Letrozole in Preventing Breast Cancer in Postmenopausal Women Who Are at Increased Risk for Breast Cancer Due to High Breast Density

OBJECTIVES:

Primary

• Determine the proportion of postmenopausal women who are at increased risk for the development or recurrence of breast cancer, based on high breast density (≥ grade 4), who achieve a decrease in breast density of ≥ 1 grade after treatment with letrozole for 1 year.

Secondary

• Determine whether a decrease in breast density grade is sustained at 1 year in patients treated with this drug.
• Correlate plasma estrogen profile (E1, E1S, E2) with breast density grade at baseline in these patients.
• Determine the percentage of patients with breast tissue hyperplasia and atypical hyperplasia, as assessed by histopathological examination of breast tissue biopsies, before and after treatment with this drug.
• Determine the changes in estrogen profile from baseline, at 1 year, and 1 year after cessation of this drug in these patients.
• Compare changes in predetermined specific parameters of safety at the end of 1 year of treatment with this drug with baseline evaluations of these patients.
• Determine whether modifications of these predetermined specific parameters of safety are sustained 1 year after cessation of treatment with this drug in these patients.
• Determine the general safety of 1 year of treatment with this drug in these patients.
• Compare the effects of this drug on menopause-specific quality of life of these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to breast density grade (4/6 vs 5/6 vs 6/6). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral letrozole once daily for 1 year in the absence of unacceptable toxicity.
• Arm II: Patients receive oral placebo once daily for 1 year in the absence of unacceptable toxicity.

Menopause-specific quality of life is assessed at baseline and then at 12 and 24 months.

After completion of study treatment, patients are followed at 6 months and 1 year.

PROJECTED ACCRUAL: A total of 120 patients (80 in arm I and 40 in arm II) will be accrued for this study within 12 months.

DISEASE CHARACTERISTICS:

• At increased risk for the development or recurrence of breast cancer, as defined by 1 of the following:

• Baseline mammogram indicating mammographic density occupying ≥ 25% (grade 4/6, 5/6, or 6/6) of the breast tissue

• No suspicion of breast cancer, unless subsequently ruled out
• Prior ductal carcinoma in situ (DCIS)

• Untreated disease OR > 6 months since completion of adjuvant endocrine therapy
• Receptor status of lesion is not required
• Prior invasive breast cancer

• Breast cancer must have been surgically removed at time of original diagnosis with no evidence of metastases
• No clinical evidence of breast cancer
• Acceptable quality dual-energy x-ray absorptiometry (DEXA) of the L2-L4 postero-anterior (PA) spine and hip performed within past 6 months

• Bone mass density T-score of either PA spine or hip must be ≥ 2.0 SD below the mean peak bone mass in young normal woman
• Stable chronic leukemia allowed
• Hormone receptor status:

• Hormone receptor-negative, -positive, or -equivocal tumor

PATIENT CHARACTERISTICS:

Age

• Postmenopausal

Sex

• Female

Menopausal status

• Postmenopausal, as defined by 1 of the following:

• Over 55 years of age with spontaneous cessation of menses for ≥ 1 year
• 55 years of age and under with spontaneous cessation of menses for ≤ 1 year, but amenorrheic (e.g., spontaneous or secondary to hysterectomy) AND follicle-stimulating hormone level > 34.4 IU/L
• Bilateral oophorectomy

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Not specified

Cardiovascular

• No recent unstable myocardial infarction
• No prior stroke
• No high blood pressure
• No other uncontrolled cardiovascular disease

Other

• Other prior malignancies without metastatic disease allowed
• Willing and able to complete quality of life questionnaires in either English or French
• No uncontrolled metabolic or endocrine disease
• No malabsorption syndrome

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent immunotherapy

Chemotherapy

• No concurrent chemotherapy

Endocrine therapy

• See Disease Characteristics
• At least 3 months since prior and no concurrent hormone replacement therapy or raloxifene
• At least 6 months since prior tamoxifen
• No concurrent steroid therapy
• No concurrent selective estrogen-receptor modulators
• No other concurrent endocrine or hormonal therapy

Radiotherapy

• Not specified

Surgery

• See Disease Characteristics