About 200,000 US women are diagnosed with invasive breast cancer each year. About one-third are pre-menopausal and two-thirds have tumors that express estrogen receptor alpha (ER?). These women usually receive tamoxifen therapy, which competes with estrogen for binding to the estrogen receptor, but does not stimulate tumor growth. Five-years of tamoxifen therapy reduces recurrence risk by almost half. Efforts to identify biomarkers of tamoxifen resistance-beyond the absence of ER?-have met little success. Because tamoxifen requires metabolic activation to optimize its preventive effect, markers of metabolic inhibition are ideal biomarker candidates. Studies to date have focused only on this aspect of the competition to occupy the estrogen receptor between tamoxifen (and its metabolites) and estrogen (and its compounds). However, metabolic inhibition is unlikely to strongly predict recurrence risk in all ER?+ patients. We propose an innovative perspective that incorporates both sides of the competition, as well as the estrogen receptor itself, in the only patient group (premenopausal women) for whom tamoxifen remains the first line endocrine therapy. No study has focused on pre-menopausal women, despite guidelines recommending only tamoxifen for pre- menopausal women, and despite reason to think the modification might be most important to them.
Aim #1 : Include only pre-menopausal breast cancer patients, collect data on their pharmaceutical inhibition of tamoxifen metabolism, genotype 66 genetic variants in 13 enzymes that affect the concentration of the most active tamoxifen metabolites, and evaluate the association between these variants and recurrence. ER?+ breast cancer patients whose tumor also expresses ER? may not need fully activated tamoxifen to prevent recurrence, whereas women with ER?-negative tumors probably require full metabolic capacity.
Aim #2 : Assay ER? expression, estimate the association between metabolic inhibition and recurrence in ER? strata, and evaluate interaction between metabolic inhibition and ER? status in the combined population. Women whose tumors do not make a lot of estrogen to compete with tamoxifen (17?-hydroxysteroid dehydrogenase 1d2) may not need fully activated tamoxifen to prevent recurrence, whereas women whose tumors make a lot of estrogen to compete with tamoxifen probably require full metabolic capacity.
Aim #3 : Assay 17?HSD1 and 17?HSD2 expression, estimate the association between 17?HSD1/2 ratio >1-, versus d1-and recurrence, and evaluate the interaction between metabolic inhibition and this ratio.

Public Health Relevance

Tamoxifen therapy reduces the risk of breast cancer recurrence by almost half, but is not successful in all tamoxifen-treated patients. Tamoxifen was thought to be less effective in women who carry certain genetic mutations~ now it appears that new perspectives on this topic are required. Extending earlier productive research, the proposed project will evaluate three new topics to clarify how biomarkers can help to predict the patients most likely to suffer breast cancer recurrence while taking tamoxifen.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Filipski, Kelly
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Public Health & Prev Medicine
Schools of Public Health
United States
Zip Code
Ahern, Thomas P; Cronin-Fenton, Deirdre P; Lash, Timothy L et al. (2016) Pak1, adjuvant tamoxifen therapy, and breast cancer recurrence risk in a Danish population-based study. Acta Oncol 55:734-41
Cronin-Fenton, Deirdre P; Heide-Jørgensen, Uffe; Ahern, Thomas P et al. (2015) Opioids and breast cancer recurrence: A Danish population-based cohort study. Cancer 121:3507-14
Lietzen, Lone Winther; Cronin-Fenton, Deirdre; Christiansen, Peer et al. (2015) Autoimmune diseases and breast cancer recurrence: a Danish nationwide cohort study. Breast Cancer Res Treat 149:497-504
Cronin-Fenton, Deirdre P; Damkier, Per; Lash, Timothy L (2014) Metabolism and transport of tamoxifen in relation to its effectiveness: new perspectives on an ongoing controversy. Future Oncol 10:107-22
Cronin-Fenton, Deirdre P; Christensen, Mariann; Lash, Timothy L et al. (2014) Manganese superoxide dismutase and breast cancer recurrence: a Danish clinical registry-based case-control study, and a meta-analysis. PLoS One 9:e87450
Lietzen, L W; Ahern, T; Christiansen, P et al. (2014) Glucocorticoid prescriptions and breast cancer recurrence: a Danish nationwide prospective cohort study. Ann Oncol 25:2419-25
Ahern, Thomas P; Lash, Timothy L; Damkier, Per et al. (2014) Statins and breast cancer prognosis: evidence and opportunities. Lancet Oncol 15:e461-8