.96 to 1.59)	NR/NS
Goetz et al. 201321,	Composite of disease recurrence, contralateral breast cancer, second non-breast cancer, or death at 5 years¥
	Arm A	Arm B
EM/IM and IM/IM vs. EM/EM, OR (95% CI)	1.23 (0.58 to 2.61)	1.02 (0.52 to 2.01)
PM/PM vs. EM/EM, OR (95% CI)	2.45 (1.05 to 5.73)	0.60 (0.15 to 2.37)
EM/PM and PM/IM vs. EM/EM, OR (95% CI)	1.67 (0.95 to 2.93)	0.76 (0.43 to 1.31)

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

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.^59,

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 1 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, 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 convenien ce 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 metabolizer) and recurrence of breast cancer. The RCT examining genotype-directed dosing found no difference in progression free survival between 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 overall survival, or reduce adverse events. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
Clinical Pharmacogenetics Implementation Consortium

In 2018,the Clinical Pharmacogenetics Implementation Consortium issued therapeutic recommendations for tamoxifen prescribing based on CYP2D6 genotype/metabolic phenotype.^60, 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 outcome.

National Comprehensive Cancer Network

Regarding the use of CYP2D6 genotyping before prescribing tamoxifen, the National Comprehensive Cancer Network breast cancer guidelines (v.4.2020 ) state: "The panel recommends against CYP2D6 genotype testing for women being considered for tamoxifen treatment."^61,

American Society of Clinical Oncology

In 2016, the guidelines published 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."^62,

Not applicable.

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 No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03931928	Genotype and Phenotype Guided Supplementation of TAMoxifen Standard Therapy With ENDOXifen in Breast Cancer Patients	750	Dec 2020
NCT01357772	Randomized Placebo-controlled Phase III Trial of Low-dose Tamoxifen in Women With Breast Intraepithelial Neoplasia	1400	Dec 2023

NCT: national clinical trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Genotype-Guided Tamoxifen Treatment
Genetic Testing for Tamoxifen Treatment
Tamoxifen Treatment, Genetic Testing
Amplichip
Cytochrome p450, Tamoxifen Treatment

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