CLINICAL TRIAL

Letrozole combined with gonadotropin-releasing hormone analogfor metastatic male breast cancer

Luigi Di Lauro • Patrizia Vici • Pietro Del Medico • Lucio Laudadio •

Silverio Tomao • Diana Giannarelli • Laura Pizzuti • Domenico Sergi •

Maddalena Barba • Marcello Maugeri-Sacca

Received: 15 August 2013 / Accepted: 17 August 2013 / Published online: 28 August 2013

� Springer Science+Business Media New York 2013

Abstract The role of aromatase inhibitors combined with

gonadotropin-releasing hormone analog in metastatic male

breast cancer patients remains unknown. In this retrospec-

tive study we evaluated the activity of letrozole combined

with a gonadotropin-releasing hormone analog as a first- or

second-line therapy for metastatic male breast cancer

patients. 19 men entered the study. We did not observe any

grade 3 or 4 adverse events. 2 patients (10.5 %) had com-

plete response, 7 patients (36.8 %) experienced a partial

response, 7 patients (36.8 %) had stable disease lasting

C6 months, and 3 patients (15.8 %) had progressive disease.

Overall, the disease control rate was 84.2 %. Median pro-

gression-free survival was 12.5 months (95 % CI 8.2–16.9),

median overall survival was 35.8 months (95 % CI

24.4–49.2), 1- and 2-year survival rates were 89.5 and 67 %,

respectively. Interestingly, 3 out of 4 patients treated with

the combination following disease progression while on

aromatase inhibitor monotherapy confirmed or improved the

best overall response observed in the first-line setting. The

combination of letrozole and gonadotropin-releasing hor-

mone analog is effective and safe in hormone-receptor

positive, metastatic male breast cancer patients.

Keywords Male breast cancer �Metastatic disease �Endocrine therapy � Letrozole � Gonadotropin-

releasing hormone analog

Introduction

Male breast cancer (MBC) accounts for approximately 1 %

of all breast cancer (BC) cases [1]. The estrogen-driven

nature of this disease is suggested by both clinical and

molecular evidence. A correlation exists between condi-

tions characterized by an excess of estrogen (e.g., obesity

and Klinefelter’s syndrome) and MBC [2]. Furthermore, a

recent study revealed gender-related molecular differences

in BC. Two subgroups of MBC have been identified,

defined as Luminal M1 and M2, significantly differing

from the female counterpart and mirroring an extreme

reliance on hormonal stimuli [3]. These results are con-

sistent with the National Cancer Institute’s Surveillance,

Epidemiology, and End Results database, in which 92 %

male BCs were estrogen receptor (ER)-positive, compared

to 78 % of ER-positive female BCs [4].

The rarity of this disease results in a paucity of data

about optimal medical treatment, which is substantially

extrapolated from trials conducted in female patients. A

L. Di Lauro � P. Vici � L. Pizzuti � D. Sergi � M. Barba �M. Maugeri-Sacca (&)

Division of Medical Oncology B, ‘‘Regina Elena’’ National

Cancer Institute, Via Elio Chianesi 53, 00154 Rome, Italy

e-mail: maugeri.marcello@gmail.com

P. Del Medico

Division of Medical Oncology, Reggio Calabria General

Hospital, Reggio, Italy

L. Laudadio

Division of Medical Oncology, Renzetti Hospital, Lanciano,

Italy

S. Tomao

Oncology Unit, Department of Medico-Surgical Sciences and

Biotechnologies, ‘‘Sapienza’’ University of Rome, Latina, Italy

D. Giannarelli

Division of Biostatistics, ‘‘Regina Elena’’ National Cancer

Institute, Rome, Italy

M. Maugeri-Sacca

Scientific Direction, ‘‘Regina Elena’’ National Cancer Institute,

Rome, Italy

123

Breast Cancer Res Treat (2013) 141:119–123

DOI 10.1007/s10549-013-2675-y

substantial exception is represented by hormonal therapy.

While aromatase inhibitors (AIs) are the gold standard

endocrine therapy in both the adjuvant and metastatic

setting in post-menopausal women [5], evidence of their

therapeutic potential in MBC remains largely elusive.

Consistently, tamoxifen represents the standard adjuvant

therapy for MBC patients, having demonstrated superiority

over AIs in this setting [6], and it is widely used in the

metastatic disease [2].

The different hormonal milieu in men compared to age-

matched women should be considered in order to optimize

endocrine manipulations for metastatic MBC patients.

Estradiol (E2) levels are significantly higher in older males

than in post-menopausal females [2], and an age-associated

increase in aromatase activity is well documented in males

[7]. Furthermore, approximately 20 % of circulating estro-

gens in men is directly secreted by testicles [8], thus pro-

viding a direct source of oncogenic stimuli. Furthermore, in

healthy men the administration of AIs led to a significant

decrease in E2 levels, coupled with increased levels of fol-

licle-stimulating hormone (FSH), luteinising hormone (LH),

and testosterone (T) [9, 10]. Such feedback loop increases T

levels, which may counteract the effects of AIs by feeding its

enzymatic conversion with an excess of substrate.

Therefore, we hypothesized that maximizing hormonal

suppression might be required to achieve a significant

antitumor activity. To this end, we retrospectively evalu-

ated the activity of a gonadotropin-releasing hormone

(GnRH) analog with letrozole for metastatic MBC patients

in order to explore the therapeutic potential of ‘‘complete

estrogen blockade.’’

Patients and methods

The study population was composed by metastatic MBC

patients who received a GnRH analog in association with

letrozole as a first- or second-line therapy. Patients have been

treated at four Italian oncologic centers between 2000 and

2012. The majority of patients was selected from the

‘‘Regina Elena’’ National Cancer Institute, Rome. Medical

records were reviewed in order to obtain information about

demography, molecular pathology, treatment received, and

outcomes. All patients have been treated with a GnRH ana-

log (leuprolide acetate or triptorelin acetate given intra-

muscularly at 3.75 mg every 28 days), in association with

letrozole 2.5 mg orally daily. Treatment was continued until

disease progression or unacceptable toxicity. Exclusion

criteria included previous history of AIs administered as

adjuvant therapy, negative or unknown ER status, absence of

measurable or assessable non-measurable lesions, and con-

comitant administration of chemotherapy or HER2-targeted

agents. Toxicity was graded according to the National

Cancer Institute-Common Toxicity Criteria version 4.0

(NCI-CTC v. 4.0). Tumor response was evaluated according

to the response evaluation criteria for solid tumors (RECIST

1.1). Progression-free survival (PFS) and overall survival

(OS) were calculated from the date of therapy initiation to the

date of disease progression, refusal of treatment, death from

any cause or last follow-up evaluation, respectively. PFS and

OS were analyzed according to the Kaplan–Meier method.

All statistical analyses have been performed using SPSS

statistical software version 20 (SPSS inc., Chicago, IL,

USA). This retrospective study was approved by the Ethic

Committee of ‘‘Regina Elena’’ National Cancer Institute of

Rome, the coordinating center, and was carried out accord-

ing to the Helsinki Declaration. A written informed consent

was obtained from all the enrolled patients.

Results

Nineteen men with a median age of 66 years (range, 45–75)

were included in this study. Patients’ characteristics and

response to treatment are illustrated in Table 1. Only 1

patient was diagnosed with metastatic disease at first pre-

sentation. 18 (95 %) patients were diagnosed with invasive

ductal carcinoma, whereas 1 patient (5 %) presented with

invasive papillary carcinoma. The majority of tumors were

grade 2 (58 %) or 3 (37 %), whereas one tumor was grade 1

(5 %). All tumors were ER-positive (100 %), 17 tumors

were progesterone receptor positive (89.5 %), whereas the

HER2 status was negative in 14 tumors and unknown in 5

patients. All patients had undergone modified radical mas-

tectomy. Regarding adjuvant treatments, 13 patients

received adjuvant radiotherapy (68.5 %), eight sequential

chemo- and hormone therapy (42 %), four hormone therapy

(21 %), and three chemotherapy (16 %). 11 out of 12

patients treated with adjuvant endocrine therapy received

tamoxifen. Adjuvant chemotherapeutic regimens included

cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)

in 4 patients; 5-fluorouracil, epirubicin, and cyclophospha-

mide (FEC) in 4 patients; or sequential epirubicin/cyclo-

phosphamide followed by docetaxel (EC-D) in 3 patients. 17

patients had visceral metastases (89.5 %), in 9 of them

coexisted bone metastatic disease. None of them had brain

metastases. Most of patients had two or more metastatic sites

(89.5 %). 14 patients were treated as first-line (74 %), the

remaining 5 patients as second-line (26 %). Among patients

treated with the combination as second-line, two had pre-

viously received letrozole, one exemestane, one anastrozole,

and one tamoxifen in the first-line setting. Therefore, a

GnRH analog was introduced following tumor progression

in 4 patients receiving front-line AIs.

Overall, treatment was well tolerated, and we did not

observe any grade 3 or 4 adverse events. Regarding best

120 Breast Cancer Res Treat (2013) 141:119–123

123

response, complete response (CR) was documented in 2

patients (10.5 %), partial response (PR) was observed in 7

patients (36.8 %), for an overall response rate of 47.3 %

(95 % CI 25–69.6). Stable disease (SD) lasting C6 months

was reported in 7 patients (36.8 %), translating into an

84.2 % of disease control rate (DCR). Progressive disease

(PD) was reported in 3 patients (15.8 %). DCR among men

who received the combination as first-line therapy was

85.7 %. When a GnRH analog was added after progression

while on AIs, 2 patients with a PR or SD as best overall

response with letrozole in first-line experienced comparable

outcome in second-line, whereas 1 patient with SD during

exemestane experienced a PR with letrozole plus a GnRH

analog. Finally, 1 patient with PD on anastrozole treatment

did not respond to combination therapy. Overall, median

PFS was 12.5 months (95 % CI 8.2–16.9), median OS was

35.8 months (95 % CI 24.4–49.2). 1- and 2-year survival

rates were 89.5 and 67 %, respectively. Corresponding

Kaplan–Meier survival estimates are reported in Fig. 1.

Discussion

In the present study, the largest series reported so far, we

evaluated the efficacy of a GnRH analog with letrozole in

19 MBC patients with metastatic disease. We observed an

Table 1 Description of the study sample and response to treatment

Patient Age

(years)

ER/PGR (%) Histologic

grade

RT adj CT adj HT adj Metastases First-line HT Best

response

1 73 95/0 2 No CMF Goserelin Lung – PR

2 69 90/70 3 Yes CMF – Liver, nodes – SD

3 60 60/50 3 No – – Nodes, skin – PR

4 49 100/85 2 No – TAM Liver, bone, nodes – PR

5 58 70/80 2 Yes FEC TAM Liver, nodes Exemestane (SD) PR

6 62 80/70 3 Yes – TAM Lung Anastrozole (PD) PD

7 66 85/80 2 Yes FEC TAM Liver, lung, skin Letrozole (PR) PR

8 72 80/80 2 Yes CMF – Lung, bone Letrozole (SD) SD

9 66 90/75 2 No CMF TAM Liver, bone – PD

10 75 100/100 2 No – TAM Lung, bone – CR

11 59 80/75 3 Yes FEC TAM Lung, bone – SD

12 66 90/85 1 Yes – – Liver, skin – SD

13 70 90/90 2 Yes – – Lung, bone – SD

14 68 80/70 3 Yes EC-D TAM Lung, bone, nodes – SD

15 51 70/60 2 Yes FEC TAM Bone, nodes – PR

16 62 50/0 3 No EC-D – Lung, nodes – PD

17 69 80/80 2 Yes – TAM Liver, bone – PR

18 65 90/80 2 Yes – – Liver, bone, nodes TAM (RP) SD

19 45 60/60 3 Yes EC-D TAM Liver, skin – CR

ER estrogen receptor, PGR progesterone receptor, RT radiotherapy, CT chemotherapy, HT hormone therapy, C cyclophosphamide, D docetaxel,

E epirubicin, F 5-fluorouracil, M methotrexate, TAM tamoxifen, CR complete response, PR partial response, SD stable disease, PD progressive

disease

Fig. 1 Kaplan–Meier survival

curves regarding: a PFS and

b OS

Breast Cancer Res Treat (2013) 141:119–123 121

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84.2 % of DCR, and 47.3 % of patients experienced CR/

PR.

In the last decade, novel endocrine therapies enriched

the therapeutic armamentarium for treating female BC.

Taking into account that BC arising in men is more likely

to be hormone-receptor positive than the female counter-

part [4], understanding how such new standards can be

applied to MBC is of utmost importance. Furthermore,

gene expression profile performed to compare ER-positive

male versus female BC revealed gender-related molecular

differences [11]. About 1,000 genes were differentially

regulated, resulting in different deregulated modules that

also included hormone-receptor pathways.

First attempts of manipulating the hormonal milieu

were based on surgical ablative procedures such as

orchiectomy, adrenalectomy, and hypophysectomy [12].

Even though these techniques have been associated with

overall response rates of [50 %, they have been replaced

by more acceptable medical hormonal treatment (andro-

gens, antiandrogens, steroids, estrogens, progestins) [13–

16]. In the current therapeutic scenario tamoxifen is the

mainstay of treatment, having gained widespread accep-

tance as a result of both small retrospective studies con-

ducted in the metastatic disease [13, 16], and the

superiority over AIs in the adjuvant setting [6]. Never-

theless, the success of AIs in female BC and the bio-

logical observation of intratumoural aromatase expression

in MBC prompted the evaluation of these agents in

metastatic MBC patients [5, 17]. However, until recently

the efficacy of AIs remained largely anecdotic. In 2010,

Doyen and coworkers [18] reported results from 15

patients, documenting a 53 % of DCR. Even though the

small, retrospective nature of this study and the hetero-

geneity of treatment administered (anastrozole, letrozole,

or exemestane) should be considered, investigators pro-

vided initial hints about both their activity and the ther-

apeutic relevance of inhibiting the hormonal feedback

loop. Consistently, while the efficacy of AIs was corre-

lated with a significant reduction of E2 levels, one patient

who experienced a PR presented with increased levels of

E2, LH, and FSH at tumor progression. The concept of

inhibiting the feedback loop and the correlated excess of

substrate for aromatization is further strengthened by

preclinical studies, in which prolonged administration of

AIs in animal models led to increases in FSH and T [19].

The logic behind our study was to evaluate the thera-

peutic potential of AIs in association with a GnRH analog

administered for suppressing the hypothalamic-pituitary

feedback loop. Giordano and Hortobagyi [20] first reported

two PRs in two metastatic MBC patients combining the

GnRH analog leuprolide acetate with anastrozole or le-

trozole, respectively. Recently, Zagouri and colleagues

[21] presented results from a retrospective series of 23 men

with metastatic BC who received an AI as first- or second-

line, either alone (n:6) or in combination with a GnRH

analog (n:17). Investigators reported a DCR of 82.3 %, a

median PFS of 13 months, and a median OS of 39 months.

However, they did not note better outcomes in patients

receiving the combination compared with patients treated

with AIs alone. In our study, which is comparable for size

and setting, we reported similar PFS (12.5 months) and OS

(35.8 months). Regarding the association we noted a

comparable DCR (84.2 vs. 82.4 %), which slightly

increased when considering the first-line setting (85.7 %),

and a significantly higher rate of responses (47.3 vs.

17.7 %). Interestingly, our study raised the hypothesis that

adding a GnRH analog following disease progression while

on AI therapy might be considered. Accordingly, 3 out of 4

patients treated with such sequential approach confirmed

(n:2) or improved (n:1) the best overall response observed

in the first-line. Furthermore, our study has the advantage

of an homogenous treatment, as all patients received le-

trozole. A previous series of 5 patients treated with AIs did

not report objective response to anastrozole [22], whereas

three individual cases of response to letrozole have been

reported [23–25]. However, we are aware that the study of

Doyen et al. [18], in which an equal number of patients

were treated with the same AI, did not report any appre-

ciable drug-related difference. Although no firm conclusion

can be drawn from this retrospective study, we believe that

our results may be beneficial for optimizing the medical

management of these patients. In MBC, the SWOG-S0511,

a phase II study envisioning the use of goserelin combined

with anastrozole, closed prematurely due to poor accrual

(ClinicalTrials.gov; ID: NCT00217659). Considering the

intrinsic difficult of conducting prospective clinical trials in

a rare disease, accumulating data is essential for widening

the spectrum of therapeutic opportunities. Data herein

presented suggest that letrozole in combination with a

GnRH analog represents an effective and safe treatment

option for hormone-receptor positive, metastatic MBC

patients. Apparently, the combination offers higher anti-

tumor activity compared with the monotherapy with an AI,

especially when administered as front-line. Until data from

prospective trials or large case series will not be available,

we believe that the choice of single versus dual hormonal

therapy, and eventually concomitant versus sequential

strategy, should be tailored on individual patients’ needs,

disease extension, and evolution.

Acknowledgments The authors thank Tania Merlino and Giuseppe

Loreto for technical assistance.

Conflict of interest The authors declare that they have no conflict

of interest.

122 Breast Cancer Res Treat (2013) 141:119–123

123

Ethical standards This study was approved by the Ethic Com-

mittee of ‘‘Regina Elena’’ National Cancer Institute of Rome and was

carried out according to the Helsinki Declaration. A written informed

consent was obtained from all the enrolled patients.

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