Context As endogenous estradiol increases, risk of breast cancer increases.
Raloxifene competes with endogenous estrogen for binding to estrogen receptors
in breast tissue. A woman's estradiol level may alter the effects of raloxifene
on breast cancer and other outcomes.
Objective To test the hypothesis that raloxifene reduces breast cancer risk more
in women with relatively high estradiol levels than in women with very low
Design Analysis of the Multiple Outcomes of Raloxifene Evaluation, a randomized,
double-blind, placebo-controlled trial conducted from 1994 to 1999.
Setting One hundred eighty community settings and medical practices in 25 countries
including the United States.
Participants A total of 7290 postmenopausal women aged 80 years or younger with osteoporosis
who had baseline serum estradiol concentrations measured by a central laboratory
using a sensitive assay. Women with a history of breast cancer or estrogen
use were excluded.
Intervention Participants were randomly assigned to receive 60 mg/d or 120 mg/d of
raloxifene (n = 4843) or matching placebo (n = 2447) for 4 years.
Main Outcome Measure New cases of histopathologically confirmed breast cancer in the treatment
and placebo groups, stratified by estradiol levels.
Results In the placebo group, women with estradiol levels greater than 10 pmol/L
(2.7 pg/mL) had a 6.8-fold higher rate of breast cancer (3.0% per 4 years;
95% confidence interval [CI], 1.8%-4.1%) than that of women with undetectable
estradiol levels (0.6% per 4 years; 95% CI, 0%-1.1%; P
= .005 for trend). Women with estradiol levels greater than 10 pmol/L in the
raloxifene group had a rate of breast cancer that was 76% (95% CI, 53%-88%)
lower than that of women with estradiol levels greater than 10 pmol/L in the
placebo group (absolute rate reduction, 2.2% [95% CI, 1.0%-3.5%; number needed
to treat = 45]). In contrast, women with undetectable estradiol levels had
similar breast cancer risk whether or not they were treated with raloxifene
(risk difference, −0.1%; 95% CI, −0.8% to 0.6%; P = .02 for the interaction). In this cohort, treating women with estradiol
levels greater than 10 pmol/L with raloxifene for 4 years would have avoided
47% of breast cancer cases.
Conclusions Measurement of estradiol level by sensitive assay in postmenopausal
women identifies those at high risk of breast cancer who may benefit most
from raloxifene. If confirmed, this suggests that measuring estradiol and
treating women with high estradiol levels could substantially reduce the rate
of breast cancer among postmenopausal women.