Study of Breast Cancer Prevention by Letrozole in High Risk Women

Study Overview
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Brief Summary
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This is a multi-institution double-blind placebo-controlled trial whose main objective is to determine if 6 months of letrozole (2.5 mg daily) can reduce proliferation as assessed by Ki-67 in high risk postmenopausal women on systemic hormone replacement therapy who have random periareolar fine needle aspiration (RPFNA) evidence of hyperplasia with atypia or borderline atypia, and a minimum Ki-67 of >1.5%. The primary hypothesis is that proliferation and expression of other estrogen response genes will be favorably modulated by six months of letrozole relative to placebo without substantially increasing hot flashes or worsening overall quality of life.

Detailed Description
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Subsequent to the 6 month RPFNA for assessment of biomarkers, toxicity and quality of life assessments, all women may receive optional open-label letrozole for an additional 6 months, followed by a third RPFNA and biomarker

Official Title
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Study of Breast Cancer Prevention by Letrozole in High Risk Women

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Letrozole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Post-menopausal women at high risk for development of breast cancer stable dose of hormone replacement therapy have cytomorphologic evidence of hyperplasia +/- atypia and Ki-67 expression >1.5% in benign breast epithelial cells acquired by RPFNA Serum level of 25-hydroxyvitamin D of at least 30 ng/ml prior to study entry Willing to have a repeat random periareolar fine needle aspiration (RPFNA) and mammogram at 6 months and 12 months (if participating in the open label portion of the study) following initiation of study drug Exclusion Criteria: Prior history of osteoporosis or osteoporotic fracture. Prior history of invasive breast cancer or other invasive cancer within five years from date of study entry. Current and chronic use of cyclooxygenase-2 (COX-2) specific inhibitors or NSAIDs Receiving treatment for rheumatoid arthritis or fibromyalgia Current history of poorly controlled migraines or perimenopausal symptoms Currently receiving other investigational agents. Receipt of more than 6 months of an aromatase inhibitor (anastrozole, exemestane, letrozole, etc.) at any time in the past.

Ages Eligible for Study
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Minimum Age: 30 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Letrozole<br>Letrozole, 2.5 mg daily for 6 months | Drug: Letrozole<br>* Letrozole 2.5 mg tablet daily. Then optional open label letrozole for another 6 months.<br>* Other names: Letrozole(Femara);|
| Placebo Comparator: Placebo<br>Placebo, daily for 6 months | Drug: Placebo<br>* Placebo tablet daily for 6 months then optional open label letrozole for 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Proliferation Rate (Ki-67 by Immunocytochemistry) From Baseline to 6 Months | Change in proliferation rate (percent positively stained cells for Ki-67 antigen by immunocytochemistry) in benign breast epithelial cells acquired by random periareolar fine needle aspiration (RPFNA) from women at high risk for the development of breast cancer. | Baseline to 6 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Change in Morphology by the Masood Score. | Masood score is a semi-quantitative index of increasing abnormality, thus higher values are worse. Range 6 to 24. Based on Masood S, Frykberg ER, McLellan GL, Scalapino MC, Mitchum DG, Bullard JB. Prospective evaluation of radiologically directed fine-needle aspiration biopsy of nonpalpable breast lesions. Cancer 1990; 66:1480-7. | Baseline to 6 Months | 
| Change in Mammographic Density From Baseline to 6 Months.. | Percent area of the breast considered to be at increased density, as determined by the computer program Cumulus.. | Baseline to 6 Months |