Tamoxifen and Metabolites, LC-MS/MS

Tamoxifen is an oral pro-drug, which is metabolized in the liver by various enzymes such as CYP2D6. Metabolism is critical to the efficacy of tamoxifen, since the active metabolites are more effective at blocking the estrogen receptors. Testing for tamoxifen and its metabolites provides information about the extent of tamoxifen metabolism. Concentration of the active metabolite, endoxifen, is influenced by polymorphisms (genetic variants) in the CYP2D6 gene as well as by diet, liver disease, and other drugs. The concentration of tamoxifen and its metabolites may potentially serve as a guide to dosage adjustments.¹

Testing for tamoxifen metabolites can also indicate whether a patient is adherent to treatment.

Unlike this test, genotyping accounts for only one of the factors that influence tamoxifen metabolism. Genotyping informs the physician about genetic polymorphisms present in the patient’s CYP2D6 gene. These polymorphisms can lead to reduced CYP2D6 enzymatic activity, which, in turn, can lead to reduced tamoxifen metabolism. Reduced metabolism may result in a lower concentration of endoxifen, the most active metabolite, and potentially lower treatment efficacy.

In addition, there have been several studies suggesting metabolic pathways other than CYP2D6 may generate endoxifen.² A genotype test cannot assess this. Nor can a genotype test assess the effect of patient noncompliance, diet, liver disease, or other medications. Measurement of tamoxifen and its metabolites can assess the impact of all these factors.

A low concentration of endoxifen (ie, in the lowest quintile) has been associated with a 26% higher risk of breast cancer recurrence.¹ Increasing the tamoxifen dose increases the endoxifen concentration³; thus, clinicians may want to consider dosage adjustments for patients with low endoxifen concentration.

The tamoxifen metabolites (N-desmethyl-tamoxifen, 4-hydroxy-N-desmethyl-tamoxifen [endoxifen], and 4-hydroxy-tamoxifen) have up to 33 times stronger binding to the estrogen receptor than does tamoxifen.⁴ Endoxifen and 4-hydroxy-tamoxifen bind to both the alpha and beta estrogen receptors and have similar potency in in vitro studies. Clinically, endoxifen is the more important of the two metabolites, since its concentration is typically 5 to 10 times higher than that of 4-hydroxy-tamoxifen.⁴