Exemestane and Celecoxib in Postmenopausal Women at High Risk for Breast Cancer

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.