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review article
drug therapy
Alastair J.J. Wood, M.D., Editor
in chemoprevention, a strategy in which tamoxifen has already been shown to reduce N Engl J Med 2003;348:2431-42.
the incidence of breast cancer.14,15 In this article, we review the current role of aroma- Copyright © 2003 Massachusetts Medical Society.
tase inhibitors and assess their potential for clinical use. Other reviews that may be of
interest to specialists are also available.16,17
background
mechanisms of action
Estrogen is the main hormone involved in the development and growth of breast tumors;
oophorectomy was first shown to cause regression of advanced breast cancer more than
a century ago,18 and estrogen deprivation remains a key therapeutic approach.19 Tamox-
ifen inhibits the growth of breast tumors by competitive antagonism of estrogen at its
receptor site (Fig. 1). Its actions are complex, however, and it also has partial estrogen-
agonist effects. These partial agonist effects can be beneficial, since they may help pre-
vent bone demineralization in postmenopausal women,20,21 but also detrimental, since
they are associated with increased risks of uterine cancer13,22 and thromboembolism.14
In addition, they may play a part in the development of tamoxifen resistance.23
In contrast, aromatase inhibitors markedly suppress plasma estrogen levels in post-
menopausal women by inhibiting or inactivating aromatase, the enzyme responsible for
the synthesis of estrogens from androgenic substrates (specifically, the synthesis of es-
trone from the preferred substrate androstenedione and estradiol from testosterone)
(Fig. 1). Unlike tamoxifen, aromatase inhibitors have no partial agonist activity.
sources of aromatase
Aromatase, an enzyme of the cytochrome P-450 superfamily and the product of the
CYP19 gene,24 is highly expressed in the placenta and in the granulosa cells of ovarian
follicles, where its expression depends on cyclical gonadotropin stimulation. Aromatase
is also present, at lower levels, in several nonglandular tissues, including subcutaneous
fat, liver, muscle, brain, normal breast, and breast-cancer tissue.25,26 Residual estrogen
production after menopause is solely from nonglandular sources, in particular from
subcutaneous fat. Thus, peripheral aromatase activity and plasma estrogen levels corre-
late with body-mass index in postmenopausal women.27 At menopause, mean plasma
estradiol levels fall from about 110 pg per milliliter (400 pmol per liter) to low but stable
levels of about 7 pg per milliliter (25 pmol per liter). In postmenopausal women, how-
pharmacokinetics
Anastrozole, letrozole, and exemestane are admin- Table 1. Classification of Aromatase Inhibitors.
istered orally. Anastrozole and letrozole have similar Type 1 Type 2
pharmacokinetic properties, with half-lives approx- Generation (Steroidal Inactivator) (Nonsteroidal Inhibitor)
imating 48 hours,46,47 allowing a once-daily dosing
First None Aminoglutethimide
schedule. The half-life of exemestane is 27 hours.48
Pharmacokinetic interactions between some inhib- Second Formestane Fadrozole
Rogletimide
itors and tamoxifen have been described. Amino-
glutethimide induces cytochrome P-450 activity, Third Exemestane (Aromasin) Anastrozole (Arimidex)
which reduces tamoxifen levels.49 In contrast, the Letrozole (Femara)
Vorozole
levels of anastrozole and letrozole are reduced (by
a mean of 27 percent and 37 percent, respectively)
when they are coadministered with tamoxifen, but
these reductions are not associated with impaired ma estrogen levels, but the very low plasma estrogen
suppression of plasma estradiol levels.50,51 levels in postmenopausal women and the limited
sensitivity of immunoassays have made it difficult
comparative pharmacologic efficacy to estimate precisely their relative effectiveness. In
The third-generation aromatase inhibitors have contrast, isotopic measurement of whole-body
been found in preclinical studies to be more than aromatization has greater sensitivity and allows
three orders of magnitude more potent than amino- valid comparisons among studies. This method has
glutethimide.52 All of them markedly suppress plas- demonstrated that greater inhibition is achieved
Type 1 Inhibitors
Substrate (steroidal inactivators)
O O O
O O O
OH CH2
Type 2 Inhibitors
(nonsteroidal inhibitors)
NC
N N
N N
N N
C2H5
NH2 NC CN
H3C CH3
O N O CN
CH3 H3C
Figure 2. Structures of the Main Aromatase Inhibitors and the Natural Substrate Androstenedione.
with third-generation compounds than with earli- maximal possible endocrine control of breast can-
er inhibitors: the mean degree of inhibition with cer. Results with the third-generation aromatase in-
anastrozole, exemestane, and letrozole at clinical hibitors have refuted this hypothesis and suggest
doses is greater than 97 percent,53,54 as compared further possibilities for the development of endo-
with about 90 percent for aminoglutethimide.55 crine therapy.
The increased potency of the third-generation in- Three key trials of aromatase inhibitors as first-
hibitors is associated with better clinical efficacy line therapy60-62 — all of them multicenter, double-
than that offered by aminoglutethimide or the sec- blind studies involving patients whose tumors were
ond-generation inhibitor fadrozole.56-58 hormone-receptor–positive (or of unknown recep-
Recently, subtle differences in potency between tor status) — have been published (Table 2). In the
two of the third-generation inhibitors have been largest (a study involving 907 women, with a median
demonstrated. In a small, double-blind crossover follow-up of 18 months), letrozole resulted in more
trial, letrozole was associated with greater aroma- tumor regressions and was associated with a longer
tase inhibition than anastrozole and lower plasma time to disease progression than tamoxifen (9.4 vs.
levels of estrone and estrone sulfate.54 6.0 months; P=0.0001).60 This benefit was signifi-
Aromatase has intratumoral activity in the major- cant irrespective of previous adjuvant treatment with
ity of breast carcinomas, and isotopic assays have tamoxifen, the site of disease, or knowledge of the
shown that such activity contributes substantially to estrogen-receptor status. In the other two trials,
intratumoral estrogen levels; anastrozole, letrozole, anastrozole was compared with tamoxifen, with
and exemestane all markedly inhibit it.59 Howev- conflicting results. One of them showed that anas-
er, the relative clinical significance of the effects of trozole, like letrozole, resulted in a longer time to
these agents on peripheral and intratumoral aroma- disease progression than tamoxifen (11.1 vs. 5.6
tase activity is unknown. months; P=0.005) and a trend towards more tumor
regressions.61 The other, which was similar in de-
current clinical role sign, failed to confirm these findings: for each out-
come variable, anastrozole was as effective as ta-
As already noted, the data reviewed in this article moxifen but not superior.62 Several reasons for
pertain solely to postmenopausal women; the use these differences have been proposed, including dif-
of aromatase inhibitors in premenopausal women ferences in the proportions of patients whose es-
with breast cancer who have normal ovarian func- trogen-receptor status was unknown or who had
tion is contraindicated. Their use is also, in general, previously received adjuvant tamoxifen therapy, but
contraindicated in women with estrogen-receptor– none of these explanations are entirely adequate.
negative and progesterone-receptor–negative can- Trials comparing exemestane with tamoxifen as
cer, given that such tumors are unresponsive to oth- first-line treatment are under way; promising early
er forms of endocrine therapy. results65 have led to an expanded European trial.
In summary, in advanced disease, letrozole is
advanced disease clearly superior to tamoxifen as first-line therapy.
First-Line Therapy For anastrozole, the data on superiority are contra-
One of the most important recent developments in dictory, but the drug is convincingly at least as good
therapy for breast cancer has been the demonstra- as tamoxifen.
tion that letrozole and probably also anastrozole
are superior to tamoxifen as first-line treatment for Second-Line Therapy
advanced disease. Previous trials in which tamoxi- In the 1990s, the clinical importance of several
fen was compared with other endocrine agents, third-generation inhibitors became clear when a se-
including diethylstilbestrol,1 progestins,2-4 andro- ries of trials showed them to be more effective than
gens,5 other antiestrogens,6,7 and first- and second- megestrol acetate as second-line therapy after ta-
generation aromatase inhibitors,8-12 consistently moxifen, despite some variation in the study re-
failed to show such a difference. By current stand- sults66-71 (Table 3). Trials of the second-generation
ards, these trials were underpowered, and most of inhibitors fadrozole and formestane and a trial of
them were not blinded, but nevertheless their re- another third-generation agent, vorozole, now dis-
sults were interpreted as suggesting that tamoxifen, continued from clinical study, failed to show any
through estrogen-receptor blockade, provided the such advantage.41,72,73 The margin of additional
Table 3. Trials of Aromatase Inhibitors as Compared with Megestrol Acetate as Second-Line Therapy.
% % mo mo
Buzdar et al.68 Anastrozole, 1 mg 263 10 35 4.8 Not given
Megestrol acetate, 160 mg 253 8 34 4.8 Not given
Dombernowsky Letrozole, 2.5 mg 174 24† 35 5.6 25
et al.69 Megestrol acetate, 160 mg 189 16 32 5.5 22
Buzdar et al.70 Letrozole, 2.5 mg 199 16 27 3†‡ 29
Megestrol acetate, 160 mg 201 15 24 3‡ 26
Kaufmann et al.71 Exemestane, 25 mg 366 15 37 4.7† Not reached†
Megestrol acetate, 160 mg 403 12 35 3.8 28
Goss et al.72 Vorozole, 2.5 g 225 10 24 2.6 26
Megestrol acetate, 160 mg 227 7 27 3.3 29
* Clinical benefit is shown as the total percentage of patients who had a response or whose disease stabilized for at least
six months.
† There was a significant difference from the result with megestrol acetate.
‡ There was a significant difference from the result in the third group of subjects, who received 0.5 mg of letrozole (median
time to progression, six months). Other data from this trial are not included in this table.
breast cancer seen over the past decade. It thus rep- The designs of these trials differ, and among the key
resents one of the main success stories in cancer issues addressed are the use of these agents in direct
medicine. However, the efficacy of tamoxifen is only comparison with tamoxifen, as combination thera-
partial. Furthermore, as described above, it is asso- py with tamoxifen, as sequential therapy with ta-
ciated with an increased risk of uterine cancer — moxifen for a total of five years, and as maintenance
a risk that is small in absolute terms and far out- therapy after five years of tamoxifen therapy. In the
weighed by the number of lives saved from breast first and largest of these trials (Arimidex and Tamox-
cancer, but one that is very real in the public per- ifen Alone or in Combination [ATAC] trial), which
ception. Tamoxifen also increases the incidence of has three study groups, tamoxifen is being com-
thromboembolism and often causes troublesome pared with anastrozole or with a combination of ta-
side effects, including hot flashes and vaginal dis- moxifen and anastrozole; 9366 patients have been
charge.14 Thus, despite the benefits offered by ta- enrolled. The first analysis, conducted at a median
moxifen, there is room for improvement. follow-up of 33 months, showed a small but statis-
The first trial of an aromatase inhibitor given as tically significant reduction in the rate of relapse
adjuvant therapy was started more than 20 years ago with anastrozole as compared with tamoxifen: 89
with aminoglutethimide. By today’s standards, this percent of the patients assigned to anastrozole were
study was very small, but it showed an early reduc- relapse-free at 3 years, as compared with 87 per-
tion in the risk of relapse or death; the reduction cent of those assigned to tamoxifen (relative risk
disappeared with longer follow-up.82,83 In a more reduction, 17 percent; P=0.013).85 The effect was
recent study, sequential administration of amino- seen only in patients whose tumors were known to
glutethimide after tamoxifen therapy, as compared be hormone-receptor–positive (relative risk reduc-
with tamoxifen alone,84 was associated with a trend tion, 22 percent). So far, the ATAC trial has shown
toward improved survival. no differences in the rates of death from any cause,
Trials of adjuvant therapy with the third-genera- and there have been very few breast cancer-related
tion aromatase inhibitors began roughly seven years deaths.
ago. Currently, there are at least 10 ongoing studies Of interest, the combination of anastrozole and
of the use of these agents in postmenopausal wom- tamoxifen in the ATAC trial has not been found to
en; they are scheduled to recruit almost 40,000 par- be superior to tamoxifen alone. A possible explana-
ticipants, and more such studies have been planned. tion is that tamoxifen saturates available estrogen
receptors and has partial agonist activity. The acti- ture and frequency to those of tamoxifen.60-63 Data
vated tamoxifen–estrogen-receptor complex cannot from the ATAC trial, by far the largest trial of adju-
then be further modified by anastrozole-induced de- vant therapy (and one that is not confounded by
creases in estrogen levels, and the anticancer effect tumor-related symptoms), indicate that both treat-
remains the same as that provided by tamoxifen ments are well tolerated; however, the patients
alone. Another finding, and one of potential rele- receiving anastrozole had a significantly lower in-
vance to breast-cancer prevention, is that the inci- cidence of hot flashes, vaginal bleeding, vaginal
dence of contralateral invasive breast cancer was sig- discharge, and venous thromboembolism and a
nificantly lower in the patients receiving anastrozole significantly higher incidence of musculoskeletal
alone (0.3 percent [9 cancers]) than in those re- symptoms and fractures than those receiving ta-
ceiving tamoxifen alone (1.0 percent [30 cancers], moxifen (Table 4).85
P=0.001) or combined treatment (0.7 percent [23 Differences between the aromatase inhibitors
cancers]).85 and tamoxifen in long-term adverse effects are only
These findings are promising but preliminary. starting to emerge. In contrast to findings with ta-
The absolute benefit in terms of freedom from re- moxifen, there is no evidence to suggest an in-
lapse appears to be very small thus far, and no sur- creased risk of uterine carcinoma with aromatase
vival benefit has emerged. In addition, the anastro- inhibitors (incidence, 0.1 percent, vs. 0.5 percent
zole group has had a higher rate of fractures than with tamoxifen) or venous thromboembolism (2.1
the other two groups. No data on tolerability during percent and 3.5 percent, respectively) (Table 4).85
five years of treatment with any of the inhibitors are
so far available. Long-term problems with tamoxi-
fen, especially uterine cancer, emerged only after Table 4. Incidence of Adverse Effects Associated with Anastrozole
and Tamoxifen in the ATAC Trial.*
many years’ experience. It is our view that tamoxi-
fen should remain the standard of care for most pa- Anastrozole Tamoxifen
tients with early estrogen-receptor–positive breast Adverse Effect (N=3092) (N=3094) P Value
cancer until further data become available. In pa-
percent
tients with a history of thromboembolism, how-
ever, or those in whom tamoxifen is poorly toler- Hot flashes 34.3 39.7 <0.0001
ated, adjuvant therapy with anastrozole is now a Nausea and vomiting 10.5 10.2 0.7
useful alternative. This opinion is in accord with a
Fatigue 15.6 15.2 0.5
recent American Society of Clinical Oncology evi-
dence-based technology assessment,86 which also Mood disturbance 15.5 15.2 0.7
appropriately advises against switching treatments Musculoskeletal disorder 27.8 21.3 <0.001
in women who have already begun tamoxifen ther- Vaginal bleeding 4.5 8.2 <0.001
apy. (Anastrozole has very recently been granted
fast-track approval in the United States and else- Vaginal discharge 2.8 11.4 <0.001
where for adjuvant treatment of early hormone- Endometrial cancer 0.1 0.5 0.02
receptor–positive breast cancer in postmenopausal Fracture 5.9 3.7 <0.001
women, particularly if tamoxifen is contraindi- Hip 0.4 0.4 —
cated.) Spine 0.7 0.3 —
Wrist or radius (Colles’ fracture) 1.2 0.8 —
Ischemic cardiovascular disease 2.5 1.9 0.14
adverse effects and long- term
risks and benefits Ischemic cerebrovascular event 1.0 2.1 <0.001
Any venous thromboembolic event 2.1 3.5 <0.001
The third-generation aromatase inhibitors appear
to be very well tolerated, with a remarkably low in- Deep venous thromboembolic event, 1.0 1.7 0.02
including pulmonary embolism
cidence of serious short-term adverse effects, re-
flecting the remarkable specificity of their action. Cataract 3.5 3.7 0.6
The commonest of these effects are hot flashes, vag-
inal dryness, musculoskeletal pain, and headache, * The table is modified from the ATAC Trialists’ Group,85 with the permission of
the publisher. ATAC denotes Arimidex and Tamoxifen Alone or in Combina-
but they are usually mild. Comparative trials indi- tion, and dashes indicate not available.
cate that such adverse effects are very similar in na-
follow-up) suggest, by extrapolation, that anastro- sion and must involve other biochemical effects.
zole might reduce the early incidence of breast can- Overall, current circumstantial evidence suggests
cer to an even greater extent and thus have more that there are unlikely to be major clinical differenc-
potential in chemoprevention than tamoxifen. es among these agents.
Strategies to avoid the anticipated loss of bone
density induced by aromatase inhibitors would first aromatase inhibitors in combination
need to be developed. An alternative approach might with chemotherapy
be to use a much smaller dose of aromatase inhib- No studies have compared concurrent use of aroma-
itor in order to lower the levels of circulating es- tase inhibitors and chemotherapy with sequential
trogens but not obliterate them. Such an approach use. The concurrent use of tamoxifen and chemo-
might offer a substantial chemopreventive effect therapy increases the risk of thromboembolism,105
and reduce the risk of serious long-term compli- but this problem does not appear to occur with the
cations. aromatase inhibitors.
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