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REVIEW
Aromatase inhibitors for metastatic male breast cancer:molecular, endocrine, and clinical considerations
Marcello Maugeri-Sacca • Maddalena Barba •
Patrizia Vici • Laura Pizzuti • Domenico Sergi •
Ruggero De Maria • Luigi Di Lauro
Received: 17 June 2014 / Accepted: 26 July 2014 / Published online: 13 August 2014
� Springer Science+Business Media New York 2014
Abstract Male breast cancer is a rare condition. Aro-
matase inhibitors are widely used for treating metastatic
male breast cancer patients. In this setting, their use is not
substantiated by prospective clinical trials, but is rather
driven by similarities supposedly existing with breast
cancer in postmenopausal women. This oversimplified
approach was questioned by studies addressing the
molecular and endocrine roots of the disease. In this
manuscript, we discuss relevant aspects of the current use
of aromatase inhibitors in metastatic male breast cancer in
light of the most updated evidence on the molecular
landscape of the disease and the specific changes in the
hormonal background occurring with aging. We further
point to strategies for blocking multiple hormonal pathway
nodes with the goal of improving their therapeutic poten-
tial. We searched PubMed from its inception until March
2014 for relevant literature on the use of aromatase
inhibitors in metastatic male breast cancer. Selected terms
were combined and used both as medical headings and text
words. The reference list of the suitable manuscripts was
inspected for further publications. Aromatase inhibitors
represent the mainstay of treatment in the metastatic set-
ting. Yet, efforts aimed at sharpening the therapeutic
potential of aromatase inhibitors still pose a challenge due
to the paucity of data. The choice of dual hormonal (or
sequential) therapy combining aromatase inhibitors with a
GnRH analogue may represent a valid alterative, particu-
larly if informed by cancer- and patient-related features
including molecular, endocrine, and clinic characteristics.
Keywords Male breast cancer � Aromatase inhibitors �GnRH analogue � Hormone receptor pathways
Introduction
Despite the increased incidence reported over the last
25 years, male breast cancer (MBC) is a rare disease
accounting for less than 1 % of all breast cancer (BC) cases
[1]. Its incidence rate rises gradually with age without the
typical bimodal distribution of BC in women, and median
age at diagnosis is higher in men than women (67 versus
62 years) [1]. Other than age, further risk factors include a
series of medical conditions associated with an abnormal
estrogen-to-androgen ratio (e.g., Klinefelter’s syndrome,
obesity, liver diseases, testicular abnormalities), and germ-
line mutations in BRCA1and BRCA2 [2, 3]. Additional
potential genetic susceptibility factors are mutations in
PALB2, androgen receptor (AR), CYP17, the cell-cycle
checkpoint controller CHEK2, and RAD51B [2]. It is well
known that MBC is an estrogen-driven disease. A popu-
lation-based comparison showed that 92 % of MBCs were
estrogen receptor (ER)-positive, compared to 78 % of ER-
positive female BC (FBC) [4]. Such a difference, along
with the observation that MBC occurs later in life, at a
higher stage and lower grade, provided clues on the simi-
larities between MBC and late-onset FBC. Since MBC has
been traditionally considered as a disease closely resem-
bling hormone receptor-positive FBC, anti-hormone ther-
apies are the mainstay of treatment. Aromatase inhibitors
(AIs), a class of compounds that prevents the conversion of
M. Maugeri-Sacca (&) � M. Barba � P. Vici � L. Pizzuti �D. Sergi � L. Di Lauro
Division of Medical Oncology B, ‘‘Regina Elena’’ National
Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
e-mail: [email protected]
M. Maugeri-Sacca � R. De Maria
Scientific Direction, ‘‘Regina Elena’’ National Cancer Institute,
Via Elio Chianesi 53, 00144 Rome, Italy
123
Breast Cancer Res Treat (2014) 147:227–235
DOI 10.1007/s10549-014-3087-3
androstenedione to 17b-estradiol (E2), are the gold stan-
dard endocrine therapy in both the adjuvant and metastatic
setting in ER-positive postmenopausal women [5]. How-
ever, their use in MBC is mostly extrapolated from studies
in female patients, due to the difficulty in carrying out
prospective clinical trials in such a rare disease. Several
pieces of evidence are questioning this approach, thus
sparking the debate on optimal endocrine therapy for these
patients. Firstly, a recent wave of molecular studies high-
lighted the existence of non-negligible differences between
BC arising in men and women [6, 7]. Secondly, the hor-
monal milieu in men is different from that of age-matched
women, and this leads to partly different mechanisms of
hormone-related oncogenic stimulation [8]. Finally,
whereas AIs replaced tamoxifen in postmenopausal BC
following a series of head-to-head trials, in MBC tamoxi-
fen seemed superior to AIs as adjuvant therapy [9].
Therefore, the translation of results from clinical trials
conducted in FBC in the male setting might be an over-
simplification and conceptually misleading. Herein, we
analyze the spectrum of gender-related molecular and
endocrine differences in BC and their implications for AI-
based therapy in male patients.
The molecular landscape of male breast cancer
Over the past decade, we have witnessed an unprecedented
evolution of novel biotechnologies that nowadays combine
high-throughput and multiplex capability. Massive char-
acterization efforts fragmented FBC into multiple molec-
ular entities, each one characterized by a unique gene
expression profile [10], a different incidence among ethnic
groups [11], and a different set of both deregulated path-
way nodes and genetic abnormalities [12]. To further
complicate the picture, 10 integrative clusters defined by
acquired somatic copy number aberrations were identified,
splitting many of the intrinsic subtypes [13]. Furthermore,
genome-wide comparison of multiple tumors, even
including FBC, revealed the existence of 20 distinct
mutational signatures, some ‘‘private,’’ being confined to a
single tumor, and others shared by cancers of different
origin [14]. Despite impressive progresses, the molecular
scenario of MBC remained largely unexplored until
recently, as evidence of specific molecular abnormalities
were scattered and collected from studies analyzing only
few molecular endpoints. Seminal reports exploiting
comparative genomic hybridization analysis provided ini-
tial hints on chromosomal gains and losses, and suggested
the existence of a similar pattern of chromosomal imbal-
ances in BC arising in males and females [15]. Likewise,
the evaluation of the methylation status of 25 genes
revealed that the set of most frequently hypermethylated
genes in MBC is similar to that of FBC, even though
BRCA1 and BRCA2 promoter hypermethylation was less
common in MBC [16]. Nevertheless, gender-related
molecular differences are emerging. A study focusing on
copy number changes of 21 BC-related genes found more
copy number gains of EGFR and CCND1 and less copy
number gains of EMSY and CPD in MBC versus FBC [17].
To a similar extent, in a comparative analysis of 56 MBC
with an available FBC dataset, genomic gains were
observed more frequently in MBC, whereas high-level
amplifications were more frequent in FBC [18]. First
attempts to provide a deeper molecular characterization of
MBC have been presented, albeit with the lack of inte-
grated genomic, transcriptomic, proteomic, and methylo-
mic data analysis that recently allowed to dissect the
molecular landscape of most common tumors. Unsuper-
vised hierarchical clustering of gene expression profiling of
66 primary MBC coupled with tissue microarray for
immunohistochemistry constructed for validation purposes
(extended cohort) revealed the existence of two distinct
subtypes, defined as luminal M1 (70 %) and luminal M2
(30 %) [6]. Gene ontology indicated the existence of dif-
ferent deregulated modules between the two subtypes. Up-
regulated genes in the luminal M1 subtype, which was
associated with worse prognosis, are involved in a variety
of oncogenic activities spanning from cell migration and
adhesion to angiogenesis, cell cycle, and cell division.
Interestingly, even though luminal M1 tumors were almost
all ER positive by immunohistochemistry, they presented a
low score for the ER module. Conversely, luminal M2
tumors were enriched for immune response genes and with
ER signaling-associated genes. According to the biological
relevance of the protective role of the immune response, a
positive correlation was reported between HLA positivity
and better distant metastasis-free survival. From the bio-
logical standpoint, it is arguable that the three-step process
of immunoediting [19], which leads from immune sur-
veillance to immune escape, is not completed in HLA-
expressing MBC. These two subgroups did not resemble
any of the intrinsic subgroups identified in FBC, thus
suggesting their male-restricted nature. The luminal sub-
types partly overlap with a previous genomic imbalance-
based classification identified within the same patient
cohort, and dividing MBC in two genomic subtypes: male-
simple and male-complex [18]. In more detail, 89 % of the
luminal M1 tumors were classified as male-complex,
whereas 47 % of the luminal M2 tumors as male-simple. In
an independent gene expression profiling study, 37 ER-
positive MBC and 53 ER-positive female BC, similar for
clinical and standard pathological features, were analyzed
[7]. Around 1.000 genes were found to be significantly
differentially expressed between the two groups, resulting
in distinct deregulated networks. Genes related to the AR
pathway were overexpressed in MBC, along with genes
228 Breast Cancer Res Treat (2014) 147:227–235
123
mediating protein synthesis, cytoskeletal dynamics, and
apoptosis. Conversely, a set of chemokines playing a cru-
cial role during immune response was more expressed in
female tumors along with other immune mediators. A
partially different spectrum of mitogenic signals was also
reported. The concept of a different gender-related land-
scape in hormone receptor pathways is further enforced by
a tissue microarrays study in which 251 MBC and 263
FBCs matched for grade, age, and lymph node status were
immunostained for ERa, various isoforms of ERb and
progesterone receptor (PR), AR, HER2, and a panel of
cytokeratins [20]. Luminal B and HER2 phenotypes were
not seen in males and, more importantly, two different
clusters were isolated in relation to ERa expression. While
ERa clustered with PR and its isoforms in FBC, in MBC
ERa was associated with ERb isoforms and AR. Next, by
comparing microRNA expression profiles of 23 MBC and
10 female ductal breast carcinomas, 17 significantly
deregulated microRNAs were isolated, 4 overexpressed
and 13 underexpressed in MBC [21]. Immunohistochem-
istry for HOXD10 and VEGF was performed in order to
evaluate the concordance between deregulated microRNAs
and the expression of their targets. Down-regulation of
microRNA-10b and microRNA-126 was accompanied by
high expression of their targets HOXD10 and VEGF,
respectively. Finally, despite the comprehensive genetic
landscape of MBC has not been unveiled yet, with a con-
sequent poor understanding of ‘‘driver,’’ ‘‘passenger,’’ and
‘‘actionable’’ mutations, a computational approach (CON-
EXIC: Copy Number and EXpression In Cancer) inte-
grating comparative genomic hybridization and gene
expression data to evaluate network perturbations in MBC
and FBC yielded two different, gender-specific sets of
candidate drivers [22]. While, on the one hand, these
studies pointed out that hormone receptor pathways are
among the driving forces in MBC, on the other a greater
understanding of hormone receptor signaling networks and
their vertical and lateral activators is required to overcome
the critical hurdles of intrinsic and acquired resistance to
endocrine therapies. Indeed, in FBC an extensive crosstalk
exists between hormone receptor pathways and growth
factor pathways (e.g., PI3K/Akt/mTOR and MAPK) [23].
Under hormone-deprived conditions, these signals either
sensitize ER to ligand stimulation or activate the receptor
in a ligand-independent manner [23]. Recently, ESR1acti-
vating mutations driving ER-dependent transcription have
been described and associated with therapeutic resistance
to hormonal therapy [24–27]. Having deciphered how
intracellular pathway nodes interact with ER prompted the
BOLERO-2 trial, which provided the proof-of-concept that
endocrine resistance in postmenopausal hormone-receptor-
positive BC can be antagonized by targeting intermediate
effectors of canonical pathways [28]. It remains unclear
whether these mechanisms also apply to MBC biology,
albeit there are hints of potential gender-specific molecular
modulators of AI-based therapy activity. As a paradigmatic
example, gene expression profiling studies indicated that
MBC is enriched for a different set of genes compared with
FBC, mirroring different top-ranking deregulated biologi-
cal functions that also encompass upstream activator of the
PI3 K/Akt/mTOR cascade, such as HER2 [6]. To sum up,
molecular studies presented so far, which are summarized
in Table 1, provided the biological background supporting
the use of AIs in MBC. However, a massive character-
ization of the disease illustrating the full spectrum of
molecular abnormalities is essential in improving AI-based
therapy. To this end, we believe two complementary
strategies should be pursued. Firstly, fostering implemen-
tation of existing biobanks within a collaborative network
for interdisciplinary research with a translational focus.
Included biological samples should fulfill requirements for
extensive annotation with cancer-related molecular fea-
tures and clinical data including therapy administered and
treatment outcomes. Systems biology approaches can
indeed provide a more complete view of how coexisting
molecular aberrations alter signaling networks and their
impact on clinical outcomes. As a parallel strategy,
establishing a collection of cell lines for gathering func-
tional data from in vitro and in vivo studies focused on
hormonal resistance in male MBC. This will enable
investigators to explore the interplay between hormonal
receptors and any current/potential targets placed within
canonical and emerging signal transduction pathways, thus
paving the way for biology-driven studies. To overcome
the issue of the rarity of the disease, MBC patients might
be included in clinical trials in FBC envisioning the use of
targeted agents for restoring hormone sensitivity.
The hormonal background in aging male
Together with molecular factors, the different hormonal
milieu between males and females represents a key deter-
minant for interpreting AI efficacy in MBC. The major
source of plasma E2 in males derives from peripheral
aromatization of testosterone (T) [8]. With aging,
the androgen/estrogen ratio shifts in favor of estrogens, as
the decrease in testicular and adrenal T production is not
coupled with parallel reduction of E2 levels [8]. Such an
imbalance stems from the age-associated increase of both
aromatase activity and fat mass [8]. As a result, E2 levels
are significantly higher in aged males than in post-meno-
pausal females [8]. Thus, the aromatase enzyme represents
a crucial node in supplying cancer cells with oncogenic
stimuli. Whether, on the one hand, this represents a sound
background for the use of AIs in the clinical setting,
additional endocrine factors should be taken into account
Breast Cancer Res Treat (2014) 147:227–235 229
123
Ta
ble
1M
ole
cula
rst
ud
ies
inM
BC
Au
tho
r,y
ear,
(ref
.)T
ech
no
log
yK
eyfi
nd
ing
sN
ote
s
Ru
dlo
wsk
i[1
5]
CG
HC
hro
mo
som
alg
ain
s:1
q(4
6%
),8
q(4
6%
),1
6p
(36
%),
17
q
(36
%),
Xq
(28
%),
20
q(2
6%
)an
dX
p(1
8%
)
Ch
rom
oso
mal
loss
es:
8p
(36
%),
16
q(2
8%
),1
3q
(28
%),
6q
(18
%),
11
q(1
8%
)an
d2
2q
(18
%)
Co
mm
on
pat
tern
of
imb
alan
ces
wit
hF
BC
Ko
rneg
oo
r[1
6]
MS
-ML
PA
Th
em
ost
freq
uen
tly
hy
per
met
hy
late
dg
enes
(MS
H6
,C
DH
13
,
PA
X5
,P
AX
6an
dW
T1
)si
mil
arfo
rM
BC
and
FB
C
Pro
mo
ter
hy
per
met
hy
lati
on
inE
SR
1,
BR
CA
1an
d
BR
CA
2le
ssco
mm
on
inM
BC
than
inF
BC
Ko
rneg
oo
r[1
7]
ML
PA
CN
Go
fC
CN
D1
,T
RA
F4
,C
DC
6an
dM
TD
Hse
enin
[4
0%
CN
Go
fC
CN
D1
,M
TD
H,
CD
C6
,A
DA
M9
,T
RA
F4
and
MY
C
iden
tifi
eda
po
or
pro
gn
osi
sg
rou
p
CN
Go
fE
GF
Ran
dC
CN
D1
mo
reco
mm
on
inM
BC
than
FB
C
CN
Go
fE
MS
Yan
dC
PD
less
freq
uen
tin
MB
Cth
an
FB
C
Joh
anss
on
[18
]H
igh
-res
olu
tio
nti
lin
gB
AC
arra
ys
Tw
og
eno
mic
sub
gro
up
sid
enti
fied
and
defi
ned
asm
ale-
com
ple
x
and
mal
e-si
mp
le
Joh
anss
on
[6]
GE
Pan
dT
MA
for
IHC
Tw
od
isti
nct
sub
typ
esid
enti
fied
:lu
min
alM
1(7
0%
)an
dlu
min
al
M2
(30
%)
Lu
min
alM
1tu
mo
rsen
rich
edfo
rg
enes
inv
olv
edin
cell
mig
rati
on
,
adh
esio
n,
ang
iog
enes
is,
cell
cycl
ean
dce
lld
ivis
ion
Lu
min
alM
2tu
mo
rsen
rich
edfo
rg
enes
inv
olv
edin
imm
un
e
resp
on
sean
dE
Rsi
gn
alin
g
NA
T1
and
HL
Ap
osi
tiv
ity
asso
ciat
edw
ith
bet
ter
ou
tco
mes
Ov
erla
pw
ith
mal
e-si
mp
lean
dm
ale-
com
ple
x
sub
gro
up
s
Cal
lari
[7]
GE
PA
Rp
ath
way
-rel
ated
gen
esan
dg
enes
inv
olv
edin
pro
tein
syn
thes
is,
cyto
skel
etal
dy
nam
ics
and
apo
pto
sis
ov
erex
pre
ssed
inM
BC
Ch
emo
kin
esan
dim
mu
ne
resp
on
se-r
elat
edg
enes
ov
erex
pre
ssed
in
FB
C
*1
,00
0D
iffe
ren
tial
lyex
pre
ssed
gen
esb
etw
een
MB
Can
dF
BC
Sh
aab
an[2
0]
TM
Afo
rIH
CT
wo
clu
ster
sid
enti
fied
inre
lati
on
toE
Ra
exp
ress
ion
:
ERa
/PR
and
its
iso
form
sin
FB
C
ERa
/ERb
/AR
inM
BC
Lu
min
alB
and
HE
R2
ph
eno
typ
esn
ot
seen
inM
BC
Fas
san
[21
]m
iRN
Am
icro
arra
ys
17
Der
egu
late
dm
iRN
As
inM
BC
vs
FB
C:
4O
ver
exp
ress
edm
iRN
As
(miR
-66
3,
miR
-61
8,
miR
-60
5,
miR
-
61
6)
13
Un
der
exp
ress
edm
iRN
As
(miR
-20
0b
,m
iR-1
81
c,m
iR-1
06
a,
miR
-12
5a-
5p
,m
iR-1
6,
miR
-25
,m
iR-1
00
,le
t-7
f,m
iR-1
25
b,
miR
-15
b,
miR
-42
5,
miR
-19
9a-
5p
,m
iR-2
23
)
Tar
get
der
epre
ssio
n(H
OX
D1
0an
dV
EG
F)
sug
ges
ted
by
IHC
Joh
anss
on
[22
]C
om
pu
tati
on
alb
iolo
gy
(CG
Han
dG
EX
dat
a
inte
gra
tio
n)
30
Can
did
ate
‘‘d
riv
ers’
’id
enti
fied
:
To
pam
pli
fied
gen
es:
BL
CA
P,
LA
D1
,C
YC
1,
DD
X5
1,
AR
HG
AP
30
,S
PA
G5
,T
AF
4.
To
pd
elet
edg
enes
:E
LA
C2
,T
HY
1,
LH
FP
,C
D1
64
,P
OS
TN
,
EL
F1
,F
YN
,L
AM
A4
On
lyfi
ve
ov
erla
pp
ing
‘‘d
riv
ers’
’b
etw
een
MB
Can
d
FB
C:
TA
F4
,C
D1
64
,A
RH
GA
P3
0,
CO
G3
and
SP
AG
5
CG
Hco
mp
arat
ive
gen
om
ich
yb
rid
izat
ion
,C
NA
cop
y-n
um
ber
alte
rati
on
,C
NG
cop
yn
um
ber
gai
n,
FB
Cfe
mal
eb
reas
tca
nce
r,G
EX
gen
eex
pre
ssio
n,
GE
Pg
ene
exp
ress
ion
pro
fili
ng
,IH
C
imm
un
oh
isto
chem
istr
y,
MB
Cm
ale
bre
ast
can
cer,
ML
PA
mu
ltip
lex
lig
atio
n-d
epen
den
tp
rob
eam
pli
fica
tio
n,
MS
-ML
PA
met
hy
lati
on
spec
ific-
mu
ltip
lex
lig
atio
n-d
epen
den
tp
rob
eam
pli
fica
tio
n,
TM
Ati
ssu
em
icro
arra
y
230 Breast Cancer Res Treat (2014) 147:227–235
123
for refining the therapeutic potential of these compounds.
About 20 % of E2 is directly secreted by the testes, thus
exerting tumor-promoting functions without the interme-
diate passage of aromatization. Moreover, pharmacological
inhibition of the aromatase enzyme and the consequent
drop in E2 level triggers the hypothalamic-pituitary feed-
back loop, which in turn might counteract the effects of AIs
[29–32]. Indeed, prolonged administration of anastrozole to
male adult rats led to a significant increase in testis weight
coupled with increased levels of follicle-stimulating hor-
mone (FSH), luteinising hormone (LH) and T [29]. Such
AI-mediated increases in T levels might force the road-
block imposed by AIs, by fuelling T enzymatic conversion
through an excess of substrate. Although the administration
of AIs caused a decrease in E2 levels in healthy men, a
parallel increase in FSH, LH and T was documented [30,
31], an association further strengthened by results coming
from randomized, placebo-controlled clinical trials in hy-
pogonadal elderly men [33, 34]. Therefore, adaptive
endocrine changes occurring during AI therapy might
paradoxically trigger two independent oncogenic routes.
Hormone receptor pathway-mediated stimulation of cancer
cells can be driven by both an excess of substrate for
aromatization and the stimulation of AR-related signals.
This latter mechanism, albeit not formally proven yet, can
be argued by comparing molecular studies described above
[7, 20], and evidence of tumor response with antiandrogens
[35–37]. Along with host-related factors, tumor-associated
endocrine factors further highlighted the central role of the
aromatase enzyme in the hormonal network sustaining
tumor growth. Tissue microarray documented intratumoral
aromatase (ITA) expression in 12 out of the 45 evaluated
specimens [38]. ITA positive MBC were associated with
favorable pathologic features and improved 5 year overall
survival. More recently, intratumoral E2 and T concentra-
tions were reported to be higher in MBC than in FBC, and
gene expression profile of laser capture-microdissected
tumors, focused on estrogen-induced genes previously
identified in a commercial cell line, showed that MBC and
FBC formed independent clusters, as confirmed by
immunohistochemistry for representative endpoints (RARaand RIP140) [39]. Even considering the small sample size
of these studies, they raised the hypothesis that cancer cells
are able to shape the local hormonal milieu to thrive.
Clinical experiences with AIs in metastatic MBC
The therapeutic potential of manipulating the hormonal
background for treating MBC patients is rooted in tumor
regressions observed with surgical procedures such as
orchiectomy, adrenalectomy, and hypophysectomy [40].
Even though these procedures were associated with
response rates spanning from 55 to 80 %, they have been
widely replaced by more acceptable hormonal medical
treatments. In the last decade, the use of AIs in metastatic
MBC was prompted by their success in FBC patients [5],
the initial evidence of target expression within the tumor
[38], and the plethora of tamoxifen-associated side effects
observed in men [41–43]. Despite the better tolerability of
AIs compared to tamoxifen, the controversy surrounding
their use in the metastatic setting was until recently fed by
better outcomes reported with adjuvant tamoxifen than
with AIs [9], and scattered evidence of antitumor activity
[44–46]. Consistently, while on the one hand no objective
responses were recorded in a cohort of five male patients
with metastatic disease who received anastrozole [44],
individual cases of response to letrozole were presented
[45, 46]. Taking into account the intrinsic limitations of
retrospective analyses, a first and more structured attempt
aimed at collocating AIs into the clinical practice dates
back to 2010 [47]. Fifteen metastatic patients were treated
with an AI. Complete or partial responses (CR, PR) were
recorded in six patients (40 %), and stable disease (SD) in
two patients (13 %), translating into a disease control rate
(DCR) of 53 %. The median progression-free survival
(PFS) and overall survival (OS) were 4.4 months (95 % CI
0.1–8.6) and 33 months (95 % CI 18.4–47.6), respectively.
There were no appreciable differences related to the type of
AI used (non-steroidal versus steroidal), even though no
firm conclusions can be drawn considering the small cohort
examined. Beyond providing evidence of antitumor activ-
ity, endocrine analyses conducted in six patients revealed
successful reduction of E2 levels. More importantly, in a
patient with PR increased levels of E2, LH, and FSH were
detected at tumor progression. Although anecdotic, this
finding underlies the activation of the hypothalamic-pitui-
tary feedback loop and the correlated counteraction of AI
activity. The therapeutic potential of inhibiting the hor-
monal feedback loop for potentiating AI therapy stemmed
from two PRs observed in two metastatic patients treated
with either anastrozole or letrozole combined with leu-
prolide acetate [48]. However, only in 2013 two indepen-
dent, retrospective studies tried to assess the clinical
usefulness of such a combination therapy [49, 50]. Zagouri
et al. [49] presented results from a cohort of twenty-three
patients treated with an AI as first- or second-line, mostly
letrozole or anastrozole, either alone or in combination
with a GnRH analogue. Despite confirming the decade-
long belief that AIs are an effective and safe treatment
option for metastatic MBC patients, neither tumor response
rate (SD:PR ratio with the administration of goserelin
versus AI monotherapy: 64.7:17.7 and 33.3:50.0 %,
respectively) nor OS favored the co-administration strat-
egy. In the second study presented by our group [50],
nineteen metastatic men were treated with letrozole com-
bined with a GnRH analogue as a first- or second-line
Breast Cancer Res Treat (2014) 147:227–235 231
123
therapy. DCR (84.2 %), PFS (12.5 months), and OS
(35.8 months) were fairly comparable with the study dis-
cussed above. However, among four patients for whom a
GnRH analogue was introduced following tumor pro-
gression while on front-line AI monotherapy, we noted
that three of them treated with such a sequential approach
confirmed or improved the best overall response observed
in the first-line. One patient with SD in the first-line
experienced a PR following GnRH analogue introduction
and the replacement of exemestane with letrozole at tumor
progression, and two patients treated with first-line le-
trozole confirmed the PR and SD with the introduction of a
GnRH analogue in the second-line setting. Although no
firm conclusions can be drawn, also due to the lack of
baseline and serial assessment of hormonal levels in our
study, the suggestive hypothesis emerging is that intro-
ducing a GnRH analogue at tumor progression while on AI
therapy might efficiently counteract the activation of the
hormonal loop responsible for forcing the block imposed
by AIs. Combining this observation with the not clearly
proven superiority of front-line combination therapy, it is
possible to hypothesize that a sequential approach might
extend the period during which patients experience benefit
from endocrine manipulations, thus delaying the use of
chemotherapy. Table 2 and Table 3 summarize clinical
experiences with AIs in metastatic MBC patients.
Table 2 Case reports with AIs alone or in combination with a GnRH
analogue in metastatic MBC
Author,
year, (ref.)
Patients and treatment Description
Giordano
[44]
5 patients treated with
anastrozole, 4 patients
received prior non-AI-
based endocrine therapy
No objective responses
were recorded (3 disease
stabilization and 2
disease progression)
Zabolotny
[45]
1 Patient with locally
advanced breast cancer
treated with letrozole
A major response of a
large breast tumor
Arriola
[46]
1 Treatment-naıve patient
with metastatic disease
treated with letrozole
A partial response
associated with a
decrease in estradiol
levels
Giordano
[48]
2 Patients treated with a
GnRH analogue with
either letrozole or
anastrozole. 1 patients
received a prior
treatment with an
aromatase inhibitor, and
then with a GnRH
analogue, both as
monotherapy, before
receiving the
combination
This is the first report
describing antitumor
activity by combining an
aromatase inhibitor with
a GnRH analogue
Ta
ble
3C
lin
ical
stu
die
sw
ith
AIs
alo
ne
or
inco
mb
inat
ion
wit
ha
Gn
RH
anal
og
ue
inm
etas
tati
cM
BC
Au
tho
r,y
ear,
(ref
.)P
atie
nts
(N)
Dru
g(s
)D
CR
(SD
?P
R?
CR
)
PF
San
dO
SN
ote
s
Do
yen
[47]
15
An
astr
ozo
le(N
:5)
Let
rozo
le(N
:5)
Ex
emes
tan
e(N
:5)
53
%4
.4m
on
ths
and
33
mo
nth
sE
ffici
ent
red
uct
ion
of
E2
lev
els
Incr
ease
dle
vel
so
fE
2,
LH
and
FS
Hd
etec
ted
atd
isea
se
pro
gre
ssio
n
Zag
ou
r[4
9]
23
No
n-s
tero
idal
(N:
19
)o
rst
ero
idal
(N:
4)
AI
wit
h
(N:1
7)
or
wit
ho
ut
(N:6
)a
Gn
RH
anal
og
ue
82
.3%
13
mo
nth
san
d3
9m
on
ths
No
bet
ter
ou
tco
mes
inp
atie
nts
rece
ivin
gth
eco
mb
inat
ion
Di
Lau
ro[5
0]
19
Let
rozo
lew
ith
aG
nR
Han
alo
gu
e(N
:19
)8
4.2
%1
2.5
mo
nth
san
d3
5.8
mo
nth
sH
om
og
eno
us
trea
tmen
t
Hin
tso
fan
titu
mo
rac
tiv
ity
wit
h
Gn
RH
intr
od
uct
ion
atd
isea
se
pro
gre
ssio
nw
hil
eo
nA
I
mo
no
ther
apy
CR
com
ple
tere
spo
nse
,D
CR
dis
ease
con
tro
lra
te,
OS
ov
eral
lsu
rviv
al,
PF
Sp
rog
ress
ion
-fre
esu
rviv
al,
PR
par
tial
resp
on
se,
SD
stab
led
isea
se
232 Breast Cancer Res Treat (2014) 147:227–235
123
Conclusions and future directions
The importance of manipulating the hormonal milieu for
treating MBC dates back to the 1940s, when orchiectomy
was described as a treatment for skeletal metastases [40].
Since AIs have changed the treatment paradigm of ER-
positive FBC in the post-menopausal setting, it is not sur-
prising that these agents have been exploited for treating
MBC patients. However, nowadays we have elements to
judge such an extrapolation incomplete. Even though the
secrets of the MBC genome have not been unrevealed yet,
first attempts of molecular characterization together with
knowledge on the endocrinology of aging allow to foresee
that the greater the extent of hormonal deprivation via the
inhibition of multiple nodes is (aromatase enzyme, the
hypothalamic-pituitary axis, ER, and AR), the more pro-
nounced the effects on cell viability should be. Pursuing
this biological scenario might be, however, tricky, and the
practical issue of adherence to therapy needs to be carefully
considered. The lesson we learned is that AIs are active and
produce tumor shrinkage and prolonged disease stabiliza-
tion. In 2010, in a summary of a multidisciplinary inter-
national meeting on MBC panel members drew attention to
some possible clinical trial designs [51]. In particular, a
study aimed at comparing tamoxifen versus an AI with a
safety endpoint was proposed. Beyond the intrinsic diffi-
culty in conducting randomized clinical trials in a rare
disease, as highlighted by the premature closure of the
small-sized phase II study SWOG-S0511 (ClinicalTri-
als.gov; ID: NCT00217659), in our opinion this compari-
son is no longer necessary. Firstly, because most metastatic
MBC patients have already received tamoxifen as adjuvant
therapy, whose use in this setting is recommended and
supported by clinical evidence, albeit retrospective [9].
From a biological standpoint, the efficacy of tamoxifen
rechallenge might be hindered by tumor cell plasticity, as
prolonged drug exposure elicits adaptive changes and
induces clonal evolution, thus enabling cancer cells to
evade therapy-induced death stimuli. Secondly, because at
that time the three largest studies describing the antitumor
activity of AIs were not published [47, 49, 50]. Thirdly and
more importantly, because tamoxifen-related toxic effects
and the correlated, non-negligible 20 % of discontinuation
rate is a crucial clinical issue [43]. Even though AIs should
be considered the mainstay of treatment in the metastatic
setting and efforts should be focused on sharpening their
potential, finding their exact collocation in the therapeutic
continuum, and establishing their optimal use, is still pos-
ing a challenge due to the paucity of data available so far.
Until results from prospective clinical trials or, alterna-
tively, large case series will not be available, the choice of
AI monotherapy versus dual hormonal (or sequential)
therapy combining AIs with a GnRH analogue should be
made taking into account multiple cancer- and patient-
related factors, including molecular characteristics, medi-
cal history, patient needs, comorbidities, disease evolution
and extension, and serial assessment of hormone levels. In
approaching MBC patients, planning a long-term strategy
implies to carefully weigh the endocrine-responsive nature
of the disease on the one hand and the scant information
available on the role of chemotherapy on the other hand.
Indeed, clinical experiences with palliative chemotherapy
envisioned outdated regimens used in the pre-taxane era
[52]. Moreover, the magnitude of benefit deriving from
chemotherapy is greater in endocrine-nonresponsive BC,
and potential harms from using chemotherapy in elderly
patients, in whom multiple comorbidities often coexist,
need to be carefully considered. Delaying chemotherapy as
long as possible is, therefore, a priority, at least in the
absence of life-threatening or rapidly progressive lesions,
or in the fraction of hormone-receptor-negative tumors.
Combining these observations with the not already proven
superiority of front-line combination therapy over AI
monotherapy, in our opinion the sequential strategy dis-
cussed above should be considered, especially if supported
by biochemical evidence of AI-induced hormonal changes.
Finally, placing novel treatment modalities in a therapeutic
framework aimed at manipulating the hormonal milieu
with sequential endocrine therapies is of utmost impor-
tance. To this end, while ER is an established key onco-
genic driver and relevant therapeutic target, as further
confirmed by evidence of tumor response with fulvestrant
[53], AR deserves further investigation as a therapeutic
target in light of pathway components expression in MBC,
evidence of antitumor activity with first-generation anti-
androgens [35–37], and recent successes with novel anti-
androgens in prostate cancer [54, 55].
Search strategy
Data for this review were found through searches of Pub-
Med using the terms: ‘‘male breast cancer,’’ ‘‘metastatic,’’
‘‘aromatase inhibitors,’’ ‘‘anastrozole,’’ ‘‘letrozole,’’ ‘‘exe-
mestane,’’ ‘‘GnRH analogue,’’ ‘‘tamoxifen,’’ ‘‘gene
expression profiling,’’ ‘‘comparative genomic hybridiza-
tion,’’ ‘‘tissue microarray,’’ ‘‘microRNAs,’’ ‘‘mutations,’’
‘‘subtypes,’’ ‘‘sex hormone pathways,’’ ‘‘estrogen recep-
tor,’’ ‘‘androgen receptor.’’ We did not use a date limit.
Only articles published in English were included. The
reference list was selected on the basis of scientific and
clinical relevance.
Acknowledgments We thank Tania Merlino and Ana Maria Edlisca
for technical assistance.
Conflict of interest The authors have declared no conflicts of
interest.
Breast Cancer Res Treat (2014) 147:227–235 233
123
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