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    Research Grants Awarded

    Tracking Response to Tamoxifen Prevention

    Study Section:
    Treatment

    Scientific Abstract:
    Background: We do not fully understand the mechanism of Tam-prevention with Ductal Carcinoma In-Situ (DCIS) and it is unclear whether ER expression is the optimal of predictor of response to Tam. Recently, ER alpha promoter ( ESR1 ) methylation was shown to predict response to Tam chemotherapy. Suprizingly, 1) methylation of ESR1 proved to be the best predictor of PR expression and 2) progesterone gene promoter ( PGR) methylation was a better predictor of ERalpha expression. These results suggest an important, but potentially complex, interaction between promoter methylation and hormone biology in mammary epithelial cells. Random Periareolar Fine-Needle Aspiration (RPFNA) is a research technique, prospectively validated to test for 1) short-term breast cancer risk and 2) response to prevention. In Preliminary Data 40 high-risk women with ipsilateral DCIS and contralateral atypia on initial RPFNA were recruited to take Tam prevention. Final results are available for 10 subjects. After 12 months of Tam prevention 5/10 women demonstrated a disappearance of contralateral atypia on two consecutive RPFNA at 6 month intervals and 5/10 women exhibited persistent atypia. These data demonstrate the feasibility of using RPFNA to test for response to Tam-prevention. Objective/Hypothesis: We will test whether there is a relationship between 1) ESR1/PGR promoter methylation and ER/PR expression and 2) whether hypermethylation of ESR1 predicts response to Tam prevention. We hypothesize that methylation of the ESR1 and PGR promoters are important predictors of ER/PR expression and estrogen-sensitivity. Aims/Study Design: Aim I will test whether methylation of ESR1/PGR correlates with ER/PR expression in 310 banked RPFNA samples. Aim II will test whether methylation of ESR1 predicts resistant to estrogen-mediated activation of the ERE. Defined HMEC strains and HMECs isolated from high-risk women in our prevention cohort, will be tested for estrogen-mediated ERE 1) activity and 2) co-activator recruitment. Aim III is a PILOT TRIAL that will test whether ESR1 methylation predicts response to Tam prevention. In 40 high-risk women with ipsilateral DCIS and atypia present on initial contralateral RPFNA we will test whether 1) low ER expression by IHC and/or 2) methylation of the ESR1 promoter predicts persistence of atypia after Tam for 12 mos. Benefits: Results from this study can be rapidly translated to provide biomarkers of response to anti-hormonal prevention agents.

    Lay Abstract:
    Background: Currently many women with Ductal Carcinoma in situ (DCIS) take tamoxifen (Tam) to prevent the development of breast cancer. However, we do not understand how Tam works to prevention breast cancer and we lack markers to predict who is responding. Random Periareolar Fine Needle Aspiration (RPFNA) functions like a "breast pap-spear" in its ability to sample breast cells from the whole breast of high-risk women and test response to prevention drugs such as Tam. Recently it has been shown that inactivation of the estrogen receptor gene (ESR1) by a process called methylation may be a better predictor of response to Tam than ER expression. In Preliminary Data we are testing whether Tam can eliminate atypia (damaged cells but not breast cancer) in 40 women who have atypia on initial RPFNA. Final results are available for 10 subjects. After 12 months of Tam prevention 5/10 women demonstrated a disappearance of atypia on two consecutive RPFNA at 6 month intervals and 5/10 women had persistent atypia. These data demonstrate the feasibility of using RPFNA to test for response to Tam in individual women. Objective/Hypothesis: We will test whether there is a relationship between methylation inactivation of the ERalpha gene ( ESR1) promoter, ER/PR expression and response to Tam prevention. We hypothesize that methylation of the ESR1 promoter is an important predictors of ER/PR expression and estrogen-sensitivity. Aims/Study Design: Aim I will test whether how frequently the ERalpha gene (ESR1) is inactivated by methylation in high-risk women and whether the frequency increases with how abnormal the cells are. Aim II will test whether methylation/inactivation of the ERalpha gene ( ESR1) predicts resistance to estrogen in mammary epithelial cells isolated from high-risk women in our prevention cohort. Aim III is a PILOT TRIAL that will test whether ERalpha gene ( ESR1) methylation predicts resistance to Tam prevention in 40 with ipsilateral DSIS and atypia present on initial RPFNA. Benefits: Too many women with DCIS take Tam to prevent breast cancer without any idea of whether Tam is working in their breast cells. Results from this study can be rapidly translated to provide biomarkers of response to anti-hormonal prevention agents.