Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Prevention of Breast Cancer by Letrozole in Post-menopausal Women Carrying a BRCA1/BRCA2 Mutation

Conditions
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Breast Cancer, brca1 Mutation Carrier, brca2 Mutation Carrier, Hereditary Breast/Ovarian Cancer (brca1, brca2)

Intervention / Treatment
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* Drug: letrozole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 69 Years

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>Letrozole, 1 tablet | Drug: letrozole<br> <br> * Other names: Femara;|
| Placebo Comparator: Placebo<br>Comparator, 1 tablet | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival without contralateral or unilateral invasive breast cancer at 5 years (prior breast cancer) |  | 2017 | 
| Survival without invasive breast cancer at 5 years |  | 2017 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive cancer-free survival at 10 years |  | 2022 | 
| Breast cancer in situ-free survival at 5 and 10 years |  | 2022 | 
| Relapse-free (local or metastatic disease) survival in patients with history of breast cancer at 5 and 10 years |  | 2017 and 2022 | 
| Second cancer-free survival at 5 and 10 years |  | 2017 and 2022 | 
| Event- free (local relapse or metastatic, contralateral, or second cancer) survival at 5 and 10 years |  | 2017 and 2022 | 
| Overall survival at 5 and 10 years |  | 2017 and 2022 | 
| Toxicity according to CTCAE version 3.0 |  | 2017 and 2022 | 
| Lipid tolerance or cardiovascular or bone event |  | 2017 and 2022 | 
| Quality of life according to MRS and SF36 questionnaires |  | 2017 and 2022 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, hereditary breast/ovarian cancer (BRCA1, BRCA2), BRCA1 mutation carrier, BRCA2 mutation carrier