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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02028221

Enrollment

151

Registered

2014-01-07

Start date

2014-03-07

Completion date

2022-06-14

Last updated

2023-06-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Breast Cancer Prevention

Keywords

Breast cancer prevention, metformin, Breast cancer risk reduction

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.

Interventions

DRUGMetformin

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.

DRUGPlacebo

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

FEMALE

Age

21 Years to 54 Years

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

Design outcomes

Primary

Measure	Time frame	Description
Change in Breast Density at 6 Months	baseline, 6 months	change of dense breast volume at 6 months
Change in Breast Density at 12 Months	Baseline, 12 months	Change in dense breast volume at 12 months

Secondary

Measure	Time frame
Change From Baseline in Serum IGF-1 to IGFBP-3 Ratio at 6 and 12 Months	baseline, 6 months, 12 months
Change From Baseline in Serum Testosterone Levels at 6 and 12 Months	baseline, 6 months, 12 months
Change From Baseline in Body Weight at 6 and 12 Months	baseline, 6 months, 12 months
Change From Baseline in Waist Circumference at 6 and 12 Months	baseline, 6 months, 12 months
Change From Baseline in Serum IGF-2 Levels at 6 and 12 Months	baseline, 6 months, 12 months
Change From Baseline in Serum Leptin to Adiponectin Ratio at 6 and 12 Months	baseline, 6 months, 12 months
Change From Baseline in Serum Insulin Levels at 6 and 12 Months	baseline, 6 months, 12 months

Other

Measure	Time frame
Change From Baseline in Plasma Metabolomics Profile at 6 and 12 Months	baseline, 6 months, 12 months
Change From Baseline in Metabolomics Profile in Nipple Aspirate Fluid at 6 and 12 Months	baseline, 6 months, 12 months

Countries

United States

Participant flow

Participants by arm

Arm	Count
Placebo 1 tablet daily by mouth X 4 weeks, then 1 tablet twice daily by mouth for the remaining duration of the trial (12 months) Placebo: 1 tablet daily by mouth X 4 weeks, then 1 tablet twice daily by mouth for the remaining duration of the trial (12 months)	75
Metformin 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. Metformin: 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.	76
Total	151

Baseline characteristics

Characteristic	Placebo	Total	Metformin
Age, Continuous	39.2 years STANDARD_DEVIATION 8.6	39.5 years STANDARD_DEVIATION 7.9	39.9 years STANDARD_DEVIATION 7.9
Ethnicity (NIH/OMB) Hispanic or Latino	21 Participants	55 Participants	34 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	54 Participants	95 Participants	41 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	3 Participants	2 Participants
Race (NIH/OMB) Asian	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Black or African American	4 Participants	7 Participants	3 Participants
Race (NIH/OMB) More than one race	5 Participants	9 Participants	4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	4 Participants	3 Participants
Race (NIH/OMB) White	62 Participants	126 Participants	64 Participants
Region of Enrollment United States	75 participants	151 participants	76 participants
Sex: Female, Male Female	75 Participants	151 Participants	76 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 75	0 / 76
other Total, other adverse events	61 / 75	67 / 76
serious Total, serious adverse events	7 / 75	1 / 76

Outcome results

Primary

Change in Breast Density at 12 Months

Change in dense breast volume at 12 months

Time frame: Baseline, 12 months

Population: Analysis was performed on participants who provided baseline and 12-month breast density measures

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change in Breast Density at 12 Months	-12.11 cm^3	Standard Deviation 68.11
Metformin	Change in Breast Density at 12 Months	-14.75 cm^3	Standard Deviation 47.84

Primary

Change in Breast Density at 6 Months

change of dense breast volume at 6 months

Time frame: baseline, 6 months

Population: Analysis was performed on participants who provided baseline and 6 month breast density measures

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change in Breast Density at 6 Months	-5.45 cm^3	Standard Deviation 48.91
Metformin	Change in Breast Density at 6 Months	-13.71 cm^3	Standard Deviation 56.69

Secondary