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Using follow-up data from 46,000 women who participated in the Breast Cancer
Detection Demonstration Project (BCDDP), a nationwide breast cancer screening
program conducted between 1973 and 1980, the scientists found that compared to
non-users, the relative risk for breast cancer increased by 8 percent per year for the
estrogen-progestin therapy compared to 1 percent for estrogen therapy alone in
women who had used hormones during the previous four years. There was no
increase in risk among women who had stopped either therapy for more than four
years. (Relative risk calculates the risk of developing breast cancer in the group of
women taking hormones compared to that of women not on therapy.) For women
who had used hormones during the previous four years, the average length of use was
3.6 years for the estrogen-progestin therapy compared to 10.3 years for estrogen
When the scientists looked at subgroups of women, they found increases in risk
associated with hormone replacement therapy among lean women, but not heavy
women. Compared to non-users, among lean women the rate of breast cancer
increased by 12 percent for each year of estrogen-progestin use compared to 3
percent for estrogen alone. (Leanness was measured by body mass index, BMI,
which takes into account both height and weight. See
http://www.shapeup.org/bmi/index.html. The women at increased risk in this study had
a BMI of 24.4. or less.)
For lean women, the researchers also found that the longer a woman used the
hormones, the more likely she was to develop breast cancer. In contrast, short-term
use was not associated with increased risks.
“These results, as well as those from other studies, suggest that women who take
hormones for two to three years for relief of menopausal symptoms are not at
increased risk of breast cancer,” said Catherine Schairer, Ph.D., first author of the
study from NCI’s Division of Cancer Epidemiology and Genetics, Bethesda, Md.
The data for the current study was collected between 1980-1995 by follow-up
telephone interviews and questionnaires of participants in the original BCDDP. The
study focused on women who took hormone pills; those reporting hormone use in the
form of shots, creams, or patches were excluded. Eighty-six percent of the
participants were white, 5 percent black, 2 percent Hispanic, and 5 percent
Asian-Americans. The increased risk was largely limited to lean women who had
taken the combined therapy for longer periods of time, including the last four years of
the study. Those who had stopped hormone use more than four years prior to the
diagnosis of breast cancer had about the same risk as non-users.
Estrogen therapy became available for menopausal women in the 1940s, and was
administered then in high doses without progestin. In the l970s, however, it became
clear that women who received estrogen alone had a six to eight times higher risk of
developing cancer of the endometrium (the lining of the uterus) than non-users. Since
then, researchers have found that the addition of progestin to estrogen reduces the risk
of endometrial cancer. As a result, it has become increasingly common to prescribe
estrogen-progestin replacement therapy for women who have not had a hysterectomy
(surgery to remove the uterus).
Reliable data on the effects of estrogen-progestin therapy on breast cancer risk are
only recently available. Three studies – the pooled analysis of more than 90 percent of
the world’s epidemiological data that appeared in 1997, a preliminary updated report
in1998 from the Nurses’ Health Study, and an updated analysis from a Swedish study
suggest that the estrogen-progestin regimen is associated with greater increases in
breast cancer risk than estrogen alone, consistent with the current study.
The current study, however, differs in certain aspects from others. The authors found
that hormone replacement therapy among lean women was associated with increases in
both early and later stage invasive disease whereas in the 1997 pooled analysis
increases in risk were greater for localized rather than distant or later-stage disease.
However, the 1997 report did not look at the extent of disease in lean women.
In addition, Schairer et al found increased risk of invasive ductal and lobular cancers
whereas a report last year in JAMA found that hormone replacement therapy did not
increase the occurrence of invasive ductal or lobular cancers.
Although several studies have reported beneficial effects of hormone replacement
therapy on the bone and heart, Schairer’s study as well as other data suggest possible
risks and uncertainties.
“An individual woman’s decision to take hormone replacement therapy depends on a
analysis of the risks versus the benefits which do not easily lend themselves to simple
formulas,” said Schairer. “The potential increased risk of breast cancer with hormone
replacement therapy has to be weighed against the reduced risks of bone fractures and
possible coronary heart disease. However, it does seem clear that if a decision is
made to use hormones, that estrogen alone is recommended for women without a
uterus and that hormone use for two to three years is not likely to substantially increase
the risk of breast cancer.”
Several other issues are expected to be addressed in future studies. For example, it is
not clear whether continuous progestin use carries the same risks as the use of
progestins for 15 or fewer days per month, the most common regimen in this study.
Additional studies are also needed to define the risks associated with long-term use of
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1. “Breast Cancer and Hormone Replacement Therapy.” The authors are
Collaborative Group on Hormonal Factors in Breast Cancer. Lancet, 1997; 350:
2. “Use of Estogen Plus Progestin is Associated with Greater Increase in Breast
Cancer Risk than Estrogen Alone.” The authors are Graham Colditz and B. Rosner
for the Nurses’ Health Study Research Group. American Journal of Epidemiology
3. “Hormone Replacement Therapy and the Risk of Breast Cancer with a Favorable
Histology.” The authors are Susan M. Gapstur, Monica Morrow, and Thomas A.
Sellers. JAMA. 1999;281:2091-2097.
4. “Risks of Breast and Endometrial Cancer After Estrogen and Estrogen-Progestin
Replacement.” The authors are I. Persson, E. Weiderpass, L. Bergvist, R. Bergstrom,
C. Schairer. 1999 Cancer Causes Control 1999: 10(4):253–260.