9
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 Ó 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 Á Aromatase inhibitors Á GnRH analogue Á 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 `(&) Á M. Barba Á P. Vici Á L. Pizzuti Á D. Sergi Á 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 ` Á 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

Aromatase inhibitors for metastatic male breast cancer: molecular, endocrine, and clinical considerations

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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

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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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