Principal Investigator

Adetunji T
Toriola
Awardee Organization

Washington University
United States

Fiscal Year
2023
Activity Code
R37
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Targeting RANK Pathway in Mammographic Density and Primary Breast Cancer Prevention

Women with dense breasts on mammograpm have a 4-6-fold increased risk of breast cancer. A sizeable proportion of premenopausal breast cancer cases (39%) 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 RANK, progesterone-regulated pathway gene expression, and related biomarkers associated with breast cancer risk (Secondary Aim). Approach: Study participants will be randomized (1:1) to an intervention (N=116) or placebo arm (N=116). 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: 232 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 (volumetric percent density ≥7.5% on Volpara, equivalent to BI-RADS Category C; (iv) have an increased risk of breast cancer (e.g. positive history of breast cancer in a first-degree relative, non-BRCA susceptibility genes). Target population: Annually, >3,500 premenopausal women with dense breasts aged ≥40 years undergo screening mammogram at the SCC, hence, we are confident of reaching our recruitment goals. 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.

Publications

  • Han Y, Berkey CS, Herman CR, Appleton CM, Alimujiang A, Colditz GA, Toriola AT. Adiposity Change Over the Life Course and Mammographic Breast Density in Postmenopausal Women. Cancer prevention research (Philadelphia, Pa.). 2020 May;13(5):475-482. Epub 2020 Feb 26. PMID: 32102947
  • Han Y, Lee CT, Xu S, Mi X, Phillip CR, Salazar AS, Rakhmankulova M, Toriola AT. Medication use and mammographic breast density. Breast cancer research and treatment. 2021 Sep;189(2):585-592. Epub 2021 Jul 1. PMID: 34196899
  • Akinjiyan FA, Adams A, Xu S, Wang M, Toriola AT. Plasma Growth Factor Gene Expression and Mammographic Breast Density in Postmenopausal Women. Cancer prevention research (Philadelphia, Pa.). 2022 Jun 2;15(6):391-398. PMID: 35288741
  • Keller KG, Toriola AT, Kraenzle Schneider J. Women's Health Beliefs and Intention to Use Chemoprevention for Breast Cancer. Oncology nursing forum. 2023 Aug 17;50(5):611-623. PMID: 37677763
  • Han Y, Colditz GA, Toriola AT. Changes in adiposity over the life course and gene expression in postmenopausal women. Cancer medicine. 2022 Jul;11(13):2699-2710. Epub 2022 Mar 19. PMID: 35304837
  • Mintz R, Wang M, Xu S, Colditz GA, Markovic C, Toriola AT. Hormone and receptor activator of NF-κB (RANK) pathway gene expression in plasma and mammographic breast density in postmenopausal women. Breast cancer research : BCR. 2022 Apr 14;24(1):28. PMID: 35422057
  • Salazar AS, Toriola AT. Reply to Hopper, Nguyen, and Li. JNCI cancer spectrum. 2021 Jun 14;5. (4). doi: 10.1093/jncics/pkab052. eCollection 2021 Aug. PMID: 34377933
  • Han Y, Moore JX, Colditz GA, Toriola AT. Family History of Breast Cancer and Mammographic Breast Density in Premenopausal Women. JAMA network open. 2022 Feb 1;5(2):e2148983. PMID: 35175341
  • Moore JX, Han Y, Appleton C, Colditz G, Toriola AT. Determinants of Mammographic Breast Density by Race Among a Large Screening Population. JNCI cancer spectrum. 2020 Feb 26;4(2):pkaa010. doi: 10.1093/jncics/pkaa010. eCollection 2020 Apr. PMID: 32373777
  • Odama AM, Otti V, Xu S, Adebayo O, Toriola AT. Coffee, Tea, and Mammographic Breast Density in Premenopausal Women. Nutrients. 2021 Oct 28;13. (11). PMID: 34836118
  • Colditz GA, Toriola AT. Refining the Focus on Early Life and Adolescent Pathways to Prevent Breast Cancer. Journal of the National Cancer Institute. 2021 Jun 1;113(6):658-659. PMID: 33136152
  • Salazar AS, Rakhmankulova M, Simon LE, Toriola AT. Chemoprevention Agents to Reduce Mammographic Breast Density in Premenopausal Women: A Systematic Review of Clinical Trials. JNCI cancer spectrum. 2021 Jan 22;5. (1). doi: 10.1093/jncics/pkaa125. eCollection 2021 Feb. PMID: 33554041
  • Alimujiang A, Imm KR, Appleton CM, Colditz GA, Berkey CS, Toriola AT. Adiposity at Age 10 and Mammographic Density among Premenopausal Women. Cancer prevention research (Philadelphia, Pa.). 2018 May;11(5):287-294. Epub 2018 Mar 2. PMID: 29500187
  • Han Y, Otegbeye EE, Stoll C, Hardi A, Colditz GA, Toriola AT. How does weight gain since the age of 18 years affect breast cancer risk in later life? A meta-analysis. Breast cancer research : BCR. 2024 Mar 7;26(1):39. PMID: 38454466