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Phase II Study of Metformin for Reduction of Obesity-Associated Breast Cancer Risk

Primary Purpose

Breast Cancer Prevention

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Metformin

Placebo

About this trial

This is an interventional prevention trial for Breast Cancer Prevention focused on measuring Breast cancer prevention, metformin, Breast cancer risk reduction

Eligibility Criteria

21 Years - 54 Years (Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

Premenopausal women
21-54 years of age
Have a BMI of 25 kg/m2 or greater
No change in menstrual patterns for the past 6 months preceding the time of registration
Waist circumference ≥ 35 inches or ≥ 31 inches for Asian Americans, individuals with polycystic ovary syndrome, or individuals with non-alcoholic fatty liver disease.
Have at least one other component of metabolic syndrome (103) reported below:
- Elevated triglycerides (≥ 150 mg/dL (1.7 mmol/L) or on drug treatment for elevated triglycerides
- Reduced HDL-C (< 50 mg/dL (1.3 mmol/L) or on drug treatment for reduced HDL-C
- Elevated blood pressure (≥ 130 Hg systolic blood pressure or ≥85 mm Hg diastolic blood pressure or on antihypertensive drug treatment in a patient with a history of hypertension
- Elevated fasting glucose (≥100 mg/dL)
Mammogram negative for breast cancer within the 12 months preceding the time of registration for women ≥ 50 years of age
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

Postmenopausal women
- Amenorrhea for at least 12 months (preceding the time of registration), or
- History of hysterectomy and bilateral salpingo-oophorectomy, or
- At least 55 years of age with prior hysterectomy with or without oophorectomy, or
- Age 35 to 54 with a prior hysterectomy without oophorectomy OR with a status of ovaries unknown with documented follicle-stimulating hormone level demonstrating elevation in postmenopausal range
Women who are pregnant, planning pregnancy within the next year, or breastfeeding
On treatment with any drug for diabetes
Have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any illness that would limit compliance with study requirements
Have received chemotherapy and/or radiation for any malignancy (excluding non-melanoma skin cancer and cancers confined to organs with removal as only treatment) in the past 5 years (preceding the time of registration)
Have received other investigational agents within the past 3 months (preceding the time of registration)
Have a history of lactic acidosis or risk factors for lactic acidosis
Have significant renal disease or dysfunction (creatinine ≥ 1.4 mg/dL)
Have significant hepatic dysfunction (bilirubin ≥ 1.5 x ULN unless with Gilberts syndrome or AST/ALT ≥ 3 x ULN)
Have a history of alcoholism or high alcohol consumption (average of > 3 standard drinks/day)
Have a history of allergic reactions to metformin or similar drugs
Have a history of severe claustrophobia
Have electrically, magnetically, or mechanically activated implants including cardiac pacemaker, cochlear implants, magnetic surgical clips or prostheses
Have breast implants

Sites / Locations

University of Arizona

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

Metformin

Arm Description

1 tablet daily by mouth X 4 weeks, then 1 tablet twice daily by mouth for the remaining duration of the trial (12 months)

metformin 850 mg 1 tablet taken by mouth daily X 4 weeks, then metformin 850 mg 1 tablet taken twice daily for the remaining duration of he intervention period.

Outcomes

Primary Outcome Measures

Change in Breast Density at 6 Months

change of dense breast volume at 6 months

Change in Breast Density at 12 Months

Change in dense breast volume at 12 months

Secondary Outcome Measures

Change From Baseline in Serum Insulin Levels at 6 and 12 Months

Change From Baseline in Serum IGF-1 to IGFBP-3 Ratio at 6 and 12 Months

Change From Baseline in Serum Testosterone Levels at 6 and 12 Months

Change From Baseline in Serum Leptin to Adiponectin Ratio at 6 and 12 Months

Change From Baseline in Body Weight at 6 and 12 Months

Change From Baseline in Waist Circumference at 6 and 12 Months

Change From Baseline in Serum IGF-2 Levels at 6 and 12 Months

Full Information

NCT ID

NCT02028221

First Posted

January 2, 2014

Last Updated

June 2, 2023

Sponsor

University of Arizona

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT02028221

Brief Title

Phase II Study of Metformin for Reduction of Obesity-Associated Breast Cancer Risk

Official Title

Phase II Study of Metformin for Reduction of Obesity-Associated Breast Cancer Risk

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Completed

Study Start Date

March 7, 2014 (Actual)

Primary Completion Date

November 30, 2018 (Actual)

Study Completion Date

June 14, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Arizona

Collaborators

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Overweight and obesity are well established risk factors for breast cancer that develop after menopause. The increased postmenopausal breast cancer risk in women who are overweight or obese is likely to be attributed to multiple metabolic disturbances. Metformin is a commonly used medication in diabetics to stabilize blood sugar. Association studies and laboratory studies have shown its potential to reduce the risk for development of cancer, including breast cancer. Recent pilot clinical studies in breast cancer patients suggest that metformin may only be effective in overweight or obese women with metabolic disturbances. We propose to conduct a clinical study of metformin in overweight or obese premenopausal women with metabolic disturbances. Study participants will be randomly assigned to receive metformin or placebo for 12 months. The study will evaluate whether metformin can result in favorable changes in risk features that have been associated with increased breast cancer risk. The risk features that will be examined in our study include breast density, certain proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases.

Detailed Description

High adiposity is a major risk factor for a number of chronic diseases, including type 2 diabetes, cardiovascular diseases, and certain types of cancer, including postmenopausal breast cancer. The increased postmenopausal breast cancer risk in women with high adiposity is likely to be attributed to multiple metabolic disturbances including altered circulating sex steroid hormones, hyperinsulinemic insulin resistance, altered expression and secretion of adipokines from adipose tissue, increased production of pro-inflammatory cytokines, and increased oxidative stress. Metformin, a widely used antidiabetic drug, exerts favorable effects on multiple metabolic disturbances which may lead to reduction of breast cancer risk in women with high adiposity. In addition, metformin may exert a direct effect in mammary tissue through the activation of the AMP-activated protein kinase signaling pathway, leading to an antiproliferative effect and induction of apoptosis. Recent case control and cohort studies found that treatment with metformin appears to substantially reduce the risk for development of cancer in diabetics, including breast cancer. There are a number of ongoing clinical trials of metformin in breast cancer patients. However, applicability of these trials to at risk healthy women requires further research and the concurrent or prior cancer treatments in these trials hinder the evaluation of metformin as a single agent for breast cancer risk reduction. In addition, recent clinical and animal studies suggest that metformin may only exert tumor suppressive effects in metabolic phenotypes of high adiposity and metabolic disturbances. A Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have metabolic syndrome will be conducted. This study population is at increased risk for postmenopausal breast cancer and has a high prevalence of metabolic disturbances. The overall objective of this study is to determine its potential effects on reduction of obesity-associated breast cancer risk.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Breast Cancer Prevention

Keywords

Breast cancer prevention, metformin, Breast cancer risk reduction

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

151 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

1 tablet daily by mouth X 4 weeks, then 1 tablet twice daily by mouth for the remaining duration of the trial (12 months)

Arm Title

Metformin

Arm Type

Experimental

Arm Description

metformin 850 mg 1 tablet taken by mouth daily X 4 weeks, then metformin 850 mg 1 tablet taken twice daily for the remaining duration of he intervention period.

Intervention Type

Drug

Intervention Name(s)

Metformin

Other Intervention Name(s)

Glucophage, Glumetza, Fortamet

Intervention Description

metformin 850 mg 1 tablet taken by mouth daily X 4 weeks, then metformin 850 mg 1 tablet taken twice daily for the duration of he intervention period.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

1 tablet daily by mouth X 4 weeks, then 1 tablet twice daily by mouth for the remaining duration of the trial (12 months)

Primary Outcome Measure Information:

Title

Change in Breast Density at 6 Months

Description

change of dense breast volume at 6 months

Time Frame

baseline, 6 months

Title

Change in Breast Density at 12 Months

Description

Change in dense breast volume at 12 months

Time Frame

Baseline, 12 months

Secondary Outcome Measure Information:

Title

Change From Baseline in Serum Insulin Levels at 6 and 12 Months

Time Frame

baseline, 6 months, 12 months

Title

Change From Baseline in Serum IGF-1 to IGFBP-3 Ratio at 6 and 12 Months

Time Frame

baseline, 6 months, 12 months

Title

Change From Baseline in Serum Testosterone Levels at 6 and 12 Months

Time Frame

baseline, 6 months, 12 months

Title

Change From Baseline in Serum Leptin to Adiponectin Ratio at 6 and 12 Months

Time Frame

baseline, 6 months, 12 months

Title

Change From Baseline in Body Weight at 6 and 12 Months

Time Frame

baseline, 6 months, 12 months

Title

Change From Baseline in Waist Circumference at 6 and 12 Months

Time Frame

baseline, 6 months, 12 months

Title

Change From Baseline in Serum IGF-2 Levels at 6 and 12 Months

Time Frame

baseline, 6 months, 12 months

Other Pre-specified Outcome Measures:

Title

Change From Baseline in Plasma Metabolomics Profile at 6 and 12 Months

Time Frame

baseline, 6 months, 12 months

Title

Change From Baseline in Metabolomics Profile in Nipple Aspirate Fluid at 6 and 12 Months

Time Frame

baseline, 6 months, 12 months

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

21 Years

Maximum Age & Unit of Time

54 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Premenopausal women 21-54 years of age Have a BMI of 25 kg/m2 or greater No change in menstrual patterns for the past 6 months preceding the time of registration Waist circumference ≥ 35 inches or ≥ 31 inches for Asian Americans, individuals with polycystic ovary syndrome, or individuals with non-alcoholic fatty liver disease. Have at least one other component of metabolic syndrome (103) reported below: Elevated triglycerides (≥ 150 mg/dL (1.7 mmol/L) or on drug treatment for elevated triglycerides Reduced HDL-C (< 50 mg/dL (1.3 mmol/L) or on drug treatment for reduced HDL-C Elevated blood pressure (≥ 130 Hg systolic blood pressure or ≥85 mm Hg diastolic blood pressure or on antihypertensive drug treatment in a patient with a history of hypertension Elevated fasting glucose (≥100 mg/dL) Mammogram negative for breast cancer within the 12 months preceding the time of registration for women ≥ 50 years of age Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Postmenopausal women Amenorrhea for at least 12 months (preceding the time of registration), or History of hysterectomy and bilateral salpingo-oophorectomy, or At least 55 years of age with prior hysterectomy with or without oophorectomy, or Age 35 to 54 with a prior hysterectomy without oophorectomy OR with a status of ovaries unknown with documented follicle-stimulating hormone level demonstrating elevation in postmenopausal range Women who are pregnant, planning pregnancy within the next year, or breastfeeding On treatment with any drug for diabetes Have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any illness that would limit compliance with study requirements Have received chemotherapy and/or radiation for any malignancy (excluding non-melanoma skin cancer and cancers confined to organs with removal as only treatment) in the past 5 years (preceding the time of registration) Have received other investigational agents within the past 3 months (preceding the time of registration) Have a history of lactic acidosis or risk factors for lactic acidosis Have significant renal disease or dysfunction (creatinine ≥ 1.4 mg/dL) Have significant hepatic dysfunction (bilirubin ≥ 1.5 x ULN unless with Gilberts syndrome or AST/ALT ≥ 3 x ULN) Have a history of alcoholism or high alcohol consumption (average of > 3 standard drinks/day) Have a history of allergic reactions to metformin or similar drugs Have a history of severe claustrophobia Have electrically, magnetically, or mechanically activated implants including cardiac pacemaker, cochlear implants, magnetic surgical clips or prostheses Have breast implants

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sherry Chow, PhD

Organizational Affiliation

University of Arizona

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Arizona

City

Tucson

State/Province

Arizona

ZIP/Postal Code

85719

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

34383179

Citation

Tapia E, Villa-Guillen DE, Chalasani P, Centuori S, Roe DJ, Guillen-Rodriguez J, Huang C, Galons JP, Thomson CA, Altbach M, Trujillo J, Pinto L, Martinez JA, Algotar AM, Chow HS. A randomized controlled trial of metformin in women with components of metabolic syndrome: intervention feasibility and effects on adiposity and breast density. Breast Cancer Res Treat. 2021 Nov;190(1):69-78. doi: 10.1007/s10549-021-06355-9. Epub 2021 Aug 12.

Results Reference

derived

PubMed Identifier

27430256

Citation

Martinez JA, Chalasani P, Thomson CA, Roe D, Altbach M, Galons JP, Stopeck A, Thompson PA, Villa-Guillen DE, Chow HH. Phase II study of metformin for reduction of obesity-associated breast cancer risk: a randomized controlled trial protocol. BMC Cancer. 2016 Jul 19;16:500. doi: 10.1186/s12885-016-2551-3.

Results Reference

derived

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Phase II Study of Metformin for Reduction of Obesity-Associated Breast Cancer Risk

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