|WHI Updated Analysis: No Increased Risk of Breast
Cancer with Estrogen-Alone
Estrogen-alone hormone therapy does not increase the risk of breast
cancer in postmenopausal women, according to an updated analysis
of the breast cancer findings of the Women’s Health Initiative
(WHI) Estrogen-Alone Trial.
The results contrast with the previously reported WHI Estrogen
plus Progestin Trial, which found an increase in breast cancer
over about 5 years among those taking combined hormone therapy.
The WHI is sponsored by the National Heart, Lung, and Blood Institute
(NHLBI) of the National Institutes of Health. The new analysis
is published in the April 12 issue of the Journal of the American
Over an average of about 7 years of follow-up, study participants
taking estrogen had fewer breast cancer tumors than those in the
placebo group. Women in the estrogen group were diagnosed with
breast cancer at a rate of 28 per 10,000 participants per year
versus a rate of 34 per 10,000 participants per year in the placebo
group. The difference in rates of breast cancer (6 per 10,000)
between the groups was not statistically significant, meaning it
could have occurred by chance.
The new analysis also found that participants taking estrogen
had 50 percent more abnormal mammograms that required follow-up
and underwent 33 percent (747 compared to 549) more breast biopsies.
An abnormal mammogram does not necessarily signal cancer — as shown
in this study’s results.
“Longer follow-up is needed to fully explain the reduced number
of breast cancers in women taking estrogen. However, this new analysis
does not alter the overall conclusion from the WHI that hormones,
including estrogen-alone and estrogen plus progestin, should not
be used for the prevention of chronic disease,” said NHLBI Director
and WHI Director Elizabeth G. Nabel, M.D. “The findings still support
current recommendations that hormone therapy should only be used
to treat menopausal symptoms and should be used at the smallest
effective dose for the shortest possible time.”
The WHI Estrogen-Alone Trial was stopped at the end of February
2004 because of an increased risk of stroke and no significant
effect on heart disease. The trial also found that estrogen increased
the risk of blood clots in the legs, reduced the risk of hip fractures
and had no significant effect on colorectal cancer. A separate
report on the WHI memory study found estrogen increased memory
problems. The WHI Estrogen Plus Progestin study was stopped in
2002 because of an increased risk of breast cancer and because,
overall, risks from use of the hormones outweighed the benefits.
The combination therapy increased the risk for heart attack, stroke,
and blood clots but also reduced the risk for hip and other fractures,
and colorectal cancer.
When the WHI Estrogen-Alone Trial findings were published in April
2004, the effect on invasive breast cancer was uncertain. At that
time, 218 cases of breast cancer had been reported among all estrogen
study participants and there was no in-depth analysis yet of the
cancers. The new report provides a more detailed analysis of 237
invasive breast cancers and of the mammograms in the two study
The Estrogen-Alone Trial involved 40 clinical centers and 10,739
generally healthy postmenopausal women ages 50-79 who did not have
a uterus. Estrogen-alone (without progestin) is only recommended
for women without a uterus; women with a uterus who take estrogen
have an increased risk of endometrial cancer, so they are now advised
to take estrogen combined with progestin. Participants were enrolled
in the study between 1993 and 1998 with 5310 women assigned to
active estrogen (0.625 mg/day of conjugated equine estrogens) and
5429 assigned to placebo. About 35 percent of the women had used
hormone therapy prior to the study and about 13 percent were using
hormones at the time they enrolled, but they had to be off of hormones
for at least 3 months prior to starting the trial.
Subgroup analyses found that women who had a low risk of breast
cancer — no family history, no benign breast disease, etc. — had
fewer breast cancers on estrogen, while those with higher risk
had more breast cancers on estrogen compared to placebo.
“This finding underscores the need to individualize treatment
for menopause symptoms based on a woman’s medical history and her
risk profile,” said WHI Project Officer Jacques Rossouw, M.D.
Women in the estrogen group tended to have larger tumors that
were likely to have spread to lymph nodes, a finding that suggests
estrogen might reduce the risk of smaller tumors but not larger
ones, or that smaller tumors are not diagnosed early due to changes
in breast tissue. Another subgroup analysis suggested that for
participants taking estrogen, ductal carcinomas that occur in the
milk ducts of the breast were reduced to a greater extent than
lobular carcinomas, which form in the glands where breast milk
is made. It is unknown whether any effects on breast tumors will
persist over time.
According to Stanford University’s Marcia Stefanick, Ph.D., the
study’s lead author and chair of the WHI Steering Committee, the
study improves understanding of the role of estrogen therapy in
breast cancer, though more research is needed to explain the subgroup
findings. “What is clear now is that, overall, postmenopausal women
without a uterus who choose to take estrogen-alone do not have
an increased breast cancer risk, at least over the first 7 years
of treatment. This is clinically relevant, but women who are taking
estrogen should also be aware that they will likely need more repeat
mammograms and more breast biopsies,” she said.
Rossouw said more research is needed on the role of progestin.
Participants in the Estrogen-Alone and Estrogen Plus Progestin
trials began at the same level of risk for breast cancer. According
to Rossouw, the increased risk of breast cancer found in women
taking combined hormones may be due to the effects of progestin — when
it is combined with estrogen.
To interview an NHLBI spokesperson, contact the NHLBI Communications
Office at (301) 496-4236; to interview Dr. Stefanick, call Susan
Ipaktchian, Office of Communications & Public Affairs at Stanford
University School of Medicine at (650) 725-5375. To interview a
cancer expert, call the National Cancer Institute Media Relations
Branch at (301) 496-6641.
Part of the National Institutes of Health, the National Heart,
Lung, and Blood Institute (NHLBI) plans, conducts, and supports
research related to the causes, prevention, diagnosis, and treatment
of heart, blood vessel, lung, and blood diseases; and sleep disorders.
The Institute also administers national health education campaigns
on women and heart disease, healthy weight for children, and other
topics. NHLBI press releases and other materials are available
online at: www.nhlbi.nih.gov.
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Medical Research Agency — includes 27 Institutes and
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