RANKL Inhibition and Mammographic Breast Density

Study Overview
=================
Brief Summary
-----------------
Data supporting a role for RANKL signaling in mammographic density and breast cancer development has begun to emerge, but clinical trial data providing definitive evidence that would allow the adoption of RANKL inhibition in primary breast cancer prevention are not yet available. The hypothesis is that RANKL inhibition with denosumab will decrease mammographic density in high-risk premenopausal women with dense breasts. To address this, the investigators have developed this clinical trial to quantify the impact of RANKL inhibition on mammographic density in high-risk premenopausal women with dense breasts and to determine the effect of RANKL inhibition on markers of proliferation and biomarkers of breast cancer risk. Successful demonstration that RANKL inhibition reduces mammographic density could open up additional approaches to primary breast cancer prevention in high-risk premenopausal women, who do not have dominant genetic predisposition.

Official Title
-----------------
Randomized Clinical Trial of RANKL Inhibition With Denosumab on Mammographic Density in Premenopausal Women With Dense Breasts (TRIDENT)

Conditions
-----------------
Dense Breasts

Intervention / Treatment
-----------------
* Drug: Denosumab
* Drug: Placebo
* Drug: Calcium
* Drug: Vitamin D3
* Procedure: Core needle biopsy
* Procedure: Blood draw


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female. Premenopausal (when menopausal status is uncertain, the investigators will measure follicle-stimulating hormone and estradiol to ascertain that a partcipant is premenopausal) At least 40 years of age. Dense breasts on routine mammogram (BI-RADS Category C and D) Able to understand and willing to sign an IRB-approved written informed consent document. Exclusion Criteria: History of breast or any other invasive cancer except for DCIS (ductal carcinoma in situ) who received only lumpectomy, LCIS (lobular carcinoma in situ), atypical hyperplasia, non-melanoma skin cancer, carcinoma in situ of the cervix. Current use of tamoxifen, aromatase inhibitors, or bisphosphonates, or RANKL inhibitors Concurrent participation in another cancer chemoprevention trial (unless no longer receiving the intervention). Pregnant, lactating, or planning to get pregnant while the trial is ongoing. Recent history of invasive dental procedure (e.g. tooth extraction, dental implant, oral surgery). Unhealed and/or planned dental/oral surgery. History of osteonecrosis/osteomyelitis of the jaw. History of osteoporosis or severe osteopenia.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Stratified permuted block randomized design will be used to generate the randomization table where permuted block randomization will be used for each stratum by age, with a varying block size of 4 and 6.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Denosumab<br>Subcutaneous injection of denosumab at a dose of 60 mg at two time points: baseline and 6 months Participants will also be instructed to take calcium and vitamin D supplements daily for 12 months between baseline examination and 12-month mammographic breast density examination. Mammographic breast density will be assessed at three time points in all participants: baseline, 12 months, and 24 months. A 36-month optional assessment may also occur. Biopsies and blood draws will occur for research purposes at baseline and 12 months. | Drug: Denosumab<br>* Denosumab is commercially available and will be provided at no cost to participants.<br>* Other names: Prolia;Drug: Calcium<br>* -Participants will be instructed to take calcium (600 mg) daily for 12 months between baseline examination and 12- month mammographic breast density examination.<br>Drug: Vitamin D3<br>* Participants will be instructed to take vitamin D3 (800 IU) supplements daily for 12 months between baseline examination and 12- month mammographic breast density examination.<br>Procedure: Core needle biopsy<br>* Baseline and 12 months<br>Procedure: Blood draw<br>* Baseline and 12 months<br>|
| Placebo Comparator: Placebo<br>Subcutaneous injection of the placebo at a dose of 60 mg at two time points: baseline and 6 months Participants will also be instructed to take calcium and vitamin D supplements daily for 12 months between baseline examination and 12 month mammographic breast density examination Mammographic breast density will be assessed at three time points in all participants: baseline, 12 months, and 24 months. A 36 month optional assessment may also occur. Biopsies and blood draws will occur for research purposes at baseline and 12 months. | Drug: Placebo<br>* Placebo will be made available as 1 mL sterile, non-pyrogenic water solution in a single-use prefilled syringe.<br>Drug: Calcium<br>* -Participants will be instructed to take calcium (600 mg) daily for 12 months between baseline examination and 12- month mammographic breast density examination.<br>Drug: Vitamin D3<br>* Participants will be instructed to take vitamin D3 (800 IU) supplements daily for 12 months between baseline examination and 12- month mammographic breast density examination.<br>Procedure: Core needle biopsy<br>* Baseline and 12 months<br>Procedure: Blood draw<br>* Baseline and 12 months<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mammographic breast density between the two arms as measured by volumetric percent density | -The investigators will use volumetric percent density (VPD) as the primary mammographic breast density measure. | From baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mammographic breast density between the two arms as measured by volumetric percent density |  | From baseline to 24 months | 
| Change in mammographic breast density between the two arms as measured by volumetric percent density |  | From 12 months to 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mammographic density, Breast cancer, RANKL, Denosumab, Prevention, Premenopausal