NSAID Effects on Clinical and Imaging Breast Biomarkers

To accomplish our study aims, we will conduct a non-randomized phase II trial of AI alone as
anastrozole in combination with sulindac in postmenopausal women with early stage ER+ breast
cancer who are receiving an anastrozole as their adjuvant hormonal therapy. Recruitment will
be limited to women on anastrozole to reduce heterogeneity introduced by other AIs.
Anastrozole is selected as it is the only AI available in generic form and currently
comprises almost 100% of our patient population. Approximately 100 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, 3, 9
and 15 months. A one-month run-in period followed by a 3-month observation, no agent period
will be used to identify subjects likely not to adhere to the study regimen and to determine
the extent of variability in breast density over time.

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 either control (anastrozole alone) or experimental (anastrozole + 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 between arms in diffusion weighted MRI (median
ADC value) and general pain and joint specific stiffness and pain as assessed by the BPI-SF.
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. This is anticipated to be ~75% at baseline (n=100) (provides tissue sample for cross
sectional comparative analyses with MRI features at baseline) and ~25% at 6 month follow-up
visit (n=37) (provides tissue to conduct analyses of biomarker response to intervention).
Tissue studies will include characterization of tissue histology (graded by cellularity and
stromal elements) and molecular measures of proliferation and apoptosis.

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.