KEEPS Mammographic Density And Breast Health Ancillary Study

Study Overview
=================
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.

Official Title
-----------------
KEEPS Mammographic Density And Breast Health Ancillary Study

Conditions
-----------------
Mammographic Density, Abnormal Mammogram

Intervention / Treatment
-----------------
* Drug: CEE pill
* Drug: Estradiol patch
* Drug: Active Progesterone
* Other: Placebo tablet
* Other: Placebo patch
* Other: Placebo progesterone


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 42 Years
Maximum Age: 58 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CEE pill, active progesterone<br>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 | Drug: CEE pill<br>* Conjugated equine estrogens 0.45 mg/day<br>* Other names: premarin;Drug: Active Progesterone<br>* Prometrium (micronized progesterone USP encapsulated with peanut oil) 200 mg daily for the first 12 days of each month at bedtime<br>Other: Placebo patch<br>* placebo patch<br>|
| Active Comparator: estradiol patch, active progesterone<br>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 | Drug: Estradiol patch<br>* Climara 50 mcg/day<br>* Other names: Climara 50 mcg/day;Drug: Active Progesterone<br>* Prometrium (micronized progesterone USP encapsulated with peanut oil) 200 mg daily for the first 12 days of each month at bedtime<br>Other: Placebo tablet<br>* Placebo tablet<br>|
| Placebo Comparator: placebo<br>Placebo tablet, placebo patch, placebo progesterone | Other: Placebo tablet<br>* Placebo tablet<br>Other: Placebo patch<br>* placebo patch<br>Other: Placebo progesterone<br>* placebo progesterone<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BIRADS Breast Density | Breast density prior to randomization. Frequency of the BIRADS category according to randomization status. BIRADS is a 1-4 category of breast density as assessed by a radiologist. 1= most fatty and least dense, while 4=most dense. | Baseline (Prior to Randomization) | 
| BIRADS Breast Density | Frequency of the BIRADS category 1 year after randomization. BIRADS is a 1-4 category of breast density as assessed by a radiologist. 1= most fatty and least dense, while 4=most dense. | Year 1 | 
| BIRADS Breast Density | Frequency of the BIRADS category 3-4 years after randomization. BIRADS is a 1-4 category of breast density as assessed by a radiologist. 1= most fatty and least dense, while 4=most dense. | Latest (Year 3 of 4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Abnormal Mammogram/Biopsy | Abnormal mammogram requiring additional imaging modality such as MRI or ultrasound, or a breast biopsy. Information obtained from mammography reports. | baseline to 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
mammographic density, abnormal mammogram, biopsy