NIH Stops Trial of Estrogen Plus Progestin Due to Increased Breast Cancer Risk
The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes
of Health (NIH) has stopped part of a major clinical trial early because of
concerns about an increased risk of invasive breast cancer. This part of the
Women's Health Initiative (WHI) was being conducted to evaluate the risks and
benefits of combined estrogen and progestin in healthy menopausal. This large
multi-center trial also found increases in coronary heart disease, stroke, and
pulmonary embolism in study participants on estrogen plus progestin compared
to women taking placebo pills. There were noteworthy benefits of estrogen plus
progestin, including fewer cases of hip fractures and reduced risk of colon
cancer, but on balance, the oversight committee for the study decided that,
the harm of continuing this part of the study was greater than the benefit.
This part of the study, which was scheduled to run until 2005, was stopped after
an average follow-up of 5.2 years. There were 16,608 women in this part of
the WHI study; there were 27,000 women enrolled in the WHI altogether from 1993
Participants in this component of WHI, like most women with a uterus who take
hormone therapy, were given progestin in combination with estrogen. This practice
is known to prevent endometrial cancer. A separate WHI study of estrogen alone
in women who had a hysterectomy before joining the WHI hormone program continues
unchanged because, at this point, the balance of risks and benefits of estrogen
did not cause any major or unexpected safety concerns.
The report from the WHI investigators on the estrogen plus progestin study
findings will be published in the July 17, 2002 issue of The Journal of the
American Medical Association (JAMA); because of the importance of
the information, the study is being released early on Tuesday, July 9, as an
expedited article on the JAMA
"We have long sought the answer to the question: Does postmenopausal hormone
therapy prevent heart disease and, if it does, what are the risks? The bottom-line
answer from WHI is that this combined form of hormone therapy is unlikely to
benefit the heart. The cardiovascular and cancer risks of estrogen plus progestin
outweigh any benefits - and a 26 percent increase in breast cancer risk is too
high a price to pay, even if there were a heart benefit. Similarly, the risks
outweigh the benefits of fewer hip fractures," said NHLBI Director Claude
"Menopausal women who might have been candidates for estrogen plus progestin
should now focus on well-proven treatments to reduce the risk of cardiovascular
disease, including measures to prevent and control high blood pressure, high
blood cholesterol, and obesity. This effort could not be more important: heart
disease remains the number one killer of American women," added Lenfant.
The estrogen plus progestin trial of the WHI involved 16,608 women ages 50
to 79 years with an intact uterus. An important objective of the trial was to
examine the effect of estrogen plus progestin on the prevention of heart disease
and hip fractures, and any associated change in risk for breast and colon cancer.
Importantly, the study did not address the short-term risks and
benefits of hormone replacement therapy (HRT) to treat menopausal symptoms.
About 6 million women in the U.S. are taking estrogen plus progestin for a variety
of reasons, but a recent survey of doctors reported that management of menopausal
symptoms is a treatment goal for 9 out of 10 new patient starts with combination
"Women with a uterus who are currently taking estrogen plus progestin
should have a serious talk with their doctor to see if they should continue
it. If they are taking this hormone combination for short-term relief of symptoms,
it may be reasonable to continue since the benefits are likely to outweigh the
risks. Longer term use or use for disease prevention must be re-evaluated given
the multiple adverse effects noted in WHI," said Jacques Rossouw, MD, acting
director of the WHI.
According to Rossouw, the adverse effects of estrogen plus progestin applied
to all women, irrespective of age, ethnicity, or prior disease status.
"When the estrogen-only trial is completed, a comparison of the results
of these two trials may provide a better idea of the roles of estrogen, compared
to estrogen plus progestin, in health and disease," said Marcia Stefanick,
Ph.D., chair of the WHI Steering Committee and Associate Professor of Medicine,
Stanford University, Palo Alto, California.
Women enrolled in the estrogen plus progestin study were randomly assigned
to a daily dose of estrogen plus progestin (Prempro, 0.625 mg of conjugated
equine estrogens plus 2.5 mg of medroxyprogesterone acetate) or to a placebo.
Participants were enrolled in the study between 1993 and 1998 at over 40 clinical
sites across the country.
In 2000 and again in 2001, WHI investigators complied with a recommendation
from the study's Data and Safety Monitoring Board (DSMB) to inform participants
of a small increase in heart attacks, strokes, and blood clots in women taking
hormones. The DSMB, an independent advisory committee charged with reviewing
results and ensuring participant safety, found that the actual number of women
having any one of these events was small and it did not cross the statistical
boundary established to ensure participant safety. Therefore, the group recommended
continuing the trial due to the still uncertain balance of risks and benefits.
Then, at the DSMB's regularly scheduled meeting on May 31, 2002, the data review
revealed for the first time that the number of cases of invasive breast cancer
in the estrogen plus progestin group had crossed the boundary established as
a signal of increased risk.
"In designing the trial and following the results, the safety of the patients
was of the utmost importance," said Garnet Anderson, Ph.D., a biostatistician
who led the analysis at the Fred Hutchinson Cancer Research Center, Seattle,
Washington. "Because breast cancer is so serious an event, we set the bar
lower to monitor for it. We pre-specified that the change in cancer rates did
not have to be that large to warrant stopping the trial. And the trial was stopped
at the first clear indication of increased risk," she added. She also noted
that, at that point, there was no indication of increased risk for breast cancer
in the estrogen-only (Premarin) group.
The DSMB's May 31 recommendation to stop the trial was based on the finding
of increased breast cancer risk, supported by the evidence of overall health
risks exceeding any benefits. Following the NHLBI's decision to stop the study,
the Institute and the investigators have worked intensively to develop information
materials for participants. On July 8, participants started receiving letters
informing them about the results and telling them that they should stop study
medications. Participants will be contacted by their clinical centers for further
counseling and will continue to have clinic visits so that their health outcomes
can be followed.
All WHI participants, including those in the other study components, are also
receiving a newsletter with a summary of the findings and an explanation of
risks and benefits.
Dr. Rossouw stressed the importance of understanding how the risk to an individual
woman can be low, but the risk to the population at large can be relatively
"The WHI results tell us that during 1 year, among 10,000 postmenopausal
women with a uterus who are taking estrogen plus progestin, 8 more will have
invasive breast cancer, 7 more will have a heart attack, 8 more will have a
stroke, and 18 more will have blood clots, including 8 with blood clots in the
lungs, than will a similar group of 10,000 women not taking these hormones.
This is a relatively small annual increase in risk for an individual woman.
Individual women who have participated in the trial and women in the population
who have been on estrogen and progestin should not be unduly alarmed. However,
even small individual risks over time, and on a population-wide basis, add up
to tens of thousands of these serious adverse health events," explained
The National Cancer Institute (NCI) re-emphasized the recommendation that all
women in their forties and older get screened for breast cancer with mammography
every 1 to 2 years.
"Women in the WHI, women taking hormones for any reason, and any woman
over 40 should remain committed to their regular program of breast cancer screening
to allow the earliest possible detection of breast cancer," said Leslie
Ford, MD, associate director for clinical research in NCI's Division of Cancer
"The reduction in colorectal cancer risk in the WHI is intriguing, but
the balance of harm versus benefit does not justify any woman beginning or continuing
to take estrogen plus progestin for this purpose. NCI has a number of clinical
trials under way investigating new methods to detect and prevent both colorectal
cancer and breast cancer that will provide critical information to help women
make important health decisions," added Ford.
Specific study findings for the estrogen plus progestin group compared to placebo
- A 41 percent increase in strokes
- A 29 percent increase in heart attacks
- A doubling of rates of venous thromboembolism (blood clots)
- A 22 percent increase in total cardiovascular disease
- A 26 percent increase in breast cancer
- A 37 percent reduction in cases of colorectal cancer
- A one-third reduction in hip fracture rates
- A 24 percent reduction in total fractures
- No difference in total mortality (of all causes)
The WHI involves over 161,000 women who are participating in a set of clinical
trials or an observational study. The clinical trials are designed to test promising
but unproven preventive measures for heart disease, breast and colorectal cancer,
and osteoporosis. In addition to the trials of estrogen alone and estrogen plus
progestin, other trials are studying a low-fat eating pattern and calcium/Vitamin
D supplementation. WHI is sponsored by NHLBI in collaboration with four other
components of the NIH - the National Cancer Institute, the National Institute
of Arthritis and Musculoskeletal and Skin Diseases, the National Institute on
Aging, and the Office of Research on Women's Health. Note: Wyeth-Ayerst Research
provided the medication (active hormones and placebo) for the estrogen plus
Message from Dr. Donnica: I do not recommend that any woman
currently taking HRT make any snap decisions about her therapy based upon this
news. I do recommend that any woman having questions about how this news applies
to her should speak with her healthcare provider, and review her own personal
risk--benefit profile. As always, I recommend that all women in their 40's
and above have an annual physical exam, an annual mammogram, and an annual Pap
smear with a rectal exam whether or not they take HRT. During your annual
visit, you should review all current medicines (including non-prescription
products and supplements) with your physician.
For more information about hormone replacement therapy, click here. For more information about the WHI, click
Created: 7/10/2002  - Donnica Moore, M.D.