Breast Cancer
Conditions
Brief summary
This is a non-randomized phase II trial of denosumab at 120 mg subcutaneous injection monthly in pre- and post-menopausal women diagnosed with stage 0-III breast cancer who are currently not receiving anticancer treatment with hormonal therapies, chemotherapy, or radiation. All patients will undergo quantification of breast density by MRI at baseline and after 6 months on denosumab. Because the therapeutic agent is an injectable drug, the investigators will conduct a single arm study with both pre- and post-treatment measurements to determine the extent of variability in breast density over time and a placebo treatment period or group will not be utilized. This is an investigator initiated trial and Amgen (SPONSOR) will provide the trial drug denosumab.
Detailed description
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.
Interventions
DRUGDenosumab
monthly subcutaneous injections
Sponsors
Amgen
Alison Stopeck
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
No minimum to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change of ≥ 5% in Breast Density at 6 Months | baseline, 6 months | Breast density will be measured via non-contrast MRI before and after 6 months on denosumab |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change > 1% in Breast Density | 6 months | Unadjusted Absolute Change \> 1% in breast density |
Countries
United States
Participant flow
Pre-assignment details
12 consented patients were determined to be eligible but withdrew consent before the start of the study intervention
Participants by arm
| Arm | Count |
|---|---|
| Denosumab 6 monthly subcutaneous injections of denosumab
Denosumab: monthly subcutaneous injections | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Denosumab |
|---|---|
| Age, Continuous | 59.5 years STANDARD_DEVIATION 13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Percentage of Breast Density by Magnetic Resonance Imaging | 19.74 percent |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 29 Participants |
| Region of Enrollment United States | 30 Participants |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 30 |
| other Total, other adverse events | 0 / 30 |
| serious Total, serious adverse events | 0 / 30 |
Outcome results
Primary
Relative Change of ≥ 5% in Breast Density at 6 Months
Breast density will be measured via non-contrast MRI before and after 6 months on denosumab
Time frame: baseline, 6 months
Population: 5 subjects were excluded (ineligible (n=1), withdrew consent (n=1), implants both breasts (n=1) and image artifacts (n=2).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Denosumab 120 mg Subcutaneous | Relative Change of ≥ 5% in Breast Density at 6 Months | Increase in breast density of ≥ 5% at 6 months density | 4 Participants |
| Denosumab 120 mg Subcutaneous | Relative Change of ≥ 5% in Breast Density at 6 Months | Decrease in breast density of ≥ 5% at 6 months | 13 Participants |
| Denosumab 120 mg Subcutaneous | Relative Change of ≥ 5% in Breast Density at 6 Months | No change in breast density | 8 Participants |
Comparison: The primary hypothesis for this early phase study was that at least 30% of women would experience a \>5% relative decrease in their breast density after 6 months of treatment with denosumab 120 mg subcutaneous dose once a month.p-value: 0.026Blyth-Still Casella Confidence Interval
Secondary
Absolute Change > 1% in Breast Density
Unadjusted Absolute Change \> 1% in breast density
Time frame: 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Denosumab 120 mg Subcutaneous | Absolute Change > 1% in Breast Density | >1% decrease in breast density | 13 Participants |
| Denosumab 120 mg Subcutaneous | Absolute Change > 1% in Breast Density | no change in breast density | 8 Participants |
| Denosumab 120 mg Subcutaneous | Absolute Change > 1% in Breast Density | >1% increase in breast density | 4 Participants |