Download Advances in Aromatase Inhibition

2620 Vol. 7, 2620 –2635, September 2001
Clinical Cancer Research
Review
Advances in Aromatase Inhibition: Clinical Efficacy and
Tolerability in the Treatment of Breast Cancer
Aman Buzdar1 and Anthony Howell
Department of Breast Medical Oncology, M. D., Anderson Cancer
Center, University of Texas, Houston, Texas 77030 [A. B.], and
Cancer Research Campaign Department of Medical Oncology,
Christie Cancer Research Campaign Research Centre, Christie
Hospital National Health Services Trust, Manchester, United
Kingdom [A. H.]
Introduction
The successful management of breast cancer remains a
major challenge to surgeons and oncologists in the 21st century.
Although the incidence of breast cancer varies throughout the
world, the disease is universally perceived to be a major cause
of morbidity and mortality in both pre- and postmenopausal
women.
It has long been established that estrogen is the major
hormone involved in the biology of breast cancer (1). Endocrine
agents have therefore been designed to affect the supply of
estrogens to the breast tumor, principally by blockade of estrogen activity at the receptor level or by inhibition of estrogen
production (although the widely used antiestrogen, tamoxifen, is
known to have additional modes of action, such as via production of the inhibitory growth factor transforming growth factor
␤ (2, 3) and suppression of insulin-like growth factor 1 (4), a
potent mitogen for breast cancer. Drug resistance, however,
remains a significant problem in breast cancer treatment, and
this has led to the development of a variety of endocrine agents
to extend the treatment options for breast cancer patients with
hormone-sensitive disease. The success of the approach to use
different endocrine therapies sequentially is made evident by the
fact that 25% of patients with advanced breast cancer who
eventually progress after an initial response on primary treatment are known to respond to second-line therapy with another
endocrine agent (5). In a recent study, ⬃40% of patients with
advanced breast cancer failing after an initial response to tamoxifen gained clinical benefit (clinical benefit ⫽ CR2 ⫹ PR ⫹
SD ⱖ 24 weeks) from the second-line use of a second endocrine
therapy (6).
Over the past 30 years, the antiestrogen, tamoxifen, has
Received 9/7/00; revised 3/30/01; accepted 6/1/01.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
1
To whom requests for reprints should be addressed, at Department of
Breast Medical Oncology, M. D., Anderson Cancer Center, University
of Texas, Houston, TX 77030.
2
The abbreviations used are: CR, complete response; PR, partial response; SD, stable disease; TTP, time to progression; OR, objective
response rate; TTF, time to treatment failure; UICC, Union International
Contre Cancer; HR, hazard ratio; ER, estrogen receptor; PgR, progesterone receptor; CI, confidence interval; ATAC, Arimidex, tamoxifen,
alone or in combination; ABCSG, Austrian Breast Cancer Study Group.
been the most widely used endocrine drug for the management
of all stages of breast cancer in women with estrogen-dependent
tumors, irrespective of their age and menopausal status (7–9),
and, until recently, it has maintained an unrivalled position as
the standard first-line endocrine therapy for postmenopausal
women with advanced breast cancer.
Aromatase inhibitors are endocrine agents which have a
different mode of action against breast tumors in postmenopausal women from that of tamoxifen. The first clinically available aromatase inhibitor, aminoglutethimide, was introduced for
the second-line treatment of advanced breast cancer in the late
1970s (10). But despite proven efficacy in this setting, its
widespread use was limited by its overall toxicity and its lack of
selectivity for the aromatase enzyme, which necessitated concomitant corticosteroid supplementation (11). This led to the
search for novel, more effective, and less toxic aromatase inhibitors. As a result, several aromatase inhibitors with a high
degree of selectivity for aromatase and improved tolerability
have become clinically available for the treatment of postmenopausal women with advanced breast cancer: anastrozole (1 mg
once daily); letrozole (2.5 mg once daily); fadrozole (1 mg twice
daily; available in Japan only); formestane (250 mg i.m. every 2
weeks); and exemestane (25 mg once daily; Fig. 1; Refs. 12–22).
It is the aim of this review to evaluate the clinical efficacy
and tolerability of these latest additions to this class of drugs in
the management of advanced breast cancer in postmenopausal
women and to discuss their potential for use in the adjuvant
treatment of early disease.
Pharmacology of Aromatase Inhibitors
In postmenopausal women, ovarian estrogen production
diminishes with age. In these women, estrogen concentrations
are maintained primarily via aromatase, a cytochrome-p450
enzyme complex which acts at the final step in the estrogensynthesis pathway and catalyzes the production of the estrogens,
estrone and estradiol, by extraglandular conversion from the
androgens, androstenedione, and testosterone, respectively (Fig. 2).
It is knowledge of this peripheral route of estrogen supply
in postmenopausal women that has led to the development of the
aromatase inhibitors. These drugs act by suppression of the
supply of endogenous estrogens in fat, liver, and muscle cells
and in breast tumor tissue itself. They can be divided into two
classes: steroidal and nonsteroidal drugs (23). The steroidal
class (type I) comprises primarily formestane and exemestane,
and the nonsteroidal class (type II) comprises primarily the
imide, aminoglutethimide; the imidazole, fadrozole; and the
triazoles, anastrozole and letrozole. A third nonsteroidal triazole, vorozole, has recently been withdrawn from clinical development.
Method of Administration. The newer nonsteroidal
drugs, anastrozole and letrozole, are well absorbed after oral
administration, with long terminal half-lives, allowing for oncedaily dosing (14 –16). In contrast, the first steroidal drug to
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Clinical Cancer Research 2621
Fig. 1 Chemical structures of all aromatase inhibitors under review.
Fig. 2 Enzyme pathway for estrogen synthesis from androgens via
aromatase inhibitors.
become clinically available, formestane (250 mg i.m. every 2
weeks), is subject to high first-pass metabolism when given p.o.,
and has a relatively short terminal half-life (⬃2 h), and consequently has to be administered by i.m. injection every 2 weeks
(18, 24). Exemestane, the other steroidal drug, is p.o. bioavailable and has a terminal half-life of ⬃24 h during chronic
treatment (21), allowing once-daily therapy at a dose of 25 mg
of drug (25, 26).
Mechanism of Action. Steroidal and nonsteroidal aromatase inhibitors differ in their modes of interaction with, and
their inactivation of, the aromatase enzyme. Steroidal inhibitors
compete with the endogenous substrates, androstenedione and
testosterone, for the active site of the enzyme, where they act as
false substrates and are processed to intermediates that bind
irreversibly to the active site, causing irreversible enzyme inhibition. Nonsteroidal inhibitors also compete with the endogenous substrates for access to the active site, where they then
form a coordinate bond to the heme iron atom. Therefore, they
effectively exclude both the natural substrate and oxygen from
the enzyme. The coordinate bonding is strong but reversible, so
that enzyme activity can recover if the inhibitor is removed; but
inhibition is sustained whenever the inhibitor is present. Al-
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2622 Aromatase Inhibition in Breast Cancer Treatment
though both classes of aromatase inhibitor lead to potent suppression of aromatase, the enzyme is capable of rapid regeneration, and so it is doubtful whether or not the type of inhibition
(i.e., reversible or irreversible) is of any clinical relevance.
There are currently no clinical data that compare the relative
efficacy of each type of agent. Their different modes of action,
however, allow for sequential use in patients with advanced
breast cancer, as described later.
Selectivity. The degree of selectivity of an aromatase
inhibitor for the aromatase enzyme has a bearing on both the
ease of use and the tolerability profile of the drug. For instance,
the lack of selectivity of the first-generation aromatase inhibitor
for aromatase, aminoglutethimide, led to concomitant suppression of the important corticosteroids, aldosterone and cortisol.
As a result, in clinical use, it became necessary to coadminister
a corticosteroid, such as hydrocortisone, as replacement therapy
(11). Although the second-generation aromatase inhibitor,
fadrozole, was shown to be more potent and selective (23) than
aminoglutethimide, it nevertheless demonstrated a lack of selectivity through its effect on 11-deoxycorticosterone and aldosterone concentrations as well as on sodium and potassium levels
in animals (11, 27–30).
The third-generation aromatase inhibitor, anastrozole, has a
high degree of selectivity for aromatase in clinical pharmacology studies, with no significant effects being observed on either
cortisol or aldosterone secretion at up to 10 times the daily
recommended dose after 28 days of exposure (31, 32) and also
when given for up to 3 months (33). Letrozole showed a similar
degree of enzyme selectivity after an exposure period of 28
days, (34, 35) although in a study evaluating the dosing of
letrozole 0.5 mg over a period of 12 weeks, cortisol levels were
reduced significantly at this dose after 2 months (36) while
remaining within the limits of normality (37, 38). Additionally,
a more recent study has shown significant reductions in adrenocorticorticotropic hormone-stimulated cortisol (P ⫽ 0.015)
and aldosterone (P ⫽ 0.04) concentrations after a 3-month
exposure to letrozole at the clinical dose of 2.5 mg daily (39).
Vorozole is also selective for the aromatase enzyme, as
seen from studies of 2.5 and 5 mg doses once daily, which
reported no effect on adrenal steroidogenesis (40, 41). However,
in one study at the 5-mg daily dose, vorozole led to a reduction
in cortisol, the clinical relevance of which was uncertain (42).
The higher selectivity of anastrozole, letrozole, and vorozole for
aromatase leads to improved tolerability, compared with earlier
drugs of this class, through an overall lack of adverse effect on
steroidogenesis.
In the case of the steroidal aromatase inhibitors, both
formestane (43– 45) and exemestane (26, 46) are selective for
aromatase and do not affect either cortisol or aldosterone concentrations adversely.
The available data on selectivity confirm that all of the
aromatase inhibitors developed since aminoglutethimide first
became clinically available are far more selective than the
prototype compound. More recent data from indirect clinical
pharmacology studies, however, do show variations between the
different aromatase inhibitors. For anastrozole and letrozole,
there seem to be differences in overall selectivity that, although
not seen after short-term administration, do become apparent
after longer-term exposure, i.e., up to 3 months. The clinical
relevance of such changes is not yet clear; however, although
there may not be any clinical detriment in the metastatic setting,
it would be important to monitor closely for the potential impact
in the adjuvant setting, where these compounds are likely to be
administered for up to 5 years, and where tolerability assumes
greater importance in a patient who otherwise may be “cured” of
disease.
Estrogen Suppression and Aromatase Inhibition.
Both steroidal and nonsteroidal aromatase inhibitors result in a
significant decrease in serum estrogen concentrations. Aminoglutethimide was the first nonsteroidal aromatase inhibitor to
demonstrate a high level of aromatase inhibition, but this was
not accompanied by a reduction in estrogen concentrations
comparable with that now seen with the third-generation nonsteroidal aromatase inhibitors (23). An increase in potency was
found with the second-generation drug, fadrozole (22), but,
again in comparison, the newer-generation triazole drugs, anastrozole and letrozole, both produce a much greater suppression
of estrogens, to the limits of detection of current assays, and
have demonstrated a high degree of consistency between the
inhibition of whole-body aromatase activity and estrogen suppression (16, 18, 23, 47).
Recent data have been reported from a small, double-blind,
randomized, cross-over study in 12 postmenopausal women
with advanced breast cancer, comparing plasma estrogen suppression by letrozole (2.5 mg daily) and anastrozole (1 mg daily;
48). This study showed that letrozole led to significantly greater
suppression of E1 (P ⫽ 0.019) and E1S (P ⫽ 0.0037), but not of
E2, which is widely considered to be the most important estrogen in the etiology of breast cancer. When inhibition of wholebody aromatase was examined (49), it was shown that letrozole
(⬎99.1%) achieved a greater inhibition of aromatase than did
anastrozole (mean, 96.9%). No statistical analyses of these data
have been presented to date, and the clinical relevance of such
differences between drugs of this class in their effect upon
aromatase remains questionable.
The injectable steroidal aromatase inhibitor, formestane,
also suppresses estrogen concentrations significantly, but to a
lesser extent than anastrozole (50). Formestane is associated
with inconsistent suppression of serum estradiol (50, 51),
whereby estradiol levels begin to rise between the twice-weekly
i.m. doses. This was shown in a small, randomized, comparative
study, in which formestane (250 mg i.m. every 2 weeks; n ⫽ 31)
was compared with the nonsteroidal aromatase inhibitor, anastrozole (1 mg once daily; n ⫽ 29), over 4 weeks in postmenopausal women with advanced breast cancer (50). More effective,
reliable and consistent estradiol suppression was found with
anastrozole than with formestane at the usual therapeutic doses
(79% versus 58% reduction in estradiol levels, respectively; P ⫽
0.0001). Estrone and estrone sulfate levels were also significantly suppressed to a greater extent by anastrozole compared
with formestane (estrone, 85% versus 67%, P ⫽ 0.0043; estrone
sulfate, 92% versus 67%, P ⫽ 0.0007; respectively; Ref. 50).
Recently available results indicate that the oral steroidal
aromatase inhibitor, exemestane, at daily doses of 10 –25 mg,
suppresses estrogen concentrations to 6 –15% of pretreatment
levels, showing more pronounced activity than formestane and
comparable activity with that of the clinically available, nonsteroidal aromatase inhibitors, anastrozole and letrozole (52, 53).
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Clinical Cancer Research 2623
Table 1
Efficacy results from Phase III second-line trials of anastrozole versus megestrol acetate (MA) in postmenopausal women with
advanced breast cancer (6- and 31-months’ follow-up)
European54
Parameter
OR ⫽ CR ⫹ PR (%)
Clinical benefit (%)
Median TTP (mo.)
Median survival
2-yr survival rate (%)
a
b
North American55
Combined (6 mo)58
Combined (31 mo)6
Anastrozole
1 mg o.d.
(n ⫽ 135)
MA 40
mg q.i.d.
(n ⫽ 118)
Anastrozole
1 mg o.d.
(n ⫽ 128)
MA 40
mg q.i.d.
(n ⫽ 130)
Anastrozole
1 mg o.d.
(n ⫽ 263)
MA 40
mg q.i.d.
(n ⫽ 253)
Anastrozole
1 mg o.d.
(n ⫽ 263)
MA 40
mg q.i.d.
(n ⫽ 253)
10.4
34.1
4.3
10.4
32.8
3.9
10
37
5.6
6
36
4.7
10
33
4.8
8
34
4.8
50.5
39.1
62.0
53.1
12.6
42.2
4.8
26.7 mo.
56.1
12.2
40.3
4.6a
22.5b mo.
46.3
Hormone receptor anastrozole versus MA 0.94 (P ⫽ 0.49; 97.5% CI, 0.76 –1.1).
Hormone receptor anastrozole versus MA 0.78 (P ⫽ 0.0248; 97.5% CI, 0.6040 – 0.9996).
In another report, exemestane exhibited potent aromatase inhibition in vivo and suppressed plasma levels of estrogens to the
limits of detection of current assays (25).
In conclusion, it appears that the most effective aromatase
inhibitors can provide near maximal suppression of plasma
estrogens, irrespective of their precise mode of inhibition of
aromatase. It is clear that the newer-generation aromatase inhibitors, anastrozole, letrozole, and exemestane, provide greater
suppression of estrogens than the earlier aromatase inhibitors,
aminoglutethimide, fadrozole, and formestane. The clinical data
available for the newer aromatase inhibitors versus the previous
standard therapies, megestrol acetate and tamoxifen (see below),
indicate that step-changes in estrogen suppression are clinically
important. However, the clinical relevance of the small differences in estrogen suppression between the newer aromatase
inhibitors remains to be established. Ultimately, only direct
head-to-head comparative clinical studies will provide the answers to these questions.
Clinical Efficacy
Second- and Third-line Therapy in Advanced Breast Cancer
with Nonsteroidal Aromatase Inhibitors
Anastrozole versus Megestrol Acetate. In 1995, anastrozole was the first of the newer-generation aromatase inhibitors
to become clinically available for second-line therapy in postmenopausal women with advanced breast cancer failing on an
antiestrogen, usually tamoxifen. This came after the results of
two large, Phase III studies, which were performed in parallel,
comparing oral anastrozole (1 mg or 10 mg, once daily) with
oral megestrol acetate (40 mg four times daily) in postmenopausal women with advanced breast cancer who had progressed
on tamoxifen (54, 55). The designs of each trial [one conducted
predominantly in Europe (n ⫽ 378) and the other in North
America (n ⫽ 386)] were identical and prospectively intended
to allow the data to be combined to strengthen the overall
statistical reliability of the trial results (56). Each trial was a
multicenter, randomized, controlled, parallel group, doubleblind for each anastrozole arm and open-label for megestrol
acetate. The primary objectives were to compare the three
treatment groups in terms of TTP and OR (OR ⫽ CR ⫹ PR),
and the secondary objectives were survival, time to TTF, and
response duration. Rigorous criteria for assignment of objective
response were applied on the basis of a strict interpretation of
UICC guidelines (6, 57, 58).
At a median follow-up of ⬃6 months, a combined analysis
of the above two trials showed that approximately one-third of
patients who were treated with either anastrozole (1 mg or 10
mg, once daily) or megestrol acetate (160 mg daily) derived
clinical benefit from their treatment (58). There were no statistically significant differences among the three treatment arms in
terms of efficacy (tumor response or TTP) in either trial. The
data were too immature for an analysis of survival to be performed at that time.
Intent-to-treat analyses were subsequently performed on
the mature combined data from the two trials (62% of patients
had died), when the median follow-up was 31.2 months (6). At
the clinical dose of 1 mg daily, anastrozole demonstrated a
statistically significant survival advantage over megestrol acetate, with a HR of 0.78 (P ⬍ 0.025). The median duration of
survival was 26.7 months for the anastrozole 1 mg group compared with 22.5 months for the megestrol acetate group. The HR
indicated that patients treated with anastrozole 1 mg were 22%
less likely to die over a given time period than patients treated
with megestrol acetate. Patients receiving anastrozole 10 mg
daily also showed a survival benefit compared with the patients
receiving megestrol acetate, with an HR of 0.83 and a median
duration of survival of 25.5 months (P ⫽ 0.0951), but this
difference was not statistically significant. The estimated 2-year
survival rates from the combined analysis were 56.1%, 54.6%,
and 46.3% for patients receiving anastrozole 1 mg, anastrozole
10 mg, or megestrol acetate, respectively. Clinical benefit was
seen in ⬃40% of patients in all three groups (42.3% with
anastrozole 1 mg). The data from the individual and combined
analyses of these trials are summarized in Table 1.
The authors concluded that the combined analysis clearly
demonstrated that, after disease progression with tamoxifen,
anastrozole 1 mg provides a statistically and clinically significant advantage over standard treatment with megestrol acetate.
There was no additional benefit observed for anastrozole 10 mg
over anastrozole 1 mg in terms of any of the primary end points.
These results confirmed the choice of the 1 mg dose for use in
clinical practice.
In an additional subgroup analysis of the above combined
trial data, it was shown that anastrozole was effective in patients
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2624 Aromatase Inhibition in Breast Cancer Treatment
Table 2 An overview of efficacy results from Phase III trials of second-line treatment of newer aromatase inhibitors versus megestrol acetate
(MA) in patients who have failed on tamoxifen
European and US trials combined analysis6
Dose
Aa 1 mg
o.d.
(n ⫽ 263)
Median follow-up (mo)
Median TTP (mo)
4.8
MA 40
mg q.i.d.
(n ⫽ 253)
European trial61
L 2.5
MA 40
mg o.d.
mg q.i.d.
(n ⫽ 174) (n ⫽ 189)
31
a
26.7
P ⬍ 0.025
L 2.5
mg o.d.
MA 40
mg q.i.d.
33
4.6
5.6
22.5
25.3
NS
Median survival (mo)
US trial62
5.5
NS
21.5
NS
No data published
NS
No data published
International trial71
E 25
MA 40
mg o.d.
mg o.d.
(n ⫽ 366) (n ⫽ 403)
11
4.7
3.8
P ⫽ 0.037
NR
28.4
P ⫽ 0.039
A, anastrozole; L, letrozole; E, exemestane; NS, nonsignificant; NR, not reported.
with advanced breast cancer with visceral and liver metastases
(59). The median duration of clinical benefit in patients with
visceral metastases was 16.4 months with anastrozole 1 mg (n ⫽
263) compared with 14.7 months for megestrol acetate (n ⫽
253); for liver metastases, the median duration of clinical benefit
was 17.9 months with anastrozole 1 mg compared with 9.9
months for megestrol acetate. Furthermore, in a recent report,
overall survival in patients with advanced breast cancer under
assessment in one of the large-scale, comparative Phase III trials
described above (58) was examined in relation to response type,
i.e., the survival outcome based on whether patients demonstrated either CR/PR or SD ⱖ24 weeks (termed “long SD”; Ref.
60). For anastrozole (1 mg daily), there was no difference in
estimates of 2-year survival between patients having either
CR/PR or long SD. A similar result was obtained with patients
treated with megestrol acetate (40 mg p.o. four times daily).
These data confirmed the clinical value of long SD as an
important end point in the measure of clinical efficacy in postmenopausal patients with advanced breast cancer, with predictive value for overall survival.
Letrozole versus Megestrol Acetate. Two doses of oral
letrozole (2.5 mg or 0.5 mg, once daily) were compared against
each other and against megestrol acetate (160 mg once daily) as
second-line therapy in postmenopausal women with advanced
breast cancer previously treated with antiestrogen endocrine
therapy (61). The trial design was multicenter, randomized,
controlled, double-blind, in 551 patients with locally advanced,
locoregionally recurrent, or advanced breast cancer. The primary efficacy end point was overall objective tumor response
(CR ⫹ PR), assessed by UICC criteria (62). Secondary end
points included TTP, TTF, and overall survival time.
A higher overall OR rate was obtained for letrozole 2.5 mg
compared with letrozole 0.5 mg (P ⫽ 0.004) or megestrol
acetate (P ⫽ 0.04). The clinical benefit in each letrozole arm
was ⬍35% (61). For TTP, letrozole 2.5 mg (5.6 months) was
found to be superior to letrozole 0.5 mg (5.1 months; P ⫽ 0.02)
but not to megestrol acetate (5.5 months; P ⫽ 0.07; Table 2).
For overall survival, there was a significant dose effect for
letrozole 2.5 mg (25.3 months; P ⫽ 0.03) over letrozole 0.5 mg
(21.5 months), although letrozole 2.5 mg showed no significant
survival advantage over megestrol acetate, even at an updated
analysis at a follow-up of 51 months (63). The authors concluded that letrozole 2.5 mg was superior to the 0.5 mg dose and
more effective than megestrol acetate in the treatment of ad-
vanced breast cancer in postmenopausal women previously
treated with an antiestrogen (61, 63).
In contrast, however, in a second similar, randomized,
controlled trial performed at the same time in North America,
which has not yet been published in full, letrozole did not show
this dose-dependent antitumor activity. Furthermore, there were
no statistically significant differences in terms of OR, TTP, or
survival with the 2.5-mg dose of letrozole compared with
megestrol acetate; however, the 0.5 mg dose showed improved
TTP over the progestin (64).3
Letrozole versus Aminoglutethimide. In an open-label,
randomized trial, oral, once-daily letrozole (2.5 mg and 0.5 mg)
was compared with aminoglutethimide (250 mg twice daily) in
555 postmenopausal women with advanced breast cancer previously treated with antiestrogens (65). Patients in the aminoglutethimide arm received daily oral glucocorticoid supplementation (hydrocortisone 30 mg or cortisone acetate 37.5 mg).
The primary end point was overall objective tumor response
(CR ⫹ PR). The secondary end points were TTP, TTF, and
duration of survival.
Overall, no significant differences in OR were seen in
patients receiving letrozole 2.5 mg or 0.5 mg or aminoglutethimide. The absence of a significant dose-response effect for
the two letrozole doses (0.5 mg versus 2.5 mg) is in contrast to
that found in the trial comparing the same two doses of letrozole
(P ⫽ 0.03) with megestrol acetate in a similar patient population
(61, 63).3 Letrozole 2.5 mg was, however, statistically significantly superior to aminoglutethimide in terms of overall survival, TTP, and TTF in postmenopausal women with advanced
breast cancer previously treated with antiestrogens.
Vorozole: Open-Label, Phase III Trials. In an openlabel, multicenter, parallel-group Phase III trial, a total of 452
postmenopausal women with advanced breast cancer failing on
tamoxifen were treated with either oral vorozole (2.5 mg once
daily) or megestrol acetate (40 mg four times daily; Ref. 66).
The primary end point was overall response rate. No significant
differences were found between the two groups for overall
response rate, clinical benefit [CR ⫹ PR ⫹ NC (no change) in
ⱖ6 months], TTP, or survival. It was concluded that vorozole
and megestrol acetate had similar efficacy in the treatment of
3
Internet address: http://fda.gov/ohrms/dockets/ac/backgrd/3671b_01.doc.
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Clinical Cancer Research 2625
postmenopausal women with advanced breast cancer progressing on tamoxifen.
In a second open-label, centrally randomized, multicenter
Phase III trial, postmenopausal women with advanced breast
cancer failing on tamoxifen therapy were treated with either oral
vorozole (2.5 mg once daily; n ⫽ 211) or aminoglutethimide
(250 mg twice daily; n ⫽ 213) until disease progression or death
(67). The patients in the aminoglutethimide arm also received
supplementary oral hydrocortisone (30 mg daily). There was a
higher overall response rate for patients receiving vorozole
compared with aminoglutethimide (24% versus 17%; P ⫽ 0.07);
but in terms of duration of response, TTP, TTF, and survival
time, no differences were found between the two treatment
arms. It was therefore concluded that vorozole and aminoglutethimide were equivalent with respect to clinical efficacy.
Although another open-label, comparative trial in postmenopausal patients with advanced breast cancer showed that
vorozole (2.5 mg daily) appeared to be superior to aminoglutethimide (250 mg twice daily) plus hydrocortisone (30 mg once
daily), in terms of response rate and clinical benefit (CR ⫹ PR
⫹ NC ⱖ 6 months; P ⫽ 0.07 and P ⫽ 0.017, respectively; Ref.
68), none of the studies involving vorozole has shown a significant advantage over megestrol acetate or aminoglutethimide in
terms of either TTP or overall survival. Vorozole is no longer in
clinical development.
Fadrozole versus Megestrol Acetate. At present, fadrozole is only clinically available in Japan. Two prospective,
randomized, double-blind Phase III trials of similar design were
initiated to compare fadrozole with megestrol acetate in 683
postmenopausal women with advanced breast cancer, who had
progressed on first-line or adjuvant hormonal therapy (69). The
primary efficacy end point was OR. Other efficacy end points
were TTP and survival.
In the first trial, 380 patients were randomized to receive
either fadrozole (1 mg twice daily) or megestrol acetate (40 mg
four times daily), and in the second trial, 303 patients also
received a similar regimen. Both treatment arms in each of the
two trials received matching placebos. There were no differences in the response rates from either trial between fadrozole
and megestrol acetate. The median survival time was longer in
the fadrozole group than in the megestrol acetate group in the
first trial (26.8 versus 22.8 months, respectively) and in the
megestrol acetate group compared with the fadrozole group
(25.4 versus 27.5 months, respectively) in the second trial (69).
Neither trial showed any significant differences between the two
treatments in terms of primary and secondary end points, confirming equivalence of fadrozole and megestrol acetate as second-line endocrine therapy in postmenopausal women with advanced breast cancer.
Second- and Third-Line Therapy in Advanced Breast
Cancer with Steroidal Aromatase Inhibitors
Formestane versus Megestrol Acetate. In a prospective,
randomized, crossover Phase III trial, formestane (250 mg i.m.
every 14 days) was compared with megestrol acetate (160 mg
p.o. daily) in 179 postmenopausal patients with advanced breast
cancer who were failing on tamoxifen (24). The trial was
planned to test differences in TTF. There were no significant
differences between formestane and megestrol acetate in re-
sponse rates, SD (ⱖ6 months), or TTF (3.9 versus 3.7 months,
respectively), and formestane was considered to be as effective
as megestrol acetate in this patient population. A second open
trial of formestane (250 mg i.m. every 2 weeks) versus megestrol acetate (160 mg p.o. once daily) compared the efficacy and
safety of the two drugs as second-line therapy in 547 receptorpositive or receptor-unknown postmenopausal patients with advanced breast cancer previously treated with tamoxifen (70).
There were no significant differences between formestane and
megestrol acetate in terms of median TTF and overall survival.
Formestane was considered a suitable alternative to progestins
in patients previously treated with tamoxifen.
Exemestane versus Megestrol Acetate. In a randomized,
double-blind Phase III trial, 769 postmenopausal women with
advanced breast cancer refractory to tamoxifen were randomized to receive either exemestane (25 mg p.o. daily; n ⫽ 366) or
megestrol acetate (40 mg p.o. four times daily; n ⫽ 403; Ref.
71). The overall median duration of follow-up was 48.9 weeks.
At the time of data cutoff, median survival had not been
reached, and 143 patients were still receiving study medication.
The study was designed to demonstrate equivalence between
treatment arms. The OR rate was similar in both groups, as was
the rate of overall success (CR ⫹ PR ⫹ SD ⱖ 24 weeks; 37.4%
for exemestane and 34.6% for megestrol acetate; not statistically
significant). Both median TTP (P ⫽ 0.037) and median survival
(P ⫽ 0.039), however, were significantly improved in those
patients receiving exemestane (Table 2). It was concluded that,
compared with megestrol acetate in postmenopausal women
with advanced breast cancer refractory to tamoxifen, exemestane significantly delays tumor progression and significantly
prolongs survival.
Summary and General Conclusions. Anastrozole,
letrozole, and exemestane have all demonstrated improved clinical efficacy over megestrol acetate in the second-line treatment
of postmenopausal women who have failed on tamoxifen. Although anastrozole and exemestane have both demonstrated
significantly improved survival over megestrol acetate, there has
been no statistically significant survival benefit reported with
letrozole (63). All three aromatase inhibitors, anastrozole (1 mg,
once daily), letrozole (2.5 mg, once daily) and exemestane (25
mg, once daily) have demonstrated clinical benefit in secondline use in postmenopausal with advanced breast cancer (6, 61,
71), and these newer-generation aromatase inhibitors are now
established as the second-line agents of choice in this patient
population.
First-line Therapy in Advanced Breast Cancer with
Nonsteroidal Aromatase Inhibitors
Anastrozole. In a major, large-scale, clinical trial program, anastrozole (1 mg once daily) was compared with tamoxifen (20 mg once daily) as first-line therapy in postmenopausal
women with advanced breast cancer in two international, multicenter trials involving a total of 1021 patients (72, 73). The two
trials were performed in the United States/Canada (“North
American” trial) and in Europe/South America/Australia (“European” trial). They were randomized, double-blind, doubledummy trials designed to determine whether or not the two
treatments had equivalent efficacy in this patient population.
Patients had to be eligible for endocrine therapy and have either
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2626 Aromatase Inhibition in Breast Cancer Treatment
Fig. 3 Kaplan-Meier curve for median TTP (anastrozole versus tamoxifen; North American trial).
Fig. 4 Kaplan-Meier curve for median TTP (anastrozole versus tamoxifen; European trial; receptor-positive patients).
ER-positive and/or PgR-positive tumors or tumors of unknown
receptor status. The patients were either newly diagnosed with
advanced disease or had progressed subsequent to diagnosis and
treatment for early disease. They may have received prior adjuvant endocrine therapy or chemotherapy; however, a drug-free
period of at least 1 year was required for those who had received
adjuvant tamoxifen.
The primary end points of the trials were TTP, OR, and
tolerability. There were nine prespecified adverse events for
which a statistical analysis was performed. The secondary end
points were TTF and survival. The studies were designed prospectively to allow combined analysis of the data and were
“powered” for equivalence.
In total, 353 patients from 97 centers in the United States
and Canada were entered into the North American trial (anastrozole, n ⫽ 171; tamoxifen, n ⫽ 182) and followed for a
median of 18 months (73). The two patient groups were well
balanced with respect to demographic data, and a positive tumor
ER status was confirmed in 89% of patients. Median TTP was
11.1 months for anastrozole versus 5.6 months for tamoxifen
(P ⫽ 0.005; two-sided; Fig. 3).
On the basis of the derived HR of 1.44, at any given time
point, patients receiving tamoxifen were 44% more likely to
progress than those treated with anastrozole. OR was 21% for
anastrozole and 17% for tamoxifen. Clinical benefit rates were
59% for anastrozole and 46% for tamoxifen (P ⫽ 0.0098;
two-sided retrospective analysis). These data suggest that anastrozole is superior to tamoxifen as a first-line treatment of
advanced breast cancer in postmenopausal women.
In the second trial (European), 668 postmenopausal women
with advanced breast cancer (anastrozole, n ⫽ 340; tamoxifen,
n ⫽ 328) from 83 centers worldwide were recruited and followed for a median of 19 months (72). The two patient groups
were again well balanced with respect to demographic data, but
a positive tumor ER status was only reported in ⬃45% of
patients. In this trial, median TTP was 8.2 and 8.3 months, and
OR was 32.9 and 32.6% in the anastrozole and tamoxifen arms,
respectively, confirming that anastrozole was at least as effective as tamoxifen in terms of the primary efficacy end points.
Clinical benefit rates were 56.2% for anastrozole and 55.5% for
tamoxifen.
This difference in the TTP results between the two trials
has mainly been attributed to the percentage of patients with
confirmed positive tumor ER. An exploratory subgroup analysis
for the 45% of ER-positive patients in the European trial showed
a median TTP of 8.9 months on anastrozole compared with 7.8
months on tamoxifen (Fig. 4; Ref. 72).
A prospectively planned combined analysis was performed
on the efficacy and tolerability data from the total of 1021
patients recruited into the two trials (74). The data obtained in
this large patient population indicate that anastrozole is at least
as effective as tamoxifen for the treatment of postmenopausal
women with advanced breast cancer, with an observed advantage in terms of TTP: median TTP was 8.5 months for anastrozole and 7 months for tamoxifen (HR ⫽1.12; lower 95% CI,
1.00; Table 3). A total of 57% of patients on anastrozole showed
clinical benefit compared with 52% on tamoxifen.
A subgroup analysis was performed on the combined data
from the European and North American trials. These analyses
confirmed that receptor status was a key factor affecting the
relative efficacy of anastrozole in relation to tamoxifen. Anastrozole showed a statistically significant advantage over tamoxifen in median TTP (P ⫽ 0.022; two-sided, retrospective analysis) in a combined analysis of 611 patients who were known to
be ER-positive/PgR-positive (75).
The significance of whether or not prior adjuvant treatment
impacted treatment outcome was investigated in the combined
first-line trial population. Overall, 14.2% of patients had received prior hormonal therapy, 19.5% in the North American
trial and 11.4% in the European trial.4 In 97% of cases, the prior
adjuvant hormonal therapy was tamoxifen. Although no formal
statistical analyses within subgroups were carried out, the data
observed for TTP and OR rates in those patients not receiving
prior adjuvant hormonal therapy were similar to those observed
in patients who did receive therapy, which in turn is similar to
data for the overall patient population.4
These data on the efficacy of anastrozole in the first-line
setting versus tamoxifen are supported by the results of a recently reported, independent, prospective, randomized, first-line
study in which 238 postmenopausal women with hormonesensitive, ER-positive, metastatic breast cancer, who had not
received previous therapy for advanced disease, were treated
with either anastrozole (1 mg once daily; n ⫽ 121) or tamoxifen
(40 mg daily; n ⫽ 117) (76). At the time of data cutoff, 61% of
4
AstraZeneca; data on file.
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Clinical Cancer Research 2627
Table 3 Overview of efficacy results from Phase III first-line trials of newer aromatase inhibitors versus tamoxifen in postmenopausal women
with advanced breast cancer
Anastrozole: combined US and European trials75
Anastrozole: Spanish trial76
Letrozole: US trial only77
Parameter
Anastrozole
1 mg daily
Tamoxifen
20 mg daily
Anastrozole
1 mg daily
Tamoxifen
20 mg daily
Letrozole
1 mg daily
Tamoxifen
20 mg daily
Median TTP (mo)
HR⫹veb patients only
8.5
10.7
7.0a
6.4
P ⫽ 0.022
(two-sided)
10.6
9.4
6.0
P ⫽ 0.0001
(two-sided)
Survival rate
NMb
5.3
HR ⫽ 0.77
(95% CI 0.56–0.91;
P ⬍ 0.05)
92% died
HR ⫽ 0.63;
(95% CI 0.51–0.89;
P ⬍ 0.05)
a
b
61% died
NM
Not significant.
HR⫹ve, hormone receptor-positive; NM, data not yet mature.
patients had died in the anastrozole-treated group, compared
with 92% in the tamoxifen-treated group (HR ⫽ 0.63; 95% CI,
0.51– 0.89; P ⬍ 0.05; Table 3). Median TTP was 10.6 months
for anastrozole and 5.3 months for tamoxifen, with a higher risk
of progression in the tamoxifen group, as indicated by the HR of
0.77 (95% CI, 0.56 – 0.91; P ⬍ 0.05) (79).
It was the conclusion of all of these studies that anastrozole
should now be considered as an alternative first-line treatment to
tamoxifen in postmenopausal women with advanced breast cancer.
Letrozole. Preliminary data have recently been reported
from a large, multicenter, double-blind, first-line Phase III clinical trial in postmenopausal women (n ⫽ 907) with locally
advanced or metastatic breast cancer, which compared letrozole
(2.5 mg once daily) with tamoxifen (20 mg once daily; Ref. 77).
The primary end point was TTP and secondary end points
included OR, TTF, time to response, and survival. A total of
65% of patients had ER-positive/PgR-positive status. Statistically significant superiority for letrozole was shown for the
primary end point, TTP (median TTP, 9.4 months for letrozole
versus 6.0 months for tamoxifen; P ⫽ 0.0001; Cox regression;
Table 3).
In contrast to the anastrozole trials, prior adjuvant tamoxifen in this trial was seen to impact upon subsequent response to
treatment. For instance, after adjuvant tamoxifen, patients receiving tamoxifen for metastatic disease were seen to have a low
response rate compared with letrozole (29% versus 8% for
letrozole and tamoxifen, respectively). Additional data and a full
publication from this trial are awaited.
Fadrozole. In a Phase III randomized trial, fadrozole (1
mg twice daily) was compared directly with tamoxifen (20 mg
once daily) as first-line therapy in the treatment of 221 postmenopausal women with advanced breast cancer (78). The study
was not double-blind, and patients with disease progression or
an unacceptable level of toxicity were given the opportunity to
cross over to the alternative drug where feasible. The two groups
were well balanced with respect to prognostic factors except for
metastatic disease; patients in the fadrozole arm had significantly more visceral metastases and disease than those in the
tamoxifen arm.
There was no significant difference between treatments in
terms of OR rate. TTF was longer with tamoxifen (8.5 months)
compared with fadrozole (6.1 months; P ⫽ 0.05; P ⫽ 0.09, after
Fig. 5 Kaplan-Meier curve for median TTF (fadrozole versus
tamoxifen).
adjustment for prognostic factors; Fig. 5), although duration of
response and survival were comparable in the two groups.
First-line Therapy in Advanced Breast Cancer with
Steroidal Aromatase Inhibitors
Formestane. In a comparative trial of first-line therapy
for postmenopausal women with advanced breast cancer, the
steroidal aromatase inhibitor, formestane (250 mg i.m. every 2
weeks), gave comparable results to those of tamoxifen (30 mg
p.o. daily) for both efficacy and tolerability (43). In total, 409
patients were randomized into two groups, well matched for
pretreatment characteristics, although there was a higher proportion of patients with soft tissue metastases in the formestanetreated group compared with the tamoxifen-treated group. Patients were assessed for antitumor efficacy using UICC criteria.
A total of 61 patients were not evaluable, either because they
were not eligible for the trial (mainly attributable to a lack of
confirmation of postmenopausal status) or because they were
nonevaluable for tumor response. There were no statistically
significant differences found between the two groups (n ⫽ 348)
for OR, median duration of response, and survival. However,
results significantly favored tamoxifen compared with formestane in terms of TTP (9.7 months versus 7.0 months, respectively; adjusted P ⫽ 0.003) and TTF (9.7 months versus 6.5
months; adjusted P ⫽ 0.001) compared with formestane.
Exemestane. A Phase II study was recently conducted in
which exemestane (25 mg daily) was compared with tamoxifen
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2628 Aromatase Inhibition in Breast Cancer Treatment
Table 4 Tolerability data: indirect comparison of newer aromatase inhibitors versus megestrol acetate in second-line trials
Adverse event (%)
Anastrozolea
1 mg o.d.b
Letrozolea
2.5 mg o.d.c
Exemestane71
25 mg o.d.d
Megestrol acetate
160 mg q.i.d.
Headache
Hot flushes
Nausea
Vomiting
Diarrhea
Weight gain
Rash
Dyspnea
Asthenia
Fatigue
14
13
18
10
9
3
6
11
18
NA
13
6
11
8
6
6
6
9
NAf
11
NA
13
9
3
NA
8e
2
1
NA
8
9–13
4–11
5–23
5–7
3–11
9–17
3–12
3–28
7–20
10–22
a
Adapted from Ref. 83.
Commonly reported adverse events, irrespective of causality.
c
Adverse experiences in ⬎5% of patients, irrespective of causality.
d
Adverse events considered to be drug-related.
e
Incidence of weight gain from baseline.
f
NA Data not available in published literature.
b
(20 mg daily) as first-line treatment of metastatic breast cancer
in postmenopausal women (n ⫽ 93; Ref. 79). Median TTP for
exemestane (n ⫽ 31) was 8.9 months compared with 5.2 months
for tamoxifen (n ⫽ 32), and OR (CR ⫹ PR) was 42% versus
16%, respectively. No statistical data from this Phase II study
are available at the present time. It was concluded that exemestane had promising activity in the first-line treatment of metastatic disease and warranted a Phase III trial.
Conclusions. The results of the first-line Phase III comparative trials between anastrozole and tamoxifen now support
the use of anastrozole in the first-line treatment of advanced
disease in postmenopausal women. Notwithstanding earlier investigations into the first-line use of the aromatase inhibitors
fadrozole and formestane, compared with tamoxifen in advanced breast cancer in postmenopausal women, this is the first
full report from a large-scale, randomized study of a newergeneration aromatase inhibitor having superior efficacy to that
of tamoxifen. Preliminary data have recently been reported
showing a statistically significant advantage for letrozole versus
tamoxifen in terms of TTP in the first-line treatment of advanced disease, and a full report of these data are awaited.
Tolerability of Steroidal and Nonsteroidal
Aromatase Inhibitors
Adverse Events. In clinical use, both steroidal and nonsteroidal aromatase inhibitors are generally well tolerated. The
main adverse events observed are hot flushes and gastrointestinal events, i.e., nausea and vomiting, which are either anticipated via the pharmacological actions of aromatase inhibitors or
are the most commonly seen type of events with this class of
drug (18, 21, 43, 71, 72, 80 – 82). There are, however, certain
specific side effects observed with exemestane, but not anastrozole and letrozole, that relate to the androgenic nature of the
drug.
When compared with megestrol acetate in second-line
studies in advanced breast cancer, the nonsteroidal drugs, anastrozole and letrozole, were associated with a significantly lower
incidence of weight gain (55, 61). When exemestane was compared with megestrol acetate, there was also a significantly
lower incidence of weight gain with exemestane (P ⫽ 0.001), as
would be anticipated when comparing aromatase inhibitors with
progestins in this patient population (71). However, the observed value for grade 3– 4 weight gain (excessive weight gain
⬎10% of baseline weight) of 7.6% in patients receiving exemestane is higher than that reported for the nonsteroidal aromatase
inhibitors, anastrozole and letrozole, in similar trials in a comparable patient population (Table 4; Refs. 55 and 61); this higher
value for exemestane probably reflects the androgenic nature of
the drug. Additionally, weight gain changes of ⱖ10% after
exemestane were noted in 4% of overweight patients (71).
At higher than normal therapeutic doses of exemestane
(200 mg daily), androgenic events have been reported, such as
alopecia (10%), hypertrichosis (55), hoarseness (5%), and acne
(4%; Ref. 84). Exemestane has been reported to lead to statistically significant dose-dependent falls in plasma sex hormone
binding globulin levels at the 25-mg dose level (52). At 200 mg
daily, exemestane gave rise to a case of mild hirsutism after 52
weeks’ treatment. In a Phase II trial, symptoms which may have
been androgenic in nature were reported, again using the clinical
dose of exemestane of 25 mg daily (two cases of grade 1
alopecia, one patient each with hypertrichosis and acne among
91 treated patients; Ref. 53).
In a Phase III trial comparing exemestane and megestrol
acetate, significantly more women receiving exemestane experienced hot flushes (12.0% versus 5.0%), nausea (9.2% versus
5.0%), and vomiting (2.8% versus 0.8%) than did women receiving megestrol acetate, respectively. Significantly more
women receiving megestrol acetate reported dyspnoea than did
women receiving exemestane (3.0% versus 0.3%, respectively;
Ref. 71).
In a first-line study comparing fadrozole with tamoxifen, a
4% incidence in thromboembolic events was reported in the
tamoxifen group, whereas no events were observed in fadrozoletreated patients (78). In the first-line studies comparing anastrozole with tamoxifen (72–75), anastrozole-treated patients had a
significantly lower incidence of thromboembolic events (combined analysis).4 With respect to other adverse events in these
same trials, more patients treated with anastrozole had hot
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Clinical Cancer Research 2629
flushes and vaginal dryness, whereas more patients treated with
tamoxifen had vaginal bleeding and vaginal discharge, although
the differences were not significant. Although gastrointestinal
disturbances are widely recognized as a class effect of aromatase inhibitors, it should be noted that that the incidence of
gastrointestinal disturbances was similar in the cases of anastrozole and tamoxifen in each trial [24% anastrozole versus 28%
tamoxifen, respectively (72) and 54% anastrozole versus 57%
tamoxifen, respectively (73)]. Finally, despite its lack of estrogenic effect, anastrozole showed no increase in myocardial
infarction or fractures compared with tamoxifen.
Overall, very few patients withdrew from first- or secondline comparative Phase III trials because of drug-related adverse
events with aromatase inhibitors (19, 54, 55, 61, 66, 72, 73). In
the large-scale, randomized trials of anastrozole versus tamoxifen for first-line treatment, the incidence of withdrawals was
similar in both treatment groups, showing that anastrozole is at
least as well tolerated as tamoxifen (72, 73). No tolerability data
are available, as yet, from the first-line study comparing letrozole with tamoxifen (77).
The newer-generation aromatase inhibitors have the additional advantage of simple, oral, once-daily dosing. This avoids
such problems as local reactions (7–13%) at the site of injection,
which have been reported after the twice-weekly i.m. administration of the steroidal aromatase inhibitor, formestane, thus
limiting the potential, long-term usefulness of this drug in the
adjuvant setting (11, 12, 43, 85).
Neoadjuvant Therapy with Aromatase Inhibitors
Anastrozole. A small, randomized, double-blind, singlecenter study was performed in which anastrozole (1 mg and 10
mg daily, for 3 months) was used as neoadjuvant therapy in 23
postmenopausal women with newly diagnosed, ER-rich, locally
advanced, or large (⬎3 cm), operable breast tumors (86). Anastrozole at the normal clinical dose of 1 mg daily was shown by
ultrasound measurements to be effective in leading to a decrease
in tumor volume in the great majority of patients (80.5%). This
had a dramatic influence on subsequent breast surgery, in that,
of 17 patients who would have required mastectomy at the
initiation of treatment, 15 were found to be suitable for breast
conservation after 3 months’ treatment with anastrozole. These
results suggest that anastrozole is highly effective as neoadjuvant therapy in postmenopausal women with ER-rich breast
tumors. In the same group of patients, anastrozole was shown to
suppress effectively aromatase activity within the breast,
thereby reducing endogenous estrogens (87). This observation is
compatible with the known antitumor effects of anastrozole.
In another small study in 12 postmenopausal women with
locally advanced (T3–T4) breast cancer, anastrozole 1 mg daily
for 15 weeks was evaluated for its effects on plasma and tumor
tissue estrogen levels in the same patient group (88). Treatment
with anastrozole suppressed tumor tissue concentrations of estradiol, estrone, and estrone sulfate by 88.9%, 82.3%, and
73.4%, respectively, and plasma concentrations by 86.1%,
83.9%, and 95.8%, respectively. It was concluded that anastrozole is a potent suppressor of plasma and intratumoral estrogen
levels in patients with locally advanced breast cancer.
Letrozole. In a similar study, letrozole 2.5 mg daily for 3
months as primary medical therapy was investigated for its
effects on in situ estrogen synthesis in 11 postmenopausal
women with large, primary, ER-positive breast tumors (89). Of
10 tumors which showed evidence of in situ estrogen synthesis,
9 displayed a significant decrease in activity after letrozole
treatment (P ⫽ 0.022 by sign test). It was concluded that
letrozole brought about a decrease in endogenous levels of
estrogen within the breast tumors of postmenopausal women.
Letrozole (2.5 mg daily; n ⫽ 12; 10 mg daily, n ⫽ 12) was
administered to 24 patients with ER-positive breast tumors as
primary systemic therapy (90). The patients were monitored by
monthly ultrasound and change in tumor volume over a 3-month
period. The resulting median reduction in tumor volume was
81%. Fifteen patients who would have been considered for
mastectomy before letrozole therapy were found to be suitable
for breast conservation after 3 months’ treatment with the drug.
In a double-blind, randomized, multicenter study, letrozole
(2.5 mg daily) was compared with tamoxifen (20 mg daily) as
neoadjuvant treatment of 337 postmenopausal women with ERpositive primary breast cancer, over a 4-month period (91). All
patients at baseline were not considered eligible for breastconserving surgery. The primary end point was tumor response.
Another important end point was the resultant impact of treatment on the down-staging of the extent of surgery. OR rates
were 55% for letrozole (n ⫽ 154) versus 36% for tamoxifen
(n ⫽ 170), a difference which was statistically significantly
different (P ⬍ 0.001; Mantel-Haenszel low rank test). After 4
months’ therapy, 45% of letrozole-treated patients underwent a
lumpectomy/quadrantectomy versus 35% of tamoxifen-treated
patients (P ⫽ 0.022; Mantel-Haenszel). It was concluded that
letrozole was significantly superior to tamoxifen in terms of
tumor reduction, which resulted in a superior rate of breastconserving surgery in the letrozole-treated group.
Conclusions. From the results of the above studies, both
anastrozole and letrozole are shown to be effective as neoadjuvant therapy in postmenopausal women with large, operable
breast tumors. Treatment for up to 3 months with either aromatase inhibitor led to a marked reduction in mastectomy rates.
Results to date for letrozole versus tamoxifen, and from an
indirect comparison of anastrozole with tamoxifen as neoadjuvant therapy in a similar patient population, indicate that these
newer-generation aromatase inhibitors appear to offer an advantage over neoadjuvant therapy with antiestrogens, and additional
comparative studies between these two classes of endocrine
agents are under way.
Adjuvant Therapy with Aromatase Inhibitors
Tamoxifen is the most widely used endocrine agent for the
adjuvant therapy of early breast cancer in postmenopausal
women (79). Nevertheless, tamoxifen does have limitations in
use, most notably its recognized pharmacological properties and
side effects. For instance, tamoxifen has been associated with an
increased risk of both thromboembolic events and endometrial
changes, including endometrial cancer (9, 92). It is feasible,
therefore, that other endocrine drugs can provide at least equivalent, if not superior, efficacy, together with improved tolerability, in patients with early disease. In this context, the newergeneration aromatase inhibitors are now under investigation in
the adjuvant setting (Table 5).
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2630 Aromatase Inhibition in Breast Cancer Treatment
Table 5
Key adjuvant studies with aromatase inhibitors (see Refs. 81, 82, 91, and 92)
Adjuvant study
ATAC
ARNO
ABCSG
FEMTABIG
MA.17
ICCG
NSABP (B-33)
Design
Tamoxifen alone (20 mg daily, 5 yr) versus
Tamoxifen (20 mg daily) ⫹ anastrozole (1 mg daily, 5 yr) versus
Anastrozole alone (1 mg daily 5 yr)
Tamoxifen (20 mg daily, 2 yr) followed by tamoxifen (20 mg daily, 3 yr) versus
Tamoxifen (20 mg daily, 2 yr) followed by anastrozole (1 mg daily, 3 yr)
Comparison of addition of aminoglutethimide to tamoxifen for 5 yr, followed by rerandomization to compare
anastrozole with placebo for an additional 3 yr
Tamoxifen (20 mg daily) versus anastrozole (1 mg daily) after 2-yr exposure to tamoxifen (20 mg daily)
Tamoxifen (20 mg daily, 5 yr) versus
Letrozole (2.5 mg daily, 5 yr) versus
Letrozole (2.5 mg daily, 2 yr) followed by tamoxifen (20 mg daily, 3 yr) versus
Tamoxifen (20 mg daily, 2 yr) followed by letrozole (2.5 mg daily, 3 yr)
Tamoxifen (5 yr) followed by letrozole (5 yr) versus
Tamoxifen (5 yr) followed by placebo (5 yr)
Tamoxifen (20 mg daily, 2–3 yr) followed by either tamoxifen (20 mg daily) or exemestane (25 mg daily)
for the remainder of the 5-yr period
Tamoxifen (5 yr) followed by either exemestane (25 mg daily) for 2 yr or placebo for 2 yr
Anastrozole. Anastrozole is currently being compared
directly with tamoxifen as initial adjuvant therapy in postmenopausal women with early breast cancer (82, 93–95). The ATAC
trial is a randomized, double-blind trial designed to compare the
efficacy and tolerability of 5 years of treatment with tamoxifen
with that of anastrozole versus the combination of anastrozole
and tamoxifen (92, 93). The primary end points are time to
recurrence and safety. Other criteria for evaluation include time
to distant metastases, survival, and occurrence of contralateral
breast cancer. Separate subprotocols include assessments of
pharmacokinetics, endometrial status, bone mineral density, and
quality of life. The ATAC trial has now completed recruitment
of over 9300 patients and is expected to report in the year 2001.
A second trial, the Arimidex-Nolvadex (ARNO) trial, being conducted by the German Breast Cancer Group, involves the
randomization of patients who have received adjuvant tamoxifen for 2 years to receive either anastrozole for 3 years or
tamoxifen for an additional 3 years (82, 92–94). The primary
end points in this trial are overall survival, relapse-free survival,
tolerability, and quality of life.
Two other adjuvant studies of endocrine therapy with aromatase inhibitors in early breast cancer are in progress with the
ABCSG (95). The first study compares the addition of the
first-generation aromatase inhibitor, aminoglutethimide, to tamoxifen treatment in postmenopausal patients with hormoneresponsive, stage I and stage II breast cancer. After 5 years’
endocrine treatment in either arm, patients who are recurrencefree are being rerandomized to compare anastrozole with placebo for another 3 years. In the second ABCSG study, adjuvant
tamoxifen for 3 years is being compared with adjuvant anastrozole for 3 years after 2 years’ exposure to tamoxifen in postmenopausal patients presenting with hormone-responsive, G1
and G2, stage I and stage II breast cancer.
Letrozole. The Femera-Tamoxifen Breast International
Group (FEMTABIG) trials of letrozole and tamoxifen are being
conducted by the Breast International Group to compare letrozole with tamoxifen over 5 years in postmenopausal women
with ER-positive/PgR-positive early breast cancer and to compare a sequence of adjuvant endocrine therapies versus a con-
tinuous course of a single endocrine agent. The trial consists of
an option of randomization into two single arms of either
tamoxifen (20 mg daily) or letrozole (2.5 mg daily) for 5 years
or randomization into a four-arm trial comprising either arm of
the first option above (two-arm trial); and a third arm of 3 years
of tamoxifen (20 mg daily) and then letrozole (2.5 mg daily) for
2 years; and a fourth arm of letrozole (2.5 mg daily) for 3 years
and then tamoxifen (20 mg daily) for 2 years (81, 82, 92).
Another adjuvant trial, the MA.17 study, evaluates patients
from the National Cancer Institute of Canada Clinical Trials
Group (NCIC CTG) who are disease-free after initially being
treated with 5 years of tamoxifen and then randomized to
receive either 5 years of placebo or 5 years of letrozole. This
trial also incorporates assessments of incidence of bone fractures and bone mineral density measurements together with lipid
profiles (81).
Exemestane. The steroidal aromatase inhibitor, exemestane is also being studied in the adjuvant setting (81, 82, 92). In
the International Collaboration Cancer Group (ICCG) trial, patients with early breast cancer are randomized to receive tamoxifen (20 mg daily for 2–3 years) and then either tamoxifen (20
mg daily) or exemestane (25 mg daily) for the remainder of the
5-year period (92). In the National Surgical Adjuvant Breast and
Bowel Project (NSABP; B-33) trial, patients with early breast
cancer are being randomized to receive either exemestane or
placebo for 2 years after a standard 5 years of tamoxifen therapy
(82).
Conclusions. The above adjuvant trials of aromatase inhibitors versus tamoxifen in the treatment of early breast cancer
offer the opportunity for the measurement of parameters such as
disease recurrence, contralateral breast cancer occurrence,
disease-free survival, and overall survival. It is hoped that the
current trials with anastrozole, letrozole, and exemestane as
adjuvant endocrine treatment in early breast cancer will be
beneficial in terms of efficacy, tolerability and quality-of-life
parameters in postmenopausal women. The data from the ATAC
trial will be available in the near future, and the recent data from
the first-line comparative trials between anastrozole and tamoxifen and letrozole and tamoxifen suggest that there is also
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Clinical Cancer Research 2631
Table 6
Properties of aromatase inhibitors
Aromatase
inhibitor
Class
Anastrozole
Fadrozole
Letrozole
Nonsteroidal
Nonsteroidal
Nonsteroidal
II: Inhibitor
II: Inhibitor
II: Inhibitor
1 mg daily p.o.
1 mg twice daily p.o.
2.5 mg daily p.o.
Vorozole
Nonsteroidal
II: Inhibitor
2.5 mg daily p.o.
Exemestane
Formestane
Steroidal
Steroidal
I: Inactivator
I: Inactivator
25 mg daily p.o.
250 mg twice weekly i.m.
Type
Normal clinical dose and
route of administration
Phase III clinical data available
for second-line use versus:
Megestrol acetate6,54,55,58
Megestrol acetate69
Megestrol acetate61–63
Aminoglutethimide65
Megestrol acetate66
Aminoglutethimide67,68
Megestrol acetate71
Megestrol acetate24,70
Table 7 First-line clinical trials of aromatase inhibitors
Phase III clinical data available for first-line use in advanced breast cancer.
Aromatase inhibitor
Major findings
Anastrozole vs. tamoxifen72–75
Anastrozole at least as effective as tamoxifen.
Significant difference in favor of anastrozole for patients with ER-positive and/or PgR-positive
tumors (P ⫽ 0.022; two-sided).
Numerical (nonsignificant) advantage for tamoxifen over fadrozole in terms of TTF. No
significant difference in terms of OR rate. Duration of response and survival comparable.
No statistically significant differences for OR, median duration of response, and survival. Results
significantly favored tamoxifen compared with formestane in terms of TTP and TTF.
Promising antitumor activity vs. tamoxifen in a Phase II study (n ⫽ 97). A Phase III trial is
planned.
Preliminary data available showing significant superiority for letrozole over tamoxifen in terms
of TTP.
No data available.
Fadrozole vs. tamoxifen78
Formestane vs. tamoxifen43
Exemestane vs. tamoxifen79
Letrozole vs. tamoxifen77
Vorozole
potential for aromatase inhibitors to provide an advantage over
tamoxifen in the adjuvant setting.
Overall Conclusions
The data for the second-line use of endocrine therapy with
steroidal and nonsteroidal aromatase inhibitors has fully established this class of drugs as the new treatment of choice in
postmenopausal women with advanced breast cancer failing on
prior treatment with an antiestrogen such as tamoxifen (20, 58,
61, 71). In terms of efficacy, anastrozole, letrozole, and exemestane each have shown advantages over the standard second-line
therapy, megestrol acetate. Anastrozole was the first nonsteroidal, newer-generation aromatase inhibitor to demonstrate a mature efficacy and survival advantage over another second-line
endocrine drug (58), although exemestane has now also been
reported to improve survival compared with megestrol acetate
(71). All of the newer-generation aromatase inhibitors are well
tolerated, with hot flushes and gastrointestinal disturbance being
the major adverse events reported in second-line comparative
studies. The nonsteroidal aromatase inhibitors, anastrozole and
letrozole, both display a clear benefit in terms of weight gain
over megestrol acetate.
The properties of aromatase inhibitors reviewed in this
article are shown in Table 6.
Many reviewers have attempted to draw indirect comparisons between drugs within this class of aromatase inhibitors in
an effort to identify the optimal aromatase inhibitor for the
second-line therapy of advanced breast cancer. This is fraught
with difficulties, because randomized, controlled trials involving these agents have study designs with different response
criteria and different methods of assessment in different patient
populations (20, 80). As a result, such indirect comparisons
between trials cannot possibly lead to a clear outcome in favor
of any single drug. Some investigators even have attempted to
reach conclusions based on the degree of estrogen suppression
exhibited by aromatase inhibitors; but it should be noted that the
net clinical relevance of plasma estrogen reduction still needs to
be carefully evaluated (81).
One major area of considerable interest for these newergeneration aromatase inhibitors lies in their potential for lack of
cross-resistance with other drugs of the same class, thereby
allowing the possibility for an additional response to endocrine
therapy, even after progression on second-line treatment. This is
illustrated by the response of patients to anastrozole after progression on second-line therapy with formestane (96); 9 of 12
patients who had initially achieved either a PR or SD on formestane before progressing showed additional SD on anastrozole.
Seven of these nine responding patients had ER-positive tumors.
Similarly, exemestane produced CR in 3 patients and PR in 13
patients when given to postmenopausal women with metastatic
breast cancer after progression on second-line therapy with the
nonsteroidal aromatase inhibitors, aminoglutethimide, anastrozole, letrozole, or vorozole (97). This lack of cross-resistance
might be predicted when steroidal aromatase inhibitors are used
sequentially after nonsteroidal aromatase inhibitors and vice
versa because of their different mechanisms of action on the
aromatase enzyme.
The neoadjuvant use of newer-generation aromatase inhibitors in women with ER-rich, locally advanced, or large operable breast tumors gives rise to optimism because of their ability
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2632 Aromatase Inhibition in Breast Cancer Treatment
to reduce mastectomy rates while providing an early indication
of likely tumor response to endocrine therapy.
In the first-line therapy of advanced breast cancer, anastrozole and letrozole have now challenged the position of the
long-established, standard therapy, tamoxifen, showing significant benefits in terms of TTP (74, 77). Both aromatase inhibitors
are very well tolerated, but anastrozole has shown fewer thromboembolic complications and instances of vaginal bleeding than
tamoxifen and is not associated with an increased risk of endometrial cancer. Tolerability data for letrozole in this setting are
not yet available. Undoubtedly, as more results from first-line
trials become available (Table 7), aromatase inhibitors will
become more widely used as first-line agents, as an alternative
to tamoxifen, in the treatment of postmenopausal women with
advanced disease.
There are differences in both the chemistry and the pharmacological properties of the newer-generation aromatase
inhibitors. These differences seem to have an impact upon
selectivity of the drugs for aromatase (e.g., effect on adrenocorticorticotropic hormone-stimulated cortisol levels) and may possibly have an effect on the clinical efficacy of aromatase inhibitors in the adjuvant setting on a long-term basis. Data on the
adjuvant use of anastrozole, letrozole, and exemestane will
become available in the near future; data on anastrozole is
expected to be the first to report. Although each of these
aromatase inhibitors are generally well tolerated in the metastatic setting, it will be their tolerability profiles after long-term
use in the adjuvant setting that will ultimately determine
whether or not tamoxifen is replaced as the “gold standard”
adjuvant treatment. It will be important to determine whether
there are any long-term effects on the endometrium or on
thromboembolic events and, additionally, whether any differences in “selectivity” between the drugs have any clinical consequences.
Currently, there are no data available on possible interactions between aromatase inhibitors and standard chemotherapeutic agents. The ongoing clinical trial program will provide
the answers to many of these points, the data being awaited with
great interest.
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Advances in Aromatase Inhibition: Clinical Efficacy and
Tolerability in the Treatment of Breast Cancer
Aman Buzdar and Anthony Howell
Clin Cancer Res 2001;7:2620-2635.
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