CYP2D6 Genotyping - Tamoxifen

Diagnosis

Indications for Testing

  • Pre-therapeutic testing to identify individuals who should avoid or have different dosing of medications metabolized by CYP2D6 such as tamoxifen (Nolvadex)
  • Screening of individuals with personal or family history of adverse drug event or therapy failure when exposed to CYP2D6-metabolized drugs

Laboratory Testing

  • CYP2D6 genotyping
    • Patients found to be poor or intermediate metabolizers
      • Postmenopausal – consider alternate therapies such as raloxifene or aromatase inhibitors
      • Premenopausal – tamoxifen is drug of choice
        • No guidelines exist regarding dosage adjustments based on type of metabolizer
        • Raloxifene may be an alternative therapy, if patient is found to be a poor metabolizer
    • Patients with duplications
      • Increased drug metabolism; standard tamoxifen dose may be excessive
    • Concomitant use of CYP2D6 inhibitors (such as SSRI drugs, which are frequently used to manage hot flashes or depression in cancer patients) may decrease metabolites even in patients with normal metabolism
    • No mutations detected is predictive of *1 alleles

Clinical Background

Tamoxifen is an anti-estrogen drug used in the treatment of estrogen-receptor positive (ER+) breast cancer to reduce the risk of recurrence. Mutations in CYP2D6 may lead to altered drug metabolism and reduce the concentration of active metabolite (eg, endoxifen) available. The reduction in active metabolite concentrations may reduce likelihood of response, manifested by an increased risk of recurrence of breast cancer.

Epidemiology

  • Prevalence of severely reduced CYP2D6 enzyme levels
    • Caucasian and Hispanic – 10%
    • African Americans – 2%
    • Asians – <1%

Genetics

  • Autosomal recessive inheritance for CYP2D6 sequence variants
  • Autosomal dominant for CYP2D6 duplications (increased function copy number variants)
  • Mutations in CYP2D6 are associated with altered tamoxifen metabolism
  • >80 mutations identified; some examples of alleles detected include the following
    • Functional (normal) – *2A, *2
    • Decreased function alleles – *9, *10, *17, *29, *41
    • Nonfunctional alleles – *3-*8, *12, *14
    • Increased function alleles – duplication of functional alleles

Pathophysiology

  • Tamoxifen, due to its low cost and low side-effect profile, is the drug of choice for patients with ER+ breast cancer
    • Reduces recurrence by 50% and mortality by one-third at 15-year followup
  • Efficacy depends on production of pharmacologically active metabolites such as endoxifen
  • Endoxifen binds estrogen receptors and suppresses breast cancer cell proliferation
    • Endoxifen is generated by CYP2D6-mediated reactions
      • CYP2D6 is an isoenzyme of the cytochrome P450 family
      • Cytochrome P450 family is responsible for the metabolism of about 25% of currently available drugs
      • Metabolism of tamoxifen mediated by CYP2D6 generates compounds with up to 100-fold higher potency for binding to ERs and suppressing breast cancer cell proliferation compared with parent tamoxifen
  • Tamoxifen is not useful for reducing breast cancer recurrence in individuals with greatly diminished CYP2D6 enzyme activity because active metabolites, such as endoxifen, are not produced
  • CYP2D6 genotype associations for metabolism
    • Poor metabolizer (PM)
      • Two nonfunctional CYP2D6 alleles
      • Highly impaired metabolism of the drug, causing lack of drug response
    • Intermediate metabolizer (IM)
      • One nonfunctional CYP2D6 allele and either one functional or decreased-functional allele or 2 decreased-functional alleles
      • Possible impaired metabolism of the drug
    • Rapid metabolizer (RM)
      • 2 copies of functional CYP2D6 alleles or one copy each of a functional and a decreased-functional allele
      • Normal metabolism
    • Ultrarapid metabolizer (UM)
      • >2 copies of functional CYP2D6 alleles
      • Increased metabolism; consider not using drugs metabolized by the CYP2D6 gene
      • ~5% of Caucasians are predicted to have UM phenotypes
  • Impaired hepatic function or drug-to-drug interactions (eg, strong inhibitors of CYP2D6 such as the SSRI fluoxetine) may hinder tamoxifen effectiveness irrespective of CYP2D6 genotype

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Cytochrome P450 2D6 (CYP2D6) 14 Variants and Gene Duplication 0051232
Method: Polymerase Chain Reaction/Primer Extension

Pretherapeutic testing to identify individuals who should avoid or have different dosing of medications metabolized by CYP2D6 such as tamoxifen (Nolvadex)

Screening of individuals with personal or family history of adverse drug event or therapy failure when exposed to CYP2D6-metabolized drugs

Variants tested:

  • Functional
    • *2 (2850C>T)
    • *2A (-1584C>G; 2850C>T)
  • Decreased function
    • *9 (2613-5delAGA)
    • *10 (100C>T)
    • *17 (1023C>T)
    • *29 (1659G>A)
    • *41 (2988G>A)
  • Nonfunctional
    • *3 (2549delA)
    • *4 (1846G>A)
    • *5 (gene deletion)
    • *6 (1707delT)
    • *7 (2935A>C)
    • *8 (1758G>T)
    • *12 (124G>A)
    • *14 (1758G>A)
  • Increased function
    • Duplicated functional alleles

Only CYP2D6 mutations will be detected

Phase and copy number of detected CYP2D6 mutations may not be determined

Mutations in other genes associated with drug metabolism or drug response will not be detected; presence of other mutations (eg, CYP2C19 and tamoxifen) may further impact drug metabolism

Drug metabolism may be affected by nongenetic factors

Mutation detection is not a substitute for therapeutic drug or clinical monitoring

Diagnostic errors can occur due to rare sequence variations

Genotype results should be interpreted in the context of the individual clinical situation