Letrozole in Preventing Breast Cancer in Healthy Postmenopausal Women at High Risk for Breast Cancer

Study Overview
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Brief Summary
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This randomized phase I trial studies the side effects and the best dose of letrozole in preventing breast cancer in healthy postmenopausal women at high risk for breast cancer. Chemoprevention is the use of drugs to keep breast cancer from forming or coming back. The use of letrozole may keep cancer from forming in healthy postmenopausal women at high risk for breast cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Compare the effect of lower and intermittent doses of letrozole to standard letrozole therapy on estrogen suppression in postmenopausal women at high risk for developing breast cancer. SECONDARY OBJECTIVES: I. Comparison of the effect of lower and intermittent doses of letrozole to standard therapy on signs and symptoms of estrogen deficiency, including menopausal symptoms, serum lipid profile, and serum marker of bone turnover. II. Comparison of the effect of lower and intermittent doses of letrozole to standard therapy on nuclear chromatin abnormality of breast epithelial cells collected by random periareolar fine needle aspiration (RPFNA). TERTIARY OBJECTIVES: I. Determine the prevalence of breast cancer stem cells in the fine needle breast aspirates and explore the potential intervention effect on the prevalence of breast cancer stem cells. OUTLINE: Patients are randomized to 1 of 4 treatment arms. ARM I: Patients receive 2.5 mg of letrozole orally (PO) thrice weekly for 6 months. ARM II: Patients receive 1.0 mg of letrozole PO thrice weekly for 6 months. ARM III: Patients receive 0.25 mg of letrozole PO thrice weekly for 6 months. ARM IV: Patients receive 2.5 mg of letrozole PO once daily for 6 months. After completion of study treatment, patients are followed up at week 30.

Official Title
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Phase I Dose-Finding Trial of Letrozole in Postmenopausal Women at High Risk for Breast Cancer

Conditions
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Healthy, no Evidence of Disease, Lobular Breast Carcinoma in Situ

Intervention / Treatment
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* Drug: letrozole
* Other: quality-of-life assessment
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy postmenopausal women at high risk for breast cancer will be eligible for the study; definition of menopause will be: Amenorrhea for at least 12 months, or History of hysterectomy and bilateral salpingo-oophorectomy, or At least 55 years of age with prior hysterectomy with or without oophorectomy, or Age 35 to 54 with a prior hysterectomy without oophorectomy OR with a status of ovaries unknown with documented follicle-stimulating hormone level demonstrating elevation in postmenopausal range High risk for breast cancer will be defined as: Prior histologically confirmed lobular carcinoma in situ (LCIS) treated by local excision only, or At least 1.66% probability of invasive breast cancer within 5 years using the Breast Cancer Risk Assessment Tool Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; Karnofsky 80% or above Leukocytes >= 3,000/uL Absolute neutrophil count >= 1,500/uL Platelets >= 100,000/uL Total bilirubin =< 2.0 mg/dL Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 X institutional ULN Creatinine =< 1 X institutional ULN Recent mammogram negative for breast cancer, Breast Imaging-Reporting and Data System (BIRADS) score < 3 (within the last 12 months) Ability to understand and the willingness to sign a written informed consent document; only potential participants with the ability to understand and the willingness to sign a written document will be presented with an informed consenting document Exclusion Criteria: Women diagnosed with osteoporosis (previously or on screening dual-energy X-ray absorptiometry [DEXA] for this study) and not on a stable dose of long or short-acting bisphosphonates therapy for at least 3 months will be excluded from the study; women diagnosed with osteoporosis and on raloxifene (Evista) therapy will be excluded from the study; use of calcium and/or vitamin D for osteoporosis prevention or treatment is allowed; women with osteopenia will be allowed to participate in this study Have had invasive cancer within the past five years except non-melanoma skin cancer Evidence of suspicious of malignant disease on bilateral mammogram within the past year unless ruled out by further evaluation History of prior invasive breast cancer or intraductal carcinoma in situ, or history of prior radiation therapy to the chest or breast Participants may not be receiving any other investigational agents; participants may not be concurrently enrolled in another breast cancer prevention intervention trial History of allergic reactions attributed to compounds of similar chemical or biologic composition to letrozole Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Within 3 months since prior estrogen or progesterone replacement therapy, oral contraceptives, androgens, luteinizing hormone-releasing hormone analogs, prolactin inhibitors, or antiandrogens Within 3 months since prior tamoxifen, raloxifene, or other selective estrogen-receptor modulators Within 3 months since regular use (more than 2 times a week) of prior estrogenic supplements or herbal remedies History of bleeding or clotting disorder; current or recent (within 3 months) use of Coumadin, Plavix or other systemic anticoagulant other than aspirin is not permitted if subject chooses to participate in the optional RPFNA procedure; if a subject chooses not to participate in the RPFNA procedure, prior or current treatment with systemic anticoagulants is permitted

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (2.5 mg letrozole)<br>Patients receive 2.5 mg of letrozole PO thrice weekly for 6 months. | Drug: letrozole<br>* Given orally<br>* Other names: LTZ;Other: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm II (1.0 mg letrozole)<br>Patients receive 1.0 mg of letrozole PO thrice weekly for 6 months. | Drug: letrozole<br>* Given orally<br>* Other names: LTZ;Other: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm III (0.25 mg letrozole)<br>Patients receive 0.25 mg of letrozole PO thrice weekly for 6 months. | Drug: letrozole<br>* Given orally<br>* Other names: LTZ;Other: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Arm IV (2.5 mg letrozole)<br>Patients receive 2.5 mg of letrozole PO once daily for 6 months. | Drug: letrozole<br>* Given orally<br>* Other names: LTZ;Other: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of serum estradiol suppression in postmenopausal women at high risk for breast cancer | Three one-sided two-sample t-tests will be conducted on the ratios of the mean percentage of suppression simultaneously to test for non-inferiority. A multivariate t-distribution is used to derive the critical value and the power. | Baseline to week 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum estrone levels | Three one-sided two-sample t-tests will be performed to evaluate the ratio of the mean changes (or percentage of changes) of each of the three intermittent dosing groups to that of the standard therapy control group simultaneously for each of the endpoints at an overall significance level of 5%. | Baseline to week 30 | 
| Change in serum testosterone levels | Three one-sided two-sample t-tests will be performed to evaluate the ratio of the mean changes (or percentage of changes) of each of the three intermittent dosing groups to that of the standard therapy control group simultaneously for each of the endpoints at an overall significance level of 5%. | Baseline to week 30 | 
| Menopausal symptoms as assessed by quality of life measures, as assessed by Medical Outcomes Study 36-item Short Form Health Survey (SF-36) and Menopause Specific Quality of Life Questionnaire (MENQOL) |  | Up to week 30 | 
| Nuclear chromatin abnormality as assessed by karyometry |  | Up to week 30 |