Abstract CT257: SMART 2.0 Interval breast cancer reduction study: A phase 3 randomized, double-blind, placebo-controlled trial of oral Z-endoxifen in women at high risk for breast cancer

Abstract Background: Mammographic density is well established as one of the most predictive, modifiable risk factors for breast cancer. Dense breast tissue can also make mammograms more challenging to interpret, reducing cancer detection sensitivity. Additionally, high breast density is associated with an increased risk of breast cancer recurrence. Endocrine therapies such as tamoxifen reduce mammographic density and lower the risk of breast cancer in healthy women. Moreover, modeling experiments have shown that tamoxifen has the potential to increase mammographic screening sensitivity which in turn reduces the incidence of interval cancers and larger screen-detected cancers. However, due to tamoxifen’s frequent, unfavorable systemic side effects, and its reliance on first pass metabolism in the liver, its acceptance as treatment is low and it is not effective in all women. (Z)-Endoxifen is a potent ERα inhibitor and has also been shown to degrade PKCβ1, an oncogene linked to breast cancer. The aim of SMART2.0 is to evaluate whether low-dose Endoxifen can reduce the incidence of breast cancer in high-risk women compared to placebo, based on its role in decreasing mammographic breast density. Methods and Statistical Analysis: Each year, approximately 140,000 women participate in the National Swedish Mammography Screening Program at Sdersjukhuset and St Görans Sjukhus, Stockholm, Sweden. For SMART 2.0, women who have been identified through the Profound AI Risk, 2-year risk model will be enrolled. These women will be at high risk of being diagnosed with an interval cancer. An interval cancer is one that is diagnosed between two screens and is typically more aggressive than a screen detected cancer. One-half of the participants will be randomized to receive Endoxifen, while the other half will be randomized to the placebo arm. The sample size will be based on a goal of demonstrating a relative reduction in the primary endpoint of the two-year incidence of interval breast cancer. All data will be summarized using proportions/percentages for categorical data and means/medians with standard deviations/inter-quartile ranges for quantitative outcomes. Additionally, a multivariate logistic regression model will assess this endpoint, adjusting for treatment group and relevant covariates, and testing for multiplicative interaction terms as necessary. Outcome: The goal of this study is to achieve regulatory approval for low-dose (Z)-endoxifen as a therapy to reduce the incidence of interval breast cancer in high-risk women, identified by an AI-based mammogram screening algorithm. Citation Format: Steven C. Quay, H. Lawrence Remmel, Sandra S. Hammer, Lonnissa Nguyen, Magnus Bäcklund, Mattias Hammarström, Per Hall. SMART 2.0 Interval breast cancer reduction study: A phase 3 randomized, double-blind, placebo-controlled trial of oral Z-endoxifen in women at high risk for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT257.