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

Phase 2

Completed

Conditions: Breast Cancer

Interventions: Drug: genistein
Drug: placebo
Other: laboratory biomarker analysis

Registration Number: NCT00290758

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 126

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (genistein)	genistein	Patients receive oral genistein once daily for up to 6 months.
Arm I (genistein)	laboratory biomarker analysis	Patients receive oral genistein once daily for up to 6 months.
Arm II (placebo)	placebo	Patients receive oral placebo once daily for up to 6 months.

Primary Outcome Measures

Name	Time	Method
Change in Breast Epithelial Cell Proliferation as Measured by Ki-67 Labeling	6 months - baseline	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.

Secondary Outcome Measures

Name	Time	Method
Change in Cytomorphologic Assessment of Atypia and Spectral Imaging Analysis of Atypica Features in Epithelial Cells.	6 months - baseline	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.
Breast Endocrine Environment Measured in Nipple Aspiration Fluid (NAF): Estradiol	6 months - baseline	Mean change in concentration of estradiol measured in nipple aspiration fluid assessed from baseline to 6 month follow up.
Plasma Concentration of Sex Hormone Binding Globulin (SHBG)	6 months - baseline
Measurement of Change in Concentration of Epidermal Growth Factor (EGF) Found in Nipple Aspirate Fluid (NAF)	6 months - baseline	Mean change in the concentration of EGF found in nipple aspirate fluid is assessed from baseline to 6 month follow up.
Monitor Drug Delivery by Measuring Plasma Genistein by HPLC	6 months - baseline	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.
Breast Endocrine Environment Measured in Nipple Aspiration Fluid (NAF): Cathepsin D	6 months - baseline	Mean change in concentration of Cathepsin D measured in nipple aspiration fluid assessed from baseline to 6 month follow up.
Breast Endocrine Environment Measured in Nipple Aspiration Fluid (NAF): ps2	6 month - baseline	Mean change in concentration of protein ps2 measured in nipple aspiration fluid assessed from baseline to 6 month follow up.