CYP2D6 Genotyping - Tamoxifen

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics
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Indications for Testing

  • 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

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 functional alleles
  • The International Tamoxifen Pharmacogenetics Consortium (ITPC) data is deposited in the Pharmacogenetics and Pharmacogenomics Database
  • Neither NCCN (2015) or ASCO (2009) recommend CYP2D6 genotyping to determine optimal adjuvant endocrine strategy

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
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.

Cytochrome P450 2D6 (CYP2D6) 14 Variants and Gene Duplication 0051232
Method: Polymerase Chain Reaction/Primer Extension

Limitations 

Only the targeted CYP2D6 variants will be detected by this panel

Diagnostic errors can occur due to rare sequence variations

Risk of therapeutic failure or adverse reactions with CYP2D6 substrates may be affected by genetic and nongenetic factors that are not detected by this test

This result does not replace the need for therapeutic drug or clinical monitoring

It is not always possible to identify which allele is duplicated when a CYP2D6 duplication is detected

Guidelines

NCCN Clinical Practice Guidelines in Oncology, Breast and Ovarian Cancer Genetic/Familial High-Risk Assessment: Breast and Ovarian . National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Apr 2016]

NCCN Clinical Practice Guidelines in Oncology, Breast Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Apr 2016]

General References

Algeciras-Schimnich A, O'Kane DJ, Snozek CL H. Pharmacogenomics of tamoxifen and irinotecan therapies. Clin Lab Med. 2008; 28(4): 553-67. PubMed

Berry D. CYP2D6 genotyping and the use of tamoxifen in breast cancer. J Natl Cancer Inst. 2013; 105(17): 1267-9. PubMed

Brauch H, Mürdter TE, Eichelbaum M, Schwab M. Pharmacogenomics of tamoxifen therapy. Clin Chem. 2009; 55(10): 1770-82. PubMed

Dezentjé VO, Guchelaar H, Nortier JW R, van de Velde CJ H, Gelderblom H. Clinical implications of CYP2D6 genotyping in tamoxifen treatment for breast cancer. Clin Cancer Res. 2009; 15(1): 15-21. PubMed

Duffy MJ, O'Donovan N, Crown J. Use of molecular markers for predicting therapy response in cancer patients. Cancer Treat Rev. 2011; 37(2): 151-9. PubMed

Higgins MJ, Stearns V. CYP2D6 polymorphisms and tamoxifen metabolism: clinical relevance. Curr Oncol Rep. 2010; 12(1): 7-15. PubMed

Lee S, McLeod HL. Pharmacogenetic tests in cancer chemotherapy: what physicians should know for clinical application. J Pathol. 2011; 223(1): 15-27. PubMed

Lyon E, Foster JGastier, Palomaki GE, Pratt VM, Reynolds K, Sábato F, Scott SA, Vitazka P, working group of the Molecular Genetics Subcommittee on behalf of the American College of Medical Genetics and Genomics ACMG) Laboratory Quality Assurance Committee. Laboratory testing of CYP2D6 alleles in relation to tamoxifen therapy. Genet Med. 2012; 14(12): 990-1000. PubMed

Walko CM, McLeod H. Use of CYP2D6 genotyping in practice: tamoxifen dose adjustment. Pharmacogenomics. 2012; 13(6): 691-7. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Kallak K, Baumgart J, Evers S, Poromaa S, Moby L, Kask K, Norjavaara E, Kushnir MM, Bergquist J, Nilsson K. Higher than expected estradiol levels in aromatase inhibitor-treated, postmenopausal breast cancer patients. Climacteric. 2012; 15(5): 473-80. PubMed

Medical Reviewers

Last Update: August 2016