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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: placebo; Drug: genistein

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.

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (genistein); Patients receive oral genistein once daily for up to 6 months.	Other: laboratory biomarker analysis; Correlative studies; Drug: genistein; Given orally; Other Names: CI 75610; genisteol; genisterin; prunetol; sophoricol
Placebo Comparator: Arm II (placebo); Patients receive oral placebo once daily for up to 6 months.	Drug: placebo; Given orally; Other Names: PLCB

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Khan SA, Chatterton RT, Michel N, Bryk M, Lee O, Ivancic D, Heinz R, Zalles CM, Helenowski IB, Jovanovic BD, Franke AA, Bosland MC, Wang J, Hansen NM, Bethke KP, Dew A, Coomes M, Bergan RC. Soy isoflavone supplementation for breast cancer risk reduction: a randomized phase II trial. Cancer Prev Res (Phila). 2012 Feb;5(2):309-19. doi: 10.1158/1940-6207.CAPR-11-0251.

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): March 1, 2009
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: February 9, 2006
• First Submitted That Met QC Criteria: February 9, 2006
• First Posted (Estimate): February 13, 2006

Study Record Updates

• Last Update Posted (Estimate): February 8, 2017
• Last Update Submitted That Met QC Criteria: December 14, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protective Agents; Estrogens, Non-Steroidal; Estrogens; Protein Kinase Inhibitors; Anticarcinogenic Agents; Phytoestrogens; Genistein
• Other Study ID Numbers: NCI-2009-00840 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); N01CN35157 (U.S. NIH Grant/Contract); CDR0000652922; NCI-04B3 (Other Identifier: Northwestern University); NWU03-1-04 (Other Identifier: DCP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO