Lessons from the use of aromatase inhibitors in the neoadjuvant setting.

Abstract

Postmenopausal patients with oestrogen receptor-positive locally advanced T4b, N0-1, M0 and large operable breast cancers T2>3 cm, T3, T4, N0-1 and M0 have been treated with 2.5 mg letrozole (12 patients), 10 mg letrozole (12 patients), 1 or 10 mg anastrozole (24 patients) and 20 mg tamoxifen (65 patients). There was no apparent difference in response rate between 2.5 and 10 mg letrozole. Only 17 patients with anastrozole have so far completed the 3-month treatment period. Median clinical, mammographic and ultrasound reductions in tumour volumes for patients treated with letrozole were 81% (95% confidence interval (CI) 66-88), 77% (95% CI 64-82) and 81% (95% CI 69-86) respectively and for anastrozole, values were 87% (95% CI 59-97), 73% (95% CI 58-82) and 64% (95% CI 52-76) respectively. This compares with a median reduction in tumour volume for tamoxifen-treated patients as assessed by ultrasound of 48% (95% CI 27-48). There were seven complete clinical responses (CR), sixteen patients who achieved 50% or greater reduction in tumour volume (PR) and one no change (NC) for letrozole and four CRs, twelve PRs and one progressive disease for anastrozole. Best radiological responses were one CR, twenty PRs and three NCs for letrozole and one CR, fifteen PRs and one NC for anastrozole. This study has shown that the new aromatase inhibitors, letrozole and anastrozole, are highly effective agents in the neoadjuvant setting and they should now be compared with tamoxifen as first-line treatment in a randomised study.

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Endocrine-Related Cancer (1999) 6 227-230
Endocrine-Related Cancer (1999) 6 227-230
1351-0088/99/006-227 © 1999 Society for Endocrinology Printed in Great Britain
Online version via http://www.endocrinology.org
Introduction
Neoadjuvant therapy has been used to treat large operable
and locally advanced breast cancers (Anderson et al. 1989,
Hortobagyi et al. 1996, Fisher et al. 1997). Studies to date
have concentrated mainly on the use of chemotherapy.
Few centres have evaluated neoadjuvant endocrine
therapy in hormone-sensitive large operable and locally
advanced breast cancer (Anderson et al. 1989). Studies
published using primary hormone therapy have
demonstrated high response rates in oestrogen receptor-
positive tumours (Anderson et al. 1989, Keen et al. 1997).
Although responses appear slower than those with
chemotherapy, substantial reductions in volume over a 3-
month period have been recorded (Keen et al. 1997) which
have allowed tumour downstaging.
In premenopausal women the luteinizing hormone-
releasing hormone analogue Zoladex has been assessed
(Anderson et al. 1989). In postmenopausal women the
most common neoadjuvant endocrine agent used has been
tamoxifen (Keen et al. 1997). As part of a study to assess
the effects of letrozole and anastrozole on intratumoral
aromatase, the present study has investigated the
effectiveness of letrozole and anastrozole given as primary
medical therapy (neoadjuvant) for patients with newly
diagnosed oestrogen receptor-positive locally advanced
and large operable breast cancer.
Patients and methods
Three groups of patients have been studied. All were
postmenopausal patients with oestrogen receptor-positive
breast cancers (>20 fmol/receptor per mg per cytosol
protein) or a histoscore of >80 (histoscore calculated by
multiplying the percentage of cells staining by the
intensity of staining graded from 0 to 3 (McCarty et al.
Lessons from the use of aromatase
inhibitors in the neoadjuvant setting
J M Dixon, C D B Love, L Renshaw, C Bellamy1,
D A Cameron, W R Miller and R C F Leonard
Edinburgh Breast Unit, Western General Hospital, Edinburgh, UK
1Department of Pathology, Western General Hospital, Edinburgh, UK
(Requests for offprints should be addressed to J M Dixon, Academic Office, Edinburgh Breast Unit,
Western General Hospital, Edinburgh EH4 2XU, UK)
Abstract
Postmenopausal patients with oestrogen receptor-positive locally advanced T4b, N0-1, M0 and large
operable breast cancers T2>3 cm, T3, T4, N0-1 and M0 have been treated with 2.5 mg letrozole (12
patients), 10 mg letrozole (12 patients), 1 or 10 mg anastrozole (24 patients) and 20 mg tamoxifen
(65 patients). There was no apparent difference in response rate between 2.5 and 10 mg letrozole.
Only 17 patients with anastrozole have so far completed the 3-month treatment period. Median
clinical, mammographic and ultrasound reductions in tumour volumes for patients treated with
letrozole were 81% (95% confidence interval (CI) 66-88), 77% (95% CI 64-82) and 81% (95% CI 69-
86) respectively and for anastrozole, values were 87% (95% CI 59-97), 73% (95% CI 58-82) and 64%
(95% CI 52-76) respectively. This compares with a median reduction in tumour volume for tamoxifen-
treated patients as assessed by ultrasound of 48% (95% CI 27-48). There were seven complete
clinical responses (CR), sixteen patients who achieved 50% or greater reduction in tumour volume
(PR) and one no change (NC) for letrozole and four CRs, twelve PRs and one progressive disease for
anastrozole. Best radiological responses were one CR, twenty PRs and three NCs for letrozole and
one CR, fifteen PRs and one NC for anastrozole. This study has shown that the new aromatase
inhibitors, letrozole and anastrozole, are highly effective agents in the neoadjuvant setting and they
should now be compared with tamoxifen as first-line treatment in a randomised study.
Endocrine-Related Cancer (1999) 6 227-230

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Dixon et al.: Aromatase inhibitors in the neoadjuvant setting
228
1985). Only patients with large operable or locally
advanced breast cancers without evidence of metastases
were included in this study, T2>3 cm, T3 T4b, N0-1 and
M0. Patients were M0 on the basis of normal biochemistry
and no metastases on a chest X-ray or bone scan. Patients
with inflammatory cancers, extensive peau d’orange and
satellite nodules were excluded.
Letrozole patients
Twenty-four postmenopausal patients (age range 53-84
years) were treated in sequence, the first twelve received
2.5 mg letrozole and the second twelve were treated with
10 mg letrozole. Oestrogen receptor levels varied from 40
to 890 and histoscore levels ranged from 140 to 300 in
these twenty-four patients.
Anastrozole patients
Twenty-four postmenopausal patients (age range 63-86
years) have been or are currently being treated with
anastrozole, either 1 or 10 mg, in a randomised study. As
this is an ongoing study only seventeen patients have
currently completed the 3-month study period. Histoscore
levels ranged from 120 to 300 in these seventeen patients.
It is not yet known which patients received 1 or 10 mg
anastrozole.
Tamoxifen patients
Sixty-five patients have been treated as part of an identical
protocol in our Unit with tamoxifen and data on these
patients have been published (Keen et al. 1997).
All patients gave written informed consent. Protocols
for all studies were passed by the local ethics research
committee. At the outset of the study all tumours were
measured clinically in four different directions, 45° apart
and the volume calculated using the following formula
(Forouhi et al. 1994): V=(D3×π)/6 where V is volume
and D is diameter.
They also had mammograms and using the
measurements on the oblique and craniocaudal views four
diameters were obtained. The mean diameter was
calculated and tumour volume calculated using the
formula (Forouhi et al. 1994): V=(D3×π)/6 where V is
volume and D is mean diameter.
Patients also had an ultrasound and four scans were
performed at 45° apart and tumour volume was estimated
according to the following formula (Forouhi et al. 1994):
V=(D2×d×π)/6 where V is volume, D is mean diameter
and d is mean thickness.
As part of this study patients receiving aromatase
inhibitors had a radioactive infusion of 20 MBq [3H]
androstenedione and 1.0 MBq C14-labelled oestrone in
50 ml 95% plasma protein solution and 5% ethanol 18 h
prior to surgery for assessment of peripheral and
intratumoral oestrogen production. Prior to institution of
any treatment an open biopsy was performed removing
approximately 1 g tumour for confirmation of oestrogen
receptor positivity and to provide tumour for biological
studies. Samples of tumour from patients treated with
letrozole or anastrozole were also removed for estimation
of intratumoral aromatase activity.
Patients were treated with drugs for a 3-month period.
During this time, patients were monitored at monthly
intervals and had clinical and ultrasound tumour volumes
calculated at each visit. A second mammogram was
performed at 3 months and mammographic volumes at
3 months were calculated. Percentage change in volume
was used to assess response. UICC criteria for response
demands a 50% increase in reduction, the product of the
two diameters of the tumour persisting for 1 month. This
is impractical in a period of treatment which lasts only
3 months. Modified WHO criteria for response have
therefore been utilised (WHO Handbook for Reporting
Results of Cancer Treatment 1979), partial response (PR)
being defined as a 50% or greater reduction in tumour
volume and a complete response (CR) being no
measurable tumour. Progression of disease (PD) is defined
as a greater than 25% increase in tumour volume with a no
change (NC) being defined as a volume decrease of less
than 50% or a volume increase of greater than 25%.
Results
Letrozole (2.5 mg)
There were five clinical CRs and seven PRs. Results based
on the best imaging response were one CR, ten PRs and
one NC.
Letrozole (10 mg)
There were two CRs, eight PRs and two NCs. Best
imaging responses were eleven PRs and one NC.
When comparing the results of 2.5 mg and 10 mg
letrozole, there were no apparent differences between
these groups when responses based on clincal mamm-
ographic and ultrasound changes in tumour volume were
compared. For the purposes of future comparisons,
patients treated with the two doses of letrozole have been
combined. Median clinical, mammographic and ultra-
sound reductions in tumour volume were 81% (95%
confidence interval (CI) 66-88), 77% (95% CI 64-82) and
81% (95% CI 69-86) respectively.
Anastrozole (1 or 10 mg)
This is an ongoing study and to date seventeen patients
have completed the 3-month protocol. Clinically there
were four CRs, twelve PRs and one PD. Best radiological
response was one CR, fifteen PRs and one NC. Median

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Endocrine-Related Cancer (1999) 6 227-230
229
clinical, mammographic and ultrasound reductions in
tumour volume were 87% (95% CI 59-97), 73% (95% CI
58-82) and 64% (95% CI 52-76) respectively.
Table 1 compares the data of patients treated with
letrozole or anastrozole. The two drugs produced similar
percentage reductions in tumour volume. The small
numbers of patients in this study does not allow
assessment of whether one agent is superior.
Data were available on 65 patients treated in an
identical protocol with tamoxifen (20 mg daily). Figure 1
shows the median percentage reduction in tumour volume
at 3 months in patients treated with tamoxifen, letrozole
and anastrozole. Although this was not a randomised study
both letrozole and anastrozole appear to produce greater
reductions in tumour volume than tamoxifen.
Surgical treatment of patients following
treatment by letrozole or anastrozole
Letrozole
Nine patients were suitable for breast conservation at the
outset of the treatment but by the end of the 3-month
course of letrozole all patients were eligible for treatment
by breast conservation. Histology demonstrated that all
the cancers were completely excised. There was one
complete pathological response in a patient treated with
2.5 mg letrozole and three patients had residual
microscopic disease only, two in the 2.5 mg and one in the
10 mg group.
Anastrozole
At the outset of the study fourteen out of seventeen
patients would have required a mastectomy. After
anastrozole, sixteen were suitable for breast conservation.
Histologically there were two patients who had
microscopic foci only and no patient had a complete
pathological response.
Discussion
Neoadjuvant endocrine therapy has been shown
previously to produce significant reductions in tumour
volume over a 3-month period (Keen et al. 1997). This is
the first time that the new specific aromatase inhibitors
have been used in this setting. The present study has
demonstrated high response rates with significant
numbers of patients achieving complete clinical responses
within 3 months. Such have been the reductions in tumour
volume that this short period of treatment has allowed the
majority of women to be treated with less extensive
surgery. As many of these patients are elderly and, in this
elderly population, mastectomy is associated with a 1%
mortality (Hunt et al. 1980), this is an important issue.
Results appear similar with letrozole and anastrozole
although the study does not have the power to assess
whether one agent is more effective than the other. Data
from our unit on a series of patients treated with tamoxifen
in an identical protocol indicate that the new aromatase
inhibitors appear to produce responses at least as good as
tamoxifen, with the suggestion of a greater percentage
reduction in tumour volume with these new aromatase
inhibitors when compared with tamoxifen. These data
indicate that it is time formally to assess these new
aromatase inhibitors as first-line treatment for patients
Figure 1 Reduction in tumour volume over a 3-month
period as assessed by ultrasound in patients treated with
letrozole, anastrozole or tamoxifen. Figures above each
data set represent median values with 95% CI values in
brackets.
Table 1 Comparison of reduction in clinical, mammographic and ultrasonographic volume of patients treated with a
three month course of letrozole or anastrozole
Aromatase
inhibitor No. of patients
Median % reduction
clinical volume
(95% CI)
Median % reduction
mammographic volume
(95% CI)
Median % reduction
ultrasound volume
(95% CI)
Letrozole
(2.5 mg or 10 mg)
2481 (66-88) 77 (64-82)81 (69-86)
Anastrozole
(1 mg or 10 mg)
17 87 (59-97) 73 (58-82)64 (52-76)

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Dixon et al.: Aromatase inhibitors in the neoadjuvant setting
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with large operable or locally advanced oestrogen
receptor-positive breast cancers.
There are potential weaknesses with the current study.
All patients had a wedge biopsy which may have reduced
the volume of the tumour, it may have interfered with
tumour blood supply and can make early assessment of
response difficult. All surgery was, however, performed
by a single individual (J M D) who removed approxi-
mately 1 g tissue at the initial biopsy. Any swelling
associated with the wedge biopsy did settle apart from one
patient who developed a haematoma. This patient was the
second patient treated with letrozole (2.5 mg); she
developed considerable scarring and distortion following
the haematoma which made ultrasound assessment of the
tumour difficult. This patient was recorded as having a 0%
reduction in tumour volume on ultrasound but patho-
logically she had a complete response. In no other patient
was there a problem imaging the tumour on the monthly
or 3-monthly assessments. Mammography proved
particularly useful in this elderly age group because most
elderly patients have radiolucent breasts and the tumour
can be clearly visualised. In this study there was good
agreement between all three assessments of response
indicating that 3-month percentage reduction in tumour
volume is a robust endpoint.
The superiority of letrozole and anastrozole over
conventional second-line endocrine agents in metastatic
breast cancer surprised a number of oncologists
(Dombernowsky et al. 1998). Our data suggests that it is
possible that these new agents might prove to be better in
the first-line situation than the current standard treatment,
tamoxifen. The lessons we have learned from using these
new aromatase inhibitors in the neoadjuvant setting are
that they are extremely powerful agents, they produce
significant response rates with large reductions in tumour
volume permitting less extensive surgery. Studies of these
drugs as first-line therapy are now indicated.
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