Male breast carcinoma: increased awareness needed

Male breast carcinoma is a rare condition. Few male breast cancer-specific epidemiological or clinical trial data are available - our understanding of male breast cancer thus comes from studies of female breast cancer, painting an inaccurate picture when it comes to determining contributing factors. Clinicians report an increase in diagnoses of male breast cancer but this has not been formally reported. We therefore undertook a review of data obtained from four western nations: England, Scotland, Canada and Australia. When adjusted for age, this review clearly showed an increase in the incidence of male breast cancer over a 15-year period. Reasons for the increased incidence are discussed in the context of suggested risk factors such as BRCA2 and lifestyle changes over the past few decades. The clinical management of male breast carcinoma is considered, in particular the potential role of aromatase inhibitors and fulvestrant and targeting pathways involving prolactin and androgen receptor.

England were considered over a 20-year period; a rise in incidence of one-third was observed from 185 cases in 1986 to 277 cases in 2006, which corresponded to 0.5 per 100,000 population in 1986 (95% confi dence interval, 0.4 to 0.6) and to 0.7 per 100,000 population in 2006 (95% confi dence interval, 0.6 to 0.7). A limitation in our data was incomplete information on the stage of disease at presentation, and while increases observed in absolute numbers do not account for changing denominators over time, congruent changes in the age-adjusted incidence give confi dence that these changes are real. Furthermore, our data parallel Surveillance, Epidemiology and End Results data published in 2004 showing that male breast carcinoma rates rose by 25% over a 26-year period [9] and extend our earlier observation that was limited to a subset of UK cancer registries [12].
In the absence of formal epidemiological studies, reasons for the apparent rise in male breast cancer incidence can only be speculated. It is well recognised that lifestyle changes over the latter decades of the 20th century have led to increased obesity in western nations, which is rapidly becoming a global problem. Th is may be a contributing factor as obesity is linked to cancer predisposition, and breast cancer is no exception [17,18]. Increased alcohol intake is associated with increased relative risk of breast cancer [19], which may also play a role. Much more controversially, increased exposure to so-called environmental oestrogens via diet and household products have been mooted as potential risk factors for breast cancer development [20], but there are no substantive data to support this.

General strategies
Th e general approach for managing early male breast cancer is the same as that recommended for women. Th e therapeutic modalities employed include surgery, radiotherapy and systemic therapies. As many excellent expert overviews on the subject exist [9,11,21], here we present only a brief summary. Surgical removal of the primary tumour by mastectomy or, rarely, by wide local excision is often accompanied by axillary node dissection, or, more recently, sentinel lymph node biopsy [22]. Adjuvant radiotherapy to the chest wall and draining lymphatic basin is often advised, especially in high-risk nodepositive groups, with the aim of reducing loco-regional recurrence, although there is a general lack of consensus on the optimal regimen [11]. Systemic therapies include chemotherapy, oral endocrine agents and, more recently, trastuzumab. Information on the potential benefi t of adjuvant chemotherapy in men is also scarce, although the few published data support its use as the proportion of response is similar in males to that in females [23,24].

Endocrine therapies
Th e importance of hormone manipulation in the manage ment of male breast cancer was recognised as early as the 1940s when orchidectomy was fi rst described as a treatment for skeletal metastases [25]. Patients persuaded to undergo orchidectomy were reported to experience rapid and dramatic relief of pain due to bony metastases. Proven regression of pulmonary metastases was demonstrated radiologically. Orchidectomy was also shown to elicit regression of the primary tumour in cases where it had not been removed surgically [26]. Other surgical procedures to alter the hormonal environment such as hypophysectomy and adrenalectomy have also been used. Th ese were seen to be eff ective to some extent in the prevention of progression of metastatic disease but were not commonly used in the adjuvant setting. A metaanalysis of published case series of male patients with metastatic disease reported tumour regression rates of 55% for orchidectomy (n = 355), 80% for adrenalectomy (n = 65) and 56% for hypophysectomy (n = 27), with an overall response rate of 59% in 447 patients [27]. Th ese results should be interpreted with caution given that what constituted a successful response, and how this was measured, was not clearly defi ned in the meta-analysis. Nowadays, such invasive procedures are seldom, if ever, carried out, having been superseded by more advanced medical treatments. Th ere is conclusive evidence regarding the importance of oestrogen receptor measurement in female breast cancer, as the absence of receptors accurately predicts lack of sensitivity to endocrine therapy. As hormone receptor positivity for both oestrogen receptor and proges terone receptor is proportionally higher in male breast cancer than female breast cancer [28,29], hormone therapies should be at least as eff ective in male breast cancer patients -thus most male breast cancer patients receive endocrine therapy.
Tamoxifen became established as part of the routine management of breast cancer in the 1970s [30]. Tamoxifen's effi cacy in male breast cancer was fi rst shown in a study of 24 patients, where tamoxifen treat ment produced disease regression of 37.5%, and was eff ective in treating metastases in soft-tissues, bone and lung [31]. Another study conducted on 41 patients also concluded that hormone therapy was successful in treating male breast cancer [32]. Further study has demonstrated that men treated with tamoxifen have a 51% lower risk of recurrence, comparable with that seen in women [28,33]. Although this evidence is from relatively small retrospective studies or extrapolated from results in trials treating females with breast cancer, due to its effi cacy and low cost, tamoxifen has gained widespread acceptance as the standard endocrine therapy in the treatment of hormone-sensitive male breast carcinoma [29,33,34]. Nevertheless, treatment with tamoxifen is associated with a multitude of side eff ects in men. Common problems include hair loss, skin rash, impotence, decreased libido, weight gain, hot fl ushes, mood changes, depression and insomnia. Th e incidence of these side eff ects may be as high as 62% and perhaps explains why compliance with tamoxifen is often poor [35].
Th e discovery that oestrogens are produced locally in breast tissues, by aromatisation of other sex steroid hormones [36], led to concerted eff orts to exploit this pathway as a potential therapeutic target. Unlike tamoxifen, which is a selective oestrogen receptor modulator, aromatase inhibitors (AIs) prevent the conversion of androstenedione to 17β-estradiol. Data from large random ised clinical trials in females with breast cancer, in which the effi cacy of AIs was compared with tamoxifen as an initial adjuvant endocrine therapy, or sequential (adjuvant tamoxifen or AI in either order) or extended (AI after 5 years of adjuvant tamoxifen) therapy, demonstrated a reduced risk of breast cancer recurrence compared with 5 years of tamoxifen treatment alone. AIs are now con sidered the therapy of choice for postmenopausal women with oestrogen receptor-positive breast cancer [37].
Th e use of AIs in male breast cancer was proposed due to their success in females and the identifi cation of intratumoural aromatase in male breast cancer [38,39]. Despite hopes that aromatase inhibition would be useful in the management of metastatic disease in men, initial case series have disappointingly shown negative or equivocal results. In a series of fi ve patients, none showed an objective response to treatment with anastrozole [40]. Interestingly, however, there have been three reported individual cases of response to letrozole alone in men [41][42][43]. In a recent Canadian study, eight male breast cancer patients were treated with anastrozole (three in the adjuvant setting and fi ve in the metastatic setting), with three of the cohort experiencing side eff ects including depression, decreased libido and lower-limb oedema [44]. In the same series, letrozole was prescribed to fi ve patients in the metastatic setting after prior tamoxifen treatment, with two out of fi ve experiencing oedema. Despite these side eff ects, none of the patients in this study dis continued treatment with either of these AIs.
In animal models, aromatase inhibition increases levels of follicle-stimulating hormone and testosterone but oestrogen levels are almost unchanged [45]. Moreover, a fall in oestrogen levels of 50% was seen in studies where anastrozole was given to healthy male volunteers, but this is not as dramatic as in females where AIs were shown to cause a 98% reduction. Administration of anastrozole in men, however, was also associated with a signifi cant increase of 58% in the levels of circulating testosterone [46]. By contrast, adminis tered at a similar dose to that used in women, letrozole treatment resulted in a 70 to 80% reduction in oestrogen levels in men [47]. Given that around 20% of circulating oestrogen is produced by the testis, this represents an almost total blockade of peripheral aromatisation.
In what is, to date, the most extensive description of the use of AIs for metastatic male breast cancer in the literature, Doyen and colleagues reported a complete tumour response in 13% (two patients), partial response in 27% (four patients), stable disease in 13% (two patients) and progressive disease in 47% (seven patients) [48]. Only six of the 15 patients in this study were assessed with regard to their serum oestrogen levels. In each of these cases, oestrogen levels fell below the minimum limit of detection after commencement of AI. Th e treatment response in this group varied, with three patients having partial response, one patient having stable disease and two patients showing progression [48]. Understanding why progression occurs in the almost complete absence of oestrogen requires further investigation.
Th e increase in testosterone seen after aromatase inhibition has been suggested to eff ectively overcome the oestrogenic aromatase blockade by fl ooding the enzyme pathway with substrate, leading to only modest reduction in serum oestrogen. Combination therapy with a gonadotrophin-releas ing hormone agonist eff ectively reduces the excess substrate and maximises the eff ect of aromatase inhibi tion, and has been seen to cause regression in male patients with disease refractory to aromatase inhibition alone [49]. Th is observation requires further evaluation and may allow more frequent use of AIs in males, possibly in combination with a gonadotrophinreleasing hormone agonist. Th e SWOG-S0511 trial -a small, phase 2 trial of 56 patients with recurrent or metastatic disease, in which goserelin is administered subcuta neously on day 1 followed by oral anastrozole for 28 days for 12 cycles -has been designed to help answer these questions [50]. Th is trial has completed recruitment and the results are awaited.
Other available endocrine therapies include the pure anti-oestrogen fulvestrant, a selective oestrogen receptor downregulator, currently only licensed for use in advanced breast cancer in women. Th ere are only three reports of its success in metastatic male breast cancer [51][52][53]. Th e most recent study evaluated fi ve patients with metastatic disease and observed either partial response or disease stability in three out of fi ve patients, concluding that fulvestrant should be considered as a treatment option in pretreated metastatic male breast cancer patients [53].

Other potential therapeutic strategies
Although not exclusive to male breast cancer, other putative novel therapeutic targets include prolactin receptor and androgen receptor. Th e presence of prolactin receptor in both benign and malignant male breast tissue varies according to the site of expression; benign lesions only express the receptors on the luminal surface of epithelial cells, while malignant lesions show cytoplasmic expres sion [54][55][56]. Moreover, male breast cancer was reported in the context of hyperprolactinaemia [57]. Owing to local production of prolactin in breast tissue, where it acts as a paracrine hormone [58], the potential of the targeting pathway as a putative therapeutic target is receiv ing increased attention [59]. A study of 251 male breast cancers indicated a potential role for androgen receptor as a therapeutic target following the association of androgen receptor positivity with better outcome [60], paralleling similar observations in a series of 953 female breast cancers [61] -suggesting that there is potential to explore anti-androgen therapies as a therapeutic approach.

Public education
Th e general public consider breast cancer very much a female disease, and a diagnosis of male breast cancer is often met with a sense of disbelief [62]. Pink ribbon campaigns have been hugely successful at promoting breast cancer awareness on an international level and, although direct evidence is lacking, these campaigns may have contributed to earlier detection, which makes the disease much more treatable. However, these campaigns remain very much female focused. Th e pink and blue ribbon developed by the John W Nick Foundation is aimed at promoting breast cancer awareness in men [63]. As male breast cancer incidence is undoubtedly rising, it would seem sensible to promote this in tandem with pink ribbons as a way of educating the public about the disease in men.

Conclusion
Although rates of male breast cancer are increasing, the cancer remains rare. Few direct epidemiological or clinical trial data are thus available and nearly all information used in understanding male breast cancer comes from studies of female breast cancer, which undoubtedly provides an inaccurate picture. More recently, genderrelated diff erences in gene profi les have been reported [64,65]. Although both studies emphasised caveats associated with their cohort sizes, the diff erences reported provide a stimulus to dissect out potential diff erences in the biology of male and female breast cancer. In addition, two very timely articles outlining the development of the Male Breast Cancer Consortium [66] and an International Male Breast Cancer Program [67] off er further hope for much-needed progress. Both studies will examine biomarker profi les in male breast cancer, with the latter off ering the additional prospect of a male breast cancerspecifi c clinical trial. Whilst accrual is likely to be slow, international eff ort can only facilitate this. Th ese collections will provide important resources for the study of male breast cancer, something we consider is much needed in order to advance our understanding of the biology and natural history of this rare but increasingly recognised carcinoma.

Competing interests
The authors declare that they have no competing interests.