A Pilot Study of Varying Doses of Tamoxifen in the Setting of Genetic Polymorphisms of CYP2D6
Endocrine therapy has proven to be an extremely effective therapy in breast cancer. For
women with hormone-receptor-positive tumors, tamoxifen given for as little as two years
results in a statistically significant recurrence and survival benefit. The benefits
increase as the duration of treatment increase, up to 5 years, so that among women treated
for five years, tamoxifen can result in up to a 46 percent annual reduction in the
recurrence rate and up to a 28 percent annual reduction in the death rate. This means that
about half of the recurrences and more than one fourth of the deaths each year are prevented
by tamoxifen treatment. However, despite initial successful responses, many patients on
tamoxifen relapse and die from progressive disease. Consequently, tamoxifen resistance
remains a major clinical problem in the management of breast cancer.
Tamoxifen is metabolized by cytochrome P450 2D6 (CYP2D6) to the more potent metabolites
4-hydroxy-tamoxifen (4-OH-TAM) and 4-hydroxy-N-desmethyltamoxifen (endoxifen). Variations in
the metabolic capacity of this enzyme have shown to be an independent predictor of breast
cancer relapse and death. To date, studies have not correlated tamoxifen doses to CYP2D6
genotype status or associated tamoxifen doses to endoxifen and 4-OH-tamoxifen.
We plan to examine endoxifen and 4-OH-Tam as a function of the tamoxifen dose in patients
with a genetic CYP2D6 polymorphism. We also plan to investigate other genetic variations in
the metabolism of tamoxifen. The possible identification of gene variants that alter
tamoxifen's metabolism may improve initial dose selection and therefore optimize treatment
outcome in the future.
In addition to examining polymorphisms in CYP2D6, we will examine other genes that may
influence the metabolism of medications.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Specific human 2D6 variants measurement(s) or observation(s)
every two weeks
Myra Barginear, MD
Mount Sinai School of Medicine
United States: Institutional Review Board
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