KEEPS Mammographic Density And Breast Health Ancillary Study

NCT ID: NCT02524561

Last Updated: 2017-03-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 517 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-09-30
• Study Completion Date: 2013-12-31

Brief Summary

Combined estrogen and progestin therapy has been shown to increase mammographic density and incidence of breast cancer in randomized trials. The investigators propose to examine the effects of now commonly used low-dose combined hormone therapy (HT) regimens on breast density, rates of abnormal mammogram, and circulating estrogens in the ongoing, already-funded Kronos Early Estrogen Prevention Study (KEEPS). KEEPS is a randomized clinical trial with a primary goal of examining the effects of low-dose transdermal versus oral estrogen combined with cyclic micronized progesterone on progression of subclinical atherosclerosis in recently menopausal women. Prior studies of low-dose HT have been of short duration and small size. By determining the effects of low-dose hormone therapy on the breast, the proposed ancillary study will add important information about the estimated balance of risks and benefits associated with low-dose HT and will help guide future research trials.

Detailed Description

Despite data from clinical trials showing an increased risk of breast cancer and lack of overall benefit for primary prevention with hormone therapy (HT), there is still significant usage of HT by clinicians and women for treatment of moderate-to-severe systemic menopausal symptoms. Due to the possible increased risks with these preparations, current clinical recommendations advocate utilizing the lowest dose for the shortest possible duration, but average duration is often for 2-4 years. However, the effects of commonly used low-dose HT regimens on breast density and breast cancer risk are unknown. Recent data from intervention trials support the long standing hypothesis that hormonal effects on breast cancer risk are mediated through breast density. The Kronos Early Estrogen Prevention Study (KEEPS) is an ongoing, already- funded randomized clinical trial with a primary goal of examining the effects of 4 years of low- dose transdermal versus oral estrogen combined with cyclic micronized progesterone on progression of subclinical atherosclerosis in recently menopausal women. The proposed ancillary study will efficiently examine the effects of randomized low-dose HT on key breast cancer surrogate endpoints: mammographic density and rates of abnormal mammograms. In the parent KEEPS study, a total of 720 women were randomized to oral conjugated equine estrogens (0.45 mg/d), transdermal 17-beta estradiol (50 mcg/d), or placebo, with cyclic micronized progesterone (200 mg for 12 days) for active hormonal therapy groups. All participants were required to have mammography prior to study entry as well as yearly during follow-up; blood samples also were collected at these time points. Randomization was completed in 2008. In this ancillary study, we aimed to collect mammograms from eligible women consenting to be part of the ancillary study(n=517) from baseline, year 1 and year 3 will be obtained and processed centrally to calculate mammographic density. The investigators will determine if these two low-dose HT regimens are associated with change in mammographic density. The investigators will also examine if baseline mammographic density or circulating biomarkers including estradiol, estrone, and estrone sulfate, modify or mediate changes in breast density with HT. In addition, the effects of hormonal regimens on the rates of abnormal mammogram and biopsy will be determined. By determining the effects of low-dose combined HT on the breast, the proposed study will add timely and important information about the estimated balance of risks and benefits associated with low-dose HT and will help guide future research.

Conditions

Mammographic Density; Abnormal Mammogram

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: DOUBLE

Study Groups

CEE pill, active progesterone

Conjugated equine estrogens 0.45 mg/day, placebo patch, Prometrium (micronized progesterone USP encapsulated with peanut oil) 200 mg daily for the first 12 days of each month at bedtime

Group Type: ACTIVE_COMPARATOR

CEE pill

Intervention Type: DRUG

Conjugated equine estrogens 0.45 mg/day

Active Progesterone

Intervention Type: DRUG

Prometrium (micronized progesterone USP encapsulated with peanut oil) 200 mg daily for the first 12 days of each month at bedtime

Placebo patch

Intervention Type: OTHER

placebo patch

estradiol patch, active progesterone

Transdermal estradiol, 50 mcg/day, placebo tablet, Prometrium (micronized progesterone USP encapsulated with peanut oil) 200 mg daily for the first 12 days of each month at bedtime

Group Type: ACTIVE_COMPARATOR

Estradiol patch

Intervention Type: DRUG

Climara 50 mcg/day

Active Progesterone

Intervention Type: DRUG

Prometrium (micronized progesterone USP encapsulated with peanut oil) 200 mg daily for the first 12 days of each month at bedtime

Placebo tablet

Intervention Type: OTHER

Placebo tablet

placebo

Placebo tablet, placebo patch, placebo progesterone

Group Type: PLACEBO_COMPARATOR

Placebo tablet

Intervention Type: OTHER

Placebo tablet

Placebo patch

Intervention Type: OTHER

placebo patch

Placebo progesterone

Intervention Type: OTHER

placebo progesterone

Interventions

CEE pill

Conjugated equine estrogens 0.45 mg/day

Intervention Type: DRUG

Estradiol patch

Climara 50 mcg/day

Intervention Type: DRUG

Active Progesterone

Prometrium (micronized progesterone USP encapsulated with peanut oil) 200 mg daily for the first 12 days of each month at bedtime

Intervention Type: DRUG

Placebo tablet

Placebo tablet

Intervention Type: OTHER

Placebo patch

placebo patch

Intervention Type: OTHER

Placebo progesterone

placebo progesterone

Intervention Type: OTHER

Other Intervention Names

premarin; Climara 50 mcg/day

Eligibility Criteria

Inclusion Criteria

• Women were 42-58 years of age, have had cessation of menses at or after age 40 and no menses for a minimum of 6 and a maximum of 36 months at screening.
• Subjects may or may not have had current vasomotor estrogen deficiency symptoms, had not taken estrogen- or progestogen-containing medication (oral contraceptive or hormone replacement) within 3 months of randomization, and had plasma FSH levels measured at ≥35 ng/ml and plasma E2 levels of <40 pg/ml.

Exclusion Criteria

• Subjects were excluded for increased endometrial thickness on ultrasound >5 mm, unless endometrial biopsy was negative; for LDL ≥ 190 mg/dl or triglycerides ≥ 400 at screening, or use of lipid lowering drugs.

• Minimum Eligible Age: 42 Years
• Maximum Eligible Age: 58 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Kronos Longevity Research Institute

OTHER

Sponsor Role: collaborator

Albert Einstein College of Medicine

OTHER

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: collaborator

Mayo Clinic

OTHER

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: collaborator

University of Utah

OTHER

Sponsor Role: collaborator

University of Washington

OTHER

Sponsor Role: collaborator

Yale University

OTHER

Sponsor Role: collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Rulla Tamimi

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kathy Rexrode, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

Brigham and Women's Hospital

Boston, Massachusetts, United States

Countries

United States

Other Identifiers

R01CA136918

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2009P002326

Identifier Type: -

Identifier Source: org_study_id