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Aromatase Inhibitors for Breast Cancer

in Postmenopausal Women
SUSANA M. CAMPOS
Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Key Words. Breast cancer · Aromatase inhibitor · Metastatic disease

A BSTRACT
Third-generation aromatase inhibitors are potent
inhibitors of the aromatase enzyme, which catalyzes the
last step in estrogen biosynthesis. These agents are active
against breast cancer in hormone-naïve postmenopausal
women and in women who have experienced failure of
tamoxifen or failure of tamoxifen plus other hormonal
therapy. There are two types of aromatase inhibitors,
irreversible steroidal activators (e.g., exemestane) and
reversible nonsteroidal imidazole-based inhibitors (e.g.,
anastrozole, letrozole). Recent data suggest that some
women who experience failure of one type of aromatase
inhibitor can subsequently derive benefit from the other
type. The reason for this lack of cross-resistance is
unknown. This finding of non-cross-resistance between
steroidal aromatase activators and nonsteroidal aro-
matase inhibitors offers the opportunity to increase the
number of lines of hormone therapy before making the
inevitable switch to more toxic chemotherapy, thus poten-
tially improving quality of life for postmenopausal women
with advanced disease.
Data from postmenopausal women with advanced dis-
ease suggest that steroidal and nonsteroidal aromatase
inhibitors have similar tolerability profiles; however,
emerging data suggest that there may be differences in
their effects on end organs, which may become evident
with longer term use, such as in the adjuvant or prevention
settings. Steroidal agents appear to have beneficial effects
on lipid and bone metabolism, whereas nonsteroidal
agents may have neutral or unfavorable effects. These dif-
ferences may be attributed to the androgenic effects of
steroidal agents; clinical trials are currently under way to
confirm these suspicions. The Oncologist 2004;9:126-136

INTRODUCTION This article reviews data on the two types of aromatase

For more than 30 years, the antiestrogen tamoxifen has
been the mainstay of hormonal therapy in postmenopausal
women with breast cancer, followed by megestrol acetate
and then the second-generation nonsteroidal aromatase
inhibitor aminoglutethimide. Now, based on data from
large, well-conducted clinical trials, aromatase inhibitors
have replaced megestrol acetate for use after failure of
tamoxifen [1-6] and are challenging tamoxifen as initial
therapy in women with advanced disease [7-12]. Aromatase
inhibitors also show promise for adjuvant therapy and
neoadjuvant therapy, as well as in the prevention of breast
cancer [13-16].
inhibitors and their use in postmenopausal women with
breast cancer.
MECHANISM OF ACTION OF AROMATASE
INHIBITORS
Aromatase inhibitors can be categorized by generation
and by mechanism of action. The third-generation aro-
matase inhibitors, which include exemestane, anastrozole,
and letrozole, are potent and selective inhibitors of aro-
matase activity and are the focus of this review.
The aromatase enzyme is required for the last step in
estrogen biosynthesis. The biochemical effect of aromatase

Correspondence: Susana M. Campos, M.D., M.P.H., Dana-Farber Cancer Institute, 44 Binney Street, Boston,
Massachusetts 02115, USA. Telephone: 617-632-6766; Fax: 617-632-5610; e-mail: Susana_Campos@dfci.harvard.edu
Received January 29, 2003; accepted for publication November 14, 2003. ©AlphaMed Press 1083-7159/2004/$12.00/0

The Oncologist 2004;9:126-136 www.TheOncologist.com

127
inhibitors, as measured by the degree of aromatase inhibi-
tion, is approximately 98% for each of the third-generation
agents [17-19]. This value also is reflective of the estrogen
suppression achieved in the blood with these aromatase
inhibitors.
There are two types of aromatase inhibitors, irre-
versible steroidal activators and reversible nonsteroidal
imidazole-based inhibitors. Although both types interfere
with the final step in estrogen biosynthesis, they do so by
different mechanisms. Steroidal agents, such as exemes-
tane, have an androgen structure and compete with the nat-
ural aromatase substrate androstenedione; they bind
irreversibly to the catalytic site of aromatase causing loss of
enzyme activity, and more aromatase enzyme must be pro-
duced before estrogen biosynthesis can resume. Therefore,
steroidal agents are often referred to as suicide inhibitors.
Because of their steroidal structure, exemestane and its 17-
hydroexemestane metabolite have the potential for andro-
genic effects. The binding of exemestane to the androgen
receptor is about 0.2% that of dihydrotestosterone [20], but
the affinity of 17-hydroexemestane for the androgen recep-
tor is about 100 times that of the parent compound [21].
Nonsteroidal imidazole-based agents reversibly interact
with the cytochrome P450 moiety of the enzyme [22], and
interference with estrogen biosynthesis is dependent on the
continued presence of the nonsteroidal agent [23]. Non-
steroidal agents include the second-generation agent amino-
glutethimide and the third-generation agents anastrozole and
letrozole.
The in vitro effect of aromatase inhibitors on tissue aro-
matase activity in cultured fibroblasts has been used to
demonstrate differences in the effects of steroidal and non-
steroidal agents on aromatase activity (Fig. 1). Differences
in the mechanisms of action of steroidal and nonsteroidal
aromatase inhibitors were evaluated by preincubating cul-
tured fibroblasts from mammary adipose tissue with an aro-
matase inhibitor for 18 hours and
then assaying the aromatase activ-
ity in the absence of the drug. Steroidal inhibitors
200
Paradoxically, all the reversible
nonsteroidal aromatase inhibitors
150
caused enhanced aromatase activ-
% of control
ity at one or more concentrations
tested. In contrast, exemestane and 100
formestane (a second-generation
50
Figure 1. In vitro effect of aromatase
inhibitors on tissue aromatase activity
evaluated in cultured fibroblasts. 0
The clinical significance of these
differences is unknown. Reprinted with
permission from Miller and Dixon [15].
Aromatase Inhibitors for Breast Cancer
steroidal agent) induced a marked inhibition of aromatase activ-
ity at all concentrations tested [3]. The clinical significance
of these differences is currently unknown.
CLINICAL TRIALS DEMONSTRATING EFFICACY OF
AROMATASE INHIBITORS IN POSTMENOPAUSAL
WOMEN
Each of the third-generation aromatase inhibitors has
been compared with megestrol acetate and tamoxifen in
women with advanced disease and each is being evaluated
for use in adjuvant therapy, neoadjuvant therapy, and for
prevention.
Advanced Disease
Aromatase Inhibitors after Failure of Tamoxifen
Initial research with aromatase inhibitors was con-
ducted in postmenopausal women with advanced disease
experiencing failure of tamoxifen. Each of the third-gener-
ation aromatase inhibitors was evaluated in this setting and
each demonstrated efficacy (Table 1) [1-5]. Studies com-
paring aromatase inhibitors with megestrol acetate enrolled
women whose disease became resistant to tamoxifen used
either as adjuvant therapy or for advanced disease (Fig. 2).
A substantial percentage of patients (approximately 40% in
each study) received prior tamoxifen for adjuvant therapy
only. Therefore, women enrolled in those trials were being
treated either with initial hormonal therapy for advanced
disease or after failure of tamoxifen for advanced disease.
Exemestane, 25 mg daily, was compared with megestrol
acetate, 40 mg four times daily. Exemestane was associated
with a numerically higher objective response (OR) rate; how-
ever, the difference did not reach statistical significance.
Exemestane was associated with statistically significant ben-
efits in all time-dependent variables, including duration of
clinical benefit, time to tumor progression (TTP), time to
Nonsteroidal inhibitors
Aminoglutethimide
Anastrozole
Letrozole
Formestane
Exemestane
Concentration (nm) Concentration (µm)
1 10 100 1 10 100 1 10 100 1 10 100 1 10 100
 Campos 128

Table 1. Aromatase inhibitors versus megestrol acetate for first- or second-line therapy in postmenopausal women with advanced disease who progressed after tamoxifen
Aromatase inhibitor versus megestrol acetate 160 mg daily
Exemestane 25 mg daily [1] Anastrozole 1 mg daily Letrozole 2.5 mg daily
Study 1 [3] Study 2 [2] Study 1 [4] Study 2 [5]
n of patients 366 versus 403 128 versus 128 135 versus 125 174 versus 189 199 versus 201
OR rate (%) 15.0 versus 12.4 10.2 versus 5.5 10.4 versus 10.4 23.6 versus 16.4a 16.1 versus 14.9
b
Overall clinical benefit (%) 37.4 versus 34.6 36.7 versus 35.2 34.1 versus 32.8 34.5 versus 31.7 26.7 versus 23.4
Duration of clinical benefit (months) 13.8 versus 11.3a Not reportedc Not reported 23.5 versus 14.5a 18 versus 15
a c d
Median survival (months) NR versus 28.4 Not reported Not reported 23.3 versus 21.5 29 versus 26
Median TTP (months) 4.7 versus 3.8a 5.6 versus 5.0 4.3 versus 3.9 5.6 versus 5.5 3 versus 3
a a
Median TTF (months) 3.8 versus 3.6 5.5 versus 4.1 4.0 versus 3.8 5.1 versus 3.9 3 versus 3

Abbreviation: NR = not reached; OR = complete response plus partial response.

a
Difference is statistically significant.
b
Complete response plus partial response plus stable disease ≥24 weeks.
c
Kaplan-Meier probability of median time to death (data not provided) demonstrated no statistically significant difference between groups.
d
Median survival was 84.4% for anastrozole and 77.6% for megestrol acetate (difference not statistically significant).

treatment failure (TTF), and survival time. There was an
18% relative risk reduction in TTP and a 23% risk reduction
in risk of death with exemestane versus megestrol acetate.
Exemestane was well tolerated, with a frequency of grade 3
or 4 adverse events of 4.8%, versus 7.5% for megestrol
acetate. The most frequently reported adverse events in
women treated with exemestane were low-grade hot flashes,
nausea, and fatigue. Greater weight gain was reported in
patients treated with megestrol acetate [1].
The two studies comparing anastrozole efficacy with
that of megestrol acetate did not report a statistically signif-
icant difference in key end points (OR, median survival,
TTP, TTF) between anastrozole (1 mg daily) and megestrol
acetate (160 mg daily), although results for each end point
were numerically superior for anastrozole [2, 3]. In a subse-
quent pooled analysis of these two trials conducted at a
median follow-up of 31 months, a statistically significant
survival advantage was found for anastrozole [6]. As with
the earlier individual analyses, the pooled analysis did not
identify statistically significant differences in other end
points. Both studies also evaluated 10 mg daily anastrozole
and found no statistically significant differences between the
1-mg and 10-mg doses [2, 3]. In these studies, anastrozole
and megestrol acetate were well tolerated; the most common
adverse events reported in women taking anastrozole were
asthenia, nausea, headache, hot flashes, and pain [24].
Two studies were also conducted with letrozole. One
study, by Dombernowsky and colleagues [4], compared two
doses of letrozole with megestrol acetate as second-line ther-
apy in postmenopausal women. Letrozole, at a dose of 2.5
mg, produced a significantly higher overall OR rate (24%)
than megestrol acetate (16%; p = 0.04) and than letrozole at
a dose of 0.5 mg (13%; p = 0.004). The duration of OR was
significantly longer for 2.5 mg letrozole than for megestrol
acetate; 2.5 mg letrozole was significantly superior to mege-
strol acetate and 0.5 mg letrozole in TTF. For TTP, 2.5 mg
letrozole was superior to the 0.5-mg dose but not to mege-
strol acetate. A significant dose effect on overall survival was
observed with the higher letrozole dose, compared with the
lower dose of letrozole. In contrast to the first study, the sec-
ond study, by Buzdar and colleagues [5], showed no statisti-
cally significant differences among the three treatment
groups for overall objective tumor response. Letrozole, 0.5
mg, was found to be superior to megestrol acetate in TTP and
TTF. A dose-response relationship was not noted in the sec-
ond study. Letrozole was well tolerated. The most frequent
adverse events reported in women treated with letrozole were
hot flashes, nausea, diarrhea, musculoskeletal pain, dyspnea,
and headache [4, 5].
Direct comparative data on aromatase inhibitors are
beginning to emerge. In an open-label, randomized, phase
IIIB-IV study, anastrozole (1 mg daily) was compared with
letrozole (2.5 mg daily) in 713 postmenopausal women
with advanced breast cancer whose disease became resis-
tant to tamoxifen used either as adjuvant therapy or for
advanced disease [25]. Approximately half the patients had
an unknown estrogen-receptor status. The primary end
point, TTP, was similar in both groups, as were the sec-
ondary end points, including clinical benefit, TTF, duration
of response, and duration of clinical benefit. In the overall
population, the secondary end point OR rate statistically
significantly favored letrozole (19.1% versus 12.3% for
129 Aromatase Inhibitors for Breast Cancer

First Second
line therapy line therapy

D I S E A S E
Megestrol
acetate 60% of
women

A D V A N C E D
Tamoxifen enrolled
in phase
III studies
Aromatase
inhibitor
Postmenopausal
women with early Adjuvant
breast cancer tamoxifen
T O
P R O G R E S S I O N

Figure 2. Prior hormonal therapy in

women enrolled in clinical trials compar- Megestrol
40% of
ing aromatase inhibitors with megestrol acetate
women
acetate. Approximately 40% of women enrolled
enrolled in these trials received either an in phase
aromatase inhibitor or megestrol acetate as III studies
Aromatase
initial hormonal therapy for advanced dis- inhibitor
ease and 60% received one of these agents
after failure of tamoxifen for advanced
disease.

anastrozole, p = 0.014) [25]; however, this benefit was not
seen in women with estrogen-receptor-positive disease
(17.3% for letrozole versus 16.8% for anastrozole) [26].
Both agents were well tolerated, but nausea was more com-
mon with anastrozole (11%) than with letrozole (8%) [25].
In each of these comparative studies with megestrol
acetate, the aromatase inhibitors offered a superior safety
profile, with less weight gain and significant improvements
in quality of life.
Aromatase Inhibitors versus Tamoxifen
In comparative studies with tamoxifen, each of the
third-generation aromatase inhibitors demonstrated clinical
efficacy in postmenopausal women with advanced breast
cancer (Table 2) [7-12, 27]. All the studies comparing aro-
matase inhibitors with tamoxifen enrolled postmenopausal
women whose disease became resistant to tamoxifen as
adjuvant therapy and women who were tamoxifen naïve
(Fig. 3). None of the women in those studies had previously
received tamoxifen for advanced disease. In fact, approxi-
mately 80% were tamoxifen naïve and had never even
received tamoxifen for adjuvant therapy.
The nonsteroidal aromatase inhibitors anastrozole and
letrozole demonstrated clinical efficacy as initial therapy of
postmenopausal women with advanced breast cancer in
phase III trials. Anastrozole was compared with tamoxifen in
two studies and demonstrated at least comparable efficacy in
both [9, 10]. When a combined analysis of the two anastro-
zole trials was conducted, differences in OR rate, clinical
benefit, and TTP did not reach statistical significance [27].
Letrozole was compared with tamoxifen in one study, in
which it demonstrated statistically significant superiority in
OR rate, clinical benefit, TTP, and TTF [11, 12].
The steroidal agent exemestane was compared with
tamoxifen in a randomized European Organization for
Research and Treatment of Cancer (EORTC) phase II/III
trial [7]. In the phase II portion of the study, exemestane
produced an OR rate of 40.9% and a clinical benefit of
55.7%; the corresponding values for tamoxifen were
13.6% and 42.4%, respectively [7]. The positive results of
this randomized phase II study led the EORTC to extend it
to a randomized phase III study, which is still under way.
The results of the phase III study are required to confirm
these data.
Campos 130

Table 2. Aromatase inhibitors versus tamoxifen for initial therapy of metastatic breast cancer in postmenopausal women
Aromatase inhibitor versus tamoxifen
Phase III randomized studies Phase II randomized study
Anastrozole 1 mg daily Letrozole 2.5 mg daily [11, 12] Exemestane 25 mg daily [7, 8]
Study 1 [9] Study 2 [10]
n of patients 171 versus 182 340 versus 328 453 versus 454 61 versus 59
OR rate (%) 21.1 versus 17.0 32.9 versus 32.6 32 versus 21a 40.9 versus 13.6
Clinical benefitb (%) 59.1 versus 45.6a 56.2 versus 55.5 50 versus 38a 55.7 versus 42.4
a,c a
TTP (months) 11.1 versus 5.6 8.2 versus 8.3 9.4 versus 6.0 8.9 versus 5.2
a
TTF (months) 7.6 versus 5.4 6.2 versus 6.0 9.0 versus 5.7 Not reported
a
Difference is statistically significant.
b
Complete response plus partial response plus stable disease ≥ 24 weeks.
c
Nonprotocol analysis.

Figure 3. Prior hormonal therapy in women enrolled

D I S E A S E

in clinical trials comparing aromatase inhibitors with

tamoxifen. Approximately 80% of women treated for
metastatic disease were tamoxifen naïve, while 20%
had received tamoxifen for adjuvant therapy before
progressing to advanced disease.
A D V A N C E D
80% of women

No
O

adjuvant Tamoxifen
Tamoxifen
naïve patients
I

tamoxifen
T
A
Z

Postmenopausal
women with
I
T O

early breast cancer

M
O
P R O G R E S S I O N

D
N
A
R
20% of women

Adjuvant Failed Aromatase

tamoxifen adjuvant inhibitors
tamoxifen
131 Aromatase Inhibitors for Breast Cancer

Sequential Use of Aromatase Inhibitors
There is evidence to suggest that aromatase inhibitors
may maintain their efficacy when used sequentially. The
steroidal aromatase inhibitor exemestane is effective after
failure of tamoxifen and megestrol acetate [28] and after
failure of tamoxifen and a nonsteroidal aromatase inhibitor
(e.g., aminoglutethimide, anastrozole, letrozole) [29, 30].
The nonsteroidal aromatase inhibitors are effective after
failure of exemestane [29, 30]. Clinical trials currently are
being conducted to determine the most appropriate
sequence for hormonal therapy administration.
Bertelli and colleagues evaluated the sequential use of
steroidal and nonsteroidal aromatase inhibitors in post-
menopausal women with advanced breast cancer [30].
Participants were permitted, but not required, to have had
previous chemotherapy or tamoxifen either as adjuvant ther-
apy or for advanced disease. This study is ongoing, but pre-
liminary results are available. About 60% of participants had
received previous endocrine therapy. Women receiving
exemestane as their first aromatase inhibitor were adminis-
tered anastrozole or letrozole at the time of disease progres-
sion, and women receiving letrozole or anastrozole as their
first aromatase inhibitor were given exemestane at the time
of disease progression. Women treated with exemestane as
their first aromatase inhibitor achieved an OR rate of 18.7%
and clinical benefit rate of 46.9%. OR rates and clinical ben-
efit rates were 10% and 40%, respectively, in women receiv-
ing letrozole or anastrozole after experiencing failure of
exemestane, and 4.2% and 25%, respectively, in women
receiving exemestane after experiencing failure of anastro-
zole or letrozole [30]. Other clinical studies also suggest non-
cross-resistance between steroidal and nonsteroidal agents
[29] and the effectiveness of aromatase inhibitors even after
several lines of hormonal therapy (Table 3) [1-5, 7, 9-12, 28].
The efficacy of one type of aromatase inhibitor after
failure of another is surprising, given the fact that all the
third-generation agents suppress circulating estrogen con-
centrations to a similar extent [17-19]. Although the reason
for non-cross-resistance is unknown at this time, it is possi-
bly due to structural differences among aromatase inhibitors
(i.e., steroidal versus nonsteroidal imidazole), which may
lead to different pharmacokinetic and pharmacologic pro-
files, or differences in the ways in which these agents inter-
act with the aromatase enzyme. As an example, because of
their steroidal structure, exemestane and its 17-hydroex-
emestane metabolite may have androgenic effects that con-
tribute to antitumor activity. Although clinically important
androgenic adverse events have not been reported at the rec-
ommended exemestane dose of 25 mg daily [1], hypertri-
chosis, hair loss, hoarseness, and acne were reported in
about 10% of patients treated with daily exemestane doses
of 200 mg or more [31, 32]. It is possible that, although not
clinically apparent, recommended doses of steroidal agents
may have some androgenic effects [33].
A pilot, randomized, open-label, crossover, multicenter
study (by the Spanish Breast Cancer Research Group,
GEICAM) [34] will assess the sequential use of exemestane
followed by anastrozole at progression compared with the

Table 3. Summary of aromatase inhibitor efficacy in advanced disease based on sequence of administration of hormonal therapy
Sequence of hormonal therapy Reference n OR (%) Clinical benefit (%)
Steroidal inhibitor (i.e., exemestane 25 mg daily) as last therapy
Steroidal inhibitor or tamoxifen (adj) → steroidal inhibitor [7] 61 41 56
Tamoxifen (adj) → steroidal inhibitor or tamoxifen (adj) → tamoxifen (adv) → steroidal inhibitor [1] 366 15 37
Tamoxifen → megestrol acetate → steroidal inhibitor [28] 91 13 30
Tamoxifen → nonsteroidal inhibitor → steroidal inhibitor [29, 30] 241 6.6 24
Tamoxifen → hormonal therapy → nonsteroidal inhibitor → steroidal inhibitor 24 4.2 25
Nonsteroidal inhibitor (i.e., anastrozole 1 mg daily, letrozole 2.5 mg daily) as last therapy
Nonsteroidal inhibitor or tamoxifen (adj) → nonsteroidal inhibitor [9] 171 21 59
[10] 340 33 56
[11, 12] 453 32 50
Tamoxifen (adj) → nonsteroidal inhibitor or tamoxifen (adj) → tamoxifen (adv) → nonsteroidal inhibitor [2] 135 10 34
[3] 128 10 37
[4] 174 24 35
[5] 199 16 27
Tamoxifen → aromatase inactivator → nonsteroidal inhibitor [30] 10 10 40

Abbreviations: adj = as adjuvant therapy; adv = for advanced disease.

Campos
opposite sequence in 100 postmenopausal women with hor-
mone-receptor-positive advanced breast cancer. The primary
outcome measure will be response rate.
Collectively, these data demonstrate that aromatase
inhibitors are effective treatment for advanced breast cancer
in postmenopausal women, including hormone-naïve
women and women who have experienced failure of tamox-
ifen, tamoxifen plus megestrol acetate, or multiple lines of
hormonal therapy.
Adjuvant Therapy
The use of aromatase inhibitors for adjuvant therapy is a
natural extension of their successful use in advanced disease.
Research is being conducted with each of the aromatase
inhibitors in this setting, but the first results to be released are
from the Arimidex or Tamoxifen Alone or in Combination
(ATAC) study enrolling 9,366 patients. Postmenopausal
women with operable breast cancer were randomized to
treatment with anastrozole (1 mg daily), tamoxifen (20 mg
daily), or the combination for 5 years [13]. At a median fol-
low-up of 47 months, there were no significant differences
between the tamoxifen and the combination arms. However,
anastrozole alone was superior to tamoxifen alone in disease-
free survival (p = 0.03) and time to first recurrence (p = 0.015),
with the benefits being most apparent in hormone-receptor-
positive women. There also was a lower incidence of con-
tralateral breast cancer in anastrozole-treated women versus
tamoxifen-treated women (p = 0.06), which reached statistical
significance in those who were hormone-receptor positive
(p = 0.042) [35].
Long-term safety takes on added importance in this set-
ting because adjuvant hormonal therapy is typically adminis-
tered for several years to women who are likely to experience
long-term survival. Safety data presented after 37 months of
Table 4. Adjuvant therapy studies using aromatase inhibitors
Study
National Surgical Adjuvant Breast Project (NSABP) B-33
NCIC MA17
Breast International Group (BIG) 031
Breast International Group/Femara-Tamoxifen
(BIG/FEMTA)
U.S. Oncology Group Tamoxifen and Exemestane
Adjuvant Multicenter (USON/TEAM)
NCIC Clinical Trials Group (CTG) MA27
Anastrozole × 5 years ± celecoxib × 3 years
Arimidex versus Nolvadex (ARNO)
132
treatment in the ATAC study reveal that patients treated with
anastrozole had lower rates of endometrial cancer (relative
risk [RR] = 0.25), vaginal bleeding (RR = 0.54), vaginal dis-
charge (RR = 0.25), cerebrovascular events (RR = 0.49),
thromboembolic events (RR = 0.59), and hot flashes (RR =
0.87) than women receiving tamoxifen. Anastrozole-treated
women had a higher incidence of musculoskeletal disorders
(RR = 1.28) and more fractures (RR = 1.60). Although the
percentage of women with adverse events was similar in both
arms (92.1% for anastrozole versus 93.3% for tamoxifen),
fewer women withdrew from the anastrozole arm (24.1% ver-
sus 28.3%), and significantly fewer withdrew due to adverse
events (5.6% versus 8.1%) [13]. Similar long-term data are
not yet available for the other aromatase inhibitors, but large,
randomized, clinical trials are currently maturing (Table 4).
Recently reported were the results of the National
Cancer Institute of Canada (NCIC) MA17 trial, a double-
blinded, placebo-controlled trial designed to test the effec-
tiveness of 5 years of letrozole therapy in postmenopausal
women with breast cancer who had completed 5 years of
tamoxifen. With a median follow-up of 2.4 years and at the
first interim analysis, a statistically significant difference
emerged. An estimated 4-year disease-free survival rate of
93% was noted in the letrozole arm, versus 87% in the
placebo arm. No statistically significant difference in over-
all survival was apparent at the time of this analysis. Low-
grade hot flashes and arthritis were more common in the
letrozole arm. No statistically significant difference in the
new diagnosis of osteoporosis was observed (5.8% in the
letrozole arm versus 4.5% in the placebo arm; p = 0.07).
Given the positive results of the trial, it was terminated [36].
Although this article focuses on the use of aromatase
inhibitors in postmenopausal women, it is important to
mention that there are several trials using aromatase
Treatment
Prior to randomization Randomized treatment
Tamoxifen × 5 years Exemestane × 5 years versus placebo × 5 years
Tamoxifen × 5 years Letrozole × 5 years versus placebo × 5 years
Tamoxifen × 2-3 years Tamoxifen × 3-2 years versus exemestane × 3-2 years
Letrozole × 5 years versus tamoxifen × 2 years then
letrozole × 3 years versus letrozole × 2 years then
tamoxifen × 3 years versus tamoxifen × 5 years
Tamoxifen × 5 years versus exemestane × 5 years
Exemestane × 5 years ± celecoxib × 3 years
Tamoxifen × 2 years Tamoxifen × 3 years versus anastrozole × 3 years
133
inhibitors (in the presence of ovarian function suppression)
in the adjuvant setting in premenopausal women. One such
trial is the Suppression of Ovarian Function Trial (SOFT).
This is a phase III trial evaluating the role of ovarian func-
tion suppression and exemestane as adjuvant therapy in pre-
menopausal women with endocrine-responsive breast
cancer. The Tamoxifen and Exemestane Trial (TEXT) and
Premenopausal Endocrine-Responsive Chemotherapy
(PERCHE) trial also are evaluating the use of exemestane
in premenopausal women [37, 38].
Breast Cancer Prevention
Epidemiologic studies have clearly demonstrated a link
between estrogen exposure and breast cancer development
[39]. As further evidence of this link, the antiestrogen
tamoxifen has been shown to prevent the development of
breast cancer in women with above average cancer risks
[40]. However, the use of tamoxifen has been limited by an
association with endometrial cancer, thromboembolic
events, and tolerability concerns [41].
The same rationale for the use of tamoxifen in breast
cancer prevention applies to the aromatase inhibitors.
However, since there is evidence that both estrogens and
estrogen metabolites may initiate breast cancer [42], aro-
matase inhibitors may offer added benefit. Whereas anti-
estrogens block the action of estrogens, leaving potentially
carcinogenic estrogen metabolites available to exert their
effects, aromatase inhibitors block the formation of estrogens
and, therefore, estrogen metabolites.
Initial data supporting the use of tamoxifen for preven-
tion were obtained from clinical trials demonstrating a lower
incidence of contralateral breast cancer in tamoxifen-treated
women. Likewise, early data from the ATAC trial demon-
strate a greater reduction in the incidence of contralateral
breast cancer with anastrozole than with tamoxifen, particu-
larly in women with hormone-positive disease [13].
However, in contrast to tamoxifen, aromatase inhibitors have
few tolerability concerns. Information about long-term
effects is beginning to emerge from adjuvant therapy trials.
Several trials are currently under way to assess the role
of aromatase inhibitors in breast cancer prevention (Table 5).
Table 5. Ongoing prevention trials with aromatase inhibitors
Trial
International Breast Cancer Intervention Study II (IBIS-II)
Italian Risk Reduction Aromatase Inhibitor Study (ApreS)
NCIC CTG MAP.2
NCIC CTG MAP.3
Women with Increased Serum Estradiol (WISE)
Aromatase Inhibitors for Breast Cancer
Neoadjuvant Therapy
The rationale for the use of aromatase inhibitors for
neoadjuvant therapy is to shrink hormone-responsive tumors
before surgical resection. Each of the aromatase inhibitors
has been successfully evaluated in this setting; they are asso-
ciated with dramatic reductions in aromatase activity in
breast cancer tissue and in nonmalignant surrounding tissue
and a substantial reduction in tumor volume, thus allowing
the use of breast-conserving surgery [14, 16, 43, 44].
Aromatase Inhibitor Safety in Postmenopausal Women
Aromatase inhibitors are generally well tolerated, and
adverse events are usually mild to moderate in post-
menopausal women with metastatic disease. In comparative
trials with megestrol acetate, fewer women treated with aro-
matase inhibitors discontinued treatment because of adverse
events, and weight gain was less problematic. The most
commonly reported adverse events in women treated with
aromatase inhibitors were hot flashes, nausea, vomiting,
headache, and fatigue [1-6].
The effects of chronic aromatase inhibitor administra-
tion are being assessed in adjuvant therapy and prevention
trials and will be key factors in determining the usefulness
of these agents in long-term therapy settings. Hot flashes,
cardiovascular disease, and osteoporosis are important
issues for postmenopausal women because they are at
increased risk for these complications due to age-related
loss of ovarian estrogen production. Since aromatase
inhibitors are currently used primarily in postmenopausal
women, there is considerable interest in how they affect the
incidence of hot flashes and bone and lipid metabolism.
Hot Flashes
In a small phase II study comparing exemestane with
tamoxifen for first-line hormone therapy of metastatic breast
cancer in postmenopausal women, the incidence of grade 2 or
greater hot flashes was lower with exemestane (3.2%) than
with tamoxifen (13.5%) [7], while the incidences of hot flashes
of any grade were 23.3% and 28.8%, respectively [45]. These
results are being confirmed in the phase III portion of that
study. When used for advanced disease, the incidence of hot
Treatment
Anastrozole versus placebo
Exemestane versus placebo
Exemestane versus placebo
Exemestane versus placebo versus exemestane ± celecoxib
Letrozole versus placebo
Campos
flashes of all grades with nonsteroidal aromatase inhibitors
was similar to that reported with tamoxifen [12, 27]. However,
in the ATAC adjuvant therapy trial, the incidence of hot
flashes was higher in the tamoxifen-treated group (40.3%)
than in the group treated with anastrozole alone (35.0%) [46].
Lipid Metabolism
The effect of exemestane on lipid metabolism was evalu-
ated in a subset of 122 (only 72 patients were included in the
substudy) postmenopausal women with advanced breast cancer
enrolled in a phase II/III study comparing exemestane with
tamoxifen for first-line therapy [47]. After 24 weeks of treat-
ment, there were no changes in total cholesterol, high-density
lipoprotein cholesterol, or apolipoprotein A1/apolipoprotein B
(Apo A1/B) levels in patients treated with exemestane. Among
patients treated with exemestame, there were significantly
(p = 0.012) fewer patients with >20% elevations in triglyceride
levels relative to those patients treated with tamoxifen [47].
Lipid effects of exemestane were further characterized in
a study conducted by Goss et al. in 10-month-old Sprague-
Dawley female rats. In that preclinical study, exemestane
protected against the adverse lipid effects induced by
oophorectomy [48].
Dewar and colleagues [49] report no significant lipid
changes in postmenopausal women treated with anastrozole
for fewer than 20 months. Wojtacki et al. [50] studied both
anastrozole (n = 27) and letrozole (n = 3) in postmenopausal
women for a median of 32 weeks. Their preliminary results
suggest that neither anastrozole nor letrozole affect lipid
metabolism. Harper-Wynne and coworkers [51] reported no
negative effects on lipid metabolism after 3 months of treat-
ment with letrozole. In contrast, in a study conducted in 20
postmenopausal women treated with letrozole at a dose of
2.5 mg daily for 16 weeks, there were significant increases in
total cholesterol, low-density lipoprotein cholesterol, and
Apo B levels [52].
These data suggest that the steroidal aromatase
inhibitor exemestane may have beneficial effects on lipid
metabolism that are not exhibited by the nonsteroidal
agents anastrozole and letrozole. These remain preliminary
data and must be confirmed in long-term studies.
Bone Metabolism
The study by Goss et al., evaluating the effect of
exemestane on lipid metabolism in Sprague-Dawley rats,
also evaluated the effect of exemestane on bone metabolism
[48]. Exemestane protected against the negative effects of
oophorectomy on bone metabolism. In a second study of
similar design, both exemestane and 17-hydroexemestane
protected against the negative effects of oophorectomy on
bone metabolism, while letrozole offered no benefit [53].
134
The effect of letrozole (2.5 mg daily for 3 months) on
bone metabolism was studied in 29 healthy postmenopausal
women using a marker of bone resorption. The marker
increased significantly, suggesting a possible negative impact
of letrozole on bone [51].
In the large adjuvant therapy ATAC trial, women treated
with anastrozole alone had a 7.1% incidence of fractures com-
pared with a 4.4% incidence in women treated with tamoxifen
alone. Musculoskeletal disorders were also more common in
anastrozole-treated women [46]. The greater fracture risk
noted in the ATAC trial is cause for concern when consider-
ing the use of nonsteroidal aromatase inhibitors for long-term
administration.
Preclinical data suggesting that the steroidal aromatase
inhibitor exemestane has a beneficial effect on bone metab-
olism that is not seen with nonsteroidal agents must be
confirmed in long-term clinical trials.
CONCLUSIONS
Aromatase inhibitors are supplanting tamoxifen as the
most widely used hormonal agent in the treatment of breast
cancer. They are highly effective in postmenopausal women
with advanced breast cancer, including hormone-naïve
women and women who experience failure of tamoxifen
alone or tamoxifen plus other hormonal agents [1-5, 7-12].
Emerging data also demonstrate efficacy in postmenopausal
women treated in the adjuvant [13] and neoadjuvant [14, 16,
43, 44] settings. It is postulated that similar results also will
be obtained with aromatase inhibitors in the adjuvant therapy
of premenopausal women with endocrine-responsive breast
cancer undergoing ovarian suppression [36, 37]. In addition,
aromatase inhibitors are being evaluated for prevention and
in combination with chemotherapy and targeted therapies.
Clinical trials are currently under way to determine the
comparative safety and efficacy of various aromatase
inhibitors, as well as the most appropriate sequence of admin-
istration of hormonal therapy, including tamoxifen, serum
estrogen receptor downregulators, steroidal aromatase
inhibitors, and nonsteroidal aromatase inhibitors. Current data
suggest that there is a lack of cross-resistance between
steroidal and nonsteroidal agents. Lack of cross-resistance
will allow for another hormonal therapy option before switch-
ing to chemotherapy in women with advanced breast cancer.
Data from short-term studies in metastatic disease
demonstrate that aromatase inhibitors are better tolerated
than megestrol acetate and tamoxifen. Preliminary data
comparing anastrozole with tamoxifen in the adjuvant set-
ting also support the superior tolerability of aromatase
inhibitors. Preclinical and short-term clinical data suggest
that this may not be a class effect; steroidal agents may
have beneficial effects on bone and lipid metabolism while
135
nonsteroidal agents may have neutral or detrimental
effects. It is postulated that these beneficial effects of
steroidal aromatase inhibitors may be a result of the andro-
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