Breast Cancer Res Treat
DOI 10.1007/s10549-015-3356-9
EPIDEMIOLOGY
Aromatase inhibitors in male breast cancer: a pooled analysis
Flora Zagouri1 Theodoros N. Sergentanis2 Hatem A. Azim Jr.3
Dimosthenis Chrysikos1 Meletios-Athanassios Dimopoulos1 Theodora Psaltopoulou2
Received: 16 December 2014 / Accepted: 23 March 2015
Springer Science+Business Media New York 2015
Abstract Although several studies have shown the effi-
cacy of third-generation aromatase inhibitors (AIs) in
women with breast cancer, the role of such molecules re-
mains elusive in male breast cancer patients. It is also
unknown whether the addition of gonadotropin-releasing
hormone (GnRH) analogues to AIs would be a superior
strategy or not. This pooled analysis was conducted in
accordance with the PRISMA guidelines. All studies that
examined the efficacy of AIs in metastatic male breast
cancer were considered eligible. Overall, 15 studies (105
cases) were eligible for this pooled analysis. The mean age
of the study sample was 62.8 years. ER status was positive
in all eligible cases. AI was given as first line in 61.5 % of
cases. GnRH analogue was co-administered with AI in
37.1 % of cases (n = 39). CR, PR, SD and PD were
achieved in 5.7, 23.8, 37.2 and 33.3 % of cases, respec-
tively. The median PFS and OS were equal to 10.0 and
39.0 months, respectively. Co-administration of GnRH
analogues was associated with more than threefold increase
in rates of clinical benefit (OR = 3.37, 95 % CI 1.308.73)
Electronic supplementary material The online version of this
article (doi:10.1007/s10549-015-3356-9) contains supplementary
material, which is available to authorized users.
& Flora Zagouri
florazagouri@yahoo.co.uk
1
Department of Clinical Therapeutics, Alexandra Hospital,
Medical School, University of Athens, Vas Sofias Ave &
Lourou str, 11521 Athens, Greece
2 for the treatment of hormone receptor (HR)-positive,
Department of Hygiene, Epidemiology and Medical
Statistics, Medical School, University of Athens, Athens,
Greece
3
Department of Medicine, BrEAST Data Centre, Institut Jules
Bordet, Universite Libre de Bruxelles, Brussels, Belgium
but did not seem to correlate with better PFS or OS. No
statistically significant associations between the examined
outcomes and the other parameters were noted. Available
data suggest that AIs may potentially play a promising role
in the optimal therapeutic strategy for metastatic male
breast cancer patients. Especially, co-administration of AI
with a GnRH analogue seems to increase the rate of clinical
benefit and could be more effective, warranting further
consideration.
Keywords Male breast cancer
Aromatase inhibitors

Hormonal treatment
GnRH analogues
Introduction
Male breast cancer is an uncommon malignancy, with an
occurrence of one case per 100,000 people in Europe and
comprises less than 1 % of all breast cancers [1, 2]. Due to
the rarity of this neoplasm, it is hard to conduct prospective
clinical trials; therefore, the management strategies are
based on limited retrospective studies and clinical man-
agement of female breast cancer. According to ESMO and
NCCN guidelines, tamoxifen is the gold-standard adjuvant
endocrine therapy in male breast cancer and plays an im-
portant role in the metastatic setting [35]. On the other
hand, little is known about other endocrine therapies in
patients who were already exposed to tamoxifen.
Aromatase inhibitors (AIs) prevent the conversion of
androstendione to 17b-estradiol and are extensively used
postmenopausal women with breast cancer [36]. Although
the superiority of third-generation AIs (exemestane, anas-
trozole and letrozole) over tamoxifen in women has been
documented in several studies [79], the role of such
123

molecules remains elusive in male breast cancer patients. It
is also unknown whether the addition of gonadotropin-re-
leasing hormone (GnRH) analogues to AI would be a su-
perior strategy or not. GnRH are known to desensitize the
pituitary GnRH receptors resulting in a reduction of
luteinizing hormone (LH) and follicle-stimulating hormone
(FSH) as well as a fall in testicular testosterone and
estrogens, while the remaining estrogens, produced through
peripheral aromatization, may be blocked with AIs. Hence,
the combination strategy of AIs with GnRH analogues hold
promiseat least in theoryto improve clinical outcomes
in metastatic male breast cancer patients but this remains to
be demonstrated [1014].
In this manuscript, we report the first pooled analysis of
the literature synthesizing all available data coming from
case reports/case series and evaluating the efficacy and
safety of aromatase inhibitors in male breast cancer.
Materials and methods
Selection of studies and data abstraction
This pooled analysis was conducted according to the
PRISMA guidelines [15]. The protocol of this analysis has
been approved by the Institutional Review Board of
Alexandra Hospital, Medical School, National University
of Athens, Greece and is available upon request. Eligible
articles were sought in PUBMED from 1 January 1980 to
15 October 2014. The search strategy included the
following keywords: breast[ti] AND (neoplasms OR neo-
plasm OR cancer OR cancers OR carcinoma OR carcino-
mas) AND (aromatase inhibitors OR anastrozole OR by each eligible study (CR, PR and SD grouped together,
letrozole OR exemestane) AND (male[ti] OR men[ti]).
All reports or studies that examined the efficacy (re-
sponse and/or survival) of third-generation AIs (anastro-
zole, letrozole, exemestane) in metastatic male breast
cancer and reported data regarding efficacy, regardless of
sample size, were eligible for this pooled analysis. Studies
with AIs administration in male breast cancer patients
without reporting any data on efficacy were excluded from
this analysis. In this pooled analysis, in case of adminis-
tration of AI in different lines of treatments, only the first
administration of AI was considered eligible. Moreover,
the first time of co-administration of AI and GnRH ana-
logues, was considered eligible for this analysis, irrespec-
tively of administration of GnRH analogues or AI in a
previous line of treatment; in that case, the subjects were
censored at the moment of transition to the second treat-
ment (regarding the first treatment). Moreover, cases with
co-administration of AI with other chemotherapeutic
agents or hormonal manipulations other than GnRH ana-
logues were excluded from this analysis.
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Breast Cancer Res Treat
Only articles in English, German, Spanish and French
were considered eligible for this pooled analysis. Two in-
vestigators (FZ and DC), working independently and
blindly to each other, searched the literature and performed
data abstraction. Reviews were not eligible, while all
prospective and retrospective studies, as well as case re-
ports, were eligible for this pooled analysis. In addition, in
a snowball procedure we evaluated all references in
relevant reviews and eligible articles retrieved by our
search strategy, in an attempt to identify additional studies
and conference abstracts.
The following data were collected: first author, year of
publication, type of aromatase inhibitor, co-administration
of GnRH analogues, characteristics of patient population
(pathological type, initial stage, grade, ER, PR and HER2
status, ki-67), age (years), previous treatments (hormonal
treatment, chemotherapy), line of treatment, response
[complete response (CR), partial response (PR), stabiliza-
tion of the disease (SD), progression of the disease (PD)],
type of metastases (visceral, bone) median overall survival
(OS) in months, median progression-free survival (PFS) in
months and complications.
Quantitative synthesis and statistics
Regarding the quantitative synthesis (pooled analysis) of
the published studies, two sets of calculations were per-
formed. First, the descriptive statistics were calculated.
KaplanMeier survival curves were estimated for PFS and
OS, separately by the co-administration GnRH analogues or
not, for the graphical presentation of results. Second, factors
potentially associated with i. clinical benefit, as defined
versus PD), and ii. PFS and iii. OS were evaluated; to this
end, univariate logistic regression analyses and univariate
Cox regression analyses were performed, respectively. The
potentially prognostic factors that were examined were the
following: co-administration of GnRH analogues, type
of AI (exemestane vs. anastrozole/letrozole), age at AI
administration, lines of treatment, grade, initial stage at
diagnosis, HER2 status, PR status, adjuvant hormonal
treatment, adjuvant chemotherapy, visceral metastases and
bone metastases. In case of not estimable odds ratios, due to
the presence of a zero cell in the corresponding 2 9 2 table,
the p values were derived from Fishers exact test. In case of
not estimable hazard ratios, due to the occurrence of zero
events in an examined subgroup, the p-values were derived
from log-rank test, as appropriate.
The statistical analysis should be deemed explorative
given the questionable comparability of cases among the
various studies. Statistical analysis was performed with
STATA/SE 13 statistical software (StataCorp, College
Station, TX, USA).
Breast Cancer Res Treat

Abstracts identified and

screened
39

Irrelevant articles excluded

5
Reviews
13

Irrelevant articles excluded to

various reasons

(language restrictions: 1; AI
administered in the adjuvant
setting: 2; lack of data
pertaining to efficacy: 4;
aromatase inhibitors other
than these of the third
generation: 1
8 Articles retrieved through the
MEDLINE search
13
Conference abstracts / articles
retrieved as references of
relevant articles
2

Articles retrieved through the MEDLINE search + conference

abstracts
15
(102 patients individuals/ 105 cases)

Fig. 1 Stages of the search strategy

Results cases, 102 patients individuals as three patients were in-

The search strategy retrieved 39 articles. Among them, five
were irrelevant, 13 were reviews, eight were excluded due
to various reasons [2, 1622] (language restrictions [16],
AI administered in the adjuvant setting [2, 17], lack of data
pertaining to efficacy [1821], aromatase inhibitors other
than these of the third generation [22] ) and 13 were
eligible [10, 11, 2333] ). The snowball procedure
yielded two additional conference abstracts/articles that
were included [34, 35]. Of note, the case by Baumgartner
et al. [36], retrieved through the references of eligible ar-
ticles, was excluded from our analysis due to reporting
reasons as OS and PFS were not provided, while best re-
sponse was not clearly defined. Overall, 15 studies (105
cluded both at the AI group and AI plus analogue group)
were eligible for this pooled analysis (Suppl Tables 1, 2).
The aforementioned steps are illustrated in detail in Fig. 1.
The mean age of the study sample was 62.8 years (SD
10.0, median 63). The majority of cases (86.5 %) presented
with IDC, whereas 13.5 % presented with ILC. Stage at
initial diagnosis was as follows: stage I 13.5 %, II 32.4 %,
III 37.9 % and IV 16.2 %. Half of the cases had a grade 3
carcinoma (50 %), followed by grade 2 (44 %) and grade 1
(6 %). ER was positive in all eligible cases, PR was positive
in the vast majority of cases (94.7 %) and HER2 was
negative in 97.0 % of male breast cancer cases; the mean ki-
67 positivity percentage was 31.0 % (SD 13.5, median
30.0). Adjuvant hormonal treatment was administered in

123

Fig. 2 KaplanMeier survival estimate regarding progression-free
survival, by co-administration of GnRH analogue
Fig. 3 KaplanMeier survival estimate regarding overall survival, by
co-administration of GnRH analogue
67.2 % of cases where this information was provided. As far
as previously given adjuvant chemotherapy, 26.1 % of cases
had received anthracycline- and taxane-based chemotherapy;
18.5 % had received anthracycline-based chemotherapy;
4.6 % had received taxane-based chemotherapy; 16.9 % had
received other regimens, whereas the majority of cases
(33.9 %) had not received any adjuvant chemotherapy. In
one case, trastuzumab was co-administered with anastrozole
as maintenance therapy.
AI was given as first line therapy for metastatic disease
in 61.5 % of cases, as second line in 25.3 %, while as third
line or beyond in 13.2 % of cases. 77.8 % of cases at AI
administration had visceral metastases, whereas in 40.7 %
of them bone metastases existed; of note, in 12.3 % of the
total cases only bone metastases were present without the
presence of visceral metastases. Anastrozole or letrozole
was given in 85.2 % of cases, whereas exemestane was
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Breast Cancer Res Treat
Fig. 4 KaplanMeier survival estimate regarding progression-free
survival, by line of treatment
administered in 14.8 %. Of note, GnRH analogue was co-
administered with aromatase inhibitor in 37.1 % of cases
(n = 39).
Regarding best response, in 5.7 % of cases CR was
achieved, in 23.8 % PR was noted, in 37.2 % of cases SD
was recorded, whereas in 33.3 % PD was observed. The
median PFS was equal to 10.0 months, while the median
OS was equal to 39.0 months. KaplanMeier survival es-
timate regarding progression-free survival and overall
survival is depicted in Figs. 2, 3, and 4.
Table 1 presents the results of univariate logistic re-
gression and univariate Cox regression analyses regarding
clinical benefit, PFS and OS, respectively. Co-administra-
tion of GnRH analogues was associated with more than
threefold increase in rates of clinical benefit (OR = 3.37,
95 % CI 1.308.73, versus no administration of GnRH
analogues, Fig. 5) but did not seem to correlate with
better PFS (HR = 0.89, p = 0.740) or OS (HR = 0.75,
p = 0.563). No statistically significant associations between
the examined outcomes and type of AI, age at administration
of AI, lines of treatment, grade, initial stage at diagnosis,
HER2 status, PR status, adjuvant hormonal treatment, ad-
juvant chemotherapy, visceral metastases or bone metas-
tases were noted.
Discussion
Our results indicate that AIs represent an effective and
safe treatment option for HR-positive metastatic male
breast cancer patients, with a median progression-free
survival equal to 10 months. We found that co-adminis-
tration of GnRH analogues was associated with more than
threefold increase in clinical benefit rate, suggesting that
this combination seems to be potentially more effective
Breast Cancer Res Treat

Table 1 Results of univariate logistic regression (regarding clinical benefit) and univariate Cox regression (regarding factors associated with
PFS/OS) analyses
Parameters Category or increment Clinical benefit PFS OS
OR (95 % CI) p HR (95 % CI) p HR (95 % CI) p

Co-administration of GnRH Yes versus no 3.37 (1.30 0.012 0.89 0.740 0.75 0.563
analogues 8.73) (0.451.77) (0.281.99)
Type of AI Exemestane versus anastrozole/ 1.14 0.855 0.59 0.283 2.02 0.195
letrozole (0.284.67) (0.221.55) (0.705.84)
Age at administration of AI Cmedian versus \ median 1.75 0.266 1.70 0.163 1.10 0.847
(0.654.70) (0.813.60) (0.432.78)
Lines of treatment 2nd line or beyond versus 1st 0.87 0.791 1.19 0.622 1.09 0.854
line (0.322.37) (0.602.38) (0.452.65)
Grade Grade 3 versus grade 1/2 0.75 0.710 0.74 0.505 0.87 0.772
(0.163.41) (0.311.78) (0.342.21)
Initial stage at diagnosis Stage IV versus stage I/II/III 1.74 0.636 0.50 0.261 0.61 0.638
(0.1817.22) (0.151.67) (0.084.68)
HER2 status Positive versus negative Not estimable [0.999 1.51 0.690 Not estimable 0.725
(0.2011.54)
PR status Positive versus negative 4.14 0.335 0.35 0.168 0.17 0.148
(0.2374.70) (0.081.56) (0.021.88)
Adjuvant hormonal treatment Yes versus no 1.03 0.963 0.81 0.621 0.33 0.181
(0.303.49) (0.341.90) (0.061.68)
Adjuvant chemotherapy Yes versus no 1.42 0.567 1.33 0.511 1.87 0.552
(0.434.66) (0.573.10) (0.2414.67)
Visceral metastases Yes versus no 2.80 0.067 0.79 0.749 Not estimable 0.565
(0.938.44) (0.183.39)
Bone metastases Yes versus no 1.69 0.321 1.17 0.687 1.57 0.364
(0.604.75) (0.542.56) (0.594.15)
Bold cells denote statistically significant associations

p value derived from Fishers exact test; the OR was not estimable due to the presence of a zero cell in the corresponding 2 9 2 table

p value derived from log-rank test; the HR was not estimable due to the occurrence of zero events in an examined subgroup

In preclinical models, administration of AIs correlated

Fig. 5 Column chart showing the percentage (%) of response (PD,
SD, PR and CR) for patients in whom GnRH analogues were co-
administered with AIs (red columns) versus patients that did not
receive GnRH analogues (blue columns)
than AIs alone in metastatic male breast cancer patients; a
finding that has never been previously reported in the
literature.
with significant increase in the levels of FSH and testos-
terone, but not estradiol (E2) [13, 26]. However, in healthy
men, administration of AIs resulted in a significant re-
duction in E2 levels, along with an increase in FSH, LH,
and testosterone levels [14, 26]. Consequently, this in-
crease in testosterone levels may overcome aromatase in-
hibition, limiting the efficacy of AIs [2, 18]. Therefore, it
seems that the combination treatment of AIs with GnRH
analogues may maximize the effect of aromatase inhibi-
tion. In our analysis, despite the threefold increase in rates
of clinical benefit, no significance difference in OS and
PFS was observed between cases of AIs and cases with co-
administration of GnRH analogues; the lack of statistical
significance was due to the limited number of cases with
data regarding PFS and OS as only a subset of eligible
studies reported on survival.
Of note, hormonal treatment seems to represent the
cornerstone of therapy for metastatic male breast cancer,
taking into consideration that breast cancer in men exhibit

123

a high rate of hormone receptor positivity. According to
our pooled analysis, it is interesting enough that AIs seem
to remain a reliable treatment option for male patients
beyond the first line. Currently, tamoxifen is the most ex-
tensively used hormonal therapy for male breast cancer,
despite the fact that results stem from relatively small
retrospective studies [18, 37]; other medical hormonal
manipulations are androgens, steroids, antiandrogens, pro-
gestins and estrogens [3840]. Moreover, the use of ful-
vestrant in male breast cancer is safe, with promising
efficacy data; however, further clinical and pharmacoki-
netic investigations are warranted before its use becomes a
common practice [41, 42].
Concerning the limitations of this study, one cannot ig-
nore that this pooled analysis was confined to case series/-
case reports, a fact that might have biassed our findings.
More specifically, case series are often not published unless
there is an adverse event or an interesting outcome that is
surprising to the clinician; hence, a firm conclusion cannot
be drawn. Therefore, expanding beyond the 105 reported
cases of AIs administration that were included in our study,
so as to look on a larger scale, seems to be important. Of
note, a large registry project currently ongoing by the
EORTC is gathering medical information and tumour sam-
ples from male breast cancer patients (www.clinicaltrials.
gov; ID: NCT01101425). Moreover, prospective investiga-
tion of this treatment option is needed to draw definitive
conclusions; the data of a phase II trial in metastatic male
breast cancer patients, in which goserelin is given in com-
bination with anastrozole, are awaited with interest (SWOG-
S0511 trial; www.clinicaltrilas.gov; ID: NCT00217659).
In conclusion, available data suggest that AIs may po-
tentially play a promising role in the optimal therapeutic
strategy for metastatic male patients with breast cancer di-
agnosis. Especially, co-administration of AI with a GnRH
analogue seems to increase the rate of clinical benefit and
could be more effective, warranting further consideration.
Conflict of interest The authors have declared no conflicts of
interest.
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