Tamoxifen and CYP2D6: Does Genotype Matter?

Current tamoxifen guidelines are clear: Drugs that interfere with the formation of active tamoxifen metabolites are important to consider and relevant to patient care, but genetic polymorphisms that do the same are not. But based on the data available, the question of whether CYP2D6 polymorphisms impact breast cancer survival and recurrence has not been fully answered. It is important for clinicians to understand treatment guidelines and their possible deficiencies in order to best meet the individual needs and concerns of their patients. By: Dr. Richard Malik

Abstract
Current oncology guidelines clearly advise caution on the coadministration of tamoxifen with medications that decrease the formation of active tamoxifen metabolites. Medications classified as strong inhibitors of tamoxifen biotransformation reduce plasma concentrations of active metabolites by as much as 64%. Although genetic polymorphisms that adversely affect CYP2D6 enzyme function can reduce the formation of active tamoxifen metabolites by as much as 74%, San Antonio Breast Cancer Symposium Recommendations discourage testing for CYP2D6 polymorphisms. The standard of care is clear: Drugs that interfere with the formation of active tamoxifen metabolites are important to consider and relevant to patient care, but genetic polymorphisms that do the same are not. Based on the data available to date, the question of whether CYP2D6 polymorphisms impact breast cancer survival and recurrence has not been fully answered. Definitive prospective research has not been completed, and there are possible deficiencies in the studies used to establish current guidelines. It is important for clinicians to understand both treatment guidelines and their possible deficiencies in order to best meet the individual needs and concerns of their patients. This paper discusses these issues.

Introduction
Drugs that interfere with the biotransformation of tamoxifen into active metabolites through cytochrome P450 enzymes are classified as significant interactants, and caution is advised about coadministration of these drugs with tamoxifen.^1,2 Controversy exists about whether or not women taking tamoxifen should be screened for cytochrome P450 enzyme variants that lead to lower circulating levels of active metabolites. This article briefly reviews the relevant pharmacokinetics, accepted standard of care, discordant research, and dissenting opinions in order to support informed clinical decision making.

Tamoxifen Therapy Indications and Benefits
Tamoxifen is a relatively inexpensive mainstay of treatment for estrogen receptor positive (ER+) breast cancer. It is used either to reduce the size of tumors before surgical removal or, more commonly, for 5 or more years to lower the risk of breast cancer recurrence and improve long-term survival after surgery and chemotherapy.³ According to National Comprehensive Cancer Network guidelines, premenopausal breast cancer patients are treated with tamoxifen for at least 5 years.⁴ Women who are postmenopausal at diagnosis are recommended at least 5 years of adjuvant endocrine therapy with either tamoxifen or an aromatase inhibitor. If, during treatment, the premenopausal patient becomes postmenopausal, she may either continue taking tamoxifen or switch to an aromatase inhibitor. According to the most recent Cochrane review on tamoxifen for early breast cancer, 5 years of tamoxifen therapy reduces 10-year mortality for both node-negative and node-positive disease (NNT 17 and 9, respectively).^5,6 According to the Early Breast Cancer Trialists Collaborative Group (EBCTCG), the relative risk reduction of breast cancer recurrence after 5 years of tamoxifen therapy is 39%.⁷

After the initial 5 years of adjuvant endocrine therapy, an additional 5 years of adjuvant endocrine therapy is now a recommended consideration for ER+ women due to recent research that shows improved outcomes with 10 years of tamoxifen therapy compared to 5 years; 10 years of treatment has an NNT of 27 for breast cancer recurrence and an NNT of 35 for breast cancer mortality when compared to 5 years of treatment.⁸

Tamoxifen is also used for breast cancer prevention in women older than 35 years with a calculated Gail Model 5-year risk of invasive breast cancer greater than 1.67%.⁹ Gail Model uses the patient’s medical history, age, and family history to calculate risk of breast cancer over the next 5 years and until age 90. The Gail Model risk calculators are easily accessible on the internet.^10,11

Tamoxifen: Mechanism of Action and Metabolism
Tamoxifen metabolism is complex and not completely understood. Tamoxifen is a nonsteroidal selective estrogen receptor modulator (SERM) hormone therapy used in breast cancer that strongly inhibits the effects of estrogen in breast tissue.¹² Tamoxifen is a prodrug that is metabolized by several cytochrome P450 enzymes in phase I detoxification. CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 transform tamoxifen into both active and inactive metabolites. For many years, 4-hydroxy-tamoxifen has believed to be primarily responsible for the clinical activity; however, the CYP2D6 metabolites 4-hydroxy-tamoxifen and endoxifen have equal affinity for the estrogen receptor.¹³ Because serum concentrations of endoxifen are 6 to 12 times higher than 4-hydroxy-tamoxifen in patients receiving long-term tamoxifen therapy, many think endoxifen is the most significant tamoxifen metabolite.¹⁴

Polymorphisms are phenotypic differences in a population that can stop or impair enzyme function. CYP2D6 polymorphisms are common in all ethnic groups, and more than 100 allelic variants with varying impact on CYP2D6 enzyme function have been reported.¹⁵ Caucasians may be the most affected: 7% carry a single type CYP2D6 null allele with no enzymatic activity, and studies indicate that 5.5%–7% of the Caucasian population are classified as CYP2D6 poor metabolizers (PM) with 2 genes that confer poor enzymatic function.^16,17 Common variant alleles with decreased activity are also found in 50% of Asians and 24% of African and African American populations.¹⁸

Hypothetically, tamoxifen may be less effective in breast cancer patients who are CYP2D6 poor metabolizers than in patients who are extensive metabolizers (EM) with 2 fully functional wild type CYP2D6 genes. Poor metabolizers have only 26% the plasma endoxifen concentration as their EM counterparts.¹⁹Medications classified as strong inhibitors of tamoxifen biotransformation reduce plasma concentrations of active metabolites by as much as 64%.²⁰ However, it is not clear if even a 74% reduction in endoxifen concentration is pharmacodynamically or clinically relevant.^21,22

Although several retrospective studies have been published, the research is not definitive, and some results are contradictory. To date, an important question has not been clearly answered: Does poor endogenous CYP2D6 function affect outcomes for breast cancer patients taking tamoxifen?

San Antonio Breast Cancer Symposium Recommendations and Criticisms
A retrospective analysis from 2010 using data from the 1998–2003 Breast International Group (BIG) 1-98 Trial found that there was no association between CYP2D6 status and breast cancer outcomes in early breast cancer patients taking tamoxifen.²³ This research was originally reported at the 2010 San Antonio Breast Cancer Symposium and, for most in the oncology community, laid to rest the question of whether CYP2D6 testing is necessary or warranted for improving early breast cancer outcomes.²⁴ Unfortunately, several questions and areas of controversy persist. Problems commonly cited with the BIG 1-98 study include the following.

• It was a retrospective study; prospective studies are required for more precise assessment of relative or absolute risk. Truly prospective research has not yet been published, but there are 2 ongoing prospective clinical trials: the Eastern Cooperative Oncology Group E3108 and European CYPTAMBRUT-2. These may better elucidate important factors that determine response to tamoxifen therapy for women with breast cancer.
• Only 9% of participants in the BIG 1-98 study were taking medications that inhibit CYP2D6 function, so it did not provide data on outcomes for poor metabolizers of tamoxifen taking drugs that inhibit CYP2D6.²⁵
• Pharmacogenetic experts point out that the study data departs from Hardy-Weinberg equilibrium predictions for polymorphism frequency in a population; the frequency of polymorphisms is not consistent with what is seen in the general population and may indicate faulty genotyping methods and/or results. BIG 1-98 performed genotyping on the tumor genome instead of the host genome.²⁶ Because cancer cells undergo numerous genetic and epigenetic changes, the tumor genome may no longer be representative of the patient’s genome.

Conflicting Research
The research findings on CYP2D6 metabolism and breast cancer outcomes is mixed; the BIG 1-98 is not a meta-analysis and is not necessarily representative of or in agreement with all research. The Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8, another retrospective study in a primarily caucasian population, indicates poor functioning CYP2D6 variants are associated with a 2.4-fold increase of breast cancer recurrence in women treated with only tamoxifen for 5 years. In this study, genotype samples were more carefully taken from host tissue, and results are within Hardy-Weinberg equilibrium predictions for the most important, but not all, alleles. It is important to note that the increased risk of recurrence found in ABCSG 8 after 5 years of tamoxifen alone is negated when 5 years of tamoxifen is followed by anastrozole, an aromatase inhibitor.²⁷

CYP2D6 genotype testing is not condoned by the American Society of Clinical Oncology and is not part of the National Comprehensive Cancer Network guidelines.

In a very small retrospective study in patients with metastatic breast cancer treated with tamoxifen, Lammers et al found a non-significant trend toward decreased time to recurrence and a significant 2.09 hazard ratio (HR) for overall survival in CYP2D6 poor metabolizers compared to their extensive metabolizer counterparts. Genotype results from this study are within Hardy-Weinberg equilibrium predictions. Lammers et al also found a statistically significant 3.55 HR for overall survival and 2.97 HR for time to progression when comparing patients taking medication that inhibits CYP2D6 function compared to those who were not.²⁸

Clinical Options
The undeniable controversy over the effects of CYP2D6 metabolism on breast cancer outcomes in tamoxifen therapy may be more clearly answered when prospective research results are published. But until that time, clinicians are still left with the task of guiding their patients toward clinically relevant treatment. While considering the points discussed in this article, it is possible to have a reasonable approach toward supporting our breast cancer patients who are prescribed tamoxifen. The author recommends the following considerations.

• Understand that the current consensus guidelines do not recommend CYP2D6 genotype testing. Most patients are not likely to benefit from testing. If you recommend testing for your patient, counsel her on why you are doing so and how her oncologist may respond.
• Encourage patients taking tamoxifen to avoid medications that interfere with tamoxifen metabolism. Selective serotonin reuptake inhibitors (SSRIs) are commonly used for tamoxifen-induced hot flashes. Fluoxetine and paroxetine are strong inhibitors of CYP2D6, but venlafaxine, citalopram, and escitalopram do not significantly affect enzyme activity.²⁹ From the natural medicine pharmacopeia, goldenseal appears to have significant CYP2D6 inhibitory effects, while melatonin, valerian, and kava kava do not.^30,31
• Consider CYP2D6 genotype testing for patients taking a medication known to significantly inhibit the enzyme in spite of the possible interaction. This may provide information on the magnitude of effect for an individual patient and encourage a change in medication or provide clinical guidance for increasing the tamoxifen dosage.
• Discourage genotype testing for patients whose only treatment option is tamoxifen (eg, premenopausal women, cases of DCIS) unless an increase in tamoxifen dosage would be contemplated. Poor CYP2D6 metabolizers have lower plasma levels of 4-hydroxy-tamoxifen and endoxifen, which may be raised by increasing the tamoxifen dosage.
• Consider CYP2D6 genotype testing for postmenopausal patients deciding between tamoxifen and aromatase inhibitor therapy. CYP2D6 genotype testing may provide useful information that supports the decision-making process.
• Consider CYP2D6 genotype testing for patients whose anxiety about effective treatment may be alleviated by the results or a subsequent increase in tamoxifen dosage.

CYP2D6 genotype testing is not condoned by the American Society of Clinical Oncology and not part of the National Comprehensive Cancer Network guidelines. However, for some women who are considering adjuvant endocrine therapy options, preliminary clinical studies and tamoxifen pharmacodynamics support the possible role of CYP2D6 genotype testing in limited circumstances. This testing can provide a more personalized approach to medicine. It can help a woman weigh the personal costs and benefits when choosing between tamoxifen and an aromatase inhibitor. It can help address a premenopausal woman’s concern about ensuring effective treatment with tamoxifen. Additional research is needed to more clearly understand the role of CYP2D6 metabolism in breast cancer outcomes, and that research may more clearly define the role, if there is any, for CYP2D6 genotype testing.

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