Aromatase inhibitors as adjuvant therapy for breast cancer

Aromatase inhibitors as adjuvant
therapy for breast cancer
What have we learned from ATAC and other recent trials?
A dministration of tamoxifen mended in May 2002 that tamoxifen
for 5 years has been consid-
continue to be considered standard
ered standard adjuvant ther-
therapy, given the compelling, exten-
apy for women with primary estrogen
sive, and long-term data on tamoxifen
receptor-positive breast cancer. Recent
treatment.1 However, because of the
trials of aromatase inhibitors — hor-
ATAC trial findings and other study
monal agents that dramatically reduce
results suggesting better outcomes in
circulating estrogen levels in post-
women who had received aromatase
menopausal women — have indicated
inhibitors than in those who had been
that superior results can be achieved
treated with tamoxifen, ASCO also
by using anastrozole (Arimidex) in-
recommended that the choice of ad-
stead of tamoxifen or by substituting
juvant therapy be dependent on a dis-
anastrozole or exemestane (Aromasin)
cussion of all available data between
for tamoxifen during ongoing tamoxi-
physician and patient.1
fen therapy. Other data indicate that
Recently, an updated efficacy
use of letrozole (Femara) after com-
analysis of the ATAC trial data has
pletion of 5 years of tamoxifen therapy
shown that the benefits of anastrozole
is associated with prolonged disease-
treatment compared with tamoxifen
free survival.
increase over time.2 At the time of
this analysis, patients had a median
ATAC trial
follow-up of 47 months; of those pa-
The multicenter, multinational
tients receiving either agent alone,
Arimidex or Tamoxifen Alone or in
84% completed 3 years of follow-up
Combination (ATAC) trial random-
and 47% completed 4 years of fol-
ized 9,366 postmenopausal women
low-up. Anastrozole treatment (n =
with early invasive breast cancer to 5
3,125) was associated with a signifi-
years of treatment with anastrozole or
cant improvement in time to recur-
tamoxifen alone or in combination;
rence in the intent-to-treat popula-
84% of these patients were estrogen
tion compared with tamoxifen (n =
receptor-positive. The main analysis
3,116); the hazard ratio for time to
of the study’s outcome, initially re-
recurrence associated with anastrozole
ported in 2001, showed that after a
versus tamoxifen was 0.83 (95% CI,
median follow-up of 33 months, anas-
0.71–0.96; P = 0.015). Among those
trozole alone was superior to tamoxi-
patients with known estrogen recep-
fen alone with regard to disease-free
tor-positive status, the hazard ratio
survival (hazard ratio, 0.83) and time
for time to recurrence associated with
to recurrence (hazard ratio, 0.79); no
anastrozole versus tamoxifen was 0.78
difference in disease-free survival was
(95% CI, 0.65–0.93; P = 0.007).
seen between tamoxifen and the com-
As shown in Table 1, the absolute
bination treatment.
difference in breast cancer event rates
After the trial’s outcome was re-
between the two groups increased
ported, the American Society of
over time both in the intent-to-treat
Clinical Oncology (ASCO) recom-
population and in the population
Summary by Matt Stenger, MS; reviewed by
with known estrogen receptor-posi-
Lee S. Schwartzberg, MD, FACP, The
tive status. Compared with tamoxi-
West Clinic.
fen, treatment with anastrozole was
Volume 1/Number 1
May/June 2004 ■ COMMUNITY ONCOLOGY 19

---

Community Translations
TABLE 1
(n = 2,362) for the remainder of the
ATAC trial: breast cancer event rates in intent-to-treat population and
5-year treatment course. After a me-
in estrogen receptor-positive patients by year of follow-up
dian follow-up of 30.6 months, 449

Intent-to-treat population
Estrogen receptor-positive population
first events (local or metastatic recur-
Year
Anastrozole Tamoxifen Difference
Anastrozole
Tamoxifen
Difference
rence, contralateral breast cancer, or
death) had occurred, including 183
1
2.5%
2.3%
– 0.2%
1.5%
1.5%
0%
in the exemestane-treated group and
2
5.1%
6.4%
1.3%
3.5%
5.2%
1.7%
266 in the tamoxifen-treated group.
3
7.7%
9.4%
1.7%
5.9%
7.7%
1.8%
The unadjusted hazard ratio for
4
9.8%
12.1%
2.3%
7.8%
10.4%
2.6%
events in the exemestane treatment
From Klijn.2
group, compared with the tamoxifen
group, was 0.68 (Table 2). The 32%
TABLE 2
reduction in risk by switching to the
Intergroup Exemestane Study: analysis of outcomes in breast cancer
aromatase inhibitor corresponded to
survivors taking exemestane vs tamoxifen
an absolute benefit in disease-free
Outcome
Hazard ratio (95% CI)
P value
survival of 4.7% (95% CI, 2.6%–
First event-free survival
0.68 (0.56–0.82)
0.00005
6.8%) at 3 years after randomization
Breast cancer-free survival, censoring
0.63 (0.51–0.77)
0.00001
(91.5% for exemestane vs 86.8% for
deaths in patients without recurrence
tamoxifen).
or contralateral breast cancer
Exemestane treatment was also
Distant disease-free survival
0.66 (0.52–0.83)
0.0004
associated with significant improve-
Risk of contralateral breast cancer
0.44 (0.20–0.98)
0.04
ments in disease-free survival, in-
Overall survival
0.88 (0.67–1.16)
0.37
cluding fewer local and distant recur-
rences, as well as new tumors in the
CI = confidence interval. From Coombes et al.4
contralateral breast, compared with
also associated with a reduced num-
for up to 5 years. After a median fol-
similar indices of disease-free survival
ber of recurrences at all breast can-
low-up of 24 months, there were 26
in patients who were continued on
cer sites, including those associated
events in the tamoxifen group (19 re-
tamoxifen. There was no difference,
with poorer prognoses — eg, ipsilat-
currences, 5 second primary tumors, 2
however, between the two treatment
eral breast (26 for anastrozole vs 38
deaths in the absence of disease pro-
groups with regard to overall survival
for tamoxifen), chest wall (37 vs 40),
gression) and 10 in the anastrozole
at the time of analysis.
axillary lymph nodes (13 vs 23), and
group (8 recurrences, 2 second pri-
supraclavicular/internal
mammary
mary tumors). With adjustment for
Aromatase inhibitors after
(20 vs 30). The latest findings in the
age, nodal involvement, tumor grade,
completion of tamoxifen
ATAC trial thus continue to favor the
and treatment of primary tumors, the
Another large-scale study has
use of anastrozole over tamoxifen as
hazard ratio for relapse in women
demonstrated that letrozole therapy
adjuvant therapy in postmenopausal
switched to anastrozole, compared
after 5 years of tamoxifen therapy
women with estrogen receptor-posi-
with continuing on tamoxifen treat-
significantly improves disease-free
tive disease.
ment, was 0.36 (95% CI, 0.17–0.75;
survival.5 In a double-blind, multi-
P = 0.006).
national trial, 5,187 postmenopausal
Additional studies
The recently reported Intergroup
women who had received approxi-
An Italian study, presented at the
Exemestane Study has similarly
mately 5 years of tamoxifen treatment
San Antonio Breast Cancer Sym-
shown that switching from tamoxifen
for early-stage breast cancer were
posium in 2003, also has shown that
to exemestane as adjuvant therapy is
randomized to receive placebo or le-
switching patients from tamoxifen to
associated with clinical benefits.4
trozole for 5 years. At the time of the
anastrozole is associated with marked
In this trial, 4,742 postmenopausal
first scheduled interim analysis (pre-
benefits.3 In this trial, 426 postmeno-
patients who had tumors that were
specified at 171 events), patients had
pausal women with node-positive, es-
estrogen receptor-positive or of un-
a median follow-up of 2.4 years. A
trogen receptor-positive disease who
known receptor status and who had
total of 207 local or metastatic recur-
had received tamoxifen for at least 2
no recurrence of their cancer after 2–
rences of breast cancer or new prima-
years were randomized to continue
3 years of tamoxifen treatment were
ry cancers in the contralateral breast
with tamoxifen treatment (n = 218)
randomized to continue tamoxifen
had occurred, consisting of 75 in the
or switch to anastrozole (n = 208)
(n = 2,380) or switch to exemestane
letrozole group and 132 in the place-
20 COMMUNITY ONCOLOGY ■ May/June 2004
www.CommunityOncology.net

---

TABLE 3
ommended that the trial be halted
Disease-free and overall survival by year in patients receiving letrozole
after the first interim analysis.
or placebo after 5 years of tamoxifen therapy
References

Letrozole
Placebo
Difference (95% CI)
Disease-free survival (%)


1. Winer EP, Hudis C, Burstein HJ, et al.
American Society of Clinical Oncology tech-
1 year
98.6
97.8
0.8 (0.0–1.5)
nology assessment on the use of aromatase
2 years
96.7
94.8
1.9 (0.6–3.3)
inhibitors as adjuvant therapy for women with
hormone receptor-positive breast cancer: sta-
3 years
95.2
90.2
5.0 (2.7–7.3)
tus report 2002. J Clin Oncol 2002;20:3317–
4 years
92.8
86.8
6.0 (2.0–10.1)
3327.
Overall survival (%)


2. Klijn J, for the ATAC Trialists’ Group.
The ATAC (anastrozole, tamoxifen, alone or in
1 year
99.8
99.7
0.1 (–0.2–0.4)
combination) trial — an efficacy update, focus-
2 years
98.9
98.6
0.3 (–0.5–1.1)
ing on breast cancer (BC) events, based on a
median follow-up of 47 months. In: Program/
3 years
97.7
96.9
0.8 (–0.8–2.3)
Proceedings of the 39th Annual Meeting of the
4 years
96.0
93.6
2.4 (–0.9–5.6)
American Society of Clinical Oncology; May
31–June 3, 2003; Chicago, Ill. Abstract 338.
CI = confidence interval. From Goss et al.5 Used with permission from the New England Journal of Medicine.
3. Boccardo F, Rubagotti A, Amoroso D,
Copyright © 2003 Massachusetts Medical Society. All rights reserved.
et al. Anastrozole appears to be superior to
bo group. The estimated 4-year dis-
nal bleeding was more frequent in
tamoxifen in women already receiving adjuvant
tamoxifen treatment. Breast Cancer Res Treat
ease-free survival rate in the letrozole
the placebo group. New diagnoses of
2003;82(suppl 1):S6–7. Abstract 3.
group was significantly greater than
osteoporosis occurred in 5.8% of the
4. Coombes RC, Hall E, Gibson LJ, et al.
that in the placebo group (92.8% vs
letrozole group and 4.5% of the pla-
A randomized trial of exemestane after two to
86.8%,
three years of tamoxifen therapy in postmeno-
P ≤ 0.001 [Table 3]). Overall
cebo group; the two groups had simi-
pausal women with primary breast cancer. N
survival did not differ significantly
lar rates of fracture.
Engl J Med 2004;350:1081–1092.
between the two groups.
Given the finding of prolonged
5. Goss PE, Ingle JN, Martino S, et al. A
Low-grade hot flashes, arthritis,
disease-free survival and an appar-
randomized trial of letrozole in postmenopaus-
al women after five years of tamoxifen therapy
arthralgia, and myalgia were more
ent trend in improved overall survival
for early-stage breast cancer. N Engl J Med
frequent in the letrozole group; vagi-
with letrozole treatment, it was rec-
2003;349:1793–1802.
The community oncologists’ view
WE ASKED TWO COMMUNITY ONCOL-
ifen for about half of his clinic’s breast
static disease to treating cancer at
ogists whether the results of the
cancer patients. As more experience
earlier and earlier stages.
ATAC trial and other research on
is gained, Dr. Ahmad reported, phy-
She started using anastrozole be-
aromatase inhibitors have impacted
sicians will most likely convert most
cause of the long duration of follow-
their choice of adjuvant therapy for
of their patients to aromatase inhibi-
up data available from the ATAC
patients with breast cancer.
tors. “If a patient requests Arimidex,”
trial but encountered “significant in-
Dr. Shamoon Ahmad, US Oncol-
he said, “after a discussion of options,
tolerance due to arthritis, especially
ogy, Las Vegas, NV, believes the data
it is prescribed.”
in younger postmenopausal wom-
are still maturing but look promis-
en.” These patients are switched to
ing. Concerns about the potential
Aromatase inhibitors will
letrozole or exemestane (Aromasin).
risk of osteoporosis with letrozole
likely be started earlier
More recently, she has begun us-
(Femara) has made him cautious,
Our other responder, a medical
ing letrozole as first-line therapy
however. The availability of more
oncologist who heads a community
with fewer arthritic complaints but
osteoporosis data and recommenda-
practice in southern California, feels
is contemplating switching to ex-
tions for its prevention in letrozole-
that as even more data indicate the
emestane based on newer data and
treated patients will likely sway his
benefits of aromatase inhibitors over
the low incidence of hot flashes as-
opinion regarding use of this drug
tamoxifen, they are likely to be in-
sociated with this drug.
in the future.
troduced earlier in the treatment of
Is reimbursement an issue? No,
Currently, he is prescribing anas-
breast cancer, just as adjuvant therapy
says Dr. Ahmad, but our California
trozole (Arimidex) in lieu of tamox-
itself has moved from use in meta-
oncologist points out that “when
continued on page 22
Volume 1/Number 1
May/June 2004 ■ COMMUNITY ONCOLOGY 21

---

Community Translations
choose aromatase inhibitors. Their
there is an alternative available that
Oncologists’ view
concern about the risk of blood clots
may even be more effective.”
continued from page 21
and uterine cancer makes my patients
“Certainly, if a patient has a fairly
patients have to pay, the current cost
overwhelmingly choose an aroma-
low risk of recurrence and significant
of tamoxifen versus that for an aro-
tase inhibitor over tamoxifen, even
bone loss,” she concluded, “use of
matase inhibitor has had several pa-
with the increased risk of bone loss.
tamoxifen along with exercise, cal-
tients come back requesting tamoxi-
Having just dealt with one cancer,
cium, and vitamin D can be a cost-
fen.” She added, “When cost is not
even a very rare risk of uterine cancer
effective alternative to aromatase in-
an issue, patients almost invariably
is not acceptable to my patients when
hibitors used with bisphosphonates.”
22 COMMUNITY ONCOLOGY ■ May/June 2004
www.CommunityOncology.net

---