Inflammation, Cancer, Pain, Hypertension
Conditions
Keywords
breast cancer, breast density, chemoprevention
Brief summary
This study has two purposes. One is to determine if daily sulindac decreases breast density; a risk factor for breast cancer development. The second is to determine whether sulindac reduces pain and stiffness associated with regular use of aromatase inhibitors given for the treatment of breast cancer.
Detailed description
To accomplish our study aims, we will conduct a phase II, single are trial of sulindac in postmenopausal women with early stage ER+ breast cancer who are receiving an aromatase inhibitor as adjuvant hormonal therapy. Approximately 75 breast cancer patients, stable on AI therapy (minimum of 3 months) for the treatment of their breast cancer will receive sulindac 150 mg bid for 12 months. Breast imaging will be conducted at baseline, 6 and 12 months. The primary endpoint of the study will be change in the appearance of the contralateral, uninvolved breast as measured by quantitative Fat Water Ratio (FWR-MRI) mapping at 12 months in response to sulindac therapy. As changes in breast density in the contralateral, uninvolved breast will be the primary endpoint of the study, patients with bilateral breast cancer or those patients undergoing bilateral mastectomies or reconstruction surgery will be ineligible. Secondary endpoints of the trial include 12 month change in general pain and joint specific stiffness and pain as assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). A number of exploratory endpoints are planned and include comparison of MRI measures of the breast, tissue biomarkers, and pain at 6 months as early indicators of 12 month responses. For the tissue biomarkers, core needle biopsies will be obtained in a subset of women who consent to the procedure from the uninvolved contralateral breast at baseline and at 6 months. Tissue studies will include characterization of tissue histology (graded by cellularity and stromal elements) and molecular measures of proliferation and apoptosis.
Interventions
DRUGSulindac
Sponsors
Stony Brook University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
No minimum to 75 Years
Healthy volunteers
No
Inclusion criteria
* Eligibility criteria will include: Postmenopausal women with of first incidence of early stage (stages 0 - III) hormone receptor positive breast cancer stabilized on anastrozole therapy for at least 3 months * Patients must have started on anastrozole and plan to continue on anastrozole therapy for a minimum of 12 months * Patients must have an unaffected, non-irradiated contralateral breast with a baseline breast density score of \> 25% as measured by standard digital mammography (BIRADs score \> 2) or magnetic resonance imaging (MRI) performed within 12 months of randomization to the study * A willingness to follow the study protocol, as indicated by provision of informed consent to participate * A willingness to avoid taking NSAIDs outside of the trial (rare NSAID use for musculoskeletal symptoms excepted) * Normal renal function as determined by a serum creatinine \< upper limit of normal * No known contraindication to NSAID use * Normotensive or controlled blood pressure (\< 140/90) on a single anti-hypertensive medication
Exclusion criteria
* Current or anticipated need for daily aspirin or NSAID use including aspirin for cardiovascular protection * Known intolerance to NSAIDs * Age \> 75 years * History of cardiovascular disease including prior myocardial infarction, angina, stroke, or transient ischemic attack (TIA) * Diabetes requiring drug therapy * Current smoker * History of Uncontrolled hypertension * Blood pressure \> 140/90 at baseline by home monitoring * History of GI ulcers, chronic GERD, or GI bleeding in the past 5 years * History of a bleeding diathesis or current anticoagulant therapy * Daily therapy with H2 blockers or protein pump inhibitors * 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 |
|---|---|---|
| Change in Breast Density Measured as Fat to Water Ratio by Magnetic Resonance Imaging | Baseline and 12 months | Adjusted estimates of relative change in percent breast density by magnetic resonance imaging |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Muscle and Joint Pain and Stiffness | Baseline and 12 months | The endpoint for arthralgia is change from baseline in Total Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index scores on a scale at 12 months. The Western Ontario and McMaster Universities Index is a self-administered questionnaire consisting of 24 items divided in 3 subscales: Pain, Stiffness, and Physical Function. Scores on the scale range from 0 to 96 for total WOMAC where 0 represents the best health status and 96 the worst possible status. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Arterial Blood Pressure at 12 Months | Change in blood pressure between Baseline and 12 months | Adjusted estimate of change in mean arterial blood pressure in each study arm at 12 months in each study arm. |
Countries
United States
Participant flow
Recruitment details
All patients were enrolled at the University of Arizona Cancer Center and at the Stony Brook Cancer Center.
Pre-assignment details
Patients assigned to receive sulindac were required to complete a NSAID washout period.
Participants by arm
| Arm | Count |
|---|---|
| Sulindac (Clinoril) Women taking aromatase inhibitors for adjuvant therapy for their breast cancer will receive 150 mg of sulindac twice daily for 12 months. They will receive up to 4 MRI within 12 months.
Sulindac | 50 |
| Observational Women taking aromatase inhibitors for adjuvant therapy for their breast cancer will continue their treatment and will be monitored with MRI and standard of care tests at 6 and 12 months. | 50 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | MRI intolerant | 1 | 6 |
| Overall Study | Stopped taking AI Aromatase Inhibitor | 1 | 5 |
| Overall Study | Withdrawal by Subject | 6 | 4 |
Baseline characteristics
| Characteristic | Sulindac (Clinoril) | Observational | Total |
|---|---|---|---|
| Age, Continuous | 62.6 years STANDARD_DEVIATION 5.5 | 64.2 years STANDARD_DEVIATION 6.6 | 63.4 years STANDARD_DEVIATION 6.1 |
| Race/Ethnicity, Customized Asian, Non-Hispanic | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Black, Non-Hispanic | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized White, Non-Hispanic | 44 Participants | 46 Participants | 90 Participants |
| Region of Enrollment United States | 50 Participants | 50 Participants | 100 Participants |
| Sex: Female, Male Female | 50 Participants | 50 Participants | 100 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 1 / 50 |
| other Total, other adverse events | 25 / 50 | 0 / 0 |
| serious Total, serious adverse events | 3 / 50 | 1 / 50 |
Outcome results
Primary
Change in Breast Density Measured as Fat to Water Ratio by Magnetic Resonance Imaging
Adjusted estimates of relative change in percent breast density by magnetic resonance imaging
Time frame: Baseline and 12 months
Population: Breast density data were unavailable for 4 participants in the observation group due to MRI intolerance. This reduced the sample size for the outcome of change in breast density for the observation arm compared to the secondary endpoints.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sulindac (Clinoril) | Change in Breast Density Measured as Fat to Water Ratio by Magnetic Resonance Imaging | -9.8 percent change in breast density |
| Observational | Change in Breast Density Measured as Fat to Water Ratio by Magnetic Resonance Imaging | -3.6 percent change in breast density |
Comparison: The study was designed to assess change in breast density using fat/water MRI after 12 months of sulindac intervention in postmenopausal breast cancer patients taking aromatase inhibitors for the treatment of estrogen receptor positive breast cancer. A non-randomized observation arm was included with the same eligibility criteria to assess change in breast density over 12 months using the fat/water MRI method of quantifying breast density. Change was examined separately for each arm.p-value: <0.05Mixed Models Analysis
Secondary
Muscle and Joint Pain and Stiffness
The endpoint for arthralgia is change from baseline in Total Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index scores on a scale at 12 months. The Western Ontario and McMaster Universities Index is a self-administered questionnaire consisting of 24 items divided in 3 subscales: Pain, Stiffness, and Physical Function. Scores on the scale range from 0 to 96 for total WOMAC where 0 represents the best health status and 96 the worst possible status.
Time frame: Baseline and 12 months
Population: Questionnaires for patient reported outcomes were completed at baseline for 50 participants in both sulindac and the observation group.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sulindac (Clinoril) | Muscle and Joint Pain and Stiffness | -5.85 score on a scale |
| Observational | Muscle and Joint Pain and Stiffness | -0.25 score on a scale |
p-value: <0.05Mixed Models Analysis
Other Pre-specified
Change in Mean Arterial Blood Pressure at 12 Months
Adjusted estimate of change in mean arterial blood pressure in each study arm at 12 months in each study arm.
Time frame: Change in blood pressure between Baseline and 12 months
Population: Blood pressure was available at baseline for 50 participants in both the sulindac and observation group.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sulindac (Clinoril) | Change in Mean Arterial Blood Pressure at 12 Months | 0.77 mm Hg |
| Observational | Change in Mean Arterial Blood Pressure at 12 Months | 1.52 mm Hg |
p-value: <0.05Mixed Models Analysis