KEEPS Mammographic Density And Breast Health Ancillary Study

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 KEEPS, 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, digital mammograms (available on 510
participants) from baseline, year 1 and year 3 will be obtained and processed centrally to
calculate mammographic density. We will determine if these two low-dose HT regimens are
associated with change in mammographic density. We 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.

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.