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Principal Investigator: Adetunji T Toriola
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $569,887
Funding agency: National Cancer Institute
ABSTRACT
Women with dense breasts on mammogram have a 4-6-fold increased risk of breast cancer. A sizeable
proportion of premenopausal breast cancer cases (29%) are attributable to having dense breasts.
Observational and clinical trial data have shown that a decrease in breast density translates to a reduction in
breast cancer incidence. Hence, interventions to reduce breast density could prevent breast cancer. However,
adult dietary and lifestyle modifications have not been shown to reduce mammographic density. Therefore,
identifying a pathway that can be targeted to reduce breast density and breast cancer incidence is crucial. The
receptor activator of nuclear factor-κB (RANK) pathway regulates the development of the lobulo-alveolar
mammary structures, activates downstream signaling cascades involved in breast cancer and is the major
mediator of progesterone-driven expansion of mammary stem cells. The RANK pathway is associated with
mammographic density and breast cancer risk. This has led to a strong interest in inhibiting RANK ligand
(RANKL) signaling to prevent breast cancer. Nevertheless, clinical trial data providing definitive evidence that
would allow the adoption of RANKL inhibition in reducing dense breasts and prevent breast cancer are not yet
available. We, thereby, propose to (i) perform a randomized clinical trial to quantify the effect of RANKL
inhibition with denosumab on mammographic density in high-risk premenopausal women with dense breasts
(Primary Aim); (ii) determine the effect of RANKL inhibition on breast tissue gene expression, metabolome,
and biomarkers associated with breast cancer (Secondary Aim). Approach: Study participants will be
randomized (1:1) to an intervention (N=105) or placebo arm (N=105). Intervention: The intervention arm will
receive two subcutaneous injections of denosumab (60 mg), one at baseline, and a second at 6 months. The
placebo arm will receive two subcutaneous placebo injections at baseline, and 6 months. We will use Volpara
software to assess mammographic density at baseline, and 12 months. Volpara quantifies volumetric
measures of density; volumetric percent density (VPD) allowing us to test differences in change in
mammographic density at 12 months among women assigned to intervention vs. placebo. Study population:
210 women undergoing annual screening mammography at the Siteman Cancer Center (SCC), St. Louis, MO.
Inclusion criteria: (i) premenopausal; (ii) ≥40 years of age; (iii) dense breasts (BI-RADS Category C and D –
equivalent to volumetric percent density ≥7.5% on Volpara. Target population: premenopausal women with
dense breasts aged ≥40 years undergo screening mammogram at the Joanne Knight Breast Health Center at
Siteman Cancer Center and affiliated hospitals. Impact: Study findings could open up additional therapeutic
approaches in primary breast cancer prevention for high-risk premenopausal women with dense breasts, who
do not have dominant genetic predisposition.
Terms: <1st degree relative><21+ years old><Address><Adoption><Adult><Adult Human><Age Years><Antibodies><Biological Markers><Blood><Blood Reticuloendothelial System><Breast><Breast Cancer><Breast Cancer Prevention><Breast Cancer Risk Factor><Breast Tissue><Breast biopsy><Cancer Center><Cancers><Categories><Cell Communication and Signaling><Cell Signaling><Chemoprevention><Clinical><Clinical Trials><Computer software><Corpus Luteum Hormone><DNA Synthesis Factor><Data><Delta4-pregnene-3,20-dione><Development><Diet Modification><Dietary Modifications><Dominant Genetic Conditions><Dominant trait><Endothelial Cell Growth Factor><Evaluation><FGF><Fibroblast Growth Factor><Fibroblast Growth Factor Gene Family><Fibroblast Growth Regulatory Factor><First Degree Relative><Future><Gene Expression><Genes><Genetic Dominant><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic propensity><Goals><Health><History><Hospitals><Incidence><Inherited Predisposition><Inherited Susceptibility><Injections><International><Intervention><Intervention Strategies><Intervention Studies><Intracellular Communication and Signaling><Life Style Modification><Ligands><Malignant Breast Neoplasm><Malignant Neoplasms><Malignant Tumor><Mammary Gland Parenchyma><Mammary Gland Tissue><Mammogram><Mammographic Density><Mammographic screening><Mammography><Measures><Mediator><Needles><Nuclear><Participant><Pathway interactions><Placebos><Pre-Menopause><Pre-menopausal Period><Predisposition gene><Pregn-4-ene-3,20-dione><Pregnenedione><Premenopausal><Premenopausal Period><Premenopause><Progenitor Cells><Progesterone><Progesterone Receptors><Progestin Receptors><Proliferating><Randomized><Receptor Inhibition><Receptor Protein><Recording of previous events><Sham Treatment><Signal Transduction><Signal Transduction Systems><Signaling><Software><Structure><Subcutaneous Injections><Susceptibility Gene><Tamoxifen><Target Populations><Testing><Therapeutic><Therapeutic Progesterone><Time><Transforming Growth Factors><Translating><Tumor Growth Factors><Woman><adulthood><aged><annual screening><arm><bio-markers><biologic marker><biological signal transduction><biomarker><biomarker signature><breast cancer risk><breast density><breast epithelium><density><developmental><diet alteration><dietary alteration><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><high risk><histories><inclusion criteria><indexing><innovate><innovation><innovative><interest><intervention arm><intervention research><interventional research><interventional strategy><interventional study><interventions research><lifestyle modification><malignancy><malignant breast tumor><mammary><mammary cancer prevention><mammary epithelium><mammary tumor prevention><mammographic Imaging><mammographic breast density><mammographic examinations><mammographic exams><mammography screening><metabolome><metabonome><neoplasm/cancer><parent grant><participant enrollment><pathway><patient enrollment><pre-menopausal><predict responsiveness><predicting response><predictive signature><predisposing gene><premenopausal status><prevent breast cancer><randomisation><randomization><randomized, clinical trials><randomly assigned><receptor><receptor expression><recruit><routine screening><screening><screenings><sham therapy><side effect><stem cells><study population><subcutaneous><subdermal><subdermal injection><susceptibility allele><susceptibility locus><susceptibility variant><transforming growth factors Animal growth regulators><treatment arm><ultrasound>