http://bmj.com/cgi/content/full/323/7326/1381
BMJ 2001;323:1381-1382 ( 15 December )
Editorials
Hormone replacement therapy and the breast
We should worry about the increase in the
risk of breast cancer
Breast density increases in 17% to 73% of women who use hormone replacement
therapy depending on how breast density is assessed. No clear
relation exists between duration of therapy and change in density on
mammography. Combinations of oestrogen and progestogen increase
breast density more than oestrogen alone. Continuous use of combined
preparations of oestrogen and progestogen increase density more than
their sequential use.2
Hormone replacement therapy affects both the sensitivity and
specificity of breast screening. This is because the efficacy of
breast screening depends on the decreasing breast density seen with
age.
In a recent study of 103 770 women from Australia the sensitivity of two
year mammographic screening in women aged 50-69 was 64.3% (95%
confidence interval 57 to 72) in those given hormone replacement
therapy compared with 79.8% (76 to 84) in non-users.3 There
were also more interval cancers, false negatives (odds ratio 1.60 (1.04 to
2.21), and false positives (1.12 (1.04 to 1.19) and a
significant reduction in specificity in women taking hormone replacement
therapy. In countries where hormone replacement therapy is widely
used this reduction in the sensitivity of mammography could
undermine the capacity of population based mammographic screening
programmes to reduce mortality due to breast cancer.3
The combined analysis of studies of early hormone replacement therapy
reported an increased risk of breast cancer of 1.023 for each
year of use, the risk being 1.35 (1.21 to1.49) for women who
took hormone replacement therapy for five or more years.4 There
were too few data to correlate type of hormone replacement therapy
and risk. More recent studies have reported significantly higher
levels of risk of breast cancer in women taking combined oestrogen
and progestogen preparations compared with women taking oestrogen
alone.5-9
The annual increased risk varied from 4% to 9% for combined
preparations compared with 1% to 3.3% for oestrogen alone. Excess
risk at five years was higher, ranging from 25% to 40% for oestrogen
and progestogen combined compared with a range of 1% to 17% for
oestrogen alone. The relative risk of developing breast cancer after
10 or more years' use of oestrogen and progestogen together was
2.43 (1.79 to 3.30) in one study.8
Continuous combined preparations containing a testosterone derived
progestogen also appear to be associated with a significantly greater
risk than the use of sequential oestrogen and progestogen.8 Such
is the concern surrounding the use of combined oestrogen and
progestogen preparations that it was recently stated that "the
burden of proof should no longer be on epidemiologists and other
investigators to demonstrate that such agents increase the risk of
breast cancer; rather it should shift to the proponents of their use
to demonstrate that they do not."10
Most studies have found that breast cancers that develop in women on hormone
replacement therapy are smaller, less clinically advanced, have a
lower rate of node positivity, are better differentiated and are of
more favourable histological type than cancers that develop in women
who do not use hormone replacement therapy. Consistent with these
findings, most studies have shown either a reduction or no
significant effect of hormone replacement therapy on mortality due
to breast cancer. Studies published so far have been based on
preparations many of which are no longer in common use, and in most
follow up has been less than 10 years. One large study of
1 121 700 nurses recruited in 1976 reported after 18 years
of follow up that there was excess mortality due to breast cancer in
women who had taken hormone replacement therapy for five years or
longer (relative risk 1.45, 1.01 to 2.09).11
It may be time to reassess the value of hormone replacement therapy. Some
doubt that its benefits in reducing the risk of bone loss exceed its
risk,12
and evidence suggests that there is an increased risk in the rate of
coronary events with short term hormone replacement therapy and a
decreased risk with only long term use.13 The
current evidence suggests that the effects of hormone replacement
therapy on the breast, particularly the effects of combinations of
oestrogen and progestogen on breast density and risk of breast
cancer, also need to be considered. The use of progestogens and
their mode of delivery need particular attention. One option is
delivering progestogen directly to the uterus and combining this
with systemic oestrogen
this should alleviate
menopausal symptoms while limiting the risk of breast cancer.
Alternative agents to control menopausal symptoms, such as tibolone,
a synthetic steroid with weak oestrogen, androgenic, and
progestogenic activity but with few apparent ill effects on the
breast, need to be considered for women with no residual cyclical hormonal
production. The evidence that hormone replacement therapy reduces
the effectiveness of breast screening and causes breast cancer in
women over the age of 50 is clear; the challenge for clinicians
is to control menopausal symptoms while limiting these unwanted
effects.
J M Dixon
Edinburgh Breast Unit, Western General
Hospital, Edinburgh EH4 2XU jmd@wght.demon.co.uk
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hormone replacement therapy on breast cancer risk: risk; estrogen versus
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Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L,
Hoover R. Menopausal oestrogen and estrogen-progestin replacement therapy and
breast cancer risk. JAMA 2000; 283: 485-491 |
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Inst 2000; 92: 1100-1101 |
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Colditz GA, Hankinson SE, Hunter DJ, et al. The use of
estrogen and progestins and the risk of breast cancer in postmenopausal
women. N Engl J Med 1995; 332: 1589-1593 |
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Grady D, Cummings SR. Postmenopausal hormone therapy for
prevention of fractures. JAMA 2001; 285: 2909-2910 |
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Grodstein M, Manson JE, Stampfer MJ. Postmenopausal
hormone use and secondary prevention of coronary events in the nurses' health
study: a prospective, observational study. Ann Intern Med 2001; 135:
1-8 |
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