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Neoadjuvant Endocrine Therapy for Breast Cancer: An Overlooked Option?

Neoadjuvant Endocrine Therapy for Breast Cancer: An Overlooked Option?

ABSTRACT: For many oncologists, neoadjuvant treatment for breast cancer is synonymous with preoperative cytotoxic chemotherapy, regardless of tumor characteristics. Preoperative therapy with an endocrine agent is generally considered suitable only for the frail elderly or the medically unfit. However, favorable information regarding third-generation aromatase inhibitors in the treatment of all stages of breast cancer prompts a reconsideration of this bias. In light of the fact that neoadjuvant therapy with aromatase inhibitors is restricted to postmenopausal women with strongly estrogen-receptor–positive tumors, the assumption that neoadjuvant combination chemotherapy is more efficacious than a third-generation aromatase inhibitor can be reasonably questioned. It is particularly remarkable that the outcome of a comparison of adjuvant tamoxifen vs anastrozole (Arimidex)—the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial—in more than 6,000 patients was predicted by a neoadjuvant trial that showed an efficacy advantage for a third-generation aromatase inhibitor (letrozole [Femara]) compared to tamoxifen in a sample of 337 patients after only 4 months of treatment. The potential of the neoadjuvant setting in efforts to identify new biologic agents that could build on the effectiveness of adjuvant aromatase inhibitors is therefore beginning to be appreciated. Finally, neoadjuvant therapy with an aromatase inhibitor could be considered a sensitivity test of endocrine therapy that might be incorporated into strategies to individualize treatment according to response. For this possibility to be realized, however, a better understanding of the relationship between surrogates from the neoadjuvant setting and the long-term outcome of adjuvant aromatase inhibitor therapy will have to be established through practice-setting clinical trials.

Neoadjuvant chemotherapy for
breast cancer is indicated for
tumors that are not suitable
for modified radical mastectomy or
to increase the chance of breast-conserving
surgery for tumors considered
operable only with modified radical
mastectomy. However, neoadjuvant
therapy has several further advantages
besides the potential to improve
surgical outcomes in patients with
large tumors. First, the response of
the primary tumor provides an in vivo
test of drug sensitivity, which might
be of value in identifying patients at
high risk of relapse despite a course
of standard adjuvant chemotherapy.
Second, repeat sampling of the tumor
before and after treatment enables research
on the mechanisms of drug
action and predictive biomarkers. Unfortunately,
however, the theoretical
advantage of improved long-term systemic
control as a result of neoadjuvant
chemotherapy[1] has never been
demonstrated in large randomized
studies.[2,3] Thus, neoadjuvant chemotherapy
remains a largely optional
aspect of breast cancer therapy, except
in patients who truly have locally
advanced disease.

The use of neoadjuvant endocrine
therapy is fairly uncontroversial
among patients too unfit to receive
chemotherapy or who choose not to
undergo this more toxic form of treatment.
However, for patients who could
be reasonably treated with either approach,
the knowledge base for the
neoadjuvant use of aromatase inhibitors
is still too limited for many
physicians to accept the routine application
of this treatment. For example,
an international expert panel convened recently to consider neoadjuvant
treatment concluded that hormonal
manipulation is not currently a
standard of care for preoperative treatment
of operable breast cancer but is
a "second choice" for selected patients
including the elderly, women
with impaired organ function, poor
performance status, or those who are
considered a poor surgical risk, as well
as women who are unwilling to accept
the side effects associated with
chemotherapy.[4] Nonetheless, the
panel encouraged research and
recommended trials to optimize the
neoadjuvant treatment of estrogenreceptor
(ER)-positive, locally advanced
disease.

Historical Experience
With Tamoxifen

Early studies of the use of endocrine
therapy for the treatment of primary
carcinomas of the intact breast
were mostly small, phase II trials of
tamoxifen alone without surgery in
elderly or unfit, poor surgical candidates.[
5] The majority of patients in
these studies did not undergo definitive
surgery, and hormone-receptor
expression analysis was not an eligibility
criterion. These issues probably
account for the poor long-term results
and contributed to the misconception
that endocrine treatment of primary
breast cancer is not efficacious. For
example, in one study, more than 60%
of patients treated with primary
tamoxifen therapy developed progressive
disease after 5 years, although
almost 50% initially responded to
treatment.[6]

It was, therefore, no surprise that a
meta-analysis of the long-term results
of two trials comparing primary
tamoxifen to initial surgery followed
by tamoxifen demonstrated that primary
tamoxifen therapy was associated
with an increased risk of death
from breast cancer.[7] Clearly, primary
tamoxifen therapy is a suboptimal
therapeutic approach that can
almost never be recommended. It is
fair to argue that a similar result would
have been achieved with chemotherapy
alone because, in follow-up, patients
with good initial responses to
neoadjuvant chemotherapy also show
poor local control without definitive
surgery.[8]

Unquestionably, surgery remains
an indispensable aspect of the management
of breast cancer regardless
of the nature of the neoadjuvant therapy.
Although interest in primary
tamoxifen therapy waned as a result
of these data, interest persisted in the
use of tamoxifen for a few months as
neoadjuvant therapy in older patients
with ER-positive disease. For example,
a study in Edinburgh treated 100
patients over the age of 70 with ERrich
breast cancers.[9] Using volume
reductions determined by ultrasound
as a measure of response, 73 patients
experienced significant tumor regression.
Similar conclusions regarding
an acceptable level of efficacy for neoadjuvant
tamoxifen therapy in older
patients were drawn from a smaller
study conducted at the M. D. Anderson
Cancer Center.[10]

Neoadjuvant Aromatase
Inhibitor Therapy

The introduction of third-generation
aromatase inhibitors encouraged
further research on neoadjuvant endocrine
treatment. An initial phase II
experience with neoadjuvant letrozole
(Femara) in Edinburgh was encouraging,
with a response rate of 92%
documented in 24 postmenopausal
women with ER-positive, locally advanced
breast cancer treated for 3
months prior to surgery.[11] All 15
patients who initially required mastectomy
were subsequently able to
undergo breast conservation.

The same investigators recently
reviewed their phase II experiences
in more than 100 patients treated with
3 months of tamoxifen, letrozole,
anastrozole (Arimidex), or exemestane
(Aromasin).[12] Their conclusion
that aromatase inhibitors were
likely to be more effective neoadjuvant
therapy than tamoxifen stimulated
the activation of several
randomized controlled trials to confirm
this hypothesis.

Letrozole
The first and currently only adequately
powered study to report to
date was a randomized, double-blind,
multicenter study (Letrozole 024) that
compared the activity of 4 months of
preoperative letrozole vs tamoxifen
in 337 postmenopausal women with
ER- and/or progesterone receptor
(PR)-positive breast cancer.[13] At
baseline, none of the patients were
eligible for breast-conserving surgery,
with 14% considered inoperable. The
letrozole group had a significantly
higher objective clinical response rate
compared to the tamoxifen group
(55% vs 36%, P < .001). Secondary
end points that supported this conclusion
included ultrasound response
(35% vs 25%, P = .042), mammographic
response (34% vs 16%, P < .001), and breast-conserving surgery
rates (45% vs 35%, P = .022).

In a prospective central analysis of
hormone-receptor status, a small number
of ER- and PR-negative tumors
were detected. This led investigators
to modestly underestimate the value
of neoadjuvant endocrine treatment,
and the adjusted analysis is presented
in Table 1. This study also illustrated
the strong relationship between ERexpression
levels (determined by the
Allred score) and the likelihood of
response (Figure 1). As long as ER is
expressed at high levels (Allred score
of 7 and 8), response rates of 60% to
70% can be expected.

Anastrozole
Preliminary data on neoadjuvant
anastrozole have also been reported.
Only one of these studies has been
published in the peer-reviewed literature,[
14] and most of the ongoing investigations
carry caveats associated
with abstract presentations and single-
institution experiences.

A recently reported Russian study
randomized 87 postmenopausal women
with ER-rich tumors to anastrozole,
tamoxifen, or the combination
of anastrozole and tamoxifen for 3
months.[15] Anastrozole was superior
to both tamoxifen and the combination
in overall response rates by
clinical palpation, mammography, and
ultrasound (70% vs 44% vs 49%,
P = .048; 55% vs 36% vs 40%,
P = .058; 44% vs 30% vs 32%,
P = .072, respectively) with a trend
toward higher breast-conservation
rates (42% vs 28% vs 30%, P = .056).

The ongoing Immediate Preoperative
Arimidex Compared to Tamoxifen
(IMPACT) trial is evaluating
anastrozole, tamoxifen, and the combination
in 330 postmenopausal women
with ER-positive operable breast
cancer.[16-18] Updated results of this
study were reported at the San Antonio
Breast Cancer Symposium in December
2003. In terms of response rates,
anastrozole and tamoxifen were no different,
although suppression of Ki67
and rates of breast-conserving surgery
were greater with anastrozole. One important
feature of the IMPACT trial is
that inoperable breast tumors are excluded
(unlike the Letrozole 024 study). As
a result, crosstrial comparisons of response
rates may be misleading.

Exemestane
The efficacy of exemestane was
evaluated in 13 postmenopausal women
with untreated large or locally advanced
ER-rich tumors after a 3-month
treatment period. Treatment was associated
with a marked reduction in aromatization
in nonmalignant breast tissue
in every patient and in breast tumor
tissue in all but one patient. The median
reduction in tumor volume by clinical
examination, ultrasound, and
mammography was 85.5%, 82.5%,
and 84%, respectively. Of 10 patients
who initially required mastectomy, 8
were able to undergo breast-conserving
surgery after treatment.[19]

A Spanish multicenter study recently
evaluated the efficacy of 6
months of exemestane in 33 women
over 65 years old with ER-rich tumors
larger than 3 cm and reported a
response rate of 50% in the first 28
patients.[20] These preliminary data
support further studies of exemestane
as neoadjuvant therapy.

Summary of Findings
In conclusion, the promising randomized
data on letrozole will soon
be supplemented by peer-reviewed
information on anastrozole and exemestane.
An outstanding question concerns
the optimal duration of
preoperative endocrine therapy. Interestingly,
preliminary data on patients
given a maximum of 8 months
of preoperative letrozole showed a
response rate of 90% vs 57% for those
receiving 4 months of treatment.[21]
Larger randomized studies will be necessary
to determine the optimal duration
of aromatase inhibitor therapy
for tumors that have responded by
4 months, but the tamoxifen experience
would suggest that for nonresponding
tumors further delays in
surgery are inappropriate.

Indirect Comparison of
Neoadjuvant Endocrine
Therapy and Chemotherapy

Postmenopausal women with hormone-
receptor-positive breast cancer
derive most adjuvant benefit from en-docrine treatment rather than chemotherapy.[
22,23] On this basis, neoadjuvant
endocrine therapy is a logical
approach to investigate in this patient
subpopulation. The design of a practice-
setting trial that would compare
neoadjuvant therapy with an aromatase
inhibitor (investigational arm)
to chemotherapy (standard therapy
arm) requires an estimate of the efficacy
of neoadjuvant chemotherapy.
Data on this issue are difficult to compile,
however, because the results of
trials of neoadjuvant chemotherapy
are not often reported according to
age, hormone-receptor status, and age.
In addition, neoadjuvant chemotherapy
studies, like breast cancer studies
in general, enroll very few women
over age 70. Arguably, robust data on
the effectiveness of neoadjuvant chemotherapy
in postmenopausal women
with strongly ER-positive disease
simply do not exist.

Side Effects
One of the most striking advantages
of neoadjuvant therapy with aromatase
inhibitors over chemotherapy is the lower
toxicity level. Aside from short-term
reversible side effects, chemotherapyassociated
leukemia and cardiomyopathy
are more common in older patients
and should be taken into account when
considering the risk-benefit ratio for
the administration of cytotoxic drugs
in postmenopausal women.

A hypothetical advantage of neoadjuvant
endocrine therapy is that it
can be regarded as an in vivo sensitivity
test of endocrine therapy. Patients
who achieve a response might
have a better chance of survival and
could perhaps avoid chemotherapy.
Although preliminary data support the
hypothesis that patients with primary
tumors that respond to tamoxifen
survive longer than nonresponders
(Figure 2),[6] large-scale studies will
be required to generate more confident
predictions regarding the relationship
between response to
neoadjuvant aromatase inhibitor therapy
and survival from breast cancer.

Neoadjuvant Anthracycline-Based
Chemotherapy in ER-Positive Disease

In unselected patients, anthracycline-
based neoadjuvant chemothera-py is associated with a high response
rate. However, evidence shows that
responsiveness is attenuated (to < 5%)
in ER-positive disease. For example,
in an M. D. Anderson Cancer Center
study of neoadjuvant chemotherapy
with FAC (fluorouracil [5-FU], doxorubicin
[Adriamycin], and cyclophosphamide
[Cytoxan, Neosar]), of
43 patients who achieved a complete
pathologic response after four cycles,
only 3 had ER-positive disease. Since
the total number of known ER-positive
tumors in this data set was 106,
the pathologic complete response rate
can be calculated to be only 2.8%
with this regimen.[24]

This low pathologic complete response
rate is comparable to the response
rate observed with 4 months
of letrozole (1.3%). Other studies have
reported decreased objective response
rates to neoadjuvant chemotherapy
in patients with ER-positive disease.[
25,26] These results reflect the
results of the Oxford overview, in which
the proportional reduction in recurrence
with chemotherapy among women aged
50 to 69 years with ER-poor disease
(30%) appeared to be nearly twice that
of women with ER-positive disease
(18%)-a difference that was statistically
significant.[23] Thus, it is reasonable
to conclude that chemotherapy
responsiveness is attenuated in ER-positive
disease, and research to improve
neoadjuvant therapy in this subset of
patients is highly justifiable.

Several approaches could be considered-
for example, incorporation
of a taxane. However, questions remain
regarding the benefits of adjuvant
regimens incorporating paclitaxel
in ER-positive disease,[27] and the
addition of further cytotoxic agents is
not necessarily the correct investigational
approach to take in older patients.
Another approach that has been
fairly well investigated is to combine
tamoxifen with chemotherapy. Unfortunately,
no evidence demonstrates
that neoadjuvant chemoendocrine
therapy is superior to chemotherapy
alone,[28,29] and in the adjuvant setting,
tamoxifen actually antagonizes
the therapeutic benefits of adjuvant
CAF (cyclophosphamide, doxorubicin,
5-FU).[30]

Improvements in
Surgical Outcomes

Even though the pathologic complete
response rate is low, the degree
of tumor regression with neoadjuvant
aromatase inhibitor therapy is unquestionably
sufficient to improve surgical
outcomes. In the Letrozole 024
study, all patients were either ineligible
for breast-conserving surgery or
were deemed inoperable at baseline.
T2 tumors were included only if they
were considered ineligible for an initial
attempt at breast-conserving surgery.
After treatment with letrozole,
45% of patients underwent successful
breast-conserving surgery, with the rate increasing to 61% among patients
with T2 tumors. Comparable estimates
with neoadjuvant chemotherapy are
difficult to make because the rate of
conversion to breast-conserving surgery
is not usually reported according
to ER status, age, or menopausal status.
In addition, many neoadjuvant
chemotherapy trials, including the
National Surgical Adjuvant Breast and
Bowel Project (NSABP) B-18 trial,
included a large number of small tumors
eligible for lumpectomy at
baseline.

Table 2 compares the intended and
actual surgical outcomes in NSABP
B-18 and Letrozole 024. This comparison
must exclude T1 tumors,
which were not studied in the Letrozole
024 trial, and arguably T2 tumors
as well, because NSABP B-18
allowed the entry of T2 tumors that
were eligible for breast conservation
at presentation. Only 3% of patients
with > T2 tumors were considered
eligible for breast-conserving surgery
in NSABP B-18, but 22% of these
individuals underwent breast conservation
after four cycles of neoadjuvant
AC (doxorubicin, cyclophosphamide)
chemotherapy.[31] In the comparable
group of > T2 tumors in the Letro-zole 024 study, 29% were eligible for
breast conservation. One can therefore
argue that four cycles of AC in
unselected patients and 4 months of
letrozole in postmenopausal women
with ER-positive disease are broadly
similar in efficacy, in terms of improvements
in surgical outcomes.

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