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Targeting RANK Pathway in Mammographic Density and Primary Breast Cancer Prevention

Award Number: R37CA235602
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Targeting RANK Pathway in Mammographic Density and Primary Breast Cancer Prevention - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $599,882 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	002	7	7/24/2025	NON-COMPETING CONTINUATION	$599,882
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	001	6	3/5/2025	EXTENSION WITH OR WITHOUT FUNDS	$1
2025	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	5	3/5/2025	NON-COMPETING CONTINUATION	-$1
														Subtotal = $599,882

Issue Date FY: 2024 ( Subtotal = $569,887 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Cause and Prevention Research	000	6	9/4/2024	EXTENSION WITH OR WITHOUT FUNDS	$569,887
														Subtotal = $569,887

Issue Date FY: 2023 ( Subtotal = $595,446 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	5	7/7/2023	NON-COMPETING CONTINUATION	$595,446
														Subtotal = $595,446

Issue Date FY: 2022 ( Subtotal = $617,956 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	4	7/31/2022	NON-COMPETING CONTINUATION	$617,956
														Subtotal = $617,956

Issue Date FY: 2021 ( Subtotal = $624,067 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	3	7/30/2021	NON-COMPETING CONTINUATION	$624,067
														Subtotal = $624,067

Issue Date FY: 2020 ( Subtotal = $627,245 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	2	7/15/2020	NON-COMPETING CONTINUATION	$627,245
														Subtotal = $627,245

Issue Date FY: 2019 ( Subtotal = $593,908 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	1	8/5/2019	NEW	$593,908
														Subtotal = $593,908

Grand Total All Awards = $4,228,391

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Targeting RANK Pathway in Mammographic Density and Primary Breast Cancer Prevention

Award Number: R37CA235602

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/05/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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