Drugs that interfere with the actions of estrogen represent a cornerstone in the treatment of breast cancer, and are important tools with which to study the actions of estrogen in women. These drugs are increasingly effective in breast cancer, but which drug is best for each woman remains unclear. Our work in the first cycle of the Pharmacogenetics Research Network identified, through a series of laboratory and clinical studies, new genetic patterns that predict effects of the estrogen receptor modulator tamoxifen. We now propose to build on these data to examine the influence of an extended series of candidate genes on the effects of the aromatase inhibitor class of drugs and to refine the genetic signatures that predict tamoxifen effects. Our work will involve the following broad specific aims: 1) To identify common genetic variants of the human estrogen receptors and important nuclear coactivators and repressers of these receptors using a combined bioinformatic and direct sequencing approach; 2) To test the hypothesis that these variants alter gene expression or function using in vitro assays; 3) To test the contribution of variants identified during specific aim 1 and 2 to tamoxifen response in the clinical trial of tamoxifen pharmacogenetics already conducted. 4) 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. 5) 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 anastrozole, exemestane and letrozole. The results of this proposal will generate new information that, linked with our novel tamoxifen pharmacogenetics findings, will generate a series of genetic tools key to optimizing drug selection for women with breast cancer and to our understanding of the mechanisms of estrogen action. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01GM061373-06
Application #
6942538
Study Section
Special Emphasis Panel (ZRG1-GGG-B (50))
Program Officer
Long, Rochelle M
Project Start
2000-05-01
Project End
2010-07-31
Budget Start
2005-08-08
Budget End
2006-07-31
Support Year
6
Fiscal Year
2005
Total Cost
$2,295,626
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Hertz, D L; Kidwell, K M; Seewald, N J et al. (2017) Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer. Pharmacogenomics J 17:521-527
Kadakia, Kunal C; Kidwell, Kelley M; Seewald, Nicholas J et al. (2017) Prospective assessment of patient-reported outcomes and estradiol and drug concentrations in patients experiencing toxicity from adjuvant aromatase inhibitors. Breast Cancer Res Treat 164:411-419
Marcath, Lauren A; Deal, Allison M; Van Wieren, Emily et al. (2017) Comprehensive assessment of cytochromes P450 and transporter genetics with endoxifen concentration during tamoxifen treatment. Pharmacogenet Genomics 27:402-409
Robarge, Jason D; Desta, Zereunesay; Nguyen, Anne T et al. (2017) Effects of exemestane and letrozole therapy on plasma concentrations of estrogens in a randomized trial of postmenopausal women with breast cancer. Breast Cancer Res Treat 161:453-461
Hertz, Daniel L; Speth, Kelly A; Kidwell, Kelley M et al. (2017) Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients. Breast Cancer Res Treat 165:659-668
Hertz, Daniel L; Deal, Allison; Ibrahim, Joseph G et al. (2016) Tamoxifen Dose Escalation in Patients With Diminished CYP2D6 Activity Normalizes Endoxifen Concentrations Without Increasing Toxicity. Oncologist 21:795-803
Santa-Maria, Cesar A; Blackford, Amanda; Nguyen, Anne T et al. (2016) Association of Variants in Candidate Genes with Lipid Profiles in Women with Early Breast Cancer on Adjuvant Aromatase Inhibitor Therapy. Clin Cancer Res 22:1395-402
Kadakia, Kunal C; Snyder, Claire F; Kidwell, Kelley M et al. (2016) Patient-Reported Outcomes and Early Discontinuation in Aromatase Inhibitor-Treated Postmenopausal Women With Early Stage Breast Cancer. Oncologist 21:539-46
Oesterreich, Steffi; Henry, N Lynn; Kidwell, Kelley M et al. (2015) Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover. Breast Cancer Res Treat 154:263-73
Ingle, James N; Kalari, Krishna R; Buzdar, Aman U et al. (2015) Estrogens and their precursors in postmenopausal women with early breast cancer receiving anastrozole. Steroids 99:32-8

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