Bexarotene in Preventing Breast Cancer in Women at Genetic Risk

A Multicenter Randomized Double-Blind Trial Of Targretin Capsules Modifying Immunophenotypic Markers Related To Breast Cancer Progression In Breast Tissue From Genetically Identified High Risk Patients

RATIONALE: Chemoprevention therapy uses certain drugs to try to prevent the development or recurrence of cancer. It is not yet known whether bexarotene is effective in preventing breast cancer.

PURPOSE: Randomized clinical trial to study the effectiveness of bexarotene in preventing breast cancer in women who are at genetic risk of developing breast cancer.

OBJECTIVES:

• Determine whether bexarotene can modify immunophenotypic markers related to breast cancer progression in women at high genetic risk for breast cancer.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to menopausal status (women with a uterus who have not had a menstrual period for more than 1 year vs any woman over 55 years old vs women 55 years and under without a uterus whose follicle-stimulating hormone is in the postmenopausal range). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral bexarotene once daily on days 1-28.
• Arm II: Patients receive oral placebo as in arm I. In both arms, treatment continues in the absence of unacceptable toxicity or elevation of triglycerides to greater than 800 mg/dL. Patients undergo 2 breast biopsies in the same location on days 1 and 29.

Patients are followed at 30 days.

PROJECTED ACCRUAL: A total of 100 patients (50 per treatment arm) will be accrued for this study within 4 years.

DISEASE CHARACTERISTICS:

• Known carrier of a BRCA-1 or BRCA-2 mutation

  • Copy of laboratory report stating results must be available for review OR

• At risk for carrying a BRCA-1 or BRCA-2 mutation

  • At least 10% risk by Parmigiana probability model

• Must have at least 1 breast that has never been involved with cancer and has not been irradiated

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Female

Menopausal status

• Not specified

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• WBC greater than 4,000/mm^3
• Platelet count greater than 100,000/mm^3
• Hematocrit greater than 30%

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• ALT no greater than 1.5 times ULN
• Alkaline phosphatase no greater than 1.5 times ULN
• Albumin no greater than 1.5 times ULN
• No biliary tract disease

Renal

• Creatinine no greater than 1.5 times ULN

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception for 1 month before, during, and for 1 month after study therapy
• Triglycerides normal
• Thyroid-stimulating hormone and thyroxine normal
• Willing to undergo 2 duplicate needle biopsies of the breast
• Willing to undergo genetic testing for BRCA-1 and BRCA-2
• No uncontrolled hyperlipidemia
• No nontoxic goiter or thyroid enlargement
• No severe underlying chronic illness or disease
• No uncontrolled diabetes
• No history of pancreatitis
• No cancer within the past year except skin cancer or carcinoma in situ of the cervix (defined from the date of first diagnosis)
• No concurrent alcohol use (greater than 3 drinks or its equivalent per day)

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• More than 1 year since prior chemotherapy for a neoplasm

Endocrine therapy

• More than 3 months since prior postmenopausal hormonal therapy (including estrogens or progestins)
• More than 3 months since prior tamoxifen or other selective estrogen-receptor modulators
• No concurrent hormone replacement therapy
• Concurrent thyroid hormone supplementation allowed

Radiotherapy

• See Disease Characteristics

Surgery

• Not specified

Other

• More than 30 days since prior investigational medications
• More than 3 months since prior oral vitamin A supplements greater than the recommended daily requirement (5,000 IU) or therapeutic oral or topical vitamin A derivatives (e.g., isotretinoin)
• No concurrent participation in a study of an investigational agent
• No concurrent medications known to be associated with pancreatic toxicity or to increase triglyceride levels