Because of the anatomy of the male breast and the frequent dysfunction of the male psyche there is often delay in presentation with consequent upstaging of MBC. The extent of the problem is shown in Table 10.1 which gives a breakdown of stage at diagnosis in the larger MBC series which have included all-comers [1–6]. The proportion of stage III/IV cases was between 32% and 79% indicating the large burden of advanced MBC. There was no evidence of a trend towards down-staging with time so that, at present, palliative treatment is being offered to the majority of men with advanced and metastatic male breast cancer (mMBC).

Because these cases were managed by surgeons, the initial hormonal therapies were ablative: orchidectomy, adrenalectomy, and hypophysectomy. In 1942 Farrow and Adair reported that a male with bone metastases responded to orchidectomy so this intervention became the standard of care for treatment of advanced disease [7]. The psychological impact of orchidectomy on a man who had already been diagnosed with what he believed to be a female disease has not been documented but is unlikely to have been very positive. Treves wrote “The acquiescence to orchiectomy seems to us to be a triumph of medical persuasion” [8] Bezwoda reported that orchidectomy was refused by 8/14 (57%) of men to whom it was offered [9]. Nevertheless castration was regarded as the treatment of choice for advanced/metastatic MBC and in studies reporting the results of orchidectomy overall, there was a 56% response rate, as summarised in Table 10.2 [8, 10–19]. It was not until 1977 however that the International Union against Cancer (UICC) outlined objective criteria for establishing response so that prior to this there was little uniformity in reporting outcomes of treatment.

The advent of cortisone meant that it was feasible to perform bilateral adrenalectomies without killing the patient. Only relatively few men have treated in this way but the some of the publications were written by famous mid twentieth century surgeons including Charles Huggins and Sir Stanford Cade. In 1952, Huggins reported the effect of adrenalectomy in an MBC case who had relapsed with lung metastases after orchidectomy [20]. Following bilateral adrenalectomies there was remission of disease. Subsequent publications are summarised in Table 10.3 which indicates the small numbers of cases with the largest series of 10 MBC reported by Patel et al. [10, 16, 19–30]. These historical results suggest that adrenalectomy was more likely than not to achieve a response in mMBC.

If the data on response rates after adrenalectomy is sparse that relating to the effect of hypophysectomy is miniscule. None of the published series comprised more than 2 cases as is shown in Table 10.4 [10, 17, 31–35]. With the exception of the report by Luff, there was no evidence of response to hypophysectomy. Associated morbidity included diabetes insipidus, cerebrospinal fluid leakage, operative haemorrhage and meningitis

Because of these concerns about morbidity and lack of efficacy, additive rather than ablative hormonal therapies were introduced. These included high dose estrogens, progestins, antiandrogens, androgens, corticosteroids, and aminoglutethimide.

In 1944 Alexander Haddow and associates reported a series of 22 patients with advanced breast cancer treated with the synthetic estrogen triphenylchlorethylene [36]. One case was a 54 year old male who had been treated with a radical mastectomy and radiotherapy but relapsed with skin and bone metastases. He was treated with 3 grams daily of triphenylchlorethylene for 3 months and the chest wall recurrences disappeared but he died after 6 months. Huguenin used the synthetic estrogen hexoestrol to treat 2 MBC cases and both responded [37]. Treves treated 13 advanced MBC cases with a variety of estrogens, (stilboestrol, ethinylestradiol and estradiol) with a response in 2 cases given ethinylestradiol [8].

A very encouraging result of stilboestrol therapy was reported by Ogilvie who described a 66 year old male who presented with a 25 cm fungating left breast cancer [38]. Treatment was started with 60 mg daily subsequently reduced to 15 mg daily. After 7 months there was a 9 x 20 cm indurated mass. This remained unchanged for 6 years with the patient being fit and well and still working. Reporting a series of 28 MBC cases, Donegan reported that there were 3 responses in the five men treated with oestrogens ( 4 stilboestrol 1 dienestrol) [11].

In a comparatively large series of 58 MBC cases with recurrent or advanced disease, Ribeiro used diethylstilboestrol and reported that of the 55 assessable cases there was an objective response in 14 and a partial response in 7 so that overall, the response rate was 38% [15]. Kraybill et al. administered stilboestrol to 2 cases of MBC, one of whom had failed to respond to provera and another who had responded but relapsed and this achieved a response for 4 and 14 months respectively [17]. Lopez et al. also used stilboestrol to treat 2 men with advanced MBC and obtained long remissions of 20 and 33 months [39]. Bezwoda reported that all the MBC patients given stilboestrol developed gynaecomastia and fluid retention [9]. Furthermore two had thromboembolism and another two developed cardiac failure. Such side-effects together with the emergence of less toxic endocrine therapies led to the gradual discontinuation of estrogen therapy for MBC (Table 10.5).

Cyproterone acetate (CPA) is a steroidal antiandrogen with progestogenic and antigonadotropin properties. It acts by blocking the androgen receptor thereby inhibiting synthesis of androgens. As such it represents a possible alternative to orchidectomy. Lopez et al. treated 10 men who had recurrent/advanced MBC with CPA 100 mg twice daily [40]. Using UICC response criteria they reported that 7 (70%) responded for a median duration of 8 months (Table 10.6).

Flutamide is a non-steroidal anti-androgen which competitively blocks the androgen receptor. Doberauer used a combination of the gnRH analogue buserelin as a nasal spray and flutamide tablets 250 mg thrice daily to treat 5 men with advanced MBC [41]. There were 4 partial remissions lasting for a median of 15 months.

Di Lauro et al. treated 36 metastatic MBC cases with either CPA alone (14) or in combination with a gnRH analogue (22) [42]. The overall response rate was 53% and there were 4 complete responses and 15 partial responders. No response was seen in the 3 men whose tumours did not have androgen receptors.

Progestins have been used often as second or third-line treatment. In 1961 Geller et al. reported an objective tumour response in a male with metastatic disease who was treated with delalutin (17-alpha hydroxy progesterone caproate) [43]. Results of treatment with medroxyprogesterone acetate (MPA) and megestrol show great variation, probably because of different sequences of administration so that any potential effects may have been lost as a result of prior systemic therapy. Kraybill et al. used MPA as first-line treatment of mMBC in 3 men refusing orchidectomy and reported responses in 2, lasting for 3 and 10 months [17].

Lopez et al. administered synchronous chemotherapy (cyclophosphamide, methotrexate and vincristine CMFV to a 55 year-old with lung metastases with no response being observed [39]. A second 67 year old with bone metastases was treated with CMF and MPA which led to a partial response. Bezwoda used MPA as second line treatment in 8 cases and 3 responded, all of whom had previously received tamoxifen with some benefit [9]. Duration of response was between 4 and 7 months. After treatment with palliative CMF, in a patient with soft tissue and bone metastases Doberauer et al. administered MPA but unfortunately the disease progressed. Karakuzu et al. reported a 58-year-old who had rapidly progressive skin metastases from MBC and had previously received FAC and tamoxifen [44]. They used a combination of megestrol and external beam radiotherapy but were unable to control the disease. As salvage therapy in previously treated mMBC there appears to be little benefit from using progestins (Table 10.7).

There are anecdotal reports of responses in mMBC using various androgens but these may be examples of publication bias. Donegan used fluoxymesterone (halotestin) in a 72-year old man who had relapsed with chest wall disease 7 months after radical mastectomy [11]. This achieved a partial response which lasted for 16 months. Horn and Roof reported 2 men who had relapsed after orchidectomy and were then given 7α, 17β-dimethyltestosterone (Calusterone) [45]. Both showed a response of bone and lung metastases for 5 months and 7 months. Reporting results from MD Anderson Hospital, Kantarjian et al. used androgens, type unspecified to treat 3 men with mMBC, 2 of whom had responded to prior orchidectomy and one of these had a second response [18]. The male who had not responded to orchidectomy also failed to respond to androgens.

The selective estrogen receptor modulator (SERM) tamoxifen has now been used extensively to treat advanced or metastatic MBC. From Guy’s Hospital, Cantwell et al. were the first to report a beneficial effect [46]. All 3 patients responded, 2 for >1 year and the third for 10 months. This was followed by a flurry of publications, many of which were series comprising only one case. Patterson et al. treated 31 mMBC cases with varying doses of tamoxifen in a multi-centre study [47]. Complete or partial response occurred in 15 (48%) and 5 achieved static disease. In terms of site of metastatic disease site, for those with visceral dominant 5/10 responded compared with 2/5 (40%) with bone-secondaries and 8/15 (53%) with predominantly soft tissue-disease.

Becher et al. treated 2 men with tamoxifen after both had refused orchidectomy and one who had been heavily pre-treated had static disease for 54 months [48]. In a multicentre study 31 metastatic MBC cases were treated with tamoxifen and a complete or partial response was seen in 15 (48%), together with a further 5 who had stable disease.

Ribeiro et al. reported a series of 24 mMBC cases in which tamoxifen achieved a complete response in 5 and a partial response in 4 [49]. Of 8 cases treated at MD Anderson Hospital only 2 responded [18]. Bezwoda treated 12 cases of whom 58% responded and 5 were known to have ER+ve tumours [9]. Among 5 cases given tamoxifen of whom only one was known to be ER+ve, Doberauer reported static disease in 4 [41]. Results are summarised in Table 10.8.