Hormone-Replacement Therapy and Breast

Hormone-replacement therapy and breast cancer
Review
Hormone-replacement therapy and breast

cancer
Jo Marsden
Hormone-replacement therapy (HRT) has been available

for many years, but the important question of its place in
development and progression of breast cancer remains
controversial; provision of reliable risk estimates has been
hampered by a lack of controlled data. Observational
evidence suggests that the risk of breast cancer may be
increased only if HRT is used long term (ie, for longer than
10 years) and that the risk falls when use ceases.
Systematic bias and the lack of adequately powered
studies prevent any firm clinical recommendations about
the prescription of differing HRT regimens and risk, or the
effect of HRT on breast-cancer proliferation and mortality.
This review aims to summarise current clinical data,
justifying the need for prospective controlled trials in
healthy women as well as those at higher risk of breast
cancer or with a personal history of the disease.
Figure 1. A full body x-ray scan. Women who do not take hormone
replacement therapy after menopause are at greater risk of bone
weakening and osteoporosis-related fractures.
Lancet Oncol 2002; 3: 30311
Hormone-replacement therapy (HRT) is the most effective

intervention to date for the relief of oestrogen-deficiency
symptoms resulting from the decline in ovarian function
that promotes the menopause. HRT also lowers the longterm risk of osteoporosis-related fractures (figure 1), which
have significant morbidity and mortality, and associated
costs to the health-care system.1 Despite estimates from
observational evidence of a 3550% decrease in
cardiovascular disease with HRT exposure, the place of this
treatment in the primary and secondary prevention of
cardiovascular disease is now controversial because
randomised trials have shown no benefit and have even
raised the possibility of a short-term increase in risk.2,3 There
is growing evidence that HRT may slow the progression of
Alzheimers disease and possibly decrease the risk of largebowel carcinoma.4
HRT is not without risk, however. For a woman with an
intact uterus, unopposed oestrogen-replacement therapy is
associated with a risk of endometrial carcinoma of up to ten
times more than a woman without such exposure, but the
concomitant prescription of a progestagen largely mitigates
this serious adverse effect.5 Observational studies have
shown a three-fold increase in the risk of venous
thromboembolism in HRT users during the first years of
use, and caution is now recommended when prescribing
HRT for women with personal or strong family history of
venous thromboembolic disease.6 A predominant concern,
however, is that the benefit obtained from the menopause
on risk of breast cancer will be eliminated by HRT, because
oestrogen is essential for growth of breast-cancer cells. The
debate about HRT has been widened further with its
THE LANCET Oncology Vol 3 May 2002
http://oncology.thelancet.com
increasing use for the palliation of oestrogen-deficiency

symptoms in survivors of breast cancer. In the UK, womens
knowledge and use of HRT is increasing but fear of breast
cancer more than any other disease is an important factor
contributing towards poor compliance; only 3040%
continue HRT for longer than a year.79 Almost exclusively,
conclusions about the effect of HRT on breast-cancer risk
are based on observational data. As a result, there are many
unresolved issues about its potential influence on the
behaviour of this disease. In the absence of controlled data,
for women to be fully informed, they must be told about
current clinical uncertainty.
Serum concentrations of sex hormones and risk

of breast cancer
Female reproductive events implicated in the risk of breast
cancer, such as early age at menarche and late onset of
menopause, suggest that lifetime exposure to sex hormones,
particularly oestrogen, has an important role in the
development of breast cancer.10 Prospective studies have
shown that the risk of breast cancer is two to four times
higher for women with concentrations of endogenous
oestrogen within the highest quartile of the normal
postmenopausal range than for those with concentrations in
JM is a Surgical Fellow at the Academic Department of Surgery, The
Royal Marsden Hosptial Trust, Fulham Road, London SW2 6JJ, UK.
Correspondence: Jo Marsden, 303 Riverside Mansions, Garnet
Street, Wapping, London E1W 3TB, UK. Tel: +44 (0) 352 8171. Fax:
+44 (0) 351 5410. Email: jo_marsden@yahoo.com
303
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Review
the lowest quartile, supporting a biological mechanism for

the association between HRT and breast cancer.1113 Serum
oestrogen concentrations achieved with HRT, however,
exceed physiological concentrations observed after the
menopause (>100 pmol/L).
If serum oestrogen were the sole cause of breast-cancer
development, a consistent relation between HRT exposure
and breast-cancer risk would be expected from clinical trials,
but such a relation has not always been observed. Although
bias introduced from a lack of randomised evidence could
account for this lack of association, another possibility is that
higher serum oestrogen concentrations in women treated
with HRT may have less of an effect on breast-tumour
growth, particularly because breast-tumour oestrogen
content seems to be unaffected by menopausal status.14
There is much controversy about the effect of the
addition of a progestagen to oestrogen-replacement therapy,
because progestagens have been hypothesised both to
increase and to decrease risk of breast cancer.15 Most studies
in vivo have shown that breast epithelium proliferates most
during the luteal phase of the menstrual cycle, which
supports a mitogenic role for progesterone.16 In
premenopausal women, however, measurement of serum
progesterone concentrations suggests that higher circulating
concentrations may be associated with a lower risk of breast
cancer and better prognosis if it occurs.17,18 Conversely, in
postmenopausal women, evidence is accumulating from
epidemiological studies that combined therapy may increase
risk.1924 Extrapolation from data of premenopausal women
exposed to physiological cyclical fluctuations in serum
progesterone must allow for the variation among combined
formulations of postmenopausal replacement therapy with
oestrogen and progestagen in the timing of administration
of progestagen and the class of synthetic agent prescribed.
With cyclical combined HRT, the progestagen is prescribed
for 1014 days of the 28-day cycle; for continuous combined
therapy, a low dose of progestagen is combined with
oestrogen and both are taken for 28 days. The latter is
associated with a significantly lower rate of monthly
withdrawal bleeding, which is a common cause of noncompliance with cyclical therapy. Data obtained in vitro,
showing that the continuous application of progestagen with
oestrogen promoted sustained inhibition of proliferation in
breast epithelium, led to the hypothesis that continuous
combined HRT will protect against development of breast
cancer.25 Two classes of progestagen are prescribed in
combined HRT, derived from progesterone (C-21progesterone derivatives) or testosterone (19-nortestosterone derivatives). The latter have greater androgenic
and oestrogenic activity and theoretically may confer a
higher risk of breast cancer than the C-21-progesterone
derivatives. However, they decrease aromatase activity,
which may conversely have a favourable influence on
postmenopausal risk.26
Randomised trials of HRT and breast cancer

The only completed placebo-controlled randomised trial of
HRT accrued too few patients (168) for definitive
conclusions to be drawn.27 That study had less than 40%
304
power to detect an increase in risk among HRT users of two

times or greater. After 10 years, no breast cancers had been
diagnosed in women randomly assigned sequential
combined replacement therapy (conjugated equine
oestrogen 25 mg daily with medroxyprogesterone acetate
10 mg/day for 7 days per month), but four had occurred in
those assigned placebo (p=012). Women were then given
the opportunity to stop, continue, or start HRT; after a
further 12 years, two more breast cancers had occurred
among those who had never been exposed to HRT. Two
large randomised controlled trials are in progress to assess
the effect of HRT on risk of breast cancer: the MRC
Womens International Study of Long-Duration Oestrogen
use after Menopause (WISDOM) in the UK, and the
Womens Health Initiative trial (WHI), which was set up by
the National Institutes of Health, in the USA.28,29 Both trials
involve the prescription of conjugated equine oestrogen,
with or without medroxyprogesterone acetate, thereby
precluding a controlled assessment of other oestrogen and
progestagen regimens that are prescribed after the
menopause. The Million Women Study, a population-based
cohort of women attending for mammographic breastcancer screening in the UK, although providing useful
information about HRT use in such women, may be
vulnerable to selection bias because there is no randomised
control group. Women using HRT are more likely to have
mammographic screening, and a recent study suggested that
women attending the NHS screening programme may be at
higher risk of breast cancer than non-attenders.3032
Observational studies of HRT and breast cancer

In the absence of data from randomised trials, inferences
about the effect of HRT have to be drawn from the best
available observational evidence; the risk of systematic bias,
however, must therefore be borne in mind. Individual
studies are underpowered to compare the effects of different
HRT preparations and routes of administration, and also
there are specific biases that could lead to overestimation or
underestimation of cancer risk in these studies. Women
experiencing menopausal symptoms, and therefore seeking
HRT, tend to have lower serum oestrogen concentrations
and are leaner than women who have no symptoms;
therefore they may have a lower risk of developing breast
cancer. Risk is also reduced by an earlier age at menopause.
These factors may lead to an underestimation of breastcancer incidence if not controlled for in trials of HRT. The
healthy-user effect conversely may exaggerate risk. Women
electing to use HRT generally participate in healthpromoting behaviour including attendance for breast
screening. Recall bias could lead to underestimation or
overestimation of associated risk.
Presently, the most comprehensive and definitive data
are those from the reanalysis of individual data from 51 casecontrolled and cohort studies by the Collaborative Group for
Hormonal Factors in Breast Cancer.19 In total, this dataset
constitutes more than 90% of relevant worldwide evidence.
The main findings were that per year of use, the risk of breast
cancer with HRT was equivalent to that observed with
delaying the menopause (23% and 28%), and in common
Review
with previous meta-analyses, that the lifetime risk of breast

cancer was significantly increased with current, long-term
HRT exposure. In the subgroup of women who had used
HRT for longer than 5 years (mean duration of exposure 11
years), the relative risk of breast cancer was 135 (95% CI
121149). These data were adjusted for age at menopause.
In terms of absolute risk per 1000 women, if HRT is started
at the age of 50 years, continuous use for 5 years may be
associated with two extra breast cancers, continuous use for
10 years with six extra breast cancers, and continuous use for
15 years with 12 extra cancers. A low body-mass index was
an important predictor of breast cancer in women taking
HRT; the relative risk with use for 5 years or longer was 109
(SE 0066) for those of body-mass index below 250 kg/m2
and 105 (0092) for those of body-mass index 250 kg/m2 or
higher. Three observational studies published since the
reanalysis have also reported a similar association.2224 One
suggested explanation for this association is that the
proportional addition of oestrogen with HRT is smaller in
obese postmenopausal women than in lean women, but this
idea has not been proven. Whatever the biological
mechanism, potentially susceptible women in this subgroup
cannot be identified.
The Collaborative Groups reanalysis predominantly
investigated the effect of unopposed oestrogen-replacement
therapy. Since the majority of women prescribed HRT
require a combined preparation, the potential risk of breast
cancer associated with combined treatment must be
clarified, with particular attention to the type and timing of
progestagen dose. Evidence from the Collaborative Groups
reanalysis and observational studies published subsequently
does not support the contention that combined HRT
protects against the development of postmenopausal breast

cancer.1924 About 5% of women reviewed in the reanalysis
had been exposed to a progestagen (with or without
oestrogen). Although current, long-term use of combined
HRT was estimated to confer a greater risk of breast cancer
than oestrogen alone (relative risk for more than 5 years of
exposure 153 [SE 033]), no information was available
about the formulation of combined therapy used; overall,
the small number of incident breast-cancer cases on which
this risk estimate was based was deemed insufficient for the
estimate to be conclusive. Studies since the reanalysis have
been consistent in reporting an increased breast-cancer risk
with long exposure to combined therapy, but whether this
risk is greater than that conferred by oestrogen alone cannot
be assessed because data from individual studies have been
expressed in slightly different ways (table 1). Some of the
later studies assessed risk in terms of the class of progestagen
and timing of its administration, but the numbers of women
exposed to differing regimens are too small for any changes
in clinical practice to be recommended.
Studies on the effect of combined HRT on the
proliferation of breast epithelium and mammographic
breast density provide further support for a positive
association with increased risk of breast cancer. They do not,
however, resolve the important issue of how risk may be
influenced by differing formulations of therapy. Disparate
results have been reported from clinical studies assessing the
combined effect of oestrogen and progestagen on the
biological behaviour of both normal and malignant breast
epithelium. Lack of randomised controlled data, variation in
the methods used to assess cellular proliferation, and
importantly, the possibility that results obtained reflect an
Table 1. Epidemiological studies of HRT and risk of breast cancer published since the 1997 reanalysis by the Collaborative
Group for Hormonal Factors in Breast Cancer
Ref
Duration of HRT use
Relative risk of breast cancer (95% CI unless otherwise stated)

Unopposed oestrogen
CHRT
SHRT
CCHRT
109 (SE 25)*

14 (0923)
n=28
17 (1126)
n=44
..
..
103 (098108)
n=137
044
107 (102111)
n=409
00005
103 (094113)
n=102
027
119 (109131)
n=135
00002
p for trend
<4 years
003 (001006)
n=234
0001
>4 years
012 (002025)
n=52
001
11 (0817)
n=26
15 (1024)
n=22
Per 5 years
106 (097115)
n=742
018
138 (113268)
n=320
00015
109 (088130)
n=105
044
19
>5 years
134 (SE 009)

n=558
153 (SE 033)

n=58
20
21
Per year
16 years
1033 (SE 084)*

10 (0614)
n=23
11 (0717)
n=35
>6 years
22
Per year
p for trend
23
24
Per year
p for trend
124 (107145)
n=425
0005
CHRT, combined oestrogen and progestagen, type and pattern of progestagen prescription not documented; SHRT, sequential combined HRT; CCHRT, continuous combined
HRT. *Number of cases not stated. Values given for women using combined HRT with 19-nor-testosterone progestagen derivatives. Values given for women with body-mass
index <244 kg/m2. HRT prescribed predominantly 0625 mg conjugated equine oestrogen with or without medroxyprogesterone acetate (C-21-progesterone derivative).
305
Review
HRT withdrawal response are all factors potentially

confounding interpretation of these results. Review of
prospective studies in which HRT has clearly been
administered up to the day of biopsy of breast tumour
confirm that oestrogen, with or without the daily
continuous administration of a progestagen, stimulates
proliferative activity.3335 In a cross-sectional study,
comparison of epithelial cellular proliferation and density in
normal breast tissue from postmenopausal women showed
that continuous combined HRT stimulated more significant
increases in these features than oestrogen alone.34 By
contrast, one small randomised study concluded that
continuous progesterone inhibits oestrogen-induced
proliferation of breast epithelial cells.36 However, in that
study, both sex hormones were administered percutaneously
into the breast, which may result in significant increases
amounts of these hormones in breast tissue; therefore
extrapolation of these findings directly to conventional oral
or transdermal HRT may be inappropriate.
In the placebo-controlled randomised Postmenopausal
Estrogen/Progestin Interventions (PEPI) trial, mammographic breast density increased in a significantly greater
proportion of women assigned combined oestrogen and
progestagen therapy than in the groups allocated unopposed
oestrogen or placebo.37 Of particular interest, the timing of
administration of the C-21-progesterone prescribed,
medroxyprogesterone acetate, had no significant influence
on the proportion of women who developed increases in
grade of breast density (conjugated equine oestrogen plus
cyclical medroxyprogesterone acetate 235% [95% CI
119351] compared with conjugated equine oestrogen plus
daily medroxyprogesterone acetate 194% [95% CI
99289]). Increased mammographic breast density is an
independent risk factor for the development of breast
cancer, but the assumption that HRT-induced
mammographic changes confer the same degree of risk as
natural increases in breast density may be incorrect
(figure 2).
HRT and risk of fatal breast cancer

An important finding of the Collaborative Group reanalysis
was that the risk of breast cancer fell rapidly after cessation of
HRT; by 5 years the estimated risk was no greater than that
in women without any history of exposure. This finding
provides the strongest evidence that HRT acts as a promoter
of pre-existing breast cancer rather than an initiator of
malignant transformation in the breast. In stimulating
growth of cancer cells, HRT would be expected to have an
adverse effect on mortality from breast cancer and to
decrease disease-free survival if prescribed to women with
the disease but, paradoxically, this does not seem to be
the case.
Most studies that have looked at death from breast
cancer have found lower disease-specific mortality in healthy
HRT users than in non-users.38,39 The Nurses Health Study,
however, has shown an increase in mortality from breast
cancer with current use of HRT for longer than 10 years.40
Inconsistencies in definitions of HRT use and duration of
therapy, together with a lack of information about the type
306
Yes
Hysterectomy?
Oestrogen
Oestrogen only
No
Oestrogen and
progestogen
Menopause
confirmed?
No
Progestogen
Yes
Combination
of A and B
or Combination
Packs C
Patient wants
periods?
Yes
Combination
packs
No
Continuous
combined
Figure 2. Decision-making processes in hormone replacement therapy.
of HRT prescribed, preclude review by meta-analysis. One

study took factors related to treatment of breast cancer into
consideration, which could influence outcome, but
conclusions are limited by the small number of events.41
Despite the lack of difference in the proportions of women
treated with breast-conserving surgery, with positive
excision margins, and receiving radiotherapy, chemotherapy, or tamoxifen treatment, the cumulative rate of
ipsilateral recurrence was significantly higher with HRT
(p=002) and that of distant metastases lower (p=001), with
a trend, of borderline significance, towards a reduction in
breast-cancer mortality at 10 years. No increase in the rate of
contralateral breast cancer was observed with previous HRT
exposure.
The observational nature of these studies precludes
assessment of the extent to which bias (ie, the healthy-user
effect, publication, selection, and lead-time biases)
influenced outcome. HRT exposure has been associated with
a significant increase in the proportion of women presenting
with smaller, better-differentiated, localised breast
tumours.19,42,43 In the absence of accurate information about
the frequency of mammographic screening and clinical
examination in studies comparing HRT users with nonusers, we cannot tell whether this favourable association is
due to detection bias or a true biological effect of HRT.
Investigators from the Iowa Womens Health Study have
reported a positive association between HRT exposure and
the development of tubular, mucinous, and medullary breast
tumours, but not invasive ductal or lobular carcinomas.43
The survival of women treated for the more prognostically
favourable low-grade carcinoma types (tubular and
mucinous carcinoma) is similar to that of the general
population.44 Medullary carcinomas, however, have a
Review
complex karyotype similar to those described for ductal and

lobular carcinoma, and there is controversy about
classification of this type as a good-prognosis tumour.45 The
conclusion that HRT may have a selective growthpromoting effect on tumours with a more favourable
outcome is not substantiated by this study, and no
satisfactory explanation has been put forward to support a
differential effect of HRT according to histological category
of invasive disease.
Endogenous oestrogen has an important role in the
growth regulation of breast cancer positive for oestrogen
receptors (ER). This role is exemplified by the clear survival
benefits obtained through the antioestrogenic effect of the
selective oestrogen-response modulator, tamoxifen, in
women with ER-positive disease and the decreases in the
frequency of ER-positive breast cancer with the use of
tamoxifen and raloxifene.4648 These findings imply that the
growth-promoting effect of HRT may be determined by the
hormonal sensitivity of the breast tumour. Case reports of
regression of breast cancer after withdrawal of HRT have
been quoted in support of this hypothesis despite a lack of
information about the tumour ER status of affected
women.49 The few studies that have assessed the influence of
HRT on cellular proliferation according to expression of sex
steroid receptors imply that the stimulatory effect may be
restricted to ER-positive cells; however, for the most part,
sample sizes are small and confidence intervals wide.33,34,50
This aspect of HRT prescribing requires further
investigation, particularly since there are two distinct
subtypes of ER ( and ) in human breast, and their role in
the control of epithelial growth and response to HRT
remains to be clarified.51
Further evidence supporting the idea that HRT may not
promote aggressive disease behaviour is provided by
mammographic screening studies. HRT reduces the
sensitivity of screening mammography (648% [95% CI
579718] in HRT users vs 775% [95% CI 738809] in
non-users) and may therefore decrease the detection rate of
breast cancer with screening.52 However, preliminary data
suggest that prognostic features may be no worse in HRT
users presenting with interval cancers that were missed in
the initial screening round than in women with cancers
detected at screening. No significant differences in tumour
histological type, size, grade, or axillary nodal involvement
have been reported in screen-detected or interval cancers
between HRT users and non-users,52,53 which suggests that
the inadvertent exposure of established breast cancer to HRT

may not confer a survival disadvantage. However, long-term
follow-up with survival data is necessary to substantiate this
conclusion.
HRT and women at high risk of breast cancer

Familial breast cancer
Tumours developing in women at high risk of breast cancer

owing to inherited mutations in the BRCA1 and BRCA2
genes, which account for 75% of familial disease, may have
a hormone-resistant phenotype in that most are of high
grade and negative for ER and progesterone receptor.54 The
failure of tamoxifen to lower the rate of breast cancer,
according to the interim analysis of the randomised Royal
Marsden Hospital chemoprevention trial, has been
attributed to the recruitment of younger women, selected
on the basis of a family history of breast cancer, who are
more likely to have inherited mutations in BRCA1 and
BRCA2.55 Reproductive factors do, however, seem to be
important as shown by the study of Rebbeck and
colleagues,56 in which prophylactic bilateral oophorectomy
in carriers of BRCA1 mutations decreased the rates of both
ovarian and breast carcinoma. HRT exposure might be
expected to be detrimental in such high-risk women, but
the use of add-back HRT to ameliorate oestrogendeficiency symptoms after oophorectomy has not been
associated with an obvious reduction in the benefit
achieved.56 The Collaborative Group reported a similar
pattern of risk in women with a family history of breast
cancer compared with those without a significant family
history who were exposed to HRT, but the 99% CI were
very wide and bracketed unity. However, insufficient
documentation of family history precluded risk analysis
according to whether women were likely to have an
inherited genetic predisposition to developing this disease.
Benign breast disease
The influence of HRT on breast-cancer risk in women with

benign breast disease has not been extensively investigated.
Although most studies have not shown an increase in risk,
failure to classify benign disease according to the associated
risk of breast cancer prevents clear interpretation of
most published studies. A retrospective review of a cohort
of patients with accurate histological classification of
benign breast disease concluded that the use of HRT did
not influence risk and should not be contraindicated
Table 2. Breast-cancer risk, benign breast disease, and the effect of HRT57
Classification of benign disease
Without ERT
With ERT
RR (95% CI)
RR (95% CI)
Proliferative disease with atypical cell changes

(atypical ductal or lobular hyperplasia)
253 (100630)
287 (130630)
Proliferative disease without atypia

(multiple cysts, duct papillomata, sclerosing adenosis)
21
113 (069190)
29
137 (088210)
All proliferative benign disease (duct ectasia,

solitary cysts, fibroadenoma)
26
127 (081200)
36
152 (100230)
Complex fibroadenoma
146 (053400)
157 (072340)
RR, relative risk; ERT, estrogen replacement therapy. Complex fibroadenoma is defined as a fibroadenoma containing cysts >3 mm diameter, sclerosing adenosis, epithelial
calcification, or papillary apocrine change.
307
Review
in such women (table 2).57 However, further detailed

evidence is required in view of the small numbers of
incident breast-cancer cases on which these risk estimates
were based.
accompanying increase in serum oestrogen concentrations

was not associated with a decrease in time to disease
progression.33,64,65 The effect of HRT on prognosis in
survivors of breast cancer has been the subject of a growing
number of published observational studies. None have
reported a reduction in disease-free or cause-specific
survival with the use of HRT, even in women whose
tumours were ER positive (table 3). A recent review of
published data from 11 such studies in which HRT was
taken for a mean of 30 months estimated a relative risk of
recurrence of 082 (95% CI 058115).79 Collectively these
studies suggest that other, as yet, unknown factors are
probably involved in determining whether HRT-induced
cellular proliferation becomes clinically significant, however,
this idea requires confirmation from randomised,
prospective studies.
A pilot, randomised study of HRT in the UK showed that
women with breast cancer thought that the management of
oestrogen-deficiency symptoms was an important part of
their care and that they would be willing to take part in a
randomised trial, despite the clinical uncertainty associated
with use of HRT in this setting.59 Of patients eligible to take
part in this study (postmenopausal women with early-stage
breast cancer experiencing oestrogen-deficiency symptoms),
40% agreed to do so, and more than 80% in the allocated
treatment groups were continuing with HRT or no
treatment as assigned after 6 months. Fear of recurrence was
an important reason for women to refuse to take part, and
many wished to avoid other HRT side-effects such as
withdrawal bleeding and the perceived risk of weight gain.
After the successful implementation of this pilot study,
larger multicentre trials are underway in the UK and
Scandinavia to find out more reliably the effect of HRT on
the disease-free and overall survival of symptomatic women
with breast cancer. These trials are also expected to provide
information on whether ER status is relevant when
prescribing HRT in this group of women.
Effect of HRT on prognosis in survivors of breast

cancer
Increasing numbers of women are experiencing a premature
menopause and oestrogen deficiency symptoms as a result of
treatment for breast cancer (eg, direct ovarian ablation, the
antioestrogenic effects of tamoxifen, or chemotherapyinduced ovarian failure). Although osteoporosis and arterial
disease are important long-term health concerns for women
surviving breast cancer, the treatment of oestrogendeficiency symptoms presents the most important clinical
question in this group of women. Iatrogenic symptoms can
be more severe and persist for longer than those experienced
by healthy postmenopausal women, and they have a
significant negative influence on quality of life.58,59
Traditionally, HRT has been absolutely contraindicated in
women with a previous diagnosis of breast cancer for fear of
stimulating disease progression. Low-dose progestagens, the
gonadotropin-mimetic agent tibolone, venlafaxine, and
clonidine may be promising options, but long-term data on
their efficacy, side-effect profiles, and safety in survivors of
breast cancer are lacking.6063 In view of the proven efficacy of
HRT and the fact that short-term exposure (less than 5
years) does not appear to increase the risk of breast cancer,
HRT is increasingly being prescribed to symptomatic
patients.
Although oestrogen exposure in vivo increases the
number of proliferating breast-cancer cells, administration
of HRT to patients with breast cancer has not substantiated
the concern that this exposure may be harmful.
Administration of oestrogen-replacement therapy before
palliative chemotherapy did not increase the latters
therapeutic benefit but, irrespective of tumour ER status, the
Table 3. Observational studies of HRT after breast cancer
Ref
Disease stage
Type of HRT
Median duration
of use (months; range)
Median follow-up
(months; range)
Recurrences
Deaths
66
50
III
O, CCHRT
36
>24
67
25
IIV
Not stated
352 (678)*
Not stated
68
35
IIV
O, SHRT
146 (144)
43
69
43
III
Not stated
31 (24142)
144 (46342)
70
67
Not known
O only
94 (1154)
94 (1454)
71
167
III
P, SHRT, CCHRT
192 (3264)
84 (4-360)
Not stated
72
120
IIV
O, CHRT
288 (12127)
Not stated
73
76
III
O, SHRT+T
66 (632)*
833 (881)*
74
21
III
O, SHRT
28 (372)*
108 (28180)*
75
210
III
Not stated
46 (188)
Not stated
17
76
190
IIII
O only
336 (318)*
Not stated
Not stated
77
207
III
O, CHRT
Not stated
Not stated
15
78
174
III
O, CHRT
15
Not stated
16
O, unopposed oestrogen; P, unopposed progestagen; T, testosterone; CHRT, combined HRT but type of progestagen and pattern of prescription not stated; SHRT, sequential
combined HRT; CCHRT, continuous combined HRT. *Values are means with their respective ranges or SE. RR of recurrence with CHRT 067 (95% CI 038116). Maximum
duration not stated, study indicated that some patients used HRT for longer than 76 months.
308
An important consideration in prescribing of HRT to

women with breast cancer is whether it may antagonise the
antiproliferative effect of tamoxifen on the breast.
Concurrent tamoxifen use has been documented in some
observational studies, but numbers of patients are far too
small for any conclusions to be drawn. Their collective effect
on risk of breast cancer was not a primary hypothesis of
the Royal Marsden Hospital and Italian tamoxifen
chemoprevention trials and, therefore, interim analyses
showing no influence of HRT on risk of breast cancer or the
preventive efficacy of tamoxifen should be treated with
caution.55,80 With the exception of its antioestrogenic effect
on the breast, the activity of tamoxifen on other tissue
systems seems to be influenced by endogenous serum
oestrogen concentrations. In postmenopausal women,
tamoxifen has predominantly oestrogenic effects on bone,
lipid metabolism, blood coagulation, and the endometrium,
but in premenopausal women its effects on these systems
seem to be antioestrogenic.81,82 In postmenopausal women,
tamoxifen and oestrogen have a cumulative benefit on bone
mineral density, but no additive effect has been observed on
lipid profiles.81 Both HRT and tamoxifen increase the risk of
thromboembolic disease, but whether these respective risks
are additive in combination is unknown.82 The consequences
of the interaction between tamoxifen and oestrogen on these
other tissue systems are relevant, and more detailed
investigation is needed.
Conclusion
Endogenous oestrogen is implicated in the aetiology of
breast cancer, but the role of HRT remains to be clarified.
Collectively, observational studies provide evidence that
short-term use of HRT for the relief of oestrogen-deficiency
symptoms does not significantly increase the risk of breast
cancer. They do, however, provide evidence for an increase
in risk with current, long-term exposure to HRT (longer
than 10 years). How risk varies with the type of HRT
prescribed is still unclear, although the addition of a
progestagen seems unlikely to have a protective effect.
Whatever formulation of HRT is used, risk of breast cancer
falls after cessation of treatment, thus HRT probably
promotes the growth of established breast cancer rather than
initiating malignant change. However, this growthstimulating effect does not affect mortality adversely in
women exposed to HRT before or after a diagnosis of breast
cancer. Whether the stimulatory effect is restricted to
hormone-sensitive disease remains to be found out. The
challenge for future research will be to identify women who
may be at increased risk from HRT exposure. Since this
increase in risk is small, this process is likely to be difficult.
Search strategy and selection criteria

Published data for this review were identified by searches of
Medline, CancerLit, EMBASE, and references from relevant
articles. Searches were performed using the key phrases
hormone replacement therapy, breast cancer oestrogen,
deficiency symptoms, and breast cancer mortality.
Randomised and non-randomised studies reported in English
were included.
Review
Results from current randomised trials of HRT in

healthy women are likely to define risk more reliably. For
women at high risk of breast cancer, or survivors of the
disease, there is no evidence that HRT has an adverse effect
on outcome, but studies have been uncontrolled and
therefore inconclusive. In the absence of reliable data,
outside of the context of a clinical trial, the uncertainty
about HRT should be explained fully to women and the
advice of a cancer geneticist or breast-cancer specialist be
sought as appropriate.
Conflict of interest
JM is the joint Principal Investigator of the national UK randomised

trial of HRT in women with a history of early stage breast cancer. She
has also been sponsored by Wyeth, Solvay Healthcare Ltd, Organon,
and Orion to attend and speak at various conferences. Consultancy fees
have also been recieved from Wyeth and Organon, along with fees from
Novartis for the preparation of educational material.
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