CYP2D6 Genotyping - Tamoxifen

Variants in CYP2D6 may lead to altered metabolism of its substrate drugs. This may lead to unexpected changes in parent drug concentrations and/or active metabolites that change the efficacy of treatment. Tamoxifen is just one example of a medication that relies on metabolism to an active metabolite for benefit. This anti-estrogen drug is used in the treatment of estrogen-receptor positive (ER+) breast cancer to reduce the risk of recurrence. Variants in CYP2D6 alter the concentration of tamoxifen’s active metabolite, endoxifen. This reduction in active metabolite concentrations due to decreased metabolism may reduce likelihood of response, manifested by an increased risk of recurrence of breast cancer.

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

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
    • Neither NCCN (2017) nor ASCO (2016) recommend CYP2D6 genotyping to determine optimal adjuvant tamoxifen strategy
    • Multivariant panel – used to detect the 15 most common variants involved in changes in metabolism
    • Recommendations for tamoxifen use by phenotype [Swen, 2011]
      • Poor metabolizer
        • May result in lower levels of tamoxifen active metabolites
        • Consider using aromatase inhibitors for postmenopausal women due to poor efficacy and increased risk of relapse of breast cancer with tamoxifen
      • Intermediate metabolizer
        • May result in lower levels of tamoxifen active metabolites
        • Avoid concomitant use of CYP2D6 inhibitors to avoid conversion of the intermediate metabolizer to a poor metabolizer
        • Consider using aromatase inhibitors for postmenopausal women due poor efficacy and increased risk of relapse of breast cancer with tamoxifen
      • Normal metabolizer
        • Avoid concomitant use of CYP2D6 inhibitors to avoid conversion of the normal metabolizer to an intermediate or poor metabolizer
      • Ultrarapid metabolizer
        • Gene duplication in absence of inactive or decreased activity allele
        • No recommendation
    • Concomitant use of CYP2D6 inhibitors (eg, SSRI drugs, opioids, some beta blockers) may decrease the activity score and inhibit production of metabolites even in patients with normal metabolism
    • No variants detected is predictive of *1 functional alleles
    • 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
    • The International Tamoxifen Pharmacogenetics Consortium (ITPC) maintains a database with outcome data for women who have received tamoxifen therapy

Epidemiology

  • Prevalence of severely reduced CYP2D6 enzyme levels
    • Caucasians and Hispanics – 10%
    • African Americans – 2%
    • Asians – 1%

Genetics

  • Autosomal codominant inheritance  
  • Variants in CYP2D6 are associated with altered tamoxifen metabolism
  • >100 variants identified
    • Refer to Laboratory Testing section for alleles and predicted enzyme function

Pathophysiology

  • Cytochrome P450 family
    • Responsible for metabolism of ~25% of currently available drugs
    • CYP2D6 – isoenzyme of cytochrome P450 family
      • Phenotypes and metabolic effects
        • Poor metabolizer (PM)
          • Caused by 2 no-function CYP2D6 alleles
          • Highly impaired metabolism of the drug, causing lack of drug response
        • Intermediate metabolizer (IM)
          • Caused by 1 no-function CYP2D6 allele with a reduced-function CYP2D6 allele
          • Possible impaired metabolism of the drug
        • Ultrarapid metabolizer (UM)
          • Caused by duplication of functional CYP2D6 alleles
          • Increased metabolism; consider not using drugs metabolized by the CYP2D6 gene
          • ~5% of Caucasians are predicted to have UM phenotypes
  • 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
      • 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 may not be useful for reducing breast cancer recurrence in individuals with greatly diminished CYP2D6 enzyme activity because active metabolites, such as endoxifen, are not produced
    • 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) 15 Variants and Gene Duplication 2014547
Method: Polymerase Chain Reaction/Fluorescence Monitoring

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

Guidelines

Harris LN, Ismaila N, McShane LM, Andre F, Collyar DE, Gonzalez-Angulo AM, Hammond EH, Kuderer NM, Liu MC, Mennel RG, Van Poznak C, Bast RC, Hayes DF. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016; 34(10): 1134-50. PubMed

NCCN Clinical Practice Guidelines in Oncology, Breast Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Apr 2017]

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: May 2017]

Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012; 92(4): 414-7. PubMed

General References

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, van de Velde CJ, 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 JG, 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

Province MA, Altman RB, Klein TE. Interpreting the CYP2D6 results from the International Tamoxifen Pharmacogenetics Consortium. Clin Pharmacol Ther. 2014; 96(2): 144-6. PubMed

Swen JJ, Nijenhuis M, de Boer A, Grandia L, van der Zee AH, Mulder H, Rongen GA, van Schaik RH, Schalekamp T, Touw DJ, van der Weide J, Wilffert B, Deneer VH, Guchelaar H. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther. 2011; 89(5): 662-73. 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

Powers JL, Buys SS, Fletcher D, Melis R, Johnson-Davis K, Lyon E, Malmberg EM, McMillin GA. Multi-gene and Drug Interaction Approach for Tamoxifen Metabolite Patterns Reveals Possible Involvement of CYP2C9, CYP2C19 and ABCB1. J Clin Pharmacol. 2016; PubMed

Medical Reviewers

Content Reviewed: 
April 2017

Last Update: October 2017