RANKL Inhibition and Mammographic Breast Density (TRIDENT)

The Washington University

Status and phase: Active, not recruiting; Phase 2

Conditions: Dense Breasts

Treatments: Procedure: Core needle biopsy; Drug: Placebo; Procedure: Blood draw; Drug: Vitamin D3; Drug: Denosumab; Drug: Calcium

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT04067726

201907039

Details and patient eligibility

About

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.

Enrollment: 210 patients

Sex: Female

Ages: 40+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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210 participants in 2 patient groups, including a placebo group

Denosumab

Experimental group

Description:

* 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.

Treatment:

Drug: Calcium

Drug: Denosumab

Drug: Vitamin D3

Procedure: Blood draw

Procedure: Core needle biopsy

Placebo

Placebo Comparator group

Description:

* 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.

Treatment:

Drug: Calcium

Drug: Vitamin D3

Procedure: Blood draw

Drug: Placebo

Procedure: Core needle biopsy