CYP2D6 and Tamoxifen

Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the list below.

Important Instructions: Please use CYP2D6 Activity Score to select the appropriate row in the list below.

Ultrarapid Metabolizer (Activity Score >2.25)

Clinical Implication

  • Increased CYP2D6 enzyme activity.
  • Normal response expected.

Therapeutic Recommendation

  • Use standard dose of tamoxifen.

Normal – Ultrarapid Metabolizer (Activity Score 1.5+ or 2+)*

Clinical Implication

  • Normal to increased CYP2D6 enzyme activity.
  • Normal response expected.

Therapeutic Recommendation

  • Use standard dose of tamoxifen.

Normal Metabolizer (Activity Score 1.25 – 2.25)*

Clinical Implication

  • Normal CYP2D6 enzyme activity.
  • Normal response expected.

Therapeutic Recommendation

  • Use standard dose of tamoxifen.

Intermediate – Ultrarapid Metabolizer (Activity Score 0.25+, 0.5+, 0.75+, or 1+)

Clinical Implication

  • Possible increased, normal, or decreased CYP2D6 enzyme activity. Exact activity cannot be determined because of gene duplication and assay limitations.
  • Possible reduced activation of tamoxifen and increased risk of treatment failure (e.g., high risk of breast cancer reoccurrence) OR normal activation with normal response.

Therapeutic Recommendation

  • Consider alternative: aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression if premenopausal.  If aromatase inhibitor is contraindicated, consider a higher dose (i.e., tamoxifen 40 mg/day).

Intermediate Metabolizer (Activity Score 0.25 – 1)*

Clinical Implication

  • Decreased CYP2D6 enzyme activity.
  • Reduced activation of tamoxifen and increased risk of treatment failure (e.g., high risk of breast cancer reoccurrence).

Therapeutic Recommendation

  • Consider alternative: aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression if premenopausal.  If aromatase inhibitor is contraindicated, consider a higher dose (i.e., tamoxifen 40 mg/day).

Poor Metabolizer (Activity Score 0)

Clinical Implication

  • No CYP2D6 enzyme activity.
  • Significantly reduced activation of tamoxifen and increased risk of treatment failure (e.g., high risk of breast cancer reoccurrence).

Therapeutic Recommendation

  • Use alternative: aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression if premenopausal.
  • May consider higher dose of tamoxifen (40 mg/day) if contraindications to aromatase inhibitor exist, noting that activation of tamoxifen will increase but not normalize.

Unable to Genotype or Assail Failure

  • The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

  • This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

*Previously some labs have designated an Activity Score of 1 as Normal Metabolizers

Reference

  • Goetz MP et al. Clin Pharmacol Ther. 2018 May;103(5):770-777. PMID: 29385237.

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