Genetics of Tamoxifen Response
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Tamoxifen, a selective estrogen receptor modifier, blocks estrogen receptors in the breast. It decreases the recurrence of breast cancer among women with early stage, hormone receptor positive (HR-positive) breast cancer, and also prevents breast cancer in high risk women. Tamoxifen is metabolized by the CYP2D6 enzyme to endoxifen, which has more potent activity and is the active metabolite. Recent studies have shown that at least one genetic variant inactivates the CYP2D6 and is associated with lower endoxifen levels among tamoxifen users. Some studies have also shown that women who are homozygous for the”poor metabolizing” allele are more likely to relapse; however, the association with the “poor metabolizing” allele and recurrence has not been consistent. This, more work is needed to understand the “pharmacogenetics” (i.e., clinical testing of genetic variation that gives rise to differing response to drugs) of tamoxifen.
 
 
 
 
 
 
 
 The goal of our project is to improve our understanding of genetic factors that alter tamoxifen responsiveness. Our study will test the hypothesis that a genetic test for CYP2D6 and, potentially other genes, can predict which women will receive less benefit from tamoxifen in the treatment of breast cancer. We will also test the hypothesis that the genetic test will be used by women in the clinic and that the results will lead to a change in treatment. First, we will determine whether variations in genes in the cytochrome P450 pathway (CYP3A4, CYP3A5 and CYP2C19) are associated with changes in endoxifen levels. We will test whether variations in genes in the estrogen receptor (ER) alpha and beta genes are associated with biomarkers of tamoxifen effect.
 
 
 
 
 
 
 
 Secondly, we will evaluate the association between CYP2D6 genotypes and breast cancer recurrence among tamoxifen users. We will also test genes that are selected based on the results from the first aim. For this portion of the project, we will use a combination of cross-sectional and cohort studies from ongoing clinical trials at USCF and Kaiser. Finally, we will evaluate women who are considering taking tamoxifen are interested in genetic testing forCYP2D6, and we will identify the factors that predict interest in breast cancer testing. We will follow women who opt for CYP2D6 testing in the clinic and determine whether the results of genetic testing are associated with change in treatment. For this final 3 we will initiate a new cohort of women who are candidates for tamoxifen use and give them an educational session about CYP2D6 testing. 
 
 
 
 
 
 
 
 Tamoxifen decreases the risk of breast cancer recurrence among women with hormone receptor positive tumors and also decreases the risk of breast cancer incidence among high-risk women. Recent data has found that aromatase inhibitors improve survival compared to tamoxifen in post-menopausal women. However, tamoxifen remains the standard of care among pre-menopausal women with hormone receptor positive breast cancer. Thus, all pre-menopausal women with hormone receptor positive breast cancer may be candidates for genetic testing and could benefit from the results of our study. In addition, since tamoxifen can be used for breast cancer prevention, pharmacogenetic testing for tamoxifen can have an impact on women who are at high-risk for developing breast cancer and considering tamoxifen use.