COBRA Profile

Consortium on Breast Cancer Pharmacogenomics

Abstract (July, 2005 Update)

Goals

The purpose of this proposal is to increase our understanding of how inherited polymorphisms affect normal physiologic function of estrogen, and more specifically how genetic variants contribute to the efficacy and toxicities of endocrine treatments for breast cancer. Two major pharmacologic strategies have emerged for endocrine treatment of breast cancer. The first strategy involves active pharmacologic competition with the effects of estrogen and ER in breast cancer tissues. A second strategy of endocrine treatment of breast cancer involves estrogen depletion. In postmenopausal women, the most effective and safe means of estrogen depletion is accomplished with potent inhibitors of aromatase. Aromatase inhibition is now a widely accepted therapeutic strategy for treatment of women with ER/PgR positive metastatic breast cancer, and recently reported studies have now suggested that these agents are at least effective, if not more so, than tamoxifen in the adjuvant setting, either de novo or after 2-5 years of tamoxifen therapy. The primary goal of this proposal is therefore to identify inheritable genetic variants that are associated with the efficacy and toxicity of endocrine treatment for breast cancer.

Progress

The scientific progress in the field of tamoxifen pharmacogenetics as the result of our work has included contributions from our analytical chemistry core that identified a tamoxifen metabolite that decreased in patients who were prescribed the antidepressant paroxetine. We showed that this metabolite was not 4-hydroxy-tamoxifen, the known, potent metabolite. This discovery eventually led to our successful isolation, purification, and identification of this metabolite as 4-hydroxy-N-desmethyl tamoxifen, which was subsequently named "endoxifen": the end product of the N-demethylation and hydroxylation of tamoxifen. Our subsequent studies demonstrated that endoxifen is the principal active metabolite of tamoxifen in the plasma of women with breast cancer treated with the drug. In addition, we showed in vitro that cytochrome P450 2D6 is the primary catalyst of metabolism to endoxifen, and in vivo that CYP2D6 genotype and drugs that inhibit this enzyme are associated with notably low endoxifen concentrations in women being treated for breast cancer. This change in our understanding of tamoxifen metabolism and effect has changed clinical practice through the widespread recognition that the co-prescription of drugs that inhibit CYP2D6 may compromise tamoxifen efficacy. Our group has shown that these drugs notably include the SSRIs paroxetine and fluoxetine that are widely used to treat hot flashes in women taking tamoxifen, but do not include another antidepressant venlafaxine, that appears not to alter endoxifen concentrations. In addition, through our collaboration with the Mayo Clinic, we have shown the genetic variants in CYP2D6 that associate with endoxifen concentrations also associate with the outcomes of tamoxifen treatment. In women enrolled in a randomized, prospective NCCTG breast cancer trial, those who carry variant CYP2D6 alleles had significantly greater risk of disease progression, and also less hot flashes. In further studies designed to identify receptor variants that influence tamoxifen effect, we have shown that genetic variants in the estrogen receptor genes: ER α and ER β influence the drug's effect on serum lipid profiles, on thyroid binding globulin concentrations, and on hot flashes. As a result of this work, the FDA held a meeting in October, 2006, to review the scope and strength of the evidence that supports the inclusion data on CYP2D6 in the tamoxifen label. These activities and studies lay the groundwork for our ongoing work aimed at elucidating genetic variants that associate with effects of the aromatase inhibitors, and that will inform us of important new mechanisms and clinical predictors that will ultimately improve our ability to target endocrine therapy and to better understand the action of estrogen and anti-estrogens.

Experimental Plans

• To identify common genetic variants of the human estrogen receptors and important nuclear coactivators and repressors of these receptors using a combined bioinformatic and direct sequencing approach.
• To test the hypothesis that ER_α and ER_β variants alter gene expression or function using in vitro assays.
• To test the contribution of ER_α and ER_β variants identified during specific aim 1 and 2 to tamoxifen response in the clinical trial of tamoxifen pharmacogenetics already conducted.
• To characterize the involvement of genetically polymorphic drug metabolizing enzymes in the human metabolism of the available aromatase inhibitors: letrozole, exemestane and anastrozole in vitro.
• To test the hypothesis that variants in candidate genes identified in aims 1 - 4 are associated with well curated phenotypic outcomes, including estrogen metabolite concentrations, pharmacokinetics, hot flashes, breast density, bone metabolism and serum lipid subfractions in breast cancer patients receiving exemestane and letrozole.

COBRA Team

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