Abstract OT3-15-02: A randomized, double-blind, placebo-controlled study of 4-hydroxytamoxifen topical gel in women with mammographically dense breasts
Authors: Arun Banu K. , Gierach Gretchen , Scoggins Marion E , Khan Seema , Rao Sandra S , Garber Judy , Raza Sughra , Kumar Nagi B. , Han Heather H , Heine John , Niell Bethany , Chalasani Pavani , Fitzpatrick Kimberly , Wilke Lee G , Fowler Amy , Beckwith Heather C , Mays Carrie , Abutaseh Saba , Vornik Lana , Lee Oukseub , Dimond Eileen , Perloff Marjorie , Liu Diane , Lee J. Jack , Brown Powell , Heckman-Stoddard Brandy 
Published: March 2020

Abstract
Background: Tamoxifen uptake for risk reduction has remained low due to concerns about toxicity despite the efficacy and effectiveness data available. Studies of tamoxifen in the adjuvant and preventive setting have demonstrated that a decline in mammographic density (MD) of approximately 10% is consistently associated with better outcomes. Additionally, MD is one of the strongest independent predictors of breast cancer risk, apart from older age and BRCA1/2 mutation, among women. 4-hydroxytamoxifen topical gel (4-OHT) is a transdermal agent, shown in preliminary studies to be well-tolerated with similar decreases in Ki-67 to oral tamoxifen in presurgical DCIS studies and significant drug concentration in breast parenchyma but very low levels in the systemic circulation. This study examines changes in MD, a potential surrogate biomarker of prevention activity, as the primary endpoint for this one-year early-phase prevention trial using 4-OHT gel in high risk women.
Trial design: Multicenter, randomized, placebo-controlled study of 4-OHT gel (2mg per breast) versus placebo in 152 women with heterogeneously or extremely dense breast tissue for 12 months using standard of care imaging, stratified by enrollment site and baseline breast density category. The primary objective of this study is to evaluate the change in percent MD (using Cumulus software) from baseline to the week 52 in women applying 4 mg (2mg per breast) 4-OHT gel versus placebo. The secondary objectives are to compare the Cumulus vs Volpara breast density measurement methods; evaluate the percentage of women with lowering of BIRADS density; estimate percentage of women with ≥ 10% absolute decrease in quantitative MD percentage; explore patient reported experience assessed by BESS questionnaire; laboratory toxicity assessment (F VIII, vWB factor, SHBG, lipid profile); compare the 2D vs. 3D breast density measurement methods to estimate percent change in mammographic breast density; evaluate serum measurements of parent drug and related metabolite levels and factors related to 4-OHT exposures, such as IGF pathway members, CRP, estradiol, and 4-OHT; collect tissue for biomarkers (among women undergoing optional pre- and post-treatment biopsies); examine the persistence in change of mammographic density one year after 4-OHT vs. placebo gel application has stopped.
Eligibility criteria: Inclusion: Women age 40-69 years, or less than 40 years if 5-year breast cancer Gail risk is greater than/equal to 1.66%; heterogeneously or extremely dense breast tissue based on mammography. Exclusion: abnormal uterine bleeding, or prior diagnosis of endometrial hyperplasia, endometrial polyps, or endometrial cancer; prior use of SERMS and AIs, except for a maximum of 3 months and at least 12 months prior.
Statistical methods: Considering an attrition rate of 15%, 128 evaluable women are expected to have both baseline and 52-week measurements of percent MD. With 64 women in each group, there is 80% power to detect a decrease of 6% in the 4-OHT group versus 2% in the placebo group with a common standard deviation of 8% using a two-sided t-test with a significance level of 0.05. Study accrual: Activated January 2018, as of July 1, 2019, 92 patients have been recruited and 79 were randomized.
Citation Format: Banu K. Arun, Gretchen Gierach, Marion E Scoggins, Seema Khan, Sandra S Rao, Judy Garber, Sughra Raza, Nagi B. Kumar, Heather H Han, John Heine, Bethany Niell, Pavani Chalasani, Kimberly Fitzpatrick, Lee G Wilke, Amy Fowler, Heather C Beckwith, Carrie Mays, Saba Abutaseh, Lana Vornik, Oukseub Lee, Eileen Dimond, Marjorie Perloff, Diane Liu, J. Jack Lee, Powell Brown, Brandy Heckman-Stoddard. A randomized, double-blind, placebo-controlled study of 4-hydroxytamoxifen topical gel in women with mammographically dense breasts [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-15-02.