Abstract PS3-01-20: Prospective evaluation of breast mammographic density and biomarker changes induced by 4-hydroxytamoxifen gel application versus placebo to the breast of women at increased risk for breast cancer

Abstract Background: Tamoxifen uptake for risk reduction has remained low due to concerns about toxicity despite available effectiveness data. Studies of tamoxifen in the adjuvant and preventive setting have demonstrated that a 10% or greater decline in mammographic density (MD) is associated with better outcomes; however, tamoxifen metabolism and associated MD declines are variable across patients. An alternative application of a bioactive tamoxifen metabolite may reduce side effects while maintaining efficacy. 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. Therefore, we conducted a multicenter clinical trial to evaluate changes in MD in women with dense breasts induced by 4-OHT versus placebo gel when applied to the breast for 12 months. Methods: Pre- and postmenopausal women between the ages 40-69 yrs, or less than 40 yrs with 5-year Gail risk greater than 1.66%, with heterogeneously or extremely dense breast tissue, were enrolled in this study. Participants were randomized (1:1): 2 mg 4-OHT gel or Placebo gel for 12 months (mo), applied daily to each breast. Participants underwent baseline mammograms, blood draws for toxicity and research biomarkers, and optional breast biopsy, all of which were repeated at the end of 12 mo. The primary endpoint was to estimate and compare the percent change in MD (measured on cranio-caudal mammograms using Cumulus) from baseline to mo 12 between 2 groups. With 64 women in each group, there is 80% power to detect a decrease in density of 6% in the 4-OHT gel vs 2% in the placebo group with a common SD of 8% using a two-sided t-test with a significance level of 0.05. Secondary endpoints included tolerability, measurement of drug metabolites in breast tissue and plasma, and research biomarkers. Results: This prospective, randomized, double-blind, placebo-controlled phase II study randomized 158 participants from Sept 2017 to October 2020 across 6 centers. 123 participants had both baseline and month 12 mammograms, 61 in 4-OHT and 62 in Placebo. The mean (standard deviation) breast density decrease over 12 month was 6.30% (9.11%) in the 4-OHT gel arm and 5.77% (11.24%) in the Placebo arm. The changes in breast density from baseline to month 12 were not significantly different between the two treatment arms (Hotelling’s T2 test p-value = 0.09). For those with available research biopsies, in the placebo arm (N=18), all 4-OHT and metabolite levels were below the quantifiable level (BQL). In the treatment arm (N=12), at months 6 and 12, 10 patients had Z-4-OHT tissue levels above BQL with an average of 10.09 ng/g. No grade 3/4 toxicity was observed in either arm. Twenty-nine participants (thirteen 4-OHT and sixteen Placebo) had 41 gr 1 or 2 adverse events related to the application of gel. Drug exposure serum toxicity, including FVIII and vWB, was not different between treatment arms. IGF-1 levels decreased from baseline to month 12 in both arms; the difference was not statistically significant, whereas IGFBP-3 increased significantly at month 12 in the 4-OHT arm (p=0.04). Conclusion: This prospective double-blind randomized study did not demonstrate a significant difference in the change of MD from baseline to the 12-month treatment between the 4-OHT arm and the placebo arm. The 4-OHT gel was well tolerated, and drug and metabolites were measurable in the breast tissue. Serum IGFBP-3 was found to be increased in the 4-OHT treatment group. The effect of baseline MD characteristics by automated software measurements and other tissue biomarkers will be analyzed and reported separately. Citation Format: B. K. Arun, G. Gierach, M. Scoggins, E. A. Bowles, S. A. Khan, T. B. Bevers, S. S. Rao, J. E. Garber, S. Raza, N. B. Kumar, H. S. Han, J. Heine, B. Niell, P. Chalasani, K. Fitzpatrick, L. G. Wilke, A. Eowler, H. C. Beckwith, J. E. Kuehn-Haijder, C. Mays, L. A. Vornik, O. Lee, E. Diamond, M. Perloff, W. Dong, D. Liu, J. J. Lee, F. W. Symmans, E. Vilar-Sanchez, B. M. Heckman-Stoddard, P. H. Brown. Prospective evaluation of breast mammographic density and biomarker changes induced by 4-hydroxytamoxifen gel application versus placebo to the breast of women at increased risk for breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-01-20.