Grant Number:	5R01CA166825-05 Interpret this number
Primary Investigator:	Lash, Timothy
Organization:	Emory University
Project Title:	New and Integrated Perspectives on Modification of Tamoxifen Effectiveness
Fiscal Year:	2017

DESCRIPTION (provided by applicant): 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 (ERα). 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 ERα-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 ERα+ 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. ERα+ breast cancer patients whose tumor also expresses ERβ may not need fully activated tamoxifen to prevent recurrence, whereas women with ERβ-negative tumors probably require full metabolic capacity. Aim #2: Assay ERβ expression, estimate the association between metabolic inhibition and recurrence in ERβ strata, and evaluate interaction between metabolic inhibition and ERβ status in the combined population. Women whose tumors do not make a lot of estrogen to compete with tamoxifen (17β-hydroxysteroid dehydrogenase 1<2) 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 17βHSD1 and 17βHSD2 expression, estimate the association between 17βHSD1/2 ratio >1-, versus d1-and recurrence, and evaluate the interaction between metabolic inhibition and this ratio.





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