RATIONALE: Letrozole may prevent breast cancer in postmenopausal women with a BRCA1 or BRCA2 mutation.

PURPOSE: This randomized phase III trial is studying letrozole to see how well it works compared with a placebo in preventing breast cancer in postmenopausal women with a BRCA1 or BRCA2 mutation.

OBJECTIVES:

Primary

• Evaluate the reduction of the incidence of invasive breast cancer in postmenopausal women with the BRCA1/BRCA2 mutation treated with letrozole.

Secondary

• Determine the reduction of the incidence of in situ breast cancer in these women.
• Determine the recurrence rate of local or metastatic disease in women who have had breast cancer.
• Determine the incidence of non-breast cancer, especially ovarian, colon, or endometrial cancer.
• Assess the tolerance of this drug in terms of lipid, cardiovascular, and bone effects.
• Determine the quality of life of women treated with this drug.
• Identify serological markers that allow early diagnosis of hereditary predisposition for breast cancer.
• Conduct pharmacogenetic analysis.
• Identify biomarkers or genes involved in the occurrence of cardiovascular and rheumatologic metabolic aromatase inhibitors.
• Study the phenotypic characteristics of cancers that occur during treatment with letrozole, in particular hormonal markers (estrogen and progesterone receptor) and expression profiles of resistance to therapy.

OUTLINE: This is a multicenter study. Patients are stratified according to nature of mutation (BRCA1 vs BRCA2), oophorectomy in premenopausal state (yes vs no), and prior breast cancer (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral letrozole once daily.
• Arm II: Patients receive oral placebo once daily. Treatment in both arms continues for 5 years in the absence of unacceptable toxicity or development of cancer or recurrent disease.

Blood samples are collected periodically for pharmacogenetic studies and analysis of biomarkers or genes associated with hereditary predisposition for breast cancer, toxicities, and resistance to therapy.

After completion of study treatment, patients are followed for 5 years.

DISEASE CHARACTERISTICS:

• Must meet the following criteria:

  • With or without invasive unilateral breast cancer more than 5 years ago, with no recurrence

    • No evidence of breast cancer by mammography or MRI within the past year

  • Carrier of the BRCA1/BRCA2 deleterious mutation (nonsense mutation or stop)

  • Refused preventive mastectomy

• No prior bilateral breast cancer

• No prior bilateral mastectomy

• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

Inclusion criteria:

• Menopausal status as indicated by 1 of the following criteria:

  • Age > 60 years
  • Bilateral oophorectomy
  • Age ≤ 60 years with no hysterectomy or amenorrhea within the past 12 months
  • Age ≤ 60 years with prior hysterectomy or FSH > 20 IU/L

• Eastern Cooperative Oncology Group (ECOG) or WHO performance status 0-1

• absolute neutrophil count (ANC) > 2,000/mm^3

• Platelet count > 100,000/mm^3

• Hemoglobin > 10 g/dL

• Bilirubin normal

• ALT and AST < 2.5 times upper limit of normal

• Creatinine clearance ≥ 60 mL/min

• Adequate cardiovascular function (e.g., no history of myocardial infarction, angina pectoris, or heart failure)

• No osteoporosis by bone density scan (DEXA) within the past 2 years or prior osteoporotic fracture (femur, lumbar spine T score > -2 DS)

Exclusion criteria:

• Invasive cancer diagnosed in the past 5 years, except for basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• Prior cerebrovascular accident
• Prior cardiac ischemia
• Hypersensitivity to letrozole or its excipients, especially titanium oxide
• Renal or hepatocellular insufficiency, cholestasis, or cytolysis
• Geographical, social, or psychological reasons that preclude medical monitoring in this study
• Deprived of liberty or guardianship

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 3 months since prior and no concurrent hormone replacement therapy (e.g., thyroid-stimulating hormone)
• No prior hormonal therapy in the past year
• No concurrent participation in another therapeutic study with an experimental drug

Unicancer will share de-identified individual data that underlie the results reported. A decision concerning the sharing of other study documents, including protocol and statistical analysis plan will be examined upon request.

Unicancer will consider access to study data upon written detailed request sent to Unicancer, from 6 months until 5 years after publication of summary data.

The data shared will be limit to that required for independent mandated verification of the published results, the applicant will need authorization from Unicancer for personal access, and data will only be transferred after signing of a data access agreement.