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

• Sponsor: University of Arizona (Other)
• Overall Status: Completed
• CT.gov ID: NCT02028221
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 151
• Location: 1
• Arms: 2
• Actual Duration (Months): 99.3
• Patients Per Site Per Month: 1.5

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Prevention	Drug: Metformin; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 151 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Phase II Study of Metformin for Reduction of Obesity-Associated Breast Cancer Risk
• Actual Study Start Date: Mar 7, 2014
• Actual Primary Completion Date: Nov 30, 2018
• Actual Study Completion Date: Jun 14, 2022

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 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)	Drug: 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)
Experimental: 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.	Drug: 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.; Other Names: Glucophage Glumetza Fortamet

Outcome Measures

Primary Outcome Measures

1. Change in Breast Density at 6 Months [baseline, 6 months]

   change of dense breast volume at 6 months

2. Change in Breast Density at 12 Months [Baseline, 12 months]

   Change in dense breast volume at 12 months

Secondary Outcome Measures

1. Change From Baseline in Serum Insulin Levels at 6 and 12 Months [baseline, 6 months, 12 months]

2. Change From Baseline in Serum IGF-1 to IGFBP-3 Ratio at 6 and 12 Months [baseline, 6 months, 12 months]

3. Change From Baseline in Serum Testosterone Levels at 6 and 12 Months [baseline, 6 months, 12 months]

4. Change From Baseline in Serum Leptin to Adiponectin Ratio at 6 and 12 Months [baseline, 6 months, 12 months]

5. Change From Baseline in Body Weight at 6 and 12 Months [baseline, 6 months, 12 months]

6. Change From Baseline in Waist Circumference at 6 and 12 Months [baseline, 6 months, 12 months]

7. Change From Baseline in Serum IGF-2 Levels at 6 and 12 Months [baseline, 6 months, 12 months]

Other Outcome Measures

1. Change From Baseline in Plasma Metabolomics Profile at 6 and 12 Months [baseline, 6 months, 12 months]

2. Change From Baseline in Metabolomics Profile in Nipple Aspirate Fluid at 6 and 12 Months [baseline, 6 months, 12 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 54 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona	Tucson	Arizona	United States	85719

Sponsors and Collaborators

• University of Arizona
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Sherry Chow, PhD, University of Arizona

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 4, 2016

More Information

Publications

None provided.

• Responsible Party: University of Arizona
• ClinicalTrials.gov Identifier: NCT02028221
• Other Study ID Numbers: 1300000596; 1R01CA172444-01A1
• First Posted: Jan 7, 2014
• Last Update Posted: Jul 11, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by University of Arizona: Breast cancer prevention; metformin; Breast cancer risk reduction
• Additional relevant MeSH terms: Breast Neoplasms; Metformin

Study Results

Participant Flow

Arm/Group Title	Placebo	Metformin
Arm/Group 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) 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)	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.
Period Title: Overall Study
STARTED	75	76
COMPLETED	62	56
NOT COMPLETED	13	20

Baseline Characteristics

Arm/Group Title	Placebo	Metformin	Total
Arm/Group 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) 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)	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.	Total of all reporting groups
Overall Participants	75	76	151
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.2 (8.6)	39.9 (7.9)	39.5 (7.9)
Sex: Female, Male (Count of Participants)
Female	75 100%	76 100%	151 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	21 28%	34 44.7%	55 36.4%
Not Hispanic or Latino	54 72%	41 53.9%	95 62.9%
Unknown or Not Reported	0 0%	1 1.3%	1 0.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.3%	2 2.6%	3 2%
Asian	1 1.3%	0 0%	1 0.7%
Native Hawaiian or Other Pacific Islander	1 1.3%	0 0%	1 0.7%
Black or African American	4 5.3%	3 3.9%	7 4.6%
White	62 82.7%	64 84.2%	126 83.4%
More than one race	5 6.7%	4 5.3%	9 6%
Unknown or Not Reported	1 1.3%	3 3.9%	4 2.6%
Region of Enrollment (participants) [Number]
United States	75 100%	76 100%	151 100%

Outcome Measures

1. Primary Outcome

Title	Change in Breast Density at 6 Months
Description	change of dense breast volume at 6 months
Time Frame	baseline, 6 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Metformin
Arm/Group 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) 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)	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.
Measure Participants	41	38
Mean (Standard Deviation) [cm^3]	-5.45 (48.91)	-13.71 (56.69)

2. Primary Outcome

Title	Change in Breast Density at 12 Months
Description	Change in dense breast volume at 12 months
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Metformin
Arm/Group 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) 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)	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.
Measure Participants	43	39
Mean (Standard Deviation) [cm^3]	-12.11 (68.11)	-14.75 (47.84)

3. Secondary Outcome

Title	Change From Baseline in Serum Insulin Levels at 6 and 12 Months
Time Frame	baseline, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Change From Baseline in Serum IGF-1 to IGFBP-3 Ratio at 6 and 12 Months
Time Frame	baseline, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Change From Baseline in Serum Testosterone Levels at 6 and 12 Months
Time Frame	baseline, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Change From Baseline in Serum Leptin to Adiponectin Ratio at 6 and 12 Months
Time Frame	baseline, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Change From Baseline in Body Weight at 6 and 12 Months
Time Frame	baseline, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Change From Baseline in Waist Circumference at 6 and 12 Months
Time Frame	baseline, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Change From Baseline in Serum IGF-2 Levels at 6 and 12 Months
Time Frame	baseline, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Change From Baseline in Plasma Metabolomics Profile at 6 and 12 Months
Time Frame	baseline, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Change From Baseline in Metabolomics Profile in Nipple Aspirate Fluid at 6 and 12 Months
Time Frame	baseline, 6 months, 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	12 months
Arm/Group Title	Placebo		Metformin
Arm/Group 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) 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)		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.
All Cause Mortality
	Placebo		Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0%)		0/76 (0%)
Serious Adverse Events
	Placebo		Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/75 (9.3%)		1/76 (1.3%)
Musculoskeletal and connective tissue disorders
Joint range of motion decreased	1/75 (1.3%)		0/76 (0%)
Psychiatric disorders
Delusions	1/75 (1.3%)		0/76 (0%)
Renal and urinary disorders
Renal colic	0/75 (0%)		1/76 (1.3%)
Acute kidney injury	1/75 (1.3%)		0/76 (0%)
Reproductive system and breast disorders
Uterine hemorrhage	1/75 (1.3%)		0/76 (0%)
Uterine pain	1/75 (1.3%)		0/76 (0%)
Respiratory, thoracic and mediastinal disorders
Apnea	1/75 (1.3%)		0/76 (0%)
Pneumonitis	1/75 (1.3%)		0/76 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Metformin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/75 (81.3%)		67/76 (88.2%)
Gastrointestinal disorders
Abdominal pain	6/75 (8%)		2/76 (2.6%)
Bloating	5/75 (6.7%)		6/76 (7.9%)
Constipation	8/75 (10.7%)		5/76 (6.6%)
Diarrhea	15/75 (20%)		28/76 (36.8%)
Dyspepsia	11/75 (14.7%)		14/76 (18.4%)
Flatulence	9/75 (12%)		2/76 (2.6%)
Gastritis	4/75 (5.3%)		2/76 (2.6%)
Gastrointestinal disorders, other	8/75 (10.7%)		8/76 (10.5%)
Gastrointestinal pain	3/75 (4%)		4/76 (5.3%)
Nausea	9/75 (12%)		22/76 (28.9%)
Stomach pain	4/75 (5.3%)		9/76 (11.8%)
Vomiting	8/75 (10.7%)		3/76 (3.9%)
General disorders
Fatigue	2/75 (2.7%)		4/76 (5.3%)
Flu like symptoms	15/75 (20%)		10/76 (13.2%)
Infections and infestations
Bronchial infection	4/75 (5.3%)		2/76 (2.6%)
Otitis media	4/75 (5.3%)		0/76 (0%)
Sinusitis	4/75 (5.3%)		6/76 (7.9%)
Upper respiratory infection	19/75 (25.3%)		12/76 (15.8%)
Urinary tract infection	6/75 (8%)		4/76 (5.3%)
Vaginal infection	4/75 (5.3%)		0/76 (0%)
Injury, poisoning and procedural complications
Bruising	5/75 (6.7%)		2/76 (2.6%)
Investigations
Weight loss	6/75 (8%)		3/76 (3.9%)
Musculoskeletal and connective tissue disorders
Back pain	2/75 (2.7%)		6/76 (7.9%)
Myalgia	3/75 (4%)		4/76 (5.3%)
Nervous system disorders
Dizziness	2/75 (2.7%)		9/76 (11.8%)
Headache	13/75 (17.3%)		16/76 (21.1%)
Psychiatric disorders
Anxiety	4/75 (5.3%)		2/76 (2.6%)
Reproductive system and breast disorders
Breast pain	8/75 (10.7%)		9/76 (11.8%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/75 (1.3%)		4/76 (5.3%)
Cough	4/75 (5.3%)		4/76 (5.3%)
Surgical and medical procedures
Surgical and medical procedures, other	4/75 (5.3%)		4/76 (5.3%)
Vascular disorders
Hypertension	5/75 (6.7%)		1/76 (1.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.