Di Lauro et al. Journal of Hematology & Oncology (2015) 8:53 DOI 10.1186/s13045-015-0147-z JOURNAL OF HEMATOLOGY & ONCOLOGY RESEARCH ARTICLE Open Access Role of gonadotropin-releasing hormone analogues in metastatic male breast cancer: results from a pooled analysis Luigi Di Lauro1, Laura Pizzuti1, Maddalena Barba1,2, Domenico Sergi1, Isabella Sperduti3, Marcella Mottolese4, Carla Azzurra Amoreo4, Franca Belli5, Patrizia Vici1, Valerie Speirs6, Daniele Santini7, Ruggero De Maria2 and Marcello Maugeri-Saccà1,2* Abstract Background: Male breast cancer is a rare malignancy. Despite the lack of prospectively generated data from trials in either the adjuvant or metastatic setting, patients are commonly treated with hormone therapies. Much controversy exists over the use of gonadotropin-releasing hormone analogues in metastatic male breast cancer patients. We conducted this study to provide more concrete ground on the use of gonadotropin-releasing hormone analogues in this setting. Methods: We herein present results from a pooled analysis including 60 metastatic male breast cancer patients treated with either an aromatase inhibitor or cyproterone acetate as a monotherapy (23 patients) or combined with a gonadotropin-releasing hormone analogue (37 patients). Results: Overall response rate was 43.5 % in patients treated with monotherapy and 51.3 % with combination therapy (p = 0.6). Survival outcomes favored combination therapy in terms of median progression-free survival (11.6 months versus 6 months; p = 0.05), 1-year progression-free survival rate (43.2 % versus 21.7 %; p = 0.05), median overall survival (29.7 months versus 22 months; p = 0.05), and 2-year survival rate (64.9 % versus 43.5 %; p =0.05). Conclusions: In metastatic male breast cancer patients, the combined use of gonadotropin-releasing hormone analogues and aromatase inhibitors or antiandrogens seems to be associated with greater efficacy, particularly in terms of survival outcomes, compared with monotherapy. Collectively, these results encourage considering these agents in the metastatic setting. Keywords: Male breast cancer, Metastatic disease, Gonadotropin-releasing hormone analogue, Aromatase inhibitors, Cyproterone acetate Background that 92 % of MBC cases were estrogen receptor-positive Male breast cancer (MBC) is an uncommon malignancy [4]. Thus, antiestrogen therapy currently represents the accounting for less than 1 % of all breast cancer (BC) mainstay of treatment for these patients, even though cases [1], albeit its incidence is rising [2]. The hormone- the use of tamoxifen [5], aromatase inhibitors (AIs) driven nature of the disease was postulated in the 1940s [6–8], and fulvestrant [9, 10] was investigated only retro- [2] and corroborated over the past decades by studies spectively in small-sized cohorts. A therapeutic role for reporting on hormone receptor expression [3, 4]. Results the androgen receptor (AR) was also envisioned [11–13] from the National Cancer Institute’s Surveillance, Epi- and corroborated by immunohistochemical analysis and demiology, and End Results (SEER) database revealed gene-expression-profiling studies [3, 14]. Analysis of a large MBC cohort documented AR immunoreactivity in * Correspondence: [email protected] 64 % of cases [3], and over-expression of AR-related 1Division of Medical Oncology B, “Regina Elena” National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy pathway components was reported [14]. 2Scientific Direction, “Regina Elena” National Cancer Institute, Via Elio Chianesi Despite the wealth of hormonal treatments that have 53, 00144 Rome, Italy entered the therapeutic arena, owing to the rarity of this Full list of author information is available at the end of the article © 2015 Di Lauro et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Di Lauro et al. Journal of Hematology & Oncology (2015) 8:53 Page 2 of 5 disease and lack of prospectively generated data, a num- Patients’ characteristics are illustrated in Table 1. As ber of unsolved questions afflict daily clinical practice. A showninTable1,thegroupscompareddidnotdifferby heated argument surrounds the question of whether any of the variables considered. Overall, 37 patients re- gonadotropin-releasing hormone analogues (GnRH ana- ceived GnRH analogue-containing therapy (22 patients logues) are worth being administered in combination with CPA and 15 patients with an AI), and 23 patients with other hormonal treatments acting on peripheral were treated with GnRH analogue-free therapy (14 patients targets [7, 8, 13]. This controversy was fuelled by the ad- with CPA and 9 patients with an AI). vent of AIs [15]. In males, AIs lead to increased levels of follicle-stimulating hormone (FSH), luteinising hormone (LH), and testosterone (T) [16–20]. This phenomenon Table 1 Association between clinical-pathological features and was observed in hypogonadal men and MBC patients treatment received (N = 60) [16–20]. For MBC patients, implications of increased T Characteristic With GnRH N (%) Without GnRH N (%) p value* levels are twofold: i) the counteraction of the block im- Age posed by AIs through an excess of substrate and ii) a dir- Median 64 63 0.79 ect stimulation of cancer cells equipped with the AR [21]. Range 24–82 29–76 Briefly, the inhibition of the hypothalamic-pituitary feed- back loop, with the correlated reduction of the substrate ECOG PS for aromatization, was the rationale for combining AIs Median 1 1 0.88 with GnRH analogues. A second, though underestimated, Range 0–20–2 association strategy relates to the use of GnRH analogues Hormone receptor with antiandrogens [12, 13]. Our group reported on the status antitumor activity of antiandrogens [11, 12], a finding we Positive 32 (86.5) 19 (82.6) 0.99 recently strengthened in a larger series where hints on the Negative 2 (5.5) 2 (8.7) existence of an association between AR expression and Unknown 3 (8) 2 (8.7) clinical outcomes were also provided [13]. In this case, the Adjuvant systemic use of antiandrogens with a GnRH analogue stemmed therapy from the need to neutralize testicular and adrenal andro- Yes 19 (51) 10 (43.5) 0.60 gens, theorizing analogies in terms of androgen depend- ency between MBC and prostate cancer [13]. Indeed, our No 18 (49) 13 (56.5) group already reported on the suppression of gonadotro- Prior therapy for metastatic disease pins together with T suppression to castration levels in MBC patients who received cyproterone acetate (CPA) Yes 9 (24) 7 (30.5) 0.99 with buserelin [12]. These effects were also observed, al- No 28 (76) 16 (69.5) though to a lower extent, with CPA monotherapy [11]. Subsequent lines of Therefore, there is a common theme underlying the use of CT GnRH analogue with antiandrogens and AIs, namely, achiev- Median 1 1 0.72 ing the deepest possible T suppression to directly or indir- Range 1–21–2 ectly deprive cancer cells of a source of oncogenic stimuli, in Subsequent lines of the latter case by preventing the conversion of androstene- HT dione to 17b-estradiol operated by the aromatase enzyme. Median 1 1 0.85 By evaluating metastatic MBC (mMBC) treated with an Range 1–31–3 AI or CPA [8, 13], administered alone or combined with a GnRH analogue, we previously noted some differences fa- Dominant disease site voring the association. Nevertheless, the relatively re- Viscera 24 (64.9) 14 (60.8) stricted number of patients analyzed hindered statistically Bone 9 (24.3) 8 (34.8) 0.98 significant comparisons. Prompted by this observation, we Soft-tissue 4 (10.8) 1 (4.4) herein present results from a pooled analysis of these stud- Number of disease ies, with the inclusion of five additional patients, in order sites to gain more insights into the efficacy of GnRH analogue- 1 11 (29.7) 10 (43.4) containing hormonal therapy in mMBC patients. 2 21 (56.7) 9 (39.1) 0.99 ≥ 3 5 (13.6) 4 (17.5) Results ECOG PS: Eastern Cooperative Oncology Group Performance Status; CT: Sixty men mostly treated in the first-line metastatic setting chemotherapy; HT: hormone therapy were included in the present analysis. *Fisher exact test Di Lauro et al. Journal of Hematology & Oncology (2015) 8:53 Page 3 of 5 Stage at diagnosis was I, II, III, and IV in 11 (18.3 %), treated with monotherapy (p = 0.05) (Fig. 1). One-year 20 (33.3 %), 21 (35 %), and 8 (13.4 %) patients, respect- progression-free survival (PFS) rate also favored combin- ively. Stage I–II at diagnosis was 48 % in the monother- ation (43.2 % versus 21.7 %; p =0.05).Medianoverallsur- apy group and 52 % in the combination group. Overall, vival (mOS) was 29.7 months with combination (95 % CI = 29 patients received adjuvant systemic therapy, 10 in the 20.4–39) and 22 months (95 % CI = 15.9–28.1) with mono- monotherapy group (43.5 %) and 19 in the combination therapy (p = 0.05) (Fig. 1). Two-year survival rate was group (51 %). In the adjuvant setting, ten patients were 64.9 % in the combination group versus 43.5 % in the treated with chemotherapy, ten patients with hormone monotherapy group (p = 0.05). therapy, and nine patients with both chemotherapy and hormone therapy. Adjuvant hormone therapy consisted of tamoxifen in all but one patient who received goserelin. Discussion Adjuvant chemotherapy consisted of cyclophosphamide, Evidence on the therapeutic role of GnRH analogue as a methotrexate, and 5-fluorouracil (CMF) in 11 patients; partner for other hormonal agents in mMBC are scat- 5-fluorouracil, doxorubicin, and cyclophosphamide or tered, gathered from case reports or small retrospective 5-fluorouracil, epirubicin, and cyclophosphamide (FAC or series, and overall inconsistent [7, 8, 13, 15].