NEW ORLEANSHormone replacement therapy (HRT) remains
strongly associated with the development of breast cancer in the
minds of many. But the discerning clinician should go beyond P
values and relative risk and use the known data to make
decisions regarding this issue, John C. Arpels, MD, said at the
American Society of Breast Disease annual meeting.
His presentation was an attempt, he said, to bring clinical relevance
to the lack of definitive data on whether HRT causes a significant
increase in the risk of breast cancer. Dr. Arpels is associate
clinical professor of OBGYN and reproductive sciences, University of
California, San Francisco.
The existing evidence shows an overall 46% decrease in excessive
mortality among HRT users. HRT users have an average 50% decrease in
hip and Colles fractures plus a 90% decrease in vertebral fractures.
The rate of coronary heart disease is reduced by 40% overall, and
seven preliminary studies show 50% less senile dementia in those on
HRT, he said.
In contrast, some studies show an increase in breast cancer risk
among HRT users. However, no consistent trend of increased risk has
emerged among 63 major published studies.
A recent re-analysis of the data from 51 epidemiologic studies by the
Collaborative Group on Hormonal Factors in Breast Cancer showed a
modest 58% increase in breast cancer risk, which became significant
only with 15 years of use and actually translated into only 337 cases
out of the total 52,700 breast cancers (Lancet 350:1047, 1997).
The authors of this study, who re-computed the raw data from these
trials, calculate that this increase in risk projects to only 7 to 12
excess cases of breast cancer per 1,000 women aged 65 to 75 years
using long-term HRT. Of further interest, this excess risk
disappeared completely when HRT was discontinued for 5 years. Not
until age 60 was there a significant difference between never-users
and users of 5 to 10 years.
One is left to speculate on how, once HRT has helped to
initiate oncogenic transformation in breast epithelium, the cancer is
cured by the mere cessation of further hormonal use,
he said. How, if you start the process then stop it, does the
cancer just melt away? The doubling time for the average cancer is
such that it may take 6 to 8 years to pick up a tumor, so cancer is
occurring before women are on HRT.
Also, he said, if cancer is occurring, why did the study find a
decrease in relative risk at years 10 to 14 of use as compared to
years 5 to 9 of use (1.09 and 1.19, respectively)?
A number of biochemical factors may also be confounding the
association between HRT and breast cancer, Dr. Arpels pointed out.
The presence of the P450 aromatase enzyme in breast tissue can
convert androgens to endogenous breast estrogen against a serum
gradient. And estrogen levels found in breast duct fluid can be 10-
to 40-fold higher than estrogen levels in serum, even in women not on
exogenous HRT. So if estrogen is bad, the breast already has
it, he noted.
Additionally, among the different estrogen products, there are
differences in nuclear retention times, bound vs bioactive fractions,
and cofactors such as insulin-like growth factors. These observations
should be factored into clinical trials seeking the true risk of HRT
on breast cancer occurrence, he said.
Two large prospective trialsa European trial and the
multicenter Womens Health Initiativemay shed light on the
association between HRT and breast cancer risk. Until then, Dr.
Arpels said, it should be noted that 10 studies have shown a 10% to
40% increase in survival among women using HRT or oral contraceptives
when their breast cancer was diagnosed, probably because of
estrogen-related events that decrease the risk of metastatic spread.
These factors include antioxidative effects, enhancement of gap
junction genes that maintain control of cell diversity, increases in
humoral B-cell activation, and upregulation of the normal BRCA1
protein that prolongs tumors in a premalignant state.
Dr. Arpels also stressed that eight studies have found no difference
in disease-free interval or death rate when HRT is given to breast
The future holds the promise of agents similar to estrogen that may
exert both anticancer as well as other favorable effects. A number of
selective estrogen-receptor modulators (SERMs) as sequels to
raloxifene (Evista) are under investigation. Plant biphenolic
isoflavone phyto-estrogens are being studied as potential substitutes
for steroidal estrogens and have shown antimitogenic biochemical
properties in monkeys. And Dr. Arpels predicts a great
future for targeted tissue-specific estrogens being developed
in rodent models.
We will probably have substitutes for estrogen long before we
will know the answer to the question of whether estrogen causes
breast cancer, he commented.
[Editorss Note: The Iowa Womens Health Study of 37,105
postmenopausal women (JAMA June 9, 1999) showed no increase in the
more common breast cancer types (DCIS or invasive ductal or lobular
cancer) in HRT users. However, women taking HRT for 5 years or less
had an 81% increased risk of medullary, papillary, tubular, and
mucinous breast tumors, and those who used HRT for 5 years or more
had an increased risk of 265%.]