Study of Breast Cancer Prevention by Letrozole in High Risk Women

Phase 2

Completed

Brief Summary: 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: 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

Recruitment & Eligibility

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.

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo, daily for 6 months
Letrozole	Letrozole	Letrozole, 2.5 mg daily for 6 months

Primary Outcome Measures

Name	Time	Method
Change in Proliferation Rate (Ki-67 by Immunocytochemistry) From Baseline to 6 Months	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.

Secondary Outcome Measures

Name	Time	Method
Assessment of Change in Morphology by the Masood Score.	Baseline to 6 Months	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.
Change in Mammographic Density From Baseline to 6 Months..	Baseline to 6 Months	Percent area of the breast considered to be at increased density, as determined by the computer program Cumulus..