Tamoxifen Therapy and CYP2D6 Genotype

Introduction

Tamoxifen (brand name Nolvadex) is a selective estrogen receptor modulator (SERM) that is commonly used in both the treatment and prevention of breast cancer. When taken for 5 years, tamoxifen almost halves the rate of breast cancer recurrence in individuals who have had surgery for estrogen-receptor–positive (ER+) breast cancer.

Tamoxifen is the endocrine therapy of choice for treatment of premenopausal women with ER+ breast cancer, and an important alternative, or sequential treatment for postmenopausal women with ER+ breast cancer. In addition, tamoxifen is the only hormonal agent approved by the FDA for the prevention of premenopausal breast cancer in women who are at high risk, and the treatment of premenopausal invasive breast cancer and ductal carcinoma in situ (DCIS).

The CYP2D6 enzyme metabolizes a quarter of all prescribed drugs and is one of the main enzymes involved in converting tamoxifen into its major active metabolite, endoxifen. Genetic variation in the CYP2D6 gene may lead to increased (“ultrarapid metabolizer”), decreased (“intermediate metabolizer”), or absent (“poor metabolizer”) enzyme activity. Individuals who are intermediate or poor metabolizers may have reduced plasma concentrations of endoxifen and benefit less from tamoxifen therapy.

At this time, the FDA-approved drug label for tamoxifen does not discuss genetic testing for CYP2D6 (Table 1) (1). The National Comprehensive Cancer Network (NCCN) Breast Cancer Panel does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy (Table 2), and this recommendation is consistent with the 2010 update of the American Society of Clinical Oncology (ASCO) Guidelines (the most recent update, 2014, does not discuss pharmacogenetic testing) (2, 3).

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recently published updated guidelines for the dosing of tamoxifen based on CYP2D6 phenotype, with therapeutic recommendations for each metabolizer phenotype (Table 3). For CYP2D6 poor metabolizers, CPIC recommends using an alternative hormonal therapy, such as an aromatase inhibitor for postmenopausal women; or an aromatase inhibitor along with ovarian function suppression in premenopausal women. This recommendation is based on these approaches being superior to tamoxifen regardless of CYP2D6 genotype, and the knowledge that CYP2D6 poor metabolizers who switched from tamoxifen to anastrozole do not have an increased risk of recurrence. The CPIC recommendation also states that higher dose tamoxifen (40 mg/day) can be considered if there are contraindications to aromatase inhibitor therapy; however, the increased endoxifen concentration among CYP2D6 poor metabolizers treated with a higher tamoxifen dose does not typically reach the level as in normal metabolizers (4).

Recommendations from the Dutch Pharmacogenetics Working Group (DWPG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) also discuss using an alternative drug to tamoxifen in CYP2D6 poor metabolizers (Table 4) (5).

Drug: Tamoxifen

Tamoxifen is a SERM that is used in both the treatment and prevention of breast cancer.

For treatment, tamoxifen is used in both men and women with metastatic breast cancer, particularly among individuals with ER+ tumors. Tamoxifen is also used as adjuvant treatment among women who have undergone surgery and radiation, as this almost halves the rate of reoccurrence of breast cancer in woman with ER+ tumors. Tamoxifen reduces the risk of progression to invasive breast cancer in women with DCIS.

For prevention, tamoxifen has been shown to reduce the occurrence of contralateral breast cancer. And in women who do not have breast cancer, tamoxifen has been shown to reduce the incidence of breast cancer in women at high risk. Risk factors for breast cancer include increasing age, Caucasian race, the number of first-degree relatives with breast cancer, obesity (for postmenopausal women), and an increased exposure to estrogen (e.g., early menarche, later age of first pregnancy or no children, absence of breastfeeding, later menopause) (1, 4).

Tamoxifen acts on the estrogen receptor and has both estrogenic and anti-estrogenic actions, depending on the target tissue. In the breast tissue, it acts as an anti-estrogen (inhibitory effect) and competitively inhibits cancerous ER+ cells from receiving the estrogen they need to proliferate.

In other tissues, such as the endometrium, tamoxifen acts as an estrogen agonist (stimulatory effect) leading to some of the adverse effects associated with tamoxifen therapy. These include endometrial hyperplasia, endometrial polyps, and around a 2.5 times higher risk of developing endometrial cancer. Hot flashes are the most common side effect associated with tamoxifen use, which affect up to 80% of women, and there is also an increased risk of depression (6-8).

The antiestrogenic properties of tamoxifen are expected to affect fetal reproductive functions and increase the risk of fetal harm. Therefore, women may be advised not to become pregnant while taking tamoxifen or within 2 months of discontinuing tamoxifen, and to use barrier or nonhormonal contraception (1).

Tamoxifen also increases the risk of thromboembolic events, such as deep vein thrombosis and pulmonary embolism. The risk of tamoxifen-associated thromboembolic events is further increased when tamoxifen is coadministered with chemotherapy. The drug label for tamoxifen states that the risks and benefits of tamoxifen therapy should be carefully considered in women with a history of thromboembolic events (1).

Some studies suggest that clinicians should consider screening breast cancer individuals before prescribing adjuvant tamoxifen to identify women who are at risk of thrombotic embolic disease as a result of having the Factor V Leiden (p.R506Q) variant, or a variant in the estrogen receptor gene (ESR1) (9-12). However, a small substudy (N=81) of the national surgical adjuvant breast and bowel project breast cancer prevention (NSABP P-1) trial found no benefit in screening women for Factor V Leiden or F2 prothrombin (c.*97G>A) thrombophilia to identify women who may not be appropriate for tamoxifen therapy due to an increased risk for thromboembolic side effects (13).

Tamoxifen is inactive, and its active metabolite endoxifen (4-hydroxy-N-desmethyl tamoxifen) is thought to mediate most of its therapeutic effects. Both endoxifen and another metabolite, 4-hydroxytamoxifen, have around a 100-fold higher affinity for the ER compared with tamoxifen, but endoxifen is thought to be the major metabolite because plasma levels of endoxifen tend to be several-fold higher.

The mechanism of action of tamoxifen involves binding to the ER and inducing a conformational change that blocks or changes the expression of estrogen-dependent genes. It is also likely that tamoxifen interacts with other protein cofactors (both activators and repressors) and binds with different estrogen receptors (ER-alpha or ER-beta) to produce estrogenic and anti-estrogenic effects in different tissues (14).

The tamoxifen metabolite, norendoxifen, has also been found to act as an aromatase inhibitor in vitro (albeit at high concentrations). Aromatase inhibitors are a class of drug used to treat breast cancer and gynecomastia. They decrease the amount of estrogen available by inhibiting the conversion of steroids such as androgen into estradiol (15).

The pharmacokinetics of tamoxifen are complex, involving many enzymes (including several cytochrome P450 enzymes) and transporter proteins (including ATP-binding cassette transporters (ABC) transporters). However, CYP2D6 is thought to be important because it mediates the formation of endoxifen via the conversion of the inactive primary metabolite N-desmethyl tamoxifen.

The response to tamoxifen therapy (i.e., clinical efficacy and side effects) varies widely between individuals. This is due to a number of variables, including drug interactions (e.g., coadministration of a drug that inhibits or induces CYP2D6) and interindividual differences in drug metabolism driven by polymorphic germline CYP2D6 variant alleles (16-18).

Gene: CYP2D6

The cytochrome P450 superfamily (CYP450) is a large and diverse superfamily of enzymes that form the major system for metabolizing or detoxifying lipids, hormones, toxins, and drugs. The CYP450 genes are often very polymorphic and can result in reduced, absent, or increased enzyme activity.

The CYP2D6 enzyme is responsible for the metabolism of many commonly prescribed drugs, including antidepressants, antipsychotics, analgesics, and beta-blockers. And, CYP2D6 is the main enzyme that catalyzes the rate-limiting step in the metabolism of tamoxifen to its potent metabolite, endoxifen. Other CYP enzymes involved in tamoxifen metabolism include CYP2C9, CYP2C19, CYP2B6, CYP3A4, and CYP3A5.

CYP2D6 Alleles

The CYP2D6 enzyme catalyzes the main pathway for converting tamoxifen into its most potent metabolite, endoxifen, and together with other CYP enzymes, catalyzes the formation of 4-hydroxytamoxifen. Therefore, genetic variations in the CYP2D6 gene can influence tamoxifen metabolism (19).

The CYP2D6 gene is highly polymorphic, as over 100 star (*) alleles have been described and cataloged at the Pharmacogene Variation (PharmVar) Consortium, and each allele is associated with either normal, decreased, or absent enzyme function (Table 5).

The combination of CYP2D6 alleles that a person has is used to determine their diplotype (e.g., CYP2D6 *4/*4). Based on function, each allele can be assigned an activity score from 0 to 1, which in turn is often used to assign a phenotype (e.g., CYP2D6 poor metabolizer). However, the activity score system is not standardized across clinical laboratories or CYP2D6 genotyping platforms.

Table 5.

Activity Status of Selected CYP2D6 Alleles

CYP2D6*1 is assigned when no variant is detected and is assumed to have normal enzyme activity (CYP2D6 normal metabolizer phenotype). The CYP2D6 *2, *33, and *35 alleles are also considered to have near-normal activity.

Alleles that encode an enzyme with decreased activity include *10, *17, and *41, and alleles that encode a nonfunctioning enzyme include *3, *4, *5, and *6. There are large inter-ethnic differences in the frequency of these alleles, with *3, *4, *6, and *41 being more common in Caucasians, *10 more common in Asians, and *17 more common in Africans (20).

Additional variant alleles and their multi-ethnic population frequencies have previously been reported (21). Moreover, given the structural variability of the CYP2D6 region at chromosome 22q13.2, full gene deletion and duplication alleles, as well as complex tandem alleles with CYP2D6’s pseudogene, CYP2D7, also occur in some individuals and populations (22).

CYP2D6 Phenotypes

In the US and globally, most individuals, around 70-80%, are classified as “normal metabolizers” (also referred to as “extensive metabolizers”). They either have 2 normal function alleles (e.g., *1/*1) or one normal and one decreased function allele (e.g., *1/*41).

Individuals who have one normal function and one no function allele (e.g., *1/*4) or 2 decreased function alleles (e.g., *41/*41) are also categorized as “normal metabolizers” by recent nomenclature guidelines (23), but have also been categorized as “intermediate metabolizers” (24).

Individuals who have more than 2 normal function copies of the CYP2D6 gene are classified as “ultrarapid metabolizers,” which accounts for 1–10% of Caucasian individuals. For individuals of North African, Ethiopian and Saudi ancestry, the frequency is 16–28% (Table 6) (4).

Individuals who do not have any fully functional alleles are either intermediate metabolizers (one decreased function and one no function allele, e.g., *4/*41) or poor metabolizers (2 no function alleles e.g., *4/*4).

Approximately 6–10% of European Caucasians are poor metabolizers, mainly due to the prevalent nonfunctional *3, *4 and *5 alleles. Compared with Europeans, individuals of Asian descent are likelier to be intermediate metabolizers due to high population frequencies of the CYP2D6*10 decreased function allele. Approximately 30% of Asians and individuals of Asian descent are intermediate metabolizers. Similarly, Africans and African Americans are likelier than Europeans to be intermediate metabolizers because of the prevalence of a wide range of decreased function variants. (20, 25-27)

Table 6.

CPIC (2018). Assignment of likely CYP2D6 Phenotype based on Genotype

Linking Gene Variation with Treatment Response

Genetic variation in the CYP2D6 gene is associated with variation in plasma concentrations of endoxifen and is thought to account for up to approximately 50% of the variability in endoxifen concentrations (28).

• Individuals who are CYP2D6 poor metabolizers (activity score 0) have lower plasma endoxifen concentrations compared with normal metabolizers (with an activity score of 1.5-2.0).
• Individuals with reduced CYP2D6 activity (activity score 0.5-1) have lower plasma endoxifen concentrations compared with normal metabolizers (with an activity score of 1.5-2.0) (4).

However, while it is clear that tamoxifen biotransformation to endoxifen is highly dependent on CYP2D6 activity, the association between tamoxifen efficacy and CYP2D6 genotype or endoxifen concentration is less clear. Because the role of CYP2D6 in tamoxifen response has yet to be fully determined, CYP2D6 testing remains controversial (29-40).

Some studies conclude that the CYP2D6 genotype has minimal or no effect on tamoxifen therapy outcomes (41-45). A 2019 prospective clinical study (n=667) found no association between CYP2D6 genotype or endoxifen concentration and clinical outcome in individuals with early-stage breast cancer receiving adjuvant tamoxifen (46).

In contrast, other studies suggest that CYP2D6 variant alleles may be important predictors of tamoxifen clinical outcomes (28, 40, 47-52). In particular, in Asians, studies of populations with a high frequency of the decreased function CYP2D6*10 allele (e.g., Han Chinese), found that individuals with CYP2D6*10/*10 received less benefit from tamoxifen and poorer disease-free survival (53-55).

However, the high degree of inter-individual variability of tamoxifen metabolism and treatment outcomes is not fully accounted for by CYP2D6 variation. Additional contributors may include genetic variation in other metabolic pathways and the sequestration of lipophilic tamoxifen metabolites into fat tissues (17, 30, 48, 56).

Genetic Testing

The NIH Genetic Testing Registry (GTR) provides examples of the genetic tests that are currently available for tamoxifen response and for the CYP2D6 gene.

The CYP2D6 gene is a particularly complex gene that is difficult to genotype because of the large number of variants and the presence of gene deletions, duplications, multiplications, pseudogenes, and tandem alleles. The complexity of genetic variation complicates the correct determination of CYP2D6 diplotype.

Genetic testing is currently available for approximately 30 variant CYP2D6 alleles (over 100 alleles have been identified so far). Test results are typically reported as a diplotype, such as CYP2D6 *1/*1. However, it is important to note that the number of variants tested can vary among laboratories, which can result in diplotype result discrepancies between testing platforms and laboratories (4).

A result for copy number, if available, is also important when interpreting CYP2D6 genotyping results. Gene duplications and multiplications are denoted by “xN” e.g., CYP2D6*1xN with xN representing the number of CYP2D6 gene copies.

If the test results include an interpretation of the individual’s predicted metabolizer phenotype, such as “CYP2D6 *1/*1, normal metabolizer”, this should be confirmed by checking the diplotype and assigning an activity score to each allele (e.g., 0 for no function, 0.5 for decreased function, and 1.0 for each copy of a normal function allele, Table 6).

The CYP2D6 phenotype can be defined by the sum of the 2 activity scores, which is usually in the range of 0–3.0:

• An ultrarapid metabolizer has an activity score greater than 2
• A normal metabolizer phenotype has an activity score of 1.5–2.0
• A normal metabolizer or intermediate metabolizer has a score of 1.0
• An intermediate metabolizer has an activity score of 0.5
• A poor metabolizer has an activity score of 0 (4)

A standardized CYP2D6 genotype to phenotype assignment logic is currently being developed by an international working group of CYP2D6 experts and both the CPIC and DPWG.

Therapeutic Recommendations based on Genotype

This section contains excerpted¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

Nomenclature

Table

Nomenclature for Selected CYP2D6 Alleles

Acknowledgments

The author would like to thank Deirdre Cronin-Fenton, PhD, Associate Professor, Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark; Inge Holsappel, Pharmacist at the Royal Dutch Pharmacists Association (KNMP), The Hague, Netherlands, for reviewing the information regarding the guidelines of the Dutch Pharmacogenetics Working Group (DPWG); Stuart Scott, Assistant Professor of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; and Werner Schroth, PhD, Institute of Clinical Pharmacology, Stuttgart, Germany, for reviewing this summary.

First edition:

The author would like to thank Harold Burstein, Associate Professor of Medicine, Harvard Medical School, Boston, MA, USA; and Hiltrud Brauch, Deputy Head of the Fischer-Bosch-Institute of Clinical Pharmacology (IKP) and Head of the Breast Cancer Susceptibility and Pharmacogenomics IKP Department, Stuttgart, Germany for reviewing this summary.

Version History

To view an earlier version of this summary, please see 2014 and 2016 editions.

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