A researcher is conducting a retrospective study on breast cancer recurrence. Records of a number of patients with hormone receptor-positive, early-stage breast cancer who received adjuvant therapy with tamoxifen were evaluated. Various clinical, demographic, and drug concentration data were analyzed. A comparison of patients who had disease recurrence with those who remained cancer free showed that some of the relapsed patients had lower serum concentrations of endoxifen and 4-hydroxytamoxifen, the active metabolites of tamoxifen. Which of the following is the most likely cause of the drug's ineffectiveness in this subset of patients?
Cytochrome P450 (CYP) enzymes are a group of heme-containing proteins that are responsible for the majority of drug metabolism, which occurs predominately in the liver. Various CYP subtypes exist, with CYP3A, CYP2D, and CYP2C as the most active subtypes involved in drug metabolism. These enzymes generally function to deactivate drugs and facilitate excretion from the body by improving water solubility. However, they also metabolize certain compounds to their active forms.
Polymorphisms may occur in the genes coding for these enzymes, altering their expression or activity. Three important phenotypes exist: poor, intermediate, and rapid metabolizer. Identifying these variations on an individual basis provides a framework for optimizing therapy, predicting treatment efficacy, and minimizing toxicity.
Tamoxifen, a selective estrogen receptor modulator used in the treatment of estrogen receptor-positive breast cancer, is a prodrug metabolized by CYP2D to its active metabolite, endoxifen. Patients with genetic polymorphisms resulting in poor CYP2D activity are exposed to decreased levels of the active metabolite and have a higher risk of disease relapse.
(Choice A) Activation of downstream signal transducer proteins, such as KRAS, leads to activation of transcription factors that promote cell growth. Mutations in the KRAS gene are associated with the development of colorectal and lung cancers.
(Choice B) Decreased activity of hepatic N-acetyltransferase results in a diminished ability to metabolize drugs such as isoniazid and sulfonamides, leading to an increased likelihood of toxicity.
(Choice C) Thiopurine methyltransferase is responsible for the metabolism of thiopurine compounds such as the immunosuppressive drug 6-mercaptopurine. Enzyme deficiency leads to increased drug toxicity.
(Choice D) P-glycoprotein is a cell membrane protein that drives efflux of a number of substances out of the cell. Overexpression of p-glycoprotein in tumor cells has been identified as a cause of multidrug resistance.
Educational objective:
Cytochrome P450 enzymes found in the liver are responsible for the majority of drug metabolism. Polymorphisms occurring in the genes coding for these enzymes result in various phenotypes that differ in their rates of metabolism; individual differences in phenotype alter treatment efficacy and drug toxicity.