ABSTRACT Few risk-eligible women agree to standard endocrine interventions for breast cancer risk reduction due to fear of side effects combined with incomplete efficacy and lack of a reliable marker of response. Worry about initiation or worsening vasomotor symptoms is a common barrier. The Tissue Selective Estrogen Complex of bazedoxifene (BZA) 20 mg and conjugated estrogen (CE) 0.45 mg marketed as Duavee® is FDA-approved for relief of hot flashes and prevention of osteoporosis. Duavee® is promising for breast cancer risk reduction given the estrogen antagonist effects in the breast and uterus, and estrogen agonist properties in bone. The bazedoxifene component does not antagonize CE's favorable effects on vasomotor symptoms despite anti- tumor efficacy observed for the combination. In our pilot, 6 months of Duavee® given to symptomatic women at increased risk for breast cancer alleviated hot flashes and favorably modulated risk biomarkers of mammographic fibroglandular volume (Volpara™ fully automated assessments), benign breast tissue proliferation (Ki-67), and serum progesterone, IGF-1, and bioavailable testosterone. A phase IIB multi- institutional trial of 6 months of Duavee® vs placebo is proposed in high-risk women with vasomotor symptoms. Blood, mammogram, and benign breast tissue, and anthropomorphic and quality of life measures will be obtained at baseline. Subjects will be stratified by enrollment site, fibroglandular volume, and Ki-67; and randomized to blinded Duavee® or matched placebo for 6 months, followed by repeat assessments. The primary endpoint is change in mammographic fibroglandular volume. Secondary endpoints are change in benign breast tissue Ki-67, estrogen and progesterone receptor protein, ER and PgR target gene expression (RT-qPCR), serum IGF-1: IGFBP3, bioavailable hormones, the ratio of soluble receptor activator of nuclear factor kappa-Β ligand (sRANKL) to osteoprotegerin, and patient reported outcome measures related to vasomotor symptoms, quality of life, and cognition. Reverse phase protein array and RNA-seq are performed on benign tissue to aid in elucidation of mechanisms of action. The possible influence of BZA levels, body fat, visceral fat, insulin resistance, and inflammatory cytokines on biomarker modulation will be examined. Favorable biomarker modulation would provide evidence that Duavee® is likely to reduce risk for breast cancer and establish potential markers to predict response in a Phase III chemoprevention trial.