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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Trial of Exemestane in Postmenopausal Women With DCIS or at High Risk for Invasive Breast Cancer

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Exemestane
* Dietary Supplement: Calcium carbonate
* Dietary Supplement: Vitamin D


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exemestane<br>exemestane 25 mg by mouth (PO) every day for two years taken with calcium carbonate 1200 mg PO every day and vitamin D 400 IU PO every day Initially patients were initially planned to receive Celecoxib but the study was amended prior to any subject going on and Celecoxib was never administered to any subjects. | Drug: Exemestane<br>* exemestane 25 mg by mouth (PO) every day for two years<br>* Other names: Aromasin;Dietary Supplement: Calcium carbonate<br>* calcium carbonate 1200 mg PO every day x 2 years<br>Dietary Supplement: Vitamin D<br>* Vitamin D 400 international units PO every day x 2 years<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change in Mammographic Density at 1 Year on Exemestane |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of This Drug on Bone Mineral Density |  | 1 year | 
| Change in Breast Density at 2 Years |  | 2 years | 
| Effect of This Drug on Serum Hormones, Insulin-like Growth Factor Pathway Components, and Leptin at 3 Months and 1 Year |  | 3 months and 1 year | 
| Absolute Change of Lipid Profiles on Exemestane From Baseline |  | 1 year | 
| Effect of This Drug on Breast Tissue Trefoil Factor 1 and Proliferating Cell Nuclear Antigen Expression, Prolactin, and Breast Tissue Prolactin Receptor at 1 Year |  | 1 year | 
| Effect of Exemestane on Autocrine Prolactin and Breast Tissue Prolactin Receptor at One Year |  | 1 year | 
| Number of Serum and Breast Tissue Samples Collected for Exploratory Proteomic Profiles at One Year |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chemoprevention, Mammographic Density, Bone Mineral Density, Biomarkers, Safety, Breast Cancer, Postmenopausal