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

• Percentage change of the BMD parameters from baseline BMD values [ Time Frame: 7 years ] [ Designated as safety issue: No ]
• Percentage change of bone biomarker measurements (serum bone alkaline phosphatase and urine N-telopeptide) from baseline values [ Time Frame: 7 years ] [ Designated as safety issue: No ]

RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. The use of letrozole may stop cancer from forming or coming back in postmenopausal women who are at increased risk for breast cancer due to high breast density.

PURPOSE: This randomized phase II trial is studying how well letrozole works 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.

• Drug: letrozole
  2.5 mg PO daily for 1 year
• Other: Placebo
  2.5 mg PO daily for one 1 year

• Active Comparator: Letrozole
  Intervention: Drug: letrozole
• Placebo Comparator: Placebo
  Intervention: Other: Placebo

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