Genistein in Preventing Breast Cancer in Women at High Risk for Breast Cancer

Study Overview
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Brief Summary
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This randomized phase II trial is studying how well genistein works in preventing breast cancer in women at high risk for breast cancer. Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. The use of genistein may prevent breast cancer in women at high risk for breast cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. Determine the effect of genistein on the proliferation of breast epithelial cells obtained by fine needle aspiration (FNA), as measured by Ki-67 labeling index, in women who are at high risk for breast cancer. SECONDARY OBJECTIVE: I. Determine the effect of this drug on cellular and molecular parameters using epithelial cells obtained by FNA, nipple aspirate fluid, and blood from these patients. OUTLINE: This is a randomized, double-blind, placebo-controlled study. Patients are stratified according to menopausal status (premenopausal vs postmenopausal) and history of breast cancer (no history of breast cancer vs history of estrogen receptor [ER] positive breast cancer vs history of ER negative breast cancer). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral genistein once daily. ARM II: Patients receive oral placebo once daily. In both arms, treatment continues for up to 6 months in the absence of unacceptable toxicity. After completion of study treatment, patients are followed at 30-37 days.

Official Title
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Phase IIB Trial of G-2535 (Unconjugated Isoflavones-100) in Women at High Risk for Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: placebo
* Drug: genistein
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: No known soy intolerance At increased risk of developing breast cancer in >= 1 previously unaffected breast, as defined by any of the following: Estimated 5-year risk of developing breast cancer using the Gail model, as defined by 1 of the following: Gail score >= 1.66% Gail score >= 0.1% for women age 20-29 years Gail score >= 1.0% for women age 30-39 years Estimated 5-year risk of developing breast cancer using the Claus model: Claus score >= 1.66% Claus score >= 0.1% for women age 20-29 years Claus score >= 1.0% for women age 30-39 years Prior diagnosis of unilateral in situ or invasive breast cancer OR history of atypical hyperplasia, BRCA 1 and/or BRCA 2 positivity History of lobular carcinoma in situ No evidence of breast cancer, as determined by a negative mammogram within the past 6 months and a history and physical No previously diagnosed breast cancer unless all systemic therapy (including endocrine therapy) was completed at least 1 year ago Pre- or postmenopausal ECOG performance status 0-1 Hemoglobin > 10.0 g/dL Platelet count > 100,000/mm^3 Absolute neutrophil count > 1,000/mm^3 Creatinine < 2.0 mg/dL SGPT < 82 U/L SGOT < 68 U/L Bilirubin < 3 mg/dL* [Note: * Patients with a higher level of bilirubin due to a familial metabolism may be eligible at the discretion of the investigator] Life expectancy > 2 years Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception Must be willing to keep a dietary diary No venous thrombosis within the past year No unrecognized or poorly controlled thyroid disease No other cancer within the past 5 years except nonmelanomatous skin cancer or noninvasive cervical cancer No other medical condition that, in the opinion of the investigator, would jeopardize either the patient or the integrity of the data obtained None of the following for >= 2 weeks before the first random fine needle aspiration and during study participation: Oral contraceptives Soy supplements High soy-containing foods Fish oil supplements Multivitamins Vitamins C and E Daily aspirin or nonsteroidal Anti-inflammatory drugs No other concurrent investigational agents No concurrent warfarin or other blood thinners Female patient Exclusion Criteria: Women previously diagnosed with breast cancer will not be eligible unless all systemic therapy (including endocrine therapy) was completed at least one year previously Currently pregnant, or planning to become pregnant during the study period History of venous thrombosis within past year Medical conditions, which, in the opinion of the investigators would jeopardize either the patient or the integrity of the data obtained History of other cancer within the past five years, excluding non-melanomatous skin cancer, and non-invasive cervical cancer Known soy intolerance Unrecognized or uncontrolled thyroid disease, subjects may be on synthroid, but thyroid function must be in normal range or the patient's physician must document that the patient's thyroid is controlled. Currently receiving any other investigational agents Currently on coumadin, or other blood thinners History of breast augmentation implants. Rusults from patients who have <4000 epithelial cells in either the first or the second random Fine-needle aspiration (rFNA) will not be included in the study.

Ages Eligible for Study
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Minimum Age: 25 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: Arm I (genistein)<br>Patients receive oral genistein once daily for up to 6 months. | Drug: genistein<br>* Given orally<br>* Other names: sophoricol;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Placebo Comparator: Arm II (placebo)<br>Patients receive oral placebo once daily for up to 6 months. | Drug: placebo<br>* Given orally<br>* Other names: PLCB;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Breast Epithelial Cell Proliferation as Measured by Ki-67 Labeling | Breast epithelial tissue samples are used to measure the expression of the cell proliferation marker Ki-67, by counting the percentage of positive MIB-1 immunostained cells, denoted the Ki-67 labeling index. Mean change in the Ki-67 labeling index is assessed from baseline to 6 month follow up. | 6 months - baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of Change in Concentration of Epidermal Growth Factor (EGF) Found in Nipple Aspirate Fluid (NAF) | Mean change in the concentration of EGF found in nipple aspirate fluid is assessed from baseline to 6 month follow up. | 6 months - baseline | 
| Change in Cytomorphologic Assessment of Atypia and Spectral Imaging Analysis of Atypica Features in Epithelial Cells. | Cytologic atypia evaluation was performed on Papanicolau stained Thin Prep slides using standard criteria, which were also used for spectral spatial imaging. Cell clusters were used to generate image stacks with the Nuance LCTF-based imaging system (CRI Inc). The image data was collected as percent pixels assigned as atypical. Mean change in the percent pixels assigned atypical is assessed from baseline to 6 month follow up. | 6 months - baseline | 
| Breast Endocrine Environment Measured in Nipple Aspiration Fluid (NAF): Estradiol | Mean change in concentration of estradiol measured in nipple aspiration fluid assessed from baseline to 6 month follow up. | 6 months - baseline | 
| Monitor Drug Delivery by Measuring Plasma Genistein by HPLC | Drug delivery is measured be concentration of genistein in plasma using High Performance Liquid Chromatography (HPLC). Mean change in concentration of plasma genistein is assessed from baseline to 6 month follow up. | 6 months - baseline | 
| Plasma Concentration of Sex Hormone Binding Globulin (SHBG) |  | 6 months - baseline | 
| Breast Endocrine Environment Measured in Nipple Aspiration Fluid (NAF): Cathepsin D | Mean change in concentration of Cathepsin D measured in nipple aspiration fluid assessed from baseline to 6 month follow up. | 6 months - baseline | 
| Breast Endocrine Environment Measured in Nipple Aspiration Fluid (NAF): ps2 | Mean change in concentration of protein ps2 measured in nipple aspiration fluid assessed from baseline to 6 month follow up. | 6 month - baseline |