Long-Term Toxicities of Selective Estrogen-Receptor Modulators and Antiaromatase Agents

Long-Term Toxicities of Selective Estrogen-Receptor Modulators and Antiaromatase Agents

The dominant role of tamoxifen
in the treatment of estrogenreceptor-
positive breast cancer
for the past 40 years is being challenged
by a new class of agents-the
third-generation aromatase inhibitors.
These agents are selective in their
action, suppressing the formation of
estrogen by interfering with the aromatase
enzyme. They are categorized
according to two different mechanisms
of action:
(1) The nonsteroidal inhibitors
letrozole (Femara) and anastrozole
(Arimidex) bind reversibly to the cytochrome
P450 moiety, exposing the
enzyme-binding site. Because androstenedione
can attach to the binding
site and displace the drug, their action
is reversible and may ultimately lead
to an increase in aromatase activity.
(2) The steroidal inactivator exemestane
(Aromasin) binds irreversibly
to the enzyme, thereby reducing
aromatase activity. Despite these subtle
differences in mechanisms of action,
the third-generation aromatase
inhibitors and inactivators are equally effective in decreasing serum concentrations
of estradiol and estrone
and are superior to tamoxifen in postmenopausal
women, both as initial
hormonal therapy for advanced disease
and possibly as adjuvant therapy
as well.[1]

Conclusions about the clinical effectiveness
of the selective estrogenreceptor
modulators (SERMs) and
antiaromatase agents are derived from
independent studies and different cohorts
of patients. Most of the available
toxicity data on antiaromatase

agents come from studies in postmenopausal
women with advanced
breast cancer. Patients were treated
for less than 6 months and were followed
for a short period of time-
6 to 18 months. In contrast, the toxicity
data for the SERMs are derived
from trials in women without cancer.
Treatment was administered for 3 to
8 years, and follow-up ranged from 3
to 6 years.

Four double-blind placebo-controlled
trials of raloxifene (Evista)
and tamoxifen have provided us with
these important data. The National
Surgical Adjuvant Breast and Bowel
Project (NSABP) Breast Cancer Prevention
Trial (BCPT), the Royal
Marsden Tamoxifen or Placebo
(TAMOPLAC) trial, and the Italian
Tamoxifen Prevention Trial (ITPT)
evaluated the role of tamoxifen as
chemoprevention for breast cancer;
the Multiple Outcomes of Raloxifene
Evaluation (MORE) trial tested raloxifene
for the treatment of osteoporosis.[
2] Although these are not
the only trials that have addressed
the effect of SERMs on normal tissue,
they provide the broadest information
on the long-term effects of these agents. The designs of these trials are summarized in Table 1.

The goal of this paper is to present
a comprehensive review of the literature
and identify citations reporting
the long-term toxicities of the SERMs
tamoxifen and raloxifene and the
third-generation antiaromatase agents
anastrozole, exemestane, and letrozole,
and to compare what is known
about the clinical action of these compounds.
Our findings are summarized
in Table 2, and the accompanying
text describes the actions of the drugs
according to their effects on the end
organ or organ physiology.

Bone Densities and FracturesSERMs
The incidence of osteoporosis and
bone fractures increases in postmenopausal
women as a result of declining
estrogen levels. An early placebocontrolled
trial of adjuvant tamoxifen
in node-negative postmenopausal
breast cancer patients that prospectively
assessed bone mineral density
demonstrated an increase in this parameter
in the hip and spine for women
receiving tamoxifen. Fracture rates were not reported. Women receiving
tamoxifen in the BCPT experienced
a 31% decrease in fractures of the
hip, wrist, and spine.

The 7,705 postmenopausal women
with documented osteoporosis in
the MORE trial were randomized to
receive either raloxifene or placebo
as well as supplemental calcium and
cholecalciferol. After 40 months of
follow-up, women randomized to raloxifene
had a 2% increase in bone
mineral density of the hip compared
with the control group, and a 30%
decrease in vertebral fractures.[2]
Based on such data, it is generally
accepted that both tamoxifen and raloxifene
have favorable effects on
bone, although probably not to the
same extent as estrogen.

Antiaromatase Agents
The available data suggest that the
effect of the nonsteroidal inhibitors is
more in line with the effects of a lack
of estrogen while the steroidal inactivator,
exemestane, may have more
favorable effects. With a median follow-
up of 33 months, women in the
Arimidex, Tamoxifen Alone or in
Combination (ATAC) trial who had been randomized to anastrozole experienced
significantly more bone fractures
than women randomized to
tamoxifen.[1] Longer follow-up will
be needed before the increased fracture
rate can be attributed to osteopenia.

Serial bone densitometry was performed
in premenopausal women enrolled
in an adjuvant trial initiated by
the Austrian Breast Cancer Study
Group.[3] All the women received
goserelin (Zoladex) and either anastrozole
or tamoxifen. In a second randomization,
patients were assigned
to receive 4 mg of zoledronate (Zabel,
Zometa) every 6 months or no
additional therapy. A significant decrease
in the bone mineral density of
the hip and spine was observed among
patients receiving anastrozole alone compared with tamoxifen alone. The
follow-up in both of these adjuvant
trials is relatively short, but the data
suggest that anastrozole may decrease
bone density.

The data for letrozole are somewhat
sparse. A 3-month course of letrozole
in 32 women with benign breast
disease produced changes in serum
markers of bone metabolism consistent
with those of bone loss. A second
controlled trial of letrozole in 43 postmenopausal
women also demonstrated
an increased rate of bone resorption
and a compensatory decrease in serum
parathyroid concentrations.

Goss and colleagues have studied
the effects of exemestane on ovariectomized
Sprague-Dawley rats. After
16 weeks, the bone mineral density of the femur and spine in rats treated
with exemestane was significantly
higher than that in vehicle-treated
ovariectomized rats and was similar
to that of intact cycling rats. The principal
metabolite, 17-hydroexemestane,
prevented bone loss to a similar
degree and may account for the favorable
effects of exemestane on
bone. In this same model, letrozole
did not protect against bone loss.[4]

Anecdotally, we have documented
an increase in the bone mineral
density of the hip (53%) and spine
(57%) within 12 months of initiating
single-agent exemestane as treatment
of advanced disease. These data suggest
that exemestane may protect
bone from the loss associated with
oophorectomy, and this effect is being confirmed in ongoing clinical and preclinical studies.

The SERMs tamoxifen and raloxifene
produce an increase in bone
density and a decrease in the incidence
of bone fractures. The preclinical
and clinical data suggest that the
nonsteroidal inhibitors letrozole and
anastrozole decrease bone mineral
density, whereas exemestane protects
against bone loss or may increase
bone mineral density. The increased
bone fracture rate seen in the ATAC
trial with anastrozole is a matter for
concern. However, because tamoxifen
is known to increase bone density,
one cannot exclude the possibility
that the difference in fracture rates
reflects tamoxifen-lack more than an
adverse effect of anastrozole. More
data will be needed to determine the
long-term effects of the individual
antiaromatase agents on bone.

Lipid Profile/
Thromboembolic Events
Serial measurement of plasma lipids
in individual patients indicates that
tamoxifen produces a favorable, less
atherogenic profile than placebo in
postmenopausal women. Total cholesterol,
low-density lipoprotein (LDL)
cholesterol, lipoprotein(a), apolipoprotein
A1, and apolipoprotein B are
consistently decreased, whereas highdensity
lipoprotein (HDL) cholesterol
and triglycerides may be increased or
decreased. These changes are consistent
with estrogen-agonist effects.
However, tamoxifen does not produce
the same magnitude of change in these
parameters as seen with conventional
hormone-replacement therapy.[5]

The effect of raloxifene is similar
to that of tamoxifen. Serial lipid profiles
in women treated with raloxifene
demonstrate consistent decreases in
total cholesterol, lipoprotein (a), and
LDL cholesterol. HDL cholesterol
and triglyceride levels may be increased,
decreased, or unchanged
over baseline. Increases in apolipoprotein
A1 concentrations and
decreases in apolipoprotein B concentrations
are consistent with a decrease
in atherogenic potential.[6]
Homocysteine, also a predictor of cardiovascular disease, is decreased
in women treated with raloxifene.

Data from early controlled adjuvant
therapy trials suggest that women
treated with tamoxifen are less
likely to experience heart disease.
These findings were not supported
by the BCPT, which demonstrated
after a mean follow-up of 49 months
that tamoxifen had no impact on the
incidence of cardiovascular deaths,
even among patients with prior cardiac
disease.[7] The Early Breast
Cancer Trialists' Collaborative Group
(EBCTCG) has consistently demonstrated
an improvement in overall
survival among women treated with
tamoxifen but has been unable to
identify a decreased death rate from
cardiovascular causes.

In the MORE trial, participants were
not stratified according to cardiovascular
risk factors, and the results show
that the incidence of cardiovascular
events was comparable between
groups. However, a subset analysis of
135 women determined to be at highrisk
on the basis of recognized factors
such as prior myocardial infarction,
coronary artery bypass surgery, percutaneous
coronary intervention, diabetes,
age, smoking, hypertension, and
lipid profile, found that those assigned
to raloxifene had a significantly lower
incidence of cardiovascular events. The
Raloxifene Use for the Heart (RUTH)
study is an ongoing controlled multinational
trial designed to address the
cardiovascular effects of raloxifene in
over 10,000 women ≥ 55 years old, or
at risk for, coronary artery disease.

Antiaromatase Agents
In Sprague-Dawley rats, both
tamoxifen and toremifene (Fareston)
decreased serum cholesterol and triglyceride
levels, whereas anastrozole
did not produce a change in either.
Alterations in lipid profile have not
been observed in women treated with
anastrozole. Goss demonstrated an
adverse effect of letrozole on the lipid
profile of rats.[4] In healthy women
treated with letrozole, a significant
increase in total cholesterol, LDL
cholesterol, and apolipoprotein B levels
as well as total to HDL cholesterol
and LDL to HDL cholesterol ratios
was reported after 3 months.

Goss used the same ovariectomized
rat model described in his bone
studies to assess the effects of the
steroidal inactivator exemestane on
lipids. Exemestane completely protected
against adverse lipid changes
induced by ovariectomy, whereas
letrozole did not.[4] Women treated
with exemestane often experience a
decrease in total cholesterol and
triglyceride levels, suggesting that the
drug has no effect on atherogenic risk.
The available information suggests that
the effects of exemestane on plasma
lipid profiles may differ from those of
the nonsteroidal inhibitors.

Thromboembolic ComplicationsSERMs
The risk of venous thromboembolism
(VTE) in women with earlystage
breast cancer who are being
treated with tamoxifen is 1% to 6.8%.
This risk is higher than the increased
risk conferred by the cancer or its
therapy. Although participants in the
BCPT were healthy women without
a known predisposition to VTE, the
risk for VTE increased threefold
among women randomized to tamoxifen.
The risk was greater for women
over age 50 and appears to be comparable
to what has been reported
with conventional use of estrogen.[8]

As with tamoxifen, the incidence
of VTE is increased among women
treated with raloxifene.[8] Similar to
women in the BCPT, women participating
in the MORE trial did not have
cancer or any known predisposition to
thrombosis. The relative risk for VTE
among women in the MORE trial was
3.1, which is identical to the increased
risk for VTE associated with the use
of either tamoxifen or estrogen.[2]

Antiaromatase Agents
Fewer thromboembolic events
were seen with anastrozole than with
tamoxifen in the ATAC trial.[1] Because
tamoxifen is known to increase
the incidence of VTE, it is not clear
if anastrozole confers any increased
risk for clotting or merely causes fewer
VTEs than tamoxifen. In women
with advanced disease randomized
to either tamoxifen or an antiaromatase
agent, the incidence of VTEs was 23/506 (4.5%) for those treated with anastrozole compared with
39/511 (7.6%) for those receiving
tamoxifen. No VTEs were reported
in 946 women with advanced disease
treated with letrozole or in 527 treated
with exemestane. None of the antiaromatase
agents appear to increase
the risk of VTE.

Breast Cancer as a
Second Malignancy
The recognition that women treated
with adjuvant tamoxifen are less
likely to develop contralateral breast
cancers led to the design of the BCPT.
This trial demonstrated that women
receiving tamoxifen are less likely to
develop estrogen-receptor-positive
breast cancer than women receiving
a placebo. Results of a meta-analysis
of the chemoprevention trials with
tamoxifen support the BCPT finding
that tamoxifen decreases the incidence
of breast cancer.

The MORE trial was primarily designed
to assess the efficacy of raloxifene
in the treatment of osteoporosis,
but the incidence of breast cancer was
also considered. Women diagnosed
with breast cancer tend to have an
increase, not decrease, in bone mineral
density. Nonetheless, women receiving
raloxifene in the MORE trial were
less likely to develop breast malignancies.
Breast cancers were diagnosed in
13 of 5,129 women treated with raloxifene
compared with 27 of 2,576 in the
placebo arm (P Antiaromatase Agents
Our first glimpse of the effect of
the antiaromatase agents on the incidence
of breast cancer comes from
the ATAC trial. With a median follow-
up of 47 months, the incidence
of contralateral breast cancer was
lower in the anastrozole arm-25 of
3,125 compared with 40 of 3,116
women randomized to tamoxifen.
Until the adjuvant and chemoprevention
trials of letrozole and exemestane
have matured, it is not possible
to assess the efficacy of these agents
in the prevention of breast cancer.

Endometrial Cancer as a
Second Malignancy
The association between tamoxifen
use and an increased risk of
endometrial cancer was first appreciated
in the adjuvant therapy trials
and was recently confirmed by the
BCPT. Endometrial hyperplasia, endometrial
polyps, and possibly uterine
sarcomas are also more common
among women treated with tamoxifen.
A meta-analysis of data on
women with early breast cancer estimates
that tamoxifen increases the
risk for endometrial cancer 2.58-fold,
which is comparable to what has been
reported for women taking unopposed
estrogen. Death from tamoxifen-
related uterine cancer is
uncommon. In the BCPT, 36 cases
of endometrial cancer were diagnosed
among tamoxifen-treated patients
and 15 in the placebo arm; 50
of the 51 total cases were stage I

The preclinical studies suggesting
that raloxifene has neither an agonist
nor antagonist effect on the uterus
were supported by the MORE trial.
The incidence of endometrial abnormalities
in the MORE trial was identical
in the raloxifene and control
arms.[2] A placebo-controlled trial
of raloxifene in healthy women identified
no greater risk for vaginal
bleeding, spotting, or discharge in
the treatment arm, and ultrasonography
of the uterus indicated no obvious
structural differences between the
placebo-and drug-treated groups.[2]
Unlike tamoxifen, raloxifene does not
cause endometrial cancer.

Antiaromatase Agents
Numerous studies have examined
the effects of antiaromatase agents in
animal models. One true indicator of
estrogenic activity is the measurement
of changes in uterine development or
weight. Uterine weights were significantly
lower in nude mice treated with anastrozole or letrozole compared with
vehicle-treated (control) mice, indicating
that nonsteroidal inhibitors have no
effect on the endometrium. In rats with
DMBA-induced mammary tumors,
there was no evidence of intrinsic estrogenic
activity-either uterotropic or
antiuterotropic-following exemestane
therapy. To date, no cases of endometrial
cancer have been reported with the
use of antiaromatase agents in women
with advanced breast cancer.

In the ATAC trial, the incidence
of endometrial cancer was lower
among women treated with anastrozole
than among those treated with
tamoxifen. Because tamoxifen increases
the incidence of uterine
cancer, the trial cannot determine
whether anastrozole has any effect
on the uterus.[9] Longer follow-up in
this trial and additional data from
ongoing trials will be needed before
an adverse effect from the antiaromatase
agents can be discounted.

Quality of LifeSERMs
Many of the controlled trials of
SERMs have addressed side effects
that could affect quality of life; however,
few have conducted systematic
quality-of-life assessments. Those that
did generally report no differences
for SERMs vs placebo or SERMS vs
other adjuvant therapy.[10]

Antiaromatase Agents
Quality of life has not been extensively
studied in women receiving antiaromatase
agents. In large phase III
studies comparing quality-of-life
measures in patients receiving antiaromatase
agents or megestrol acetate,
no significant differences emerged
among women with advanced disease
in the anastrozole, letrozole, or megestrol
arms. In contrast, quality of life
was superior in postmenopausal women
with advanced disease who received
exemestane vs megestrol. In the ATAC trial, the primary quality-of-life end
point was the Treatment Outcome
Index (TOI). Preliminary analysis of
data after 2 years on study identified
no significant differences in index
scores for anastrozole vs tamoxifen, or
for the combination therapy vs tamoxifen


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