Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Radiation Induced Cancer

Bone Density Conservation Agents

Antineoplastic Agents

All Drugs and Chemicals

Anticoagulants

Other Dietary Supplements

Tamoxifen

Citric Acid

Sodium Citrate

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Selective Estrogen Receptor Modulators

Estrogen Receptor Modulators

Citrate

Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity.

Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity.

Tamoxifen Citrate

Placebo

Digital mammography

immunohistochemistry staining method

pharmacological study

laboratory biomarker analysis

protein expression analysis

pharmacogenomic studies

questionnaire administration

Fine needle aspiration

Quality of Life Assessment

Smita Bhatia, MD

Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate may fight breast cancer by blocking the use of estrogen by the tumor cells

This phase IIb trial studies how well low-dose tamoxifen citrate works in reducing breast cancer risk in radiation-induced cancer survivors.

PRIMARY OBJECTIVES:

I. To determine the impact of a two-year course of low-dose tamoxifen (tamoxifen citrate) administered at 5 mg per day on surrogate endpoint biomarkers of breast cancer (BC) risk, including: mammographic breast density (MBD), an established radiographic biomarker of BC risk; cytomorphology and proliferative index, tissue biomarkers closely linked to BC risk; and sex steroid hormones and insulin growth factors, circulating biomarkers of BC risk.

II. To establish safety and tolerability of this low-dose tamoxifen regimen, assessing both objective measures (lipid profiles, clotting factors and bone metabolism markers) and patient-reported outcomes.

III. To examine the modifying effect of demographic, clinical, and molecular characteristics on the risk: benefit ratio from this two-year low dose tamoxifen intervention.

IV. To explore the relationship between this low-dose tamoxifen regimen and clinical measures of efficacy (new breast cancer and ductal carcinoma in situ \[DCIS\] diagnoses) and toxicity (thromboembolic events, reports of hot flashes and gynecological symptoms, liver function abnormalities, and other cancer diagnoses).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive tamoxifen citrate orally (PO) once daily for 24 months in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO once daily for 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 10 years.

Low-Dose Tamoxifen Citrate in Reducing Breast Cancer Risk in Radiation-Induced Cancer Survivors

Low-Dose Tamoxifen for Radiation-Induced Breast Cancer Risk Reduction: A Phase IIB Randomized Placebo-Controlled Trial

Mammographic density was quantified as percentage of fibroglandular tissue. Using an intention-to-treat analysis, mammographic breast density (MBD) was compared between patients in the low dose tamoxifen intervention and placebo group by applying the linear mixed effects model for normally distributed data.

IGF1 will be treated as a continuous measure. The linear mixed effects model for between group comparisons of measures from 3 time points will be applied. The unstructured mean model and linear in time model will be employed.

Will be tabulated by treatment arm. Differences by treatment arm will be evaluated using Fisher exact tests.

Total cholesterol, low and high density lipoprotein, triglycerides, and anti-thrombin III enzymatic assay measurements will be treated as continuous variables. Transformed to normality as appropriate, the linear mixed effects model will be applied, using the unstructured mean model and linear in time model to assess the effects of low-dose tamoxifen on these measurements over time.

The number of pills taken out of the total prescribed in a 3-month period will be modeled as a random effects binomial regression model. The binomial rates from 8 time points (month 3-24) will be modeled as unstructured mean model with 7 indicator variables as well as polynomial models over time. The random-intercept and the random intercept and slope models will be considered. The significance of the time indicators or parameters by treatment interaction will be evaluated for treatment difference in compliance.

The outcomes will be scored as a 5-point Likert-type scale (0-4) in response to questions on how much the patients are bothered by certain symptoms. The questionnaire will be administered every 6 months. The responses will be treated as normally distributed, as ordinal or dichotomized variable, and the linear mixed effects of general linear mixed model (GLMM) methods will be applied to compare changes between treatment groups. Piecewise models will also be fitted with join point at 6 months, considering linear and curvilinear trajectories between 6 and 24 month time points.

IGF3 will be treated as a continuous measure. The linear mixed effects model for between group comparisons of measures from 3 time points will be applied. The unstructured mean model and linear in time model will be employed.

Serum bone-specific alkaline phosphatase measurements will be treated as continuous variables. Transformed to normality as appropriate, the linear mixed effects model will be applied, using the unstructured mean model and linear in time model to assess the effects of low-dose tamoxifen on these measurements over time.

Urine n-telopeptide measurements will be treated as continuous variables. Transformed to normality as appropriate, the linear mixed effects model will be applied, using the unstructured mean model and linear in time model to assess the effects of low-dose tamoxifen on these measurements over time.

National Cancer Institute (NCI)

St. Jude Children's Research Hospital

University Health Network, Toronto

University of Michigan

Dana-Farber Cancer Institute

Mayo Clinic

University of Washington

City of Hope National Medical Center

M.D. Anderson Cancer Center

University of Chicago

University of Minnesota

University of Colorado, Denver

Wake Forest University

University of Alabama at Birmingham

Principal Investigator

Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity.

Tamoxifen Citrate: 5 mg PO Daily

Digital mammography: Correlative studies

immunohistochemistry staining method: Correlative Studies

pharmacological study: Correlative Studies

laboratory biomarker analysis: Correlative Studies

protein expression analysis: correlative studies

pharmacogenomic studies: correlative studies

questionnaire administration: Ancillary studies

Fine needle aspiration

Quality of Life Assessment: Ancillary Studies

Arm I (Tamoxifen Citrate)

Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity.

Placebo: 1 tablet daily

Digital mammography: Correlative studies

immunohistochemistry staining method: Correlative Studies

pharmacological study: Correlative Studies

laboratory biomarker analysis: Correlative Studies

protein expression analysis: correlative studies

pharmacogenomic studies: correlative studies

questionnaire administration: Ancillary studies

Fine needle aspiration

Quality of Life Assessment: Ancillary Studies

Arm II (Placebo)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Canada

United States

Region of Enrollment

Slower than expected accrual, and financial constraints of supporting the study drug costs necessitated study closure before attainment of planned study enrollment.

Dr. Smita Bhatia

Mammographic Breast Density

Insulin Growth Factor Levels (IGF1)

Number of Grade 2-4 Toxicities

Total Cholesterol

Low-density lipoprotein

High-density lipoprotein

Triglycerides

Anti-thrombin III

Biomarker Levels

Percentage of Pills Taken Out of the Total Prescribed

Interrupted sleep

General aches or pains

Hot flashes

Joint pain or stiffness

Feeling unusually tired

Heartburn and/or acid stomach

Headaches

Muscle cramps or soreness

Symptoms with \>10% prevalence are reported; patients were dichotomized into 2 groups: those that rated the symptom as moderately or extremely bothersome vs. slightly or quite a bit bothersome

Number of Participants With Different Patient Reported Symptoms, Measured by Questionnaire

Insulin Growth Factor Levels (IGF3 )

Biomarker Levels - Alkaline Phosphatase

Biomarker Levels - Urine N-telopeptide

Overall Study

Nutritional and Metabolic Diseases

Symptoms and General Pathology

Obesity

Hypoglycemic Agents

Metformin

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 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.

Sherry Chow, PhD

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.

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.

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

change of dense breast volume at 6 months

Change in dense breast volume at 12 months

University of Arizona

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.

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

Change in Breast Density at 6 Months

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

Change in Breast Density at 12 Months

Baseline

6 months

12 months

The number of participants analyzed refers to the number of participants with baseline data

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Low-Dose Tamoxifen Citrate in Reducing Breast Cancer Risk in Radiation-Induced Cancer Survivors	NCT01196936	Breast Cancer	Tamoxifen Citra... Placebo Digital mammogr... immunohistochem... pharmacological... laboratory biom... protein express... pharmacogenomic... questionnaire a... Fine needle asp... Quality of Life...	25 Years -	University of Alabama at Birmingham
Phase II Study of Metformin for Reduction of Obesity-Associated Breast Cancer Risk	NCT02028221	Breast Cancer P...	Metformin Placebo	21 Years - 54 Years	University of Arizona
Low-Dose Tamoxifen Citrate in Reducing Breast Cancer Risk in Radiation-Induced Cancer Survivors	NCT01196936	Breast Cancer	Tamoxifen Citra... Placebo Digital mammogr... immunohistochem... pharmacological... laboratory biom... protein express... pharmacogenomic... questionnaire a... Fine needle asp... Quality of Life...	25 Years -	University of Alabama at Birmingham

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