1. health and fitness
2. disease
3. cancer

Maturitas 51 (2005) 75–82
Postmenopausal hormone therapy and breast cancer:
What is the problem?
Peter Kenemans
Department of Obstetrics and Gynaecology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
Received 22 October 2004; received in revised form 25 January 2005; accepted 31 January 2005
Abstract
Observational studies provide evidence that breast cancer risk is increased with long-term oral use of postmenopausal estrogen
replacement therapy (ET). Various large cohort studies have shown that the addition of a progestogen in combined hormone
replacement therapy (EPT) increases this risk further. Prospective, randomized controlled trials have confirmed this for the
continuous combined regimen. So, why not tell our patients, “Stop using ET and EPT, it is dangerous to your health!”? The answer
is: there are too many problems to allow such an oversimplified, definite statement. What is the problem? There is more than one!
The problems are as follows:
• There are many observational studies, but these are not consistent in their results.
• Relative risk increases, if any, are small and thus often statistically non-significant.
• Observational studies have inherent biases that cannot be corrected for; therefore evidence should come from randomized
clinical trials (RCTs).
• There are no RCTs that provide evidence as to the breast cancer risk with ET, compared to EPT in the same study population.
• In the three large RCTs available, the populations studied are: not representative, too old and without climacteric complaints,
and therefore lacking any indication for postmenopausal hormone therapy (HT).
• The data obtained thus far do not apply to non-oral routes, neglect the difference in progestogens, and do not address tibolone,
a valuable alternative to classical HT in Europe.
• And finally, are these epidemiological findings biologically plausible? Can estrogens cause breast cancer and why then does
the Women’s Health Initiative (WHI) RCT not find this? And how can the addition of a progestogen increase the ET risk
further as progestogens are pro-apoptotic and down-regulate estrogen receptors as well as local estrogen biosynthesis?
In conclusion, we have a problem as we cannot formulate any general advice that holds for the majority of European postmenopausal women due to lack of consistency, lack of biological plausibility, and lack of relevance of randomized clinical trial
data to our daily practical work.
So, we have a problem and not a firm basis for undisputable statements.
© 2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: Breast; Breast cancer; Estrogens; Progestogens; Proliferation; Apoptosis
E-mail address: [email protected].
0378-5122/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.maturitas.2005.02.017
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P. Kenemans / Maturitas 51 (2005) 75–82
1. Introduction
Postmenopausal hormone replacement therapy
(HT) carries both benefits and risks [1]. The problem
is, what to tell our European climacteric patients about
breast cancer risk with hormone use, when counseling
them about postmenopausal hormone therapy?
The problem is we cannot tell them anything for
sure, as the evidence available is either biased [2] (the
observational studies, like the MWS [3]) or obtained
in the wrong population which is also too old [4] like
in the randomized clinical trial (RCT) of the Women’s
Health Initiative (WHI) [5].
The lesson learned from the cardiovascular diseaseHT issue is unequivocal: we cannot rely on (even
consistent) favorable evidence from observational
studies, not even when supported by consistent favorable surrogate endpoint data. The evidence should
come from prospective randomized placebo-controlled
clinical trials [6].
As to breast cancer risk, these RCTs are sparse [7–9]
and not representative for our European climacteric
women who are looking for symptom relief. These
RCTs moreover do not address many of the European
preferences such as transdermal or intranasal application, the medicated intrauterine device or the use of
alternative drug options, like tibolone. Thus, there are
no RCT data on 50–60-year-old European women who
use micronized estradiol alone or in combination with
one of the many (but different) progestogen options that
are available in addition to medroxyprogesteron acetate
(MPA), and who mostly prefer to use this via a nonoral, transdermal or intranasal route, or who prefer to
use tibolone based on preclinical and mammographic
data [10–13].
And, finally, there is the issue of biological
plausibility, which should provide the basis for all epidemiological interpretations. Estrogens are not strong
mutagenic genotoxic carcinogens, but do seem to be
generally regarded as being able to cause clinically detectable breast cancers [14]. This is because estrogens
could cause new tumors as they bring the epithelial
breast cell into incessant mitotic activity, thereby
inducing unrepairable DNA replication errors and thus
mutations. Thus, in addition to growth stimulation of
already existing occult tumors, estrogens also initiate
or cause new breast cancers. How then can we explain
that the best available evidence, the WHI RCT, does
not find any risk increase with estrogen-only therapy
(ET) [9]?
In order to define in more detail what the real problem is, the following questions will be addressed:
1. Is exposure to estrogens a risk factor for breast cancer?
2. Do estrogens cause new breast cancers?
3. Does the addition of a progestogen influence breast
cancer risk?
4. Are tumors under HT different and less aggressive?
5. Are there transatlantic differences?
2. Is exposure to estrogens a risk factor for
breast cancer?
Classical risk factors for breast cancer include
female gender, higher age group and positive family
history. In addition, many of the risk factors involved in breast cancer are hormonal in nature [15]
(see Table 1).
Breast cancer is considered a hormone-sensitive tumor and prevention and treatment strategies make use
of anti-estrogen drugs like SERMs (tamoxifen, ralofixene), real anti-estrogens (fulvestrant) and aromatase
inhibitors [16]. In general, prevention of contra-lateral
breast cancer and of recurrences (activation of dormant
metastases) in breast cancer patients aims to maximally
reduce the exposure of breast epithelial cells to estrogens.
In summary, on the basis of both epidemiological
as well as clinical data, it is highly plausible that prolonged exposure to estrogens would induce breast cancer risk, and thus result in more breast cancers in an ET
population.
Table 1
Hormonal risk factors for breast cancer
Risk factor
High risk group
Low risk group
RR
Age at menarche
Age at menopause
Oophorectomy
Serum E2
BMI
Bone density
Breast density
<12 years
>55 years
–
High
>30
High
High
>14 years
<45 years
<35 years
Low
<23
Low
Low
1.5
2.0
3.0
3.0
2.0
3.0
6.0
Modified after Clemons and Goss (2001) [15].
P. Kenemans / Maturitas 51 (2005) 75–82
The problem is that the best available evidence, that
of the WHI RCT [9] does not find any increased risk
with long-term ET use (RR: 0.77; 95% CI: 0.59–1.01).
And various recent observational studies also failed to
find an increased breast cancer risk with ET use. This
is true, both for cohort studies [17–20] as well as for
case control studies [21–23].
3. Do estrogens cause new breast cancers?
Do estrogens induce new breast cancers, and if so,
how many extra cases per year of estrogen exposure
can we attribute to estrogen use?
When we find tumors in ET users, are these newly
induced tumors or only occult tumors that show up earlier as a result of accelerated growth through estrogeninduced proliferation?
This is a relevant question for two reasons. First, it
would surely make a difference to our patients, namely
a tumor that would not be there at all without estrogen
use is emotionally certainly different from an occult
pre-existing tumor that would show up anyhow, but
now only earlier and possibly in a less aggressive form
(this is not certain, see later).
And, second, if no more new tumors were to be induced, but only accelerated growth, finally there would
be no more tumors in the total cohort when taken over a
longer time period (e.g. 30 years). If so, after the peak,
there would be a dip in breast cancer incidence within
this population. If this is true, all calculations of attributable extra breast cancer cases per woman year of
exposure would be wrong, as there would not be any
extra cases of breast cancer over all.
Breast carcinogenesis is best described by a multistep genetic progression model [24] (see Table 2, that
Table 2
Multistep genetic progression model
Step 1
Step 2
Step 3
Step 4
Step 5
Mutational activation of oncogenes coupled with inactivation of tumor-suppressor genes
To become invasive: further mutations in at least four or
five genes (chronological order less important)
Tumor growth
Additional mutations required for metastasis
Genetic alterations over time and under (chemo) therapy
(dedifferentiation, clonal selection)
Modified after Kenemans et al. (2004) [24].
77
discerns arbitrarily five different steps within the progression model). In each of the different steps of the
model estrogens could play a role, as long as estrogen
receptors are still present within the cell.
If estrogens can induce new tumors, they would have
to induce a mutation in either step 1 or step 2 of the
model. Generally, estrogens are considered to be only
weak genotoxic carcinogens [14], too weak to really
play a role in direct DNA damage in ET users (see
Fig. 1A). However, incessant estradiol-driven mitotic
activity could result in an accumulation of DNA replication errors, which if left unrepaired could induce relevant carcinogenic mutations (see Fig. 1B) [25].
However, most probably, most breast cancers detected under ET are not induced, but growth stimulated
(step 3, see also Fig. 1C), with the theoretical advance
to being detected before step 4 (dissemination and the
forming of metastasis) occurs (see also later).
Whether ET is likely to increase lifetime risk for
breast cancer in users (so, really more new tumors in
the population), or only likely to increase short term
breast cancer risk (by accelerated growth of clinically
occult tumors) is an important difference. This question
has not been addressed thoroughly in epidemiological
studies looking at breast cancer risk with ET use. The
question still has not been answered, and thus the issue
has not been settled.
The problem is, that as long as we do not know the
answer to this question, all estimates as to extra cases of
breast cancer per years of ET exposure are unreliable.
Estimates derived from short-term studies (less than 10
years) do not allow for the correct prediction of excess
cases over a much longer period.
The conclusion is: estrogens probably induce new
tumors as well as promote the growth of occult preexisting tumors. The problem is we do not know the
proportion in which these two phenomena happen, so
we cannot realistically calculate how many extra breast
cancer cases are attributable to ET use. The large Million Women Study [3] found five extra breast cancer cases per 10,000 woman-years of ET use. The
only available randomized control trial [9] found seven
breast cancer cases fewer per 10,000 woman-years of
ET use, which is biologically implausible and shows
the lack of consistency between studies.
So, what do we tell our patients? ET causes breast
cancer? Or ET does not cause breast cancer, and it
might be even protective?
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P. Kenemans / Maturitas 51 (2005) 75–82
Fig. 1. Hormone dependent carcinogenesis. This figure depicts in a cartoon-like fashion the three possible hypothetical roles estrogens could play
in the carcinogenesis of breast tumors (modified after Kenemans and Bosman, 2003) [25]. (A) Tumor initiation by genotoxic agents. Estradiol
acts here as a genotoxic mutagenic carcinogen. The International Agency for Research on Cancer (IARC, Lyon) has classified estradiol as a
weak carcinogen, as estradiol (via its catechol metabolites) can cause free-radical mediated DNA damage to epithelial breast cells. (B) Tumor
initiation by incessant mitotic activity. Estradiol acts here as a tumor initiator, resulting from incessant mitotic activity, leading to accumulation
of unrepaired replication DNA damage with subsequent damage to the tumor suppressor genes and impairment of DNA repair and apoptosis
mechanisms. (C) Accelerated growth of pre-existing tumors. Estradiol acts here as a late stage tumor promoter via estrogen receptor mediated
proto-oncogene activation and subsequent mitotic activity and proliferation, leading to accelerated growth of pre-existing clinically occult tumors.
DNA: normal intact genome. DNA* : genome with “oncogenetic” mutations.
4. Does the addition of a progestogen influence
breast cancer risk?
Many observational studies have addressed the
issue of breast cancer risk increase with EPT use
(Table 3). The largest study on breast cancer risk with
HT use (based on over 50,000 breast cancer cases),
the Lancet re-analysis [32], concluded that there
was no evidence of marked differences in relative
risk of breast cancer between estrogen-only therapy
and combined treatment with estrogens and progestogens.
P. Kenemans / Maturitas 51 (2005) 75–82
79
Table 3
Breast cancer risk with different regimens of postmenopausal HT in the same population (long-term use)
Study
Study type
Number of cases
RRa ET
RR scEPT
RR ccEPT
Reference
Magnusson (1999)
Ross (2000)
Chen (2002)
Newcomb (2002)
Weiss (2002)
Porch (2002)
Olsson (2003)
Li (2003)
MWS (2003)
Stahlberg (2004)
Bakken (2004)
Case-control
Case-control
Case-control
Case-control
Case-control
Cohort
Cohort
Case-control
Cohort
Cohort
Cohort
3345
1897
1995
5298
1870
411c
556
975
9364
244
624
2.18b
1.06
1.84b
1.34b
0.81
0.99
0.58
1.20
1.32b
1.96b
1.0
1.89
1.38b
1.62b
1.57
1.00
1.04
1.44
2.10b
2.12b
1.94b
2.2b
2.89b
1.09
1.85
1.54b
1.54b
1.82b
3.13b
2.20b
2.40b
4.16b
3.2b
[26]
[21]
[27]
[28]
[22]
[19]
[20]
[23]
[3]
[29]
[47]
a
b
c
Relative risk, where applicable OR (Odds Ratio) or HR (Hazard Ratio).
Significantly different from non-users.
Including 73 in situ cancers.
The same group of investigators concluded in a second study, the Million Women Study [3] (based on
only 3202 breast cancer cases), that EPT had a significantly larger risk for breast cancer (RR: 2.0; 95% CI:
1.91–2.04), than ET (RR: 1.30; 95% CI: 1.22–1.38).
Recent, mostly large, observational studies, looking within the same population at breast cancer risk,
have indeed found that the addition of a progestogen
increases the breast cancer risk further. When looking
at the results of 10 large observational studies, which
looked at the breast cancer risk with the three different
regimens of HT available in the same population, there
is a slight trend to a higher risk with continuous combined EPT, when compared to sequentially combined
HT (see Table 3).
Randomized controlled trials, like the HERS [7] and
the WHI [8] confirmed a significantly increased risk
seen with continuous combined, although relative risks
found are much lower than those reported in the Million
Women Study [3]. HERS [7] found a RR of 1.27, WHI
[8] found a RR of 1.24. However, in the populations in
which these risk estimates were obtained, no data were
available as to the risk with ET. The WHI ET trial [9]
that found a RR of 0.77 for ET was done in a highly
similar, but different population because of the need to
look only at hysterectomized women.
Overall, the impression that the addition of progestogen would increase breast cancer risk compared
to that seen with estrogens alone is justified. However,
the problem is that this is hard to explain on the basis of
breast cell biology [33–45]. Breast cell homeostasis is
generally believed to result from the balance between
proliferation and apoptosis. Cell proliferation is stimulated by estrogens, while progestogens are known to
down-regulate estrogen receptor alpha and thus would
counteract proliferation [25,33].
Further, it is known that in breast tumors local
production of estradiol occurs within the tissue [34].
The maintenance of estradiol levels in tumors is independent of circulation blood levels, as most intratissue
estradiol is derived from in situ biosynthesis. Progestogens in general are known to down-regulate local
estradiol biosynthesis by influencing enzymatic pathways within breast cancer tissue. One would expect that
in this sense, tumor growth acceleration by estrogens
would also be hampered. Finally, estradiol is known to
induce an anti-apoptotic pathway via Bcl-2 [35], while
progestogens are known to stimulate apoptosis [36,37].
In conclusion, the action of a progestogen on the
estrogen-induced cellular mitotic activity is claimed by
some [36,38] to be antagonistic and by others [39,40]
as synergistic. The data are highly complex, conflicting
and confusing [41–44].
The problem is we do not know how progestogens in
vivo influence human breast cells via their two known
receptor isoforms PR-A and PR-B, which have different physiological functions via differential gene regulations. At this moment, it seems that only four genes
are uniquely regulated via PR-A, while 65 genes are
uniquely regulated by PR-B and only 25 by both receptors [45]. Furthermore, we do not know whether or not
the various clinically different progestogens might also
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P. Kenemans / Maturitas 51 (2005) 75–82
influence breast cancer risk in a different way. There
are indications that different progestogens have different effects on the breast [26,29,31]. Moreover, it is not
known which of the two combined regimens, sequentially combined or continuous combined, carries the
greater risk.
The problem is that a clear consensus regarding type
of regimen and type of progestogen cannot be reached
on the basis of existing data.
5. Are tumors under HT different, and less
aggressive?
A multitude of studies have reported that breast cancer tumors appearing in HT users are more often well
differentiated, smaller and less likely to spread to the
axillary lymph nodes [25,46]. However, not all studies found this. Most importantly, the WHI RCT [8]
reported that tumors in the users group were more
advanced (more often axillar node involvement and
slightly larger). It had been long thought that HT users
would possibly increase their risk for relatively mild
breast tumors in addition to an unchanged baseline risk
for aggressive tumors, the combination of which would
explain the better prognosis seen in many of the users.
This was also suggested by the authors of the large collaborative group reanalysis [32] that stated that excess
tumors under HT were more localized in nature. However, the Million Women Study [3] found the opposite,
explaining the increased mortality from breast cancer
seen in this study.
In conclusion, the evidence is conflicting as to
whether or not tumors detected under HT are (in
general) less aggressive and have a better prognosis
than those developing without hormones. The problem
is, what can we tell our patients?
6. Are there transatlantic differences?
This is an intriguing question. Are there transatlantic
differences with regard to drugs used in HT or in population characteristics that might influence risk? Obesity
is one of the most important risk-modifying factors that
might modify the risk for breast cancer when using HT.
Lean, non-HT users have lower concentrations of sex
hormones compared to more obese women and might
increase their breast cancer risk when starting HT more
than obese HT users would do. This has indeed been
found in various studies [3,18,26,32].
There are indications that obese women were overrepresented in the American randomized controlled
trials when compared to average early postmenopausal
women in Europe. It could also be argued that the
estrogen used in US studies, mostly conjugated equine
estrogens, may incur a different risk than the estrogens
preferentially used in Europe like micronized 17-␤
estradiol (see Table 4). Although there seems to be a
trend with a higher significant risk increase with the
European estrogen, this certainly is not proven at all. It
might be a good point to evaluate further. Some studies
that looked at different estrogens reported finding no
significant differences, like for instance the MWS [3].
Most American studies used medoxyprogesteronacetate (MPA) as the drug of choice for the
progestogen to be added to estrogens in combined HT.
In Europe, the choice of progestogens used is much
Table 4
Breast cancer risk with long-term ET: transatlantic differences?
USA (CEE)a
RRb
Reference
Europe (17␤ estradiol)
RRb
Reference
Schairer (2000)
Ross (2000)
Chen (2002)
Newcomb (2002)
Weiss (2002)
Porch (2002)
Li (2003)
WHI (2004)
1.1
1.1
1.8c
1.3c
0.8
1.0
1.2
0.8
[18]
[21]
[27]
[28]
[22]
[19]
[23]
[9]
Persson (1999)
Magnusson (1999)
MWS (2003)
Olsson (2003)
Stahlberg (2004)
Fournier (2005)
1.1
2.2c
1.3c
0.6
2.0c
1.1
[17]
[26]
[3]
[20]
[29]
[31]
a
b
c
CEE: conjugated equine estrogens.
Relative risk, where applicable OR (Odds Ratio) or HR (Hazard Ratio).
Significantly different from non-users.
P. Kenemans / Maturitas 51 (2005) 75–82
81
Table 5
Breast cancer risk with long-term EPT: transatlantic differences?
USA (MPA)a
RRb
Schairer (2000)
Ross (2000)
Chen (2002)
Newcomb (2002)
Weiss (2002)
Porch (2002)
Li (2003)
HERS (2002)
WHI (2003)
1.4c
a
b
c
1.1c
1.6c
1.5c
1.4c
1.8c
2.2c
1.3
1.2c
Reference
[18]
[21]
[27]
[28]
[22]
[19]
[23]
[7]
[8]
Europe (other progestogens)
RRb
Reference
Persson (1999)
Magnusson (1999)
MWS (2003)
Jernstr¨om (2003)
Stahlberg (2004)
Fournier (2005)
1.7c
[17]
[26]
[3]
[30]
[29]
[31]
2.4c
2.2c
2.2c
2.7c
1.3c
MPA: medroxyprogesterone acetate.
Relative risk, where applicable OR (Odds Ratio) or HR (Hazard Ratio).
Significantly different from non-users.
wider and this is reflected in the European studies
where testosterone-derived progestogens constitute
the majority of progestogens used. Looking at the
breast cancer risk data with long-term combined use
(Table 5), it will be difficult to formulate a definite conclusion. It might well be that certain subgroups using
a specific progestogen reduce their risk compared to
women who use a different progestogen [21,29,31,44].
The problem is: can we use American data to counsel European HT users?
7. Conclusion
With so many data available from preclinical and
epidemiological studies, it seems that counseling European women on breast cancer risk with HT use is a
simple task.
The problem is that it is not.
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