RANKL Inhibition and Breast Tissue Biomarkers

Study Overview
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Brief Summary
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A robust knowledge of how to reduce breast density could play a key role in breast cancer prevention in premenopausal women, but viable preventative targets to reduce breast density-associated breast cancer risk are yet to be developed. The investigators propose to investigate the effect of RANKL inhibition with denosumab on breast tissue markers in high-risk premenopausal women with dense breasts. Study findings could provide robust evidence to move forward with a clinical trial targeting RANKL inhibition in premenopausal breast cancer prevention.

Official Title
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RANKL Inhibition and Breast Tissue Biomarkers in Premenopausal Women With Dense Breasts

Conditions
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Breast Cancer Prevention, Mammographic Density

Intervention / Treatment
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* Procedure: Ultrasound-guided core needle biopsy
* Drug: Denosumab
* Procedure: Blood draw
* Drug: Calcium
* Drug: Vitamin D


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female. Premenopausal. At least 35 years of age. Dense breasts on routine mammogram. Willing to take calcium (1,200mg) and vitamin D (800 IU) daily. At increased risk for breast cancer using any of the following: Positive family history of breast cancer Breast cancer risk prediction models Able and willing to return for repeat biopsy. Able to understand and willing to sign an IRB-approved written informed consent document. Exclusion Criteria: Current use of tamoxifen, aromatase inhibitors, or bisphosphonates. Concurrently participating in another cancer chemoprevention trial (unless no longer receiving the intervention). Pregnant or lactating. Recent tooth extraction or dental procedure. Unhealed and/or planned dental/oral surgery. History of osteonecrosis/osteomyelitis of the jaw. History of osteoporosis or severe osteopenia. Unable/unwilling to return for repeat biopsy.

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Denosumab<br>An ultrasound-guided core needle breast biopsy will be performed on day 1 prior to the intervention. A single dose of subcutaneous denosumab 60mg will be administered immediately after the core biopsy on day 1. This will take place on an outpatient basis. Repeat core-needle biopsy will take place on Day 60 (+/-10 days). Blood samples will also be collected at the time of core-needle biopsy to allow for biomarker assay. Gene expression analyses will be done using NanoString nCounter gene expression system. | Procedure: Ultrasound-guided core needle biopsy<br>* Tissue collection for this research proposal will be used for research purposes only and will not inform participant care<br>Drug: Denosumab<br>* Denosumab is a human IgG2 monoclonal antibody with affinity and specificity for human RANKL<br>* Other names: Prolia;Procedure: Blood draw<br>* 20 mL of fasting whole blood will be collected before denosumab (Day 1) and one month after denosumab administration (day 60 +/- 10 days)<br>Drug: Calcium<br>* 1200mg daily<br>Drug: Vitamin D<br>* 800 IU daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of denosumab on breast tissue gene RANK pathway gene expression | -The investigators will evaluate changes in RANK pathway gene expression between baseline and day 60 using NanoString NCounter platform | Between baseline and day 60 | 
| Effect of denosumab on breast tissue gene expression in progesterone-regulated pathways | The investigators will evaluate changes in progesterone-regulated pathways gene expression between baseline and day 60 using NanoString NCounter platform. | Between baseline and day 60 | 
| Effect of denosumab on breast tissue breast tissue ki-67 proliferation | The investigators will evaluate changes in ki-67 proliferation between baseline and day 60 using immunohistochemistry | Between baseline and day 60 | 
| Effect of denosumab on breast stromal proliferation | The investigators will evaluate changes in gene expression of markers of stromal proliferation between baseline and day 60 using NanoString NCounter platform. | Between baseline and day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of breast tissue RANK pathway gene expression with circulating biomarker levels |  | 60 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mammographic density, Premenopausal, Breast cancer, Chemoprevention, Denosumab