Genetics of Tamoxifen Response

Institution: University of California, San Francisco
Investigator(s): Elad Ziv, M.D. -
Award Cycle: 2008 (Cycle 14) Grant #: 14OB-0166 Award: $803,111
Award Type: Translational Research Award
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2008)

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.




Final Report (2012)

Background and overall topic: 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. Nevertheless the test is now clinically available and being used by some clinicians.

The goal of our project was to improve our understanding of genetic factors that alter tamoxifen responsiveness. We will evaluated a series of candidate genes to determine whether they may interact with tamoxifen. We will address the question of whether the CYP2D6 gene and/or these other genes affect the risk of breast cancer recurrence among women on tamoxifen. Finally, we evaluated whether women who are interested in genetic testing to help make decisions about tamoxifen and whether the women who receive genetic testing alter their choice of treatment based on the results of the test.

Results:
(a) We determined whether variations in genes in the cytochrome P450 pathway (CYP3A4 and CYP2C9) are associated with 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.
(b) We evaluated the association between CYP2D6 genotypes and breast cancer recurrence among tamoxifen users.
(c) We evaluated women who are considering taking tamoxifen to determine whether they opt for genetic testing for CYP2D6We 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.

Our results were published in three separate peer-reviewed journal articles (see abstracts and pub links at):
http://www.ncbi.nlm.nih.gov/pubmed/21970596
http://www.ncbi.nlm.nih.gov/pubmed/22207277
http://www.ncbi.nlm.nih.gov/pubmed/22294487

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.



Clinical and biomarker predictors of side effects from tamoxifen.
Periodical:Breast Cancer Research and Treatment
Index Medicus: Breast Cancer Res Treat
Authors: Lorizio W, Wu AH, Beattie MS, Rugo H, Tchu S, Kerlikowske K, Ziv E
Yr: 2012 Vol: 132 Nbr: 3 Abs: Pg:1107-18

Pharmacogenetic testing affects choice of therapy among women considering tamoxifen treatment.
Periodical:Genome Medicine
Index Medicus: Genome Med
Authors: Lorizio W, Rugo H, Beattie MS, Tchu S, Melese T, et al, and Ziv E
Yr: 2011 Vol: 3 Nbr: 10 Abs: Pg:64

Estimation of tamoxifen metabolite concentrations in the blood of breast cancer patients through CYP2D6 genotype activity score.
Periodical:Breast Cancer Research and Treatment
Index Medicus: Breast Cancer Res Treat
Authors: Wu AH, Lorizio W, Tchu S, Lynch K, Gerona R, Ji W, Ruan W, Ruddy KJ, et al, and Ziv E
Yr: 2012 Vol: 133 Nbr: 2 Abs: Pg:677-83