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Interpretive Handbook

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Test 60340 :
Cytochrome P450 2D6 Genotype for Tamoxifen Hormonal Therapy, Saliva

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Tamoxifen is a hormonal therapy used for patients with estrogen receptor-positive breast cancer. It is a selective estrogen receptor modulator (SERM) that exerts its effect by binding to the estrogen receptor. Tamoxifen is metabolized by the cytochrome P450 enzyme system to active metabolites. Two enzymes, cytochrome P450 3A (CYP3A) and 2D6 (CYP2D6), have been identified that are both necessary to generate 4-hydroxy-N-desmethyl-tamoxifen, generically named endoxifen, the most active metabolite of tamoxifen.(1) Endoxifen is approximately 100 times more potent in estrogen receptor binding than the parent drug, tamoxifen, or the metabolite N-desmethyl tamoxifen.(2)


CYP2D6 is an enzyme involved in the metabolism of many drugs including antidepressants, antihypertensive medications, cardioactive drugs, and stimulants, as well as tamoxifen. CYP2D6-mediated drug metabolism is highly variable. Some individuals have altered CYP2D6 gene sequences that result in decreased enzyme production or production of enzyme with diminished catalytic activity. Furthermore, the entire gene can be deleted in some individuals, resulting in absent enzyme activity and poor metabolizer status.


Breast cancer patients who receive tamoxifen and who are CYP2D6 poor metabolizers produce suboptimal concentrations of endoxifen.(3) These patients have poorer outcomes, with an increased risk of breast cancer recurrence, compared to CYP2D6 extensive (normal) metabolizers.(2) Because tamoxifen metabolites exert their effect by binding to the ER, hot flashes are a common side effect. However, patients who are CYP2D6 poor metabolizers appear to have a much lower incidence of bothersome hot flashes, consistent with data demonstrating that these patients have lower concentrations of the active tamoxifen metabolites.


Polymorphisms associated with CYP2D6 poor metabolizer status are autosomal recessive. Consequently, only individuals who are homozygous or who are compound heterozygous for these polymorphisms are poor metabolizers. The following information outlines the relationship between the polymorphisms detected in the CYP2D6 genotyping assay and the effect on the activity of the enzyme produced by that allele:

Allele Designation

Nucleotide Change

Effect on CYP2D6 mRNA or Protein

Effect and Phenotype









polymorphisms detected




Normal mRNA and protein

Normal activity; predicted extensive metabolizer status for tamoxifen





Increased transcription











Nonsense mutation




No activity; predicted poor metabolizer status for tamoxifen.















mRNA splicing



gene deletion


Entire gene deleted





Nonsense mutation





Missense mutation



Stop codon





mRNA splicing





Missense mutation



100C->T 1758G->A

Missense mutation





Nonsense mutation

















Missense mutation







Activity with tamoxifen has not been determined; metabolizer status for tamoxifen unknown.









Lysine282 deletion




Missense mutation



Missense mutation



Missense mutation



mRNA splicing

Gene duplications

Whole gene duplication

Depends on the allele duplicated.

Allele duplication may result in no change in activity (duplication of deficient alleles) or potentially increase the metabolism of tamoxifen (ultrarapid metabolism).


A complicating factor in correlating CYP2D6 genotype with phenotype is that many drugs or their metabolites are inhibitors of CYP2D6 catalytic activity. For example, many antidepressants, including some of the tricyclic antidepressants and some of the selective serotonin reuptake inhibitors, especially fluoxetine and paroxetine, are particularly inhibitory to CYP2D6 activity. Other drugs that inhibit CYP2D6 activity include some cardioactive drugs (eg, quinidine and amiodarone), some drugs of abuse (eg, cocaine), methadone, many histamine H1 receptor antagonists (eg, cimetidine), celecoxib, and ritonavir. Comedication with tamoxifen and inhibitory drugs may produce a CYP2D6 poor metabolizer phenotype, even though the patient has a CYP2D6 genotype consistent with intermediate or extensive metabolism. Consequently, it is important to interpret the results of CYP2D6 genotype testing in the context of coadministered drugs. Because antidepressants are often prescribed to alleviate the hot flashes that accompany tamoxifen therapy, it is particularly important to utilize an antidepressant that does not compromise CYP2D6 activity, which could reduce tamoxifen's efficacy.


Cytochrome P450 Patient Education Brochure (Supply T526) is available upon request.

Useful For Suggests clinical disorders or settings where the test may be helpful

Determining the CYP2D6 genotype of patients considered for tamoxifen chemotherapy


Genotyping patients who prefer not to have venipuncture done

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided that includes assay information, genotype, and an interpretation indicating the patient's ability to activate tamoxifen to endoxifen.


Based on the test sensitivity and currently available CYP2D6 polymorphism carrier frequencies, persons of Caucasian descent who tested negative for the above polymorphisms would be estimated to have a <1.4% residual risk for carrying 1 or more copies of an undetected poor metabolizer allele. This residual risk may be higher or lower in other ethnic groups. The frequency of polymorphisms causing poor metabolism is highest in the Caucasian population and lower in African Americans and Asians. Patients with an extensive (normal) or intermediate metabolizer genotype may have CYP2D6 enzyme activity inhibited by a variety of medications, or their metabolites. Because antidepressants are often prescribed to alleviate the hot flashes that accompany tamoxifen therapy, it is particularly important to utilize an antidepressant that does not compromise CYP2D6 activity, which could reduce tamoxifen's efficacy. The following is a partial listing of drugs known to affect CYP2D6 activity as of the date of this report.


Drugs that inhibit CYP2D6 significantly:
















Drug-drug interactions and drug-metabolite inhibition or activation must be considered when dealing with heterozygous individuals. Drug-metabolite inhibition occurs frequently with antidepressants, resulting in inhibition of residual functional CYP2D6 catalytic activity.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Note that in patients who have received heterologous blood transfusions before a saliva sample was acquired, the saliva samples may contain donor DNA. Return to recipient genotype usually occurs after 6 weeks. Similarly, saliva samples obtained from patients after allogeneic blood or marrow transplantation can contain donor DNA. In both cases, this may result in genotyping results that reflect the genotype of the recipient, the donor, or a blend of the donor and recipient. Results obtained under these circumstances may not accurately reflect the recipient’s genotype.


CYP2D6 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's CYP2D6 status.


Direct DNA testing will not detect all of the known mutations that result in decreased or inactive CYP2D6. Absence of a detectable gene mutation or polymorphism does not rule out the possibility that a patient has an intermediate or poor metabolizer phenotype. This test does not detect polymorphisms other than those listed. Gene duplications may occur by other mechanisms and may not be detected. Other polymorphisms in the primer binding regions can affect the testing and, ultimately, the genotyping results obtained.


Patients with an ultrarapid, extensive, or intermediate metabolizer genotype may have CYP2D6 enzyme activity inhibited by a variety of medications or their metabolites. These individuals may exhibit a poor metabolizer phenotype as a result of treatment with drugs that inhibit CYP2D6 or that produce inhibitors through metabolism.


Other factors affect tamoxifen sensitivity and tamoxifen resistance. Expression of estrogen receptor beta (ER beta) in ER alpha negative tumors is a favorable prognostic indicator for tamoxifen therapy. Expression of Her2 by the tumor may result in increased resistance to tamoxifen, regardless of the CYP2D6 phenotype.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Lim YC, Desta Z, Flockhart DA, Skaar TC: Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol 2005;55:471-478

2. Goetz MP, Rae M, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical

outcomes of efficacy and hot flashes. J Clin Oncol 2005;23:9312-9318

3. Jin Y, Desta Z, Stearns V, et al: CYP2D6 genotype, anti-depressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 2005;97:30-39