Download adjuvant endocrine therapy for postmenopausal women with early

REVIEW
T
ADJUVANT ENDOCRINE THERAPY FOR
POSTMENOPAUSAL WOMEN WITH EARLY BREAST CANCER
—
Aman U. Buzdar, MD*
ABSTRACT
The safety and efficacy of tamoxifen as adjuvant endocrine therapy for postmenopausal
patients with early breast cancer (BC) has been
established. In the last decade, aromatase
inhibitors (AIs) have also been evaluated in this
setting. The results of several large, randomized
clinical trials that investigated AIs as initial treatment for up to 5 years, after 2 to 3 years of
tamoxifen, and for extended treatment after 5
years of tamoxifen have recently been reported.
In all cases, AIs have shown greater efficacy than
tamoxifen. However, the optimal role of AIs in
postmenopausal patients with early BC remains
unclear. The Technology Assessment Working
Group of the American Society of Clinical
Oncology has recommended that AIs be used for
adjuvant therapy initially or after 2 to 3 years of
tamoxifen for postmenopausal patients with hormone-receptor–positive BC. Differences in safety
and efficacy among the AIs are emerging but are
not yet fully understood. AIs are safe and generally well tolerated. They result in fewer hot flashes and gynecologic symptoms but more joint
symptoms than tamoxifen. The greatest concern
regarding the use of AIs is their association with
an increased incidence of fractures because AIs
reduce bone mineral density. The risk of cardiovascular events from AIs may vary with different
AIs and remains to be further defined. AIs are
less likely than tamoxifen to cause thromboembolic events.
(Adv Stud Med. 2006;6(10C):S984-S993)
*Professor, Department of Breast Medical Oncology,
The University of Texas M.D. Anderson Cancer Center,
Houston, Texas.
Address correspondence to: Aman U. Buzdar, MD,
Professor, Department of Breast Medical Oncology, The
University of Texas M.D. Anderson Cancer Center, 1515
Holcombe Blvd, Box 1354, Houston, TX 77030.
E-mail: [email protected].
S984
he first randomized clinical trial of adjuvant
therapy for breast cancer (BC) was conducted approximately 60 years ago. Since
then, hundreds of clinical trials have investigated a wide variety of treatment
approaches. A meta-analysis conducted by the Early
Breast Cancer Trialists’ Collaborative Group (EBCTG)
established that adjuvant systemic chemotherapy
improves the disease-free survival (DFS) time and overall survival (OS) time of patients with early stage BC.1
The EBCTG also conducted a separate meta-analysis
that showed the benefits of adjuvant endocrine therapy
and helped establish 5 years of tamoxifen as the standard
for adjuvant endocrine therapy in postmenopausal
women with early BC.2 However, the benefits associated
with tamoxifen—which were largely independent of age,
menopausal status, daily tamoxifen dose, and previous
chemotherapy—were not without risk. Treatment with
tamoxifen increased the incidence of endometrial cancer;
it approximately doubled the rate after 1 or 2 years of
tamoxifen therapy and quadrupled it after 5 years of
tamoxifen therapy.2 Furthermore, concerns regarding
thromboembolic events and the development of resistance to tamoxifen leading to disease recurrence indicated a need for alternative adjuvant therapies.
ENDOCRINE THERAPY OPTIONS
The development of tamoxifen as adjuvant therapy
for BC was based on the observation more than a century ago that oophorectomy caused BC regression in a
premenopausal patient.3 Tamoxifen, a selective estrogen-receptor modulator (SERM), causes estrogen
deprivation through competitive blockade of the estrogen receptor in breast tissue. At the same time, SERMs
act as estrogen agonists on other tissues such as
endometrium and bone. Other SERMs include raloxifene and toremifene. Raloxifene has no clinically significant antitumor activity in advanced BC and is not
indicated for BC treatment. Toremifene is indicated as
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an alternative to tamoxifen as first-line treatment of
hormone-responsive metastatic BC and appears to be
as effective as tamoxifen when given as adjuvant therapy to patients with metastatic disease.4,5 Fulvestrant is
a steroid analog with pure estrogen-receptor antagonist activity that is also indicated for metastatic BC.
The use of aromatase inhibitors (AIs) is another
approach to reducing the effects of estrogen in patients
with BC. AIs reduce circulating estrogen levels by
inhibiting aromatase, the enzyme that converts testosterone to estradiol and androstenedione to estrone. AIs
also act by directly blocking local estrogen production
in the breast tumor. Because AIs indirectly lead to
ovarian stimulation, which may result in ovarian cysts
in premenopausal females, they are not recommended
in women with normal ovarian function.
Although 3 generations of AIs exist, only the third
generation of AIs are used for the adjuvant treatment of
BC in postmenopausal women because of their superior
safety profile and convenient dosing features. AIs are
classified as type 1 or type 2, depending on their mechanism of action. Type 1 AIs are androstenedione
steroidal analogs and bind irreversibly to the aromatase
enzyme, whereas type 2 AIs are nonsteroidal and bind
reversibly to the heme group on the aromatase enzyme.
Of the third-generation AIs, exemestane is a type 1
agent, whereas anastrozole and letrozole are type 2 AIs.
During the last few years, several trials testing AIs
as adjuvant therapy for early BC in postmenopausal
women have been completed or their preliminary
results have been reported. These trials generally have
compared AIs directly with tamoxifen or have used AIs
in sequence with tamoxifen.
DIRECT COMPARISON OF AROMATASE INHIBITORS
TAMOXIFEN
AND
THE ARIMIDEX, TAMOXIFEN, ALONE OR
IN COMBINATION TRIAL
The Arimidex, Tamoxifen, Alone or in Combination
(ATAC) trial enrolled postmenopausal women to compare the safety and efficacy of tamoxifen therapy with
those of anastrozole therapy when given alone or with
tamoxifen for 5 years. Women were eligible if they had
invasive operable BC, had completed primary therapy,
and could receive adjuvant hormonal therapy. Women
(n = 9366) were randomized to receive tamoxifen, 20
mg; anastrozole, 1 mg; or both at the same dosages as
were used in monotherapy.6
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After a median follow-up of 68 months, compared
with tamoxifen, anastrozole prolonged DFS time (hazard
ratio [HR] 0.87, 95% confidence interval [CI]
0.78–0.97, P = .01) and time to recurrence (HR 0.79,
95% CI 0.79–0.90, P = .0005). However, compared with
tamoxifen, anastrozole produced the greatest benefit in
women with hormone-receptor–positive BC (DFS HR
0.83, 95% CI 0.73–0.94; time to recurrence HR 0.74,
95% CI 0.64–0.87).7 Results of retrospective subgroup
analysis suggested that the time to recurrence was substantially greater in the group with progesterone-receptor–negative BC.8 The benefit of anastrozole was
independent of prior chemotherapy or type of
chemotherapy.9 At 68 months’ median follow-up, the
time to recurrence was not different between patients
who had received prior chemotherapy and those who had
not (HR 0.89 vs 0.74, respectively; P = .021).9 Time to
distant metastases was longer (HR 0.86, 95% CI 0.740.99, P = .04) and incidence of contralateral BC was less
(HR 0.58, 42% reduction, 95% CI 12%-62%, P = .01)
in the group that received anastrozole than in the group
that received tamoxifen. In terms of the latter measure,
women with hormone-receptor–positive BC experienced
the greatest benefit (53% reduction, 95% CI 25%-71%,
P = .001).7 OS time was similar for the anastrozole and
tamoxifen groups; although, given the relatively good
prognosis of the patient population, it still may be too
early for a difference to be seen.7
THE BREAST INTERNATIONAL GROUP 1-98 TRIAL
The Breast International Group (BIG) 1-98 trial
randomized 8010 postmenopausal women with operable invasive BC that was estrogen-receptor positive,
progesterone-receptor positive, or both.10 Women
received 5 years of treatment with letrozole, 2.5 mg
daily; 5 years of treatment with tamoxifen, 20 mg
daily; letrozole for 2 years then tamoxifen for 3 years;
or tamoxifen for 2 years then letrozole for 3 years.
After a median follow-up of 25.8 months, 4-year DFS
was estimated to be 84% in the 2 groups that received
letrozole initially combined and 81.4% in the 2 groups
that received tamoxifen initially combined. Compared
with tamoxifen, letrozole reduced the risk of experiencing an event that ended a period of DFS (HR 0.81,
95% CI 0.70-0.93; P = .003), especially the risk of distant recurrence (HR 0.73, 95% CI 0.60-0.88;
P = .001). Although the supporting data were not provided, the investigators reported a beneficial effect of
letrozole monotherapy compared with tamoxifen
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monotherapy. Planned subgroup analyses showed a 5year DFS among women with node-positive cancer of
77.9% in the letrozole group and 71.4% in the tamoxifen group; in women with node-negative cancer, 5year DFS was 88.7% in both groups. The DFS
benefits of letrozole were similar for all combinations
of estrogen-receptor and progesterone-receptor status.
THE ARIMIDEX, TAMOXIFEN, ALONE OR IN
COMBINATION AND BREAST INTERNATIONAL
GROUP 1-98 TRIALS IN PERSPECTIVE
Many of the benefits of AI therapy were similar in the
ATAC and BIG 1-98 trials, although important differences exist. The ATAC trial showed that the relative
treatment benefits of anastrozole did not differ between
patients who received prior chemotherapy and those
who did not. In contrast, the BIG 1-98 trial showed the
greatest benefit of letrozole in women who had received
chemotherapy and in those with node-positive disease.
Similarly, the ATAC trial showed the greatest benefit of
anastrozole in women with estrogen-receptor–positive
and progesterone-receptor–negative tumors. Letrozole
similarly reduced the risk of an event ending DFS irrespective of progesterone-receptor status. Despite these
differences, both trials support the initial use of an AI
instead of tamoxifen as adjuvant therapy.
The important role of an AI in initial adjuvant therapy is further supported by the results of a cost-effectiveness analysis that estimated the incremental cost per
quality-adjusted life-year (QALY) gained from initial
adjuvant therapy with letrozole compared with tamoxifen or from initial adjuvant therapy with anastrozole
compared with tamoxifen.11 The incremental cost per
QALY gained was estimated to be $33 536 (95% CI $20
409–$70 566) for letrozole and $38 967 (95% CI $23
826–$81 904) for anastrozole, which indicates that therapy with an AI is cost effective for the healthcare system.
AROMATASE INHIBITOR THERAPY AFTER
2 TO 3 YEARS OF TAMOXIFEN THERAPY
An overall survival benefit when tamoxifen was
given for less than 5 years and followed by AI therapy
was preliminarily shown for aminoglutethimide, a
first-generation AI, in the GROCTA 4 trial.12 Other
studies have confirmed these results.
THE ITALIAN TAMOXIFEN ANASTROZOLE TRIAL
The Italian Tamoxifen Anastrozole (ITA) trial was
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conducted by the GROCTA 4 investigators using the
same study design as was used in GROCTA 4.
Postmenopausal women (n = 448) with node-positive,
estrogen-receptor–positive tumors who had been treated with 2 to 3 years of tamoxifen were randomized to
receive anastrozole, 1 mg daily, or to continue to
receive tamoxifen, 20 mg daily, for a total of 5 years.13
At a median follow-up of 36 months, DFS and local
recurrence-free survival (LRFS) times were longer in
the anastrozole group than in the tamoxifen group
(DFS HR 0.35, 95% CI 0.18–0.68, P = .001; LRFS
HR 0.15, 95% CI 0.03–0.65, P = .003).
An updated and pooled analysis of the GROCTA
4 and ITA trials showed that all-cause mortality and
breast-cancer–specific mortality were decreased (P = .007
or .03, respectively) by switching to anastrozole.14
THE AUSTRIAN BREAST AND COLORECTAL CANCER STUDY
GROUP TRIAL 8 AND ARIMIDEX-NOLVADEX 95 TRIAL
A prospectively planned, event-driven, combined
analysis was done of the Austrian Breast and Colorectal
Cancer Study Group Trial 8 (ABCSG 8) and ArimidexNolvadex (ARNO) 95 trial. The data analyzed were
obtained from studying 3224 postmenopausal women
with hormone-sensitive early BC.15 After completing 2
years of adjuvant tamoxifen therapy, patients were randomized to continue to receive tamoxifen, 20 or 30 mg
daily, or to receive anastrozole, 1 mg daily, for a total treatment period of 5 years. DFS 3 years after the switch was
longer in the anastrozole group than in the tamoxifen
group (HR 0.60, 95% CI 0.44–0.81, P = .0009); the
absolute benefit at 3 years was 3.1%. A separate analysis
of the ARNO 95 trial with a median follow-up of 30.1
months showed that switching to anastrozole improved
DFS (HR 0.66, 95% CI 0.44–1.00, P = .049) and OS
(HR 0.53, 95% CI 0.28–0.99, P = .045).16
THE INTERGROUP EXEMESTANE STUDY
Postmenopausal women who had received tamoxifen for 2 to 3 years were randomized to continue
receiving tamoxifen, 20 mg daily, or to switch to
exemestane, 25 mg daily, for a total of 5 years of adjuvant therapy.17,18 After a median follow-up of 58
months, DFS was greater in the exemestane group
than in the tamoxifen group (HR 0.76; 95% CI
0.66–0.88, P = .0001). The time to distant recurrence
(HR 0.83, 95% CI 0.70–0.98) and contralateral BC
(HR 0.56, 95% CI 0.32–0.97) were reduced (P = .03
or .04, respectively) in the exemestane group. OS time
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was not different between the 2 groups (HR 0.85,
95% CI 0.71–1.02, P = .08), except in those with
estrogen-receptor–positive/unknown, unilateral BC
(HR 0.83, 95% CI 0.69–1.00, P = .05).18
ITA, ABCSG 8, ARNO 95, AND INTERGROUP
EXEMESTANE STUDY IN PERSPECTIVE
Combined analysis of these trials showed that switching to AI therapy after only 2 to 3 years of tamoxifen
improved event-free and recurrence-free survival (P
<.00001) compared with 5 years of tamoxifen therapy.19
AROMATASE INHIBITORS AFTER 5 YEARS OF TAMOXIFEN
The National Surgical Adjuvant Breast and Bowel
Project B-14 trial showed that extending the duration of
tamoxifen therapy beyond 5 years offered no benefit and
instead shortened DFS time.20 For this reason, and
because 50% of all recurrences and two thirds of all
deaths from hormone-dependent BC occur after 5 years
of tamoxifen therapy,21 the role of AI therapy when given
after 5 years of tamoxifen therapy has been investigated.
THE MA.17 TRIAL
Postmenopausal women who were completing 5
years of tamoxifen were randomized to receive 5 years of
letrozole, 2.5 mg daily (n = 2593), or placebo (n =
2594).21 After a median follow-up of 30 months, women
in the letrozole group had better DFS time (HR 0.58,
95% CI 0.45–0.76, P <.001) and distant DFS time (HR
0.60, 95% CI 0.43–0.84, P = .002). Although OS time
was the same in both groups, those with node-positive
tumors in the letrozole group fared better (HR 0.61,
95% CI 0.38–0.98, P = .04). At a median follow-up of
2.4 years, the estimated 4-year DFS time in the letrozole
group was 93% compared with 87% in the placebo
group (P <.001), which represents an absolute reduction
in recurrence of 6% caused by letrozole. Because this difference exceeded a predesignated cutoff point, the trial
was closed, even though most patients had not completed 5 years of therapy.
After the trial was unblinded, women in the placebo
group were offered letrozole. An intent-to-treat analysis
was conducted at a median follow-up of 54 months.
Patients originally randomized to receive letrozole fared
better than patients whose therapy was switched from
placebo to letrozole therapy in terms of DFS (94.3% vs
91.4%, respectively; HR 0.64, 95% CI 0.52–0.79, P =
.00002), distant DFS (96.2% vs 94.9%, respectively; HR
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0.76, 95% CI 0.58–0.99, P = .041), and incidence of
contralateral BC (0.29% vs 0.47%, respectively; HR
0.61, 95% CI 0.38–0.98, P = .037), but not in terms of
OS (95.0% vs 95.1%, respectively; HR 1.00, 95% CI
0.78–1.28, P = .99).22 A separate analysis showed that the
patients in the group whose therapy was switched from
placebo to letrozole fared better than those in the placebo
group who elected no further treatment, which suggests
that AI therapy produced a benefit despite a substantial
delay in treatment after 5 years of tamoxifen therapy.23
In addition to producing clinical benefits, adding
letrozole to 5 years of tamoxifen therapy also reduces
costs. A separate analysis compared the direct medical
costs (excluding surgery) of adding 4 years of letrozole
therapy with those of not extending therapy.24 In spite
of its additional cost, by reducing BC recurrences,
adding 4 years of letrozole therapy produced a net savings of $36 314 per 100 patients treated.
THE AUSTRIAN BREAST AND COLORECTAL CANCER
STUDY GROUP TRIAL 6A
The ABCSG 6 trial showed that postmenopausal
women treated with 2 years of tamoxifen plus aminoglutethimide then 3 years of tamoxifen had a similar prognosis when compared with that of patients treated with
tamoxifen alone for 5 years. The ABCSG 6a trial randomized patients from ABCSG 6 to receive anastrozole,
1 mg daily, or no treatment for an additional 3 years.25 At
5 years’ median follow-up, fewer patients in the anastrozole group experienced disease recurrence (HR 0.64,
95% CI 0.41–0.99, P = .047). OS time was not different between the 2 groups.
THE MA.17 AND AUSTRIAN BREAST AND COLORECTAL
CANCER STUDY GROUP 6A TRIALS IN PERSPECTIVE
The benefits of adding AI therapy after 5 years of
tamoxifen therapy are clearly evident, particularly with
respect to DFS time. The benefit of AI therapy persisted despite a substantial delay in its initiation after 5
years of tamoxifen therapy, although this benefit was
blunted compared with the benefit obtainable when
AI therapy was given without delay.
DIRECT COMPARISONS OF AROMATASE INHIBITORS
Cumulative evidence suggests that there may be
differences among AIs with respect to efficacy and
safety. To determine whether 5 years of letrozole, 2.5
mg daily, and 5 years of anastrozole, 1 mg daily, pro-
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duce different results in terms of 5-year DFS time, a
phase IIIB open-label, randomized study of 4000 postmenopausal women has begun.26 Efficacy results will
not be available for several years.
Preliminary results indicate that letrozole, 2.5 mg
daily, suppresses estradiol to a greater degree than anastrozole, 1 mg daily.27 Postmenopausal women with invasive, estrogen-receptor–positive BC received 12 weeks of
letrozole, 2.5 mg daily, then 12 weeks of anastrozole, 1
mg daily (n = 27), or 12 weeks of anastrozole, 2.5 mg
daily, then 12 weeks of letrozole, 1 mg daily (n = 27). At
study end, the mean estradiol levels were 2.91 pmol/L
after anastrozole therapy and 1.87 pmol/L after letrozole
therapy (P <.0001). Compared with baseline, the mean
residual percentage of estradiol was 9.2% after anastrozole therapy and 5.6% after letrozole therapy.27 The clinical significance of more profound suppression of
estradiol by letrozole, if any, remains to be defined.
SAFETY OF AROMATASE INHIBITORS
COMPARED WITH TAMOXIFEN
AIs are generally well tolerated, and their side-effect
profile seems to be better than that of tamoxifen.
However, the long-term safety of AIs remains unclear.
Assessments generally show little impact of AIs on quality of life. Vasomotor and gynecologic symptoms, such as
hot flashes and vaginal dryness, in addition to bone/muscle aches, are the most common adverse side effects of AI
therapy.28-31 Although they occur less frequently, osteoporosis, cardiovascular events, thromboembolic events,
and endometrial cancer have received greater attention
than the more common adverse side effects (Table 1).
OSTEOPOROSIS
Many adjuvant studies have shown an increase in
osteoporosis in women treated with an AI, which generally leads to an increase in bone fracture rate.6,7,10,17,32,33
The yearly fracture rate was higher for anastrozole than
for tamoxifen after 68 months of follow-up in the ATAC
trial and remained constant over the treatment period.34
The BIG 1-98 trial showed that letrozole therapy was
associated with a greater incidence of fractures compared
with tamoxifen therapy,10 whereas the MA.17 trial
showed no difference between letrozole therapy and
placebo in this regard.23 This finding reaffirms an earlier
observation that tamoxifen has a protective effect on
bone mineral density.35 Early experience with exemestane
Table 1. Safety Overview of Aromatase Inhibitors
Thromboembolic
Event
Invasive Endometrial
Cancer
Serious/Life-threatening/
Fatal Adverse Event
Fracture
Arthralgia
ATAC7
Anastrozole
vs tamoxifen
A (11%)
T (7.7%)
(P <.0001)
A (35.6%)
T (29.4%)
(P <.0001)
A (2.8%)
T (4.5%)
(P = .0004)
A (0.2%)
T (0.8%)
(P = .02)
A (4.7%)
T (9%)
(P <.0001)
BIG 1-9810
Letrozole
vs tamoxifen
L (5.7%)
T (4.0%)
(P <.001)
L (20.3%)
T (12.3%)
(P <.001)
L (1.5%)
T (3.5%)
(P <.001)
L (0.1%)
T (0.3%)
(P = .18)
L (1.7%)
T (1.7%)
(P = NS)
ITA13
Anastrozole
vs tamoxifen
A (1.0%)
T (1.3%)
(P = .6)
—
—
—
A (10.8%)
T (12.9%)
(P = .5)
IES17
Exemestane
vs tamoxifen
E (3.1%)
T (2.3%)
(P = .08)
E (5.4%)
T (3.6%)
(P = .01)
E (1.3%)
T (2.4%)
(P = .007)
—
—
MA.1732
Letrozole
vs placebo
L (5.3%)
P (4.6%)
(P =.25)
L (25%)
P (21%)
(P <.001)
—
—
—
A = anastrozole; ATAC = Arimidex, Tamoxifen, Alone or in Combination trial; BIG 1-98 = Breast International Group 1-98 trial; E = exemestane; IES = Intergroup
Exemestane Study; ITA = Italian Tamoxifen Anastrozole trial; L = letrozole; T = tamoxifen; — = data unavailable.
Data from Howell et al.7; Thurlimann et al.10; Boccardo et al.13; Coombes et al17; and Goss.32
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suggests that use of this AI results in a modest loss of
bone from the femoral neck and a minimal loss of lumbar bone. Moreover, the Intergroup Exemestane Study
(IES) trial found more fractures in the group that
switched to exemestane than in the group that continued
to receive tamoxifen after a median of 58 months of follow-up (P = .003).18,36 The estimated increase in fracture
rate with exemestane was similar to what has been
observed in trials of anastrozole and letrozole.
CARDIOVASCULAR
A definitive conclusion regarding the cardiovascular risk of AIs as a group cannot be made because of
the small number of events that have been reported
thus far. The ATAC trial afforded the greatest amount
of evidence regarding the cardiovascular effects of AIs
and suggested that anastrozole has no deleterious effect
on cardiac health. After 68 months’ median follow-up,
no difference was found between anastrozole and
tamoxifen in the incidence of myocardial infarction,
cardiac death, or ischemic cardiovascular death in the
ATAC trial.34,37 The BIG 1-98 trial showed an increase
in grade 3 to 5 cardiac events for letrozole compared
with tamoxifen at 26 months, whereas no differences
were observed in the MA.17 trial at 2.5 years of follow-up.10,21 For exemestane, with a median follow-up
of 58 months, the IES trial found that the incidence of
myocardial infarction and cardiac death were not different for exemestane compared with tamoxifen.18
THROMBOEMBOLIC
Direct comparative trials have shown that thromboembolic events occur more frequently in patients
treated with tamoxifen than in those treated with anastrozole, exemestane, or letrozole.7,10,17,34 Because AIs do
not have estrogenic effects, this finding is not surprising. Furthermore, in the ATAC trial, cerebrovascular
events occurred less frequently in patients treated with
anastrozole than in those treated with tamoxifen.7
ENDOMETRIAL CANCER
Because of their lack of estrogenic effects on the
uterus, AIs would not be expected to increase the incidence of uterine cancer. The ATAC trial showed that
compared with tamoxifen, anastrozole caused significantly fewer endometrial cancers, whereas the BIG 198 trial showed that compared with tamoxifen,
letrozole produced a reduction in endometrial cancers
that was not statistically significant.7,10,35
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AROMATASE INHIBITION: TRANSLATION INTO
SUCCESSFUL THERAPEUTIC APPROACH
A
The results of the clinical trials discussed help clarify the role of AIs as adjuvant therapy in postmenopausal women with early BC. However, some
uncertainty remains, in part because the trials have
studied different third-generation AIs and have
administered them at different times.
Nonetheless, the Technology Assessment Working
Group convened by the American Society of Clinical
Oncology in 2004 concluded that adjuvant endocrine
therapy for a postmenopausal woman with hormonereceptor–positive BC should include an AI as initial
therapy or after tamoxifen therapy.38 Moreover, the favorable reduction in recurrence obtained from using an AI
compared with using tamoxifen in the ATAC and BIG
1-98 trials supports the initial use of an AI rather than
tamoxifen as adjuvant therapy (Table 2).6-10,15,17,21,25,39-42
Furthermore, the ABCSG 8/ARNO 95, ITA, and IES
trials have shown the benefits obtainable by switching to
AI therapy after 2 to 3 years of adjuvant tamoxifen therapy in postmenopausal women with hormone-sensitive
early BC.13,15,17 Moreover, data from the ATAC trial
showed that, during the first 2.5 years of adjuvant treatment, patients treated with anastrozole had almost 50%
the rate of first recurrences and of death after recurrence
of patients treated with tamoxifen.6 This finding suggests
that anastrozole suppresses the early peak in recurrence
that is well established to occur with tamoxifen therapy
during years 1 to 3. Moreover, the risk of recurrence was
lower with anastrozole than with tamoxifen throughout
the entire treatment period.7 Thus, instead of introducing an AI after 2 to 3 years of tamoxifen therapy, using
an AI as initial therapy might be expected to avoid some
recurrences, especially early ones.
In the absence of definitive data from clinical trials,
various investigators have utilized existing efficacy and
safety data to construct models that identify the best role
for an AI. One such model predicted the percentage of
years of life lost to recurrence in patients with estrogenreceptor–positive BC on the basis of the adjuvant therapy they received.43 At 10 years of follow-up, the model
predicted that 12.1% of years would be lost to recurrence
if tamoxifen were used alone for 5 years as adjuvant therapy. If 5 years of treatment with an AI were added to 5
years of treatment with tamoxifen, 10.9% of years of life
would be lost to recurrence. This percentage would
decrease to 9.6% if patients received 2 years of tamoxifen
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Table 2. Recurrence Rates for Adjuvant Aromatase Inhibitor Therapy
Hazard Ratio for Recurrence
(and 95% CIs where available)
AI
Sample Size
Median Follow-up
(months)
Initial treatment
for as many as 5 years:
ATAC7,8
ANA
5216*
BIG 1-9810
LET
Switching after 2–3 years vs
continued tamoxifen for 5 years:
IES17, 40
Trial
All ER+
ER+/PgR+
ER+/PgR-
68
0.74
(0.64–0.87)
0.84
(0.69–1.02)
0.43
(0.31–0.61)
8028
26
0.72
(0.61–0.86)
0.72†
0.72†
EXE
4742
31
0.70
(0.58–0.83)
0.72‡
0.63‡
ITA41
ANA
448
52
0.43
(0.25–0.73)
—
—
ABCSG 8/ARNO15
ANA
3224
28
(0.44–0.81)
0.60
(0.46–0.93)
0.66
(0.19–0.92)
0.42
Extended treatment vs placebo
after 5 years of tamoxifen:
MA.1721, 42
LET
5157
29
(0.43–0.75)
0.57
—
—
ABCSG 6a25
ANA
856
60
(0.41–0.99)
0.64
—
—
*Patients with hormone-receptor–positive tumors; †Based on similar disease-free survival time (hazard ratios 0.84 vs 0.83); ‡Based on disease-free survival time hazard ratios
of 0.66 vs 0.58 in the earlier analysis.1
ABCSG 6a = Austrian Breast and Colorectal Cancer Study Group trial 6a; ABCSG 8 = Austrian Breast and Colorectal Cancer Study Group trial 8; AI = aromatase
inhibitor; ANA = anastrozole; ARNO = Arimidex-Nolvadex trial; ATAC = Arimidex, Tamoxifen, Alone or in Combination trial; BIG 1-98 = Breast International Group
1-98 trial; CIs = confidence intervals; ER+ = estrogen-receptor positive; EXE = exemestane; IES = Intergroup Exemestane Study; ITA = Italian Tamoxifen Anastrozole
trial; LET = letrozole; PgR- = progesterone-receptor negative; PgR+ = progesterone-receptor positive; – = data unavailable.
Reprinted with permission from Cuzick et al. Br J Cancer. 2006;94:460-464.39
therapy then 3 years of AI therapy. However, according to
the model, the best choice is 5 years of therapy with an AI
alone because only 9% of years of life would be lost to
recurrence with this treatment option. The superiority of
this regimen was seen at all points up to 10 years (Figure).
A different model developed by Burstein et al provided somewhat different results.44 This model determined that switching to AI therapy after 2 years of
tamoxifen therapy yielded slightly better 10-year DFS
than therapy with an AI alone in women with estrogen-receptor–positive/progesterone-receptor–positive
BC, irrespective of lymph-node status. However, in
women with estrogen-receptor–positive/progesteronereceptor–negative BC, 5 years of treatment with an AI
alone yielded slightly better 10-year DFS than switching from tamoxifen to AI therapy, irrespective of node
S990
status. Until definitive data from clinical trials are
available, the best approach may be to select adjuvant
hormonal therapy individually after an adequate discussion of available data with each patient.
MANAGING THE TOXICITIES OF AROMATASE INHIBITORS
Various strategies for managing or preventing AI toxicities have been investigated. However, whether therapy
should be switched to another AI or tamoxifen when the
toxicity of one AI becomes intolerable is unclear.
OSTEOPOROSIS
The ability of bisphosphonates to preserve bone
mineral density in otherwise healthy postmenopausal
women is well established.45-48 However, the long-term
Vol. 6 (10C)
n
November 2006
REVIEW
CARDIOVASCULAR EVENTS
The results of the clinical trials to date
suggest that no difference exists in the risk
of a cardiovascular event with anastrozole7,37
or exemestane18 compared with tamoxifen.
The data regarding letrozole are conflicting
and involve a shorter duration of follow-up
than the anastrozole and exemestane trials.10,21 Because coronary heart disease was
not an exclusion criterion in the adjuvant
Johns Hopkins Advanced Studies in Medicine
n
Yrs lost to recurrence (%)
use of the oral bisphosphonates alendronate and riseAI trials, it is likely that a difference in cardiovascular risk
dronate is complicated by the need for daily adminisbetween AIs and tamoxifen would have been observed if
tration, gastrointestinal intolerance that limits their
one existed. Consequently, it seems reasonable to conoptimal dosing, and their poor and variable gastroinclude that cardiovascular risk should not influence the
testinal absorption. Other preparations include oral
decision to use an AI in the treatment of postweekly alendronate or monthly ibandronate. Using a sinmenopausal early BC.
gle 4-mg dose of zoledronic acid (Zometa; Novartis, East
Hanover, NJ), a recent trial showed an increase in bone
LIFESTYLE ADVICE
Although weight gain is a common consequence of
mineral density 12 months postdose in postmenopausal
tamoxifen therapy, it does not seem to be a side effect
women with low bone mineral density.49 On the basis of
these encouraging results, the Zometa/Femara Adjuvant
of AI therapy. In a study of 96 outpatients with BC
Synergy Trial (Z-FAST) was initiated.
who were receiving adjuvant therapy, in the anastroZ-FAST is a randomized, open-label trial that is comzole therapy group (n = 26), the mean weight gain was
paring the efficacy and safety of early versus delayed
not found to be clinically significant at any point durzoledronic acid therapy in preventing cancer-treatmenting 12 months of therapy.52 Nonetheless, reducing
dietary fat intake seems to be beneficial in postinduced bone loss.50 Postmeno-pausal women with stage
I-IIIA, estrogen-receptor–positive and/or progesteronemenopausal women with primary BC. The Women’s
receptor–positive BC who were starting letrozole therapy
Intervention in Nutrition Study found that reducing
were randomized to receive early or delayed treatment
dietary fat intake by one third improves the relapsewith zoledronic acid, 4 mg intravenously every 6 months.
free survival of patients with estrogen-receptor–negaPreliminary trial data showed that early zoledronic acid
tive BC, but such improvement was not found in
therapy increased bone mineral density in the lumbar
patients with estrogen-receptor–positive BC.53
spine by 1.55% and in the hip by 1.02%, whereas
CONCLUSIONS
delayed zoledronic acid therapy resulted in decreases in
bone mineral density of 1.78% in the lumbar spine and
The important role of AIs in the adjuvant treatof 1.4% in the hip.50 However, zoledronic acid is not US
Food and Drug Administration approved for the treatment of postmenopausal women with early BC is supment of bone loss or osteoporosis.
In addition to bisphosphonate therapy,
vitamin D supplementation may be helpFigure. Model Comparing Initial Use of an Aromatase Inhibitor with
ful in preventing osteoporosis in patients
Sequencing After Tamoxifen in Postmenopausal Women with
with BC who are receiving adjuvant AI
Estrogen-Receptor–Positive Breast Cancer
therapy. When 25-hydroxyvitamin D levels were analyzed in 147 postmenopausal
women with early BC who had been ran15
Cumulative percentage of yrs of life
lost to recurrence at 10- and 15-yr follow-up
domized to receive exemestane or placebo,
Carry over t 5 yrs’ 2 yrs’ tam 5 yrs’ tam
5 yrs’
most were found to be deficient in vitaAl
+3 yrs’ Al +5 yrs’ Al
tam
Indefinite 10 9.0
9.6
10.9
12.1
min D regardless of treatment group.51
10
15 13.0
13.1
14.4
17.2
5-yr
2-yr
10 9.0
15 13.4
10 9.3
15 14.0
9.6
13.7
9.9
14.5
10.9
14.4
10.9
14.7
12.1
17.2
12.1
17.2
5
5 yrs’ tam
5 yrs’ Al
3 yrs’ Al after 2 yrs’ tam
5 yrs’ Al after 5 yrs’ tam
0
0
2
4
6
8
10
Follow-up time (yrs)
AI = aromatase inhibitor; tam = tamoxifen; t = time in years.
Reprinted with permission from Buzdar et al. Clin Cancer Res. 2006;12:1037s-1048s.43
S991
REVIEW
ported by a large body of efficacy and safety data.
Consequently, an AI should be used in adjuvant therapy initially or after 2 to 3 years of tamoxifen in postmenopausal women with hormone-receptor–positive
BC. However, questions regarding the appropriate
duration of AI therapy remain unanswered. In addition, the differences between the AIs are unclear.
Although AIs are safe and generally well tolerated,
their use has been associated with a reduction in bone
mineral density, which often leads to a fracture.
However, bisphosphonate therapy appears to substantially decrease this risk. Although no difference has
been found in the rate of cardiovascular events in
patients who received AIs compared with those who
received tamoxifen, AIs seem to be less likely to cause
a thromboembolic event than tamoxifen. Ongoing
research may provide even greater clarity regarding the
role of AIs as adjuvant therapy in postmenopausal
women with early BC.
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