R01CA249437

Biomarker-Based Phase IIB Trial of (Bazedoxifene-Conjugated Estrogen) to Reduce Risk for Breast Cancer - 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, as well as 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-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.

University Of Kansas Medical Center Research Institute

TO IDENTIFY CANCER RISKS AND RISK REDUCTION STRATEGIES, TO IDENTIFY FACTORS THAT CAUSE CANCER IN HUMANS, AND TO DISCOVER AND DEVELOP MECHANISMS FOR CANCER PREVENTION AND PREVENTIVE INTERVENTIONS IN HUMANS. RESEARCH PROGRAMS INCLUDE: (1) CHEMICAL, PHYSICAL AND MOLECULAR CARCINOGENESIS, (2) SCREENING, EARLY DETECTION AND RISK ASSESSMENT, INCLUDING BIOMARKER DISCOVERY, DEVELOPMENT AND VALIDATION, (3) EPIDEMIOLOGY, (4) NUTRITION AND BIOACTIVE FOOD COMPONENTS, (5) IMMUNOLOGY AND VACCINES, (6) FIELD STUDIES AND STATISTICS, (7) CANCER CHEMOPREVENTION AND INTERCEPTION, (8) PRE-CLINICAL AND CLINICAL AGENT DEVELOPMENT, (9) ORGAN SITE STUDIES AND CLINICAL TRIALS, (10) HEALTH-RELATED QUALITY OF LIFE AND PATIENT-CENTERED OUTCOMES, AND (11) SUPPORTIVE CARE AND MANAGEMENT OF SYMPTOMS AND TOXICITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO STIMULATE TECHNICAL INNOVATION, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING, AND FOSTER PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY WOMEN AND SOCIALLY/ECONOMICALLY DISADVANTAGED PERSONS.

93.393 - Cancer Cause and Prevention Research

National Cancer Institute (NCI) [HHS - NIH]

Mission, Kansas 662052005 United States

Single Zip Code

Cancer Prevention and Control Clinical Trials Grant Program (R01 Clinical Trial Required) (PAR-18-559)

Amendment Since initial award the End Date has been extended from 01/31/26 to 07/31/26 and the total obligations have increased 386% from $852,459 to $4,143,666.