Exemestane and Celecoxib in Postmenopausal Women at High Risk for Breast Cancer
Exemestane and Celecoxib in Postmenopausal Women at High Risk for Breast Cancer
The primary goal of this 5-year study is to determine whether exemestane alone or in
 combination with celecoxib decreases breast tissue density in healthy postmenopausal women at
 high risk for breast cancer. Dense breast tissue seen on mammography has been linked to an
 increased risk of breast cancer. The study will also examine the effects of exemestane and
 celecoxib on bone density, blood hormone levels and quality of life. Exemestane, approved by
 the Food and Drug Administration for treating postmenopausal women with breast cancer, lowers
 the amount of estrogen in the body. Celecoxib, approved for treating arthritis pain and for
 reducing the number or colon polyps in an inherited syndrome, is an anti-inflammatory drug.
 Half of the women in the study will receive exemestane alone and half will receive exemestane
 and celecoxib together.

 In December 2004, the arm using exemestane and celecoxib was closed to accrual

 Postmenopausal women who are at increased risk for developing invasive breast cancer may be
 eligible to participate. Candidates are screened with breast cancer risk assessment, medical
 history and physical examination, blood tests, review of medical records, if needed, breast
 biopsy, and dual energy x-ray absorptiometry (DEXA) scan to assess bone density. For the DEXA
 scan, the subject lies still on a table for about 30 minutes while the spine and hip are
 scanned using a small amount of radiation.

 Participants take exemestane in pill form once a day for 2 years. They also take calcium and
 vitamin D pills daily to help protect bone health. They are followed in the clinic during the
 course of the study to determine the amount of drug taken and any side effects, and for the
 following tests and procedures:

 -  Medical evaluation and blood tests at after 1 and 3 months on study drugs

 -  Medical evaluation at 6 months

 -  Breast biopsy at screening and then at 12 months

 -  dual-emission x-ray absorptiometry (DEXA) scan of the spine, mammogram and routine blood
 tests before starting study drugs and then yearly for 5 years.
Background:

 Evidence from adjuvant treatment trials of invasive breast cancer with aromatase inhibitors
 suggests that these agents are superior to tamoxifen in preventing contralateral breast
 cancer and are well tolerated. These agents are promising breast cancer chemopreventive
 agents. Data on safety and effect on surrogate biomarkers in a healthy at risk population is
 lacking.

 Objectives:

 Primary:

 -The primary objective is to evaluate the study drug effects on mammographic density after
 one year on treatment.

 Secondary:

 -Secondary objectives include assessing the effect of the intervention on bone mineral
 density, serum hormones and lipids, and breast tissue biomarkers.

 Eligibility:

 Eligible patients are postmenopausal women who meet one of the following criteria:

 -  History of stage I or II breast cancer 2 years out from definitive therapy.

 -  Gail model 5 year risk greater than or equal to 1.7%

 -  History of treated ductal carcinoma in-situ (DCIS)

 -  History of high risk lesion on breast biopsy (atypical ductal hyperplasia (ADH),
 atypical lobular hyperplasia (ALH), lobular carcinoma in-situ (LCIS))

 -  Known or suspected breast cancer 1, early onset (BRCA1) or breasts cancer 2, early onset
 (BRCA2) mutation

 -  Subjects must have adequate bone mineral density by dual-emission x-ray absorptiometry
 (DEXA) scan in order to enroll.

 Design:

 -  This is an open label study of exemestane in postmenopausal women with an elevated risk
 of developing invasive breast cancer. Forty five subjects will be enrolled and receive
 standard dose exemestane (25 mg each day (QD)), calcium and vitamin D.

 -  Each subject will continue treatment for a total of two years.

 -  Changes in mammographic breast density and bone mineral density will be evaluated
 annually which will provide long term biomarker and safety information about prevention
 therapy with exemestane.
-  INCLUSION CRITERIA:

 Postmenopausal female.

 Postmenopausal defined as no menses for at least 12 months or bilateral oophorectomy. In
 unclear cases, (e.g. 50 year old who has had hysterectomy) chemical confirmation of
 postmenopausal status may be confirmed with follicle stimulating hormone (FSH) greater than
 35 U/L.

 Elevated risk for developing invasive breast cancer by virtue of one of the following
 criteria:

 Gail Model risk of greater than or equal to 1.7% over 5 years from study entry. (This is
 the same minimum level of risk required for a subject to be eligible for the recently
 completed NSABP-P1 tamoxifen breast cancer prevention trial).

 Lobular neoplasia.

 Atypical ductal hyperplasia.

 DCIS (ductal carcinoma in situ) that has been previously treated with mastectomy or
 lumpectomy and radiation, +/- tamoxifen.

 Deleterious mutations in BRCA1 or 2 OR A priori risk assessment of 20% chance or greater of
 carrying BRCA1/2 gene mutation. The BRCAPRO and Couch model will both be used to asses this
 risk. If a woman has a 20% risk of carrying a BRCA1/2 mutation by either model, she will
 meet eligibility criteria.

 Prior stage I or II breast cancer at least 2 years out from treatment for invasive disease
 and no prior use of aromatase inhibitors.

 Subjects should be willing to abstain from use of hormonal therapies (e.g. tamoxifen,
 hormone replacement therapy, oral contraceptive pills, hormone-containing intrauterine
 devices (IUDs). E-string is acceptable). Venlafaxine will be offered as supportive care for
 women with menopausal symptoms.

 Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

 Subject has been counseled regarding her options and has signed the informed consent
 document.

 Baseline dual-emission x-ray absorptiometry (DEXA) scan with bone mineral density (BMD)
 T-score greater than or equal to 2.5 at antero posterior (AP) spine.

 Hemoglobin greater than or equal to 11 g/dl.

 Creatinine less than 1.5 times the upper limits of normal.

 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) less than 2.5 times
 upper limit of normal.

 No investigational agent for the past 30 days.

 If history of cancer (other than squamous or basal cell skin cancers), subject must have no
 evidence of disease at time of enrollment AND no history of cancer directed treatment in
 the 2 years preceding enrollment.

 EXCLUSION CRITERIA:

 Current or recent chronic use (within 3 months) of hormonal medications, e.g. oral
 contraceptive pills, hormone replacement therapy, tamoxifen, raloxifene, IUD with
 progestins or corticosteroids. (Subjects on chronic topical or inhaled steroids will be
 eligible for the study.) Current use of phenytoin, carbamazepine, rifampin due to increased
 estrogen metabolism.

 History of clotting or bleeding disorder.

 History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to exemestane (e.g. anastrozole, letrozole, formestane).

 Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, or psychiatric illness/social situations that would limit compliance with study
 requirements.