Denosumab and MRI Breast Imaging

According to the results of several studies footnoted in this protocol, there is now
convincing evidence that extensive areas of radiographically-dense tissue in the breast is an
independent risk factor for the development of breast cancer. Here, the investigators
postulate that it is RANK ligand that mediates the association between breast density and
risk of breast cancer for which progesterone is one of several factors that influence the
availability of RANK ligand in mammary tissue to promote or sustain higher breast density. As
such, the investigators hypothesize that inhibition of RANK ligand with the anti-RANK ligand
antibody therapeutic agent denosumab will decrease breast density; a risk factor for breast
cancer development. The investigators will test the primary hypothesis that RANK ligand
inhibition by denosumab (Xgeva) given 120mg monthly to pre- and post-menopausal breast cancer
patients will significantly decrease breast density over 6 months. Breast density will be
assessed by magnetic resonance fat water imaging (MR-FW) of the breast. At the beginning of
the study participants will be measured for a change in breast density by MRI between
baseline 1 and baseline 2 (end of 3 months observation period). All patients will then
receive 6 months of 120 mg denosumab subcutaneously every month with repeat MR imaging to
obtain measurements after 6 months on denosumab. All participants will be asked to provide an
optional core needle breast biopsy sample at baseline and after 6 months on denosumab.

Inclusion Criteria:

- Pre or postmenopausal women with first incidence of early stage (stages 0 - III)
breast cancer who have completed all treatment and are cancer-free, which includes
women at high risk for developing invasive cancer i.e. having a breast biopsy positive
for atypical ductal or lobular hyperplasia or carcinoma in situ.

- Age ≤ 75 years

- 44 patients will be accrued as follows: a) 22 evaluable patients will be premenopausal
as defined as regular menses (24-38 days) b) 22 evaluable patients will be
postmenopausal as defined by a history of amenorrhea for at least one year or hormone
levels (estradiol/FSH) consistent with menopause if post-hysterectomy status, or
history of surgical/medical castration.

- Normal serum calcium or albumin-adjusted serum calcium between 2.0 and 2.9 mmol/L
(8.0-11.5mg/dL).

- Adequate vitamin D level (25-hydroxy vitamin D level > 20 ng/mL)

- Currently on no active treatment for breast cancer and at least 3 months post all the
treatments, with the exception of aromatase inhibitors (exemestane, anastrozole,
letrozole)

- No prior or current use of IV bisphosphonates

- No current use of oral bisphosphonates

- Patients must have an unaffected, non-irradiated contralateral breast

- Significant breast density as determined by mammography and defined by the descriptive
terms scattered fibroglandular tissue/densities, heterogeneously dense, or mostly
dense tissue in the mammography report.

- Adequate renal function defined as a serum creatinine < 1.5 x ULN or CrCl > 30mL/min

- A willingness and ability to follow the study protocol, as indicated by provision of
informed consent to participate

- Willingness to being tested for current pregnancy and use of birth control while being
treated with denosumab (pre-menopausal women only)

Exclusion Criteria:

- Age > 75 years

- Subject has known sensitivity to any of the products to be administered during the
study (e.g., mammalian derived products, denosumab, calcium, or vitamin D).

- Patients have prior history or current evidence of osteonecrosis or osteomyelitis of
the jaw.

- Patients have active dental or jaw condition which requires oral surgery, including
tooth extraction.

- Patients have non-healed dental or oral surgery, including tooth extraction.

- Patients with planned invasive dental procedures

- Subject is pregnant or breast feeding, or planning to become pregnant within 5 months
after the end of the treatment

- Subject is of child bearing potential and is not willing to use, in combination with
her partner, highly effective methods of contraception or abstinence during treatment
and for 5 months after the end of treatment

- Active infection with Hepatitis B, Hepatitis C, or Human Immunodeficiency virus (HIV)

- Any condition or disorder that compromises the ability of the subject to provide
written informed consent and/or comply with study procedures

- History of claustrophobia

- Have electrically, magnetically, or mechanically activated implants including cardiac
pacemaker, cochlear implants, magnetic surgical clips or prostheses.