Male breast cancer: Progress, prognosis and future pathways

Transcription

1 Asia Pacific Journal of Clinical Oncology 2008; 4: 6 17 doi: /j x REVIEW ARTICLE Male breast cancer: Progress, prognosis and future pathways Kathryn M FIELD, 1 Belinda CAMPBELL 2 and Richard DE BOER 1 Departments of 1 Medical Oncology, Western Hospital and 2 Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Abstract Breast cancer is one of the most commonly treated malignancies worldwide, but is rare in males. Less than one percent of all breast cancers occur in men, and breast cancer comprises less than one percent of all male malignancies. Thus, clinical experience in managing this condition is limited. In contrast to female breast cancer, much remains unknown about breast cancer in males. While there are similarities between the two, emerging data suggest that there are perhaps more differences than previously thought. Nevertheless, much of how males with breast cancer are managed continues to be extrapolated from randomised trials performed in females, due to lack of data in the male population alone. Another poorly understood aspect is the psychological impact experienced by male patients when diagnosed with what is generally thought of as a female malignancy. This review will discuss the known epidemiology, demographics, risk factors and genetic predispositions surrounding the development of breast cancer in males; as well as current surgical and radiotherapeutic interventional techniques. Histological profiles and subtypes as well as hormone receptor and HER-2 receptor status are also discussed, with an overview of chemotherapy and hormonal strategies in both the adjuvant and metastatic settings. Key words: BRCA1/ 2, male breast cancer. EPIDEMIOLOGY There are significant geographic differences in the incidence of male breast cancer. While Europe demonstrates a similar incidence to the US of approximately one in , 1 the incidence in Japan is less than five per million, 2 while in some African countries up to 15% of breast cancers are diagnosed in men. 3,4 There are also racial differences; Jewish men having a higher incidence (2.3/ /year) than non-jews. 5 There are a number of postulated mechanisms for these differences including: genetic differences between populations obesity (e.g. in the US) leading to secondary hyperestrogenism Correspondence: Dr Richard de Boer, Department of Medical Oncology, Western Hospital, Footscray, Vic. 3011, Australia. richard.deboer@wh.org.au Accepted for publication 6 December infections (e.g. in Africa) leading to liver disease and secondary hyperestrogenism increasing life expectancy in developed countries (e.g. Europe, US) thus increasing incidence. In Australia in 2001, 95 men were diagnosed with breast cancer. This compares to data from 1983 and 1984, when 43 and 49 cases of male breast cancer were diagnosed, respectively. 6 Thus, the incidence appears to be increasing. This has also been seen in the US. An American review examining rates of male breast cancer from 1973 to 1998 found a total of 2537 men with breast cancer, with a significant increase in incidence over a 26-year time period from 0.86 per population in 1973 to 1.08 per in 1998 (P < 0.001). 7 The noted increase in incidence is in contrast to European data which suggest a stable rate of around 1 in ,9 Incidence increases with age with a median age at diagnosis of 67 years (compared with 62 years for females) in one US study. 7 Another found a unimodal

2 Review of treatment for male breast cancer 7 Table 1 Risk factors for male breast cancer Genetic BRCA2 Unknown founder mutations: Incidence in Scandinavia, Ashkenazy Jews BRCA1 Klinefelter syndrome (XXY karyotype) CHEK2 mutation Cowden syndrome (PTEN mutation) Environmental Obesity: Secondary hyperestrogenism Liver disease: Secondary hyperestrogenism Prostate cancer (may be treatment-related) Exogenous estrogens Alcohol (related to liver disease) Testicular damage Radiation exposure Exposure to chemicals/high temperatures Other Increasing age Ethnic variation (combination of genetic and environmental) Not all factors are confirmed risk factors for male breast cancer. peak in incidence in males at 71 years, whereas in females a bimodal distribution is seen with peaks at 52 and 71 years. 10 Stage-for-stage, overall survival is similar between male and female patients. 11 However, males tend to present with higher stage disease, for example more positive lymph nodes and larger primary tumors. Fentiman et al. found that more than 40% of men present with Stage III or IV disease. 12 This may be due to females being more aware of breast cancer and thus presenting earlier to doctors with breast abnormalities; as well as access to screening mammography. GENETIC FACTORS There appear to be genetic associations with male breast cancer in some patients; however, the majority of cases demonstrate no strong family history of malignancy and no clear genetic contributing factors. Founder mutations in certain populations (e.g. Scandinavia and Ashkenazi Jews) result in a higher incidence of genetic associations with male breast cancer in these groups, Table 1. BRCA2 BRCA2 (tumor suppressor gene on 13q12 13) mutations are associated with breast, prostate, pancreatic, gastric cancers and melanomas. This mutation, inherited in an autosomal dominant fashion, is the commonest known genetic mutation which predisposes males to breast cancer; up to 15% of male breast cancers are attributable to this gene. 16 In a male BRCA2 carrier, the lifetime risk of breast cancer is times higher than the general population, placing the lifetime risk in these men at 6.9%. 17 If a male is found to have breast cancer and there is a positive family history, there is up to a 60 70% chance that the family carries a BRCA2 mutation. 18 BRCA1 BRCA1 (tumor suppressor gene on 17q12 21) mutations, again autosomal dominant, are associated in females with breast, ovarian and fallopian tube malignancies, as well as colon, stomach, and pancreas tumors. There are conflicting reports in the literature about the contribution of BRCA1 mutations to the incidence of male breast cancer. Although some reports indicate minimal association between BRCA1 mutations and male breast cancer, 11,19,20 other data suggest a stronger relationship. One study found a germline BRCA1 mutation in one of 25 male patients with breast cancer. 21 In an analysis of 76 male breast cancer patients, eight BRCA1 and 14 BRCA2 mutations were discovered. 22 In a study of 483 BRCA1 mutation carriers, the risk of male breast cancer was increased by a factor of Klinefelter syndrome Klinefelter syndrome is associated with gynecomastia and infertility, but also a risk of male breast cancer, up to 50 times that of the general population. 24,25 This condition, where males have a karyotype of XXY, is present in up to 7% of male breast cancer patients. 25 This may be due to elevated estradiol levels and an increased estradiol : testosterone ratio. CHEK2 CHEK2 (22q) is a cell cycle checkpoint kinase involved in DNA repair. Again, data varies as to the association of a variant, CHEK2*1100delC, with incidence of male breast cancer. An analysis of 718 families without BRCA1 or 2 mutations found the CHEK2*1100delC variant in 13.5% of individuals from families with male breast cancer (vs 1.1% in healthy individuals). 26 Other studies have not noted an association. 27,28 Cowden syndrome Cowden syndrome, an autosomal dominant cancer susceptibility syndrome, is caused by a mutation in the

3 8 KM Field et al. PTEN tumor suppressor gene, and causes benign skin lesions (hamartomas), as well as being associated with (female) breast and thyroid malignancies. There are case reports associating the PTEN mutation with male breast cancer. 20 In practice, when a male is diagnosed with breast cancer, a careful family history should be obtained, and there should be a low threshold for referral to a familial cancer clinic. NON-GENETIC RISK FACTORS A hyperestrogenic state (such as found in Klinefelter syndrome) can be present in a male due to non-genetic conditions. Men with prostate cancer and transsexuals who are treated with exogenous estrogens or antiandrogens may be at higher risk of breast cancer. 29,30 A recently published Swedish paper examined male patients with both breast and prostate cancer, and suggested that most of the apparent increased risk of male breast cancer following prostate cancer was related to estrogen or antiandrogen treatment; or in small numbers, the BRCA-2 gene. 31 At least two case reports exist of transsexual males developing breast cancer after estrogen therapy. 32,33 Liver disease such as cirrhosis can increase the serum estrogen : androgen ratio and possibly predispose to male breast cancer. It is postulated that this is the mechanism by which the incidence of male breast cancer in African countries is high; endemic infections contributing to liver disease in this population. 34 Emerging data in Western societies suggest an association between alcohol abuse, liver cirrhosis and the incidence of male breast cancer, 35,36 although not all studies support this association % of circulating estrogen in males is synthesized from the peripheral aromatization of androgens. 38 Obesity increases aromatization (the aromatase enzyme is present in adipose tissue) and has been associated with male breast cancer; being overweight or obese has been found to result in an odds ratio of >2.0 for the development of male breast cancer in multiple studies Testicular damage caused by conditions such as undescended testes, orchiectomy and mumps is postulated to be a risk factor for the development of breast cancer. 43 Gynecomastia does not appear to be linked although this remains controversial. 44 Similar to results of studies in females, radiation exposure increases the risk of breast cancer in males. 45 Other environmental factors associated with male breast cancer include exposure to high temperatures, such as blast furnaces, 5,46 and exposure to petrol and exhaust fumes, 12 Table 1. The role of smoking is unclear. 47 Finally, one study found that childless men are at a five times higher risk than fathers. This may reflect a hormonal imbalance predisposing to secondary infertility and breast cancer. 41 ASSOCIATED MALIGNANCIES Sporadic cases of male breast cancer with another primary malignancy are extremely rare, 48 with the exception of contralateral breast cancer. Epidemiological studies indicate that this risk is greatly increased, at least 30-fold higher in some series. 49,50 More commonly, if there are other malignancies present in male breast cancer patients and their relatives, a genetic factor is likely to be involved. The malignancies commonly seen with BRCA2 mutations, the commonest genetic contributor to male breast cancer, have been outlined above. HISTOPATHOLOGY Ninety percent of male breast cancers are invasive carcinomas with ductal carcinoma the predominant histologic subtype (>80%). 51 Papillary carcinoma is much less common, constituting approximately 5%. Unlike in females, lobular carcinoma is rare as the normal male breast does not develop lobules unless exposed to abnormal concentrations of estrogen (e.g. Klinefelter syndrome). 52 Other rare subtypes include medullary, mucinous and tubular carcinomas. Ductal carcinoma in situ constitutes approximately 10% of male breast carcinomas. 52 The majority of male breast cancers are of intermediate or high grade. Grade I tumors occur in 12 20% of patients, grade II in 54 58% and grade III in 17 33%, 52 Table 2. Hormone receptors Males have a higher proportion of hormone receptor positive breast cancers when matched for stage, grade Table 2 Histopathological features of male breast cancer Histological subtype Invasive ductal 93.7% (SEER registry) 7 Papillary 2.6% Mucinous 1.8% Lobular 1.5% Grade 12 I 12 20% II 54 58% III 17 33% Hormone receptor Estrogen receptor +ve >90% status Progesterone receptor +ve 80 96% HER-2/neu 5 30% overexpression

4 Review of treatment for male breast cancer 9 and age to female breast cancer patients. 51,53 Over 90% of male breast cancers are estrogen receptor (ER) positive, and 80 96% (depending on the reference source) are progesterone receptor (PR) positive. 7,52,54,55 ERa and ERb are estrogen receptor subtypes, and share homology at the DNA and ligand-binding domains. However, they are located on different genes and therefore are functionally distinct. 53 ERa is located on chromosome 6q, and ERb is located on chromosome 14q. It is known that ERb is abundantly expressed in normal breast tissue while ERa expression is much less common; however, the significance is unclear. 56 The loss of ERb in some female breast cancers may suggest that ERb has a role as a tumor suppressor. 56 In female breast cancers, expression of ERb is associated with favorable prognostic factors including ERa, PR and low tumor grade. 53,56 Investigators at St James University Hospital recently reported that ERb has increased expression in male breast cancers compared to female breast cancers. 53 The high hormone receptor pattern in male breast cancer is noteworthy in view of the lower levels of serum estradiol in men; therefore, in males there seemingly would be no growth advantage for hormone receptor positive breast tumors. The authors hypothesized that the molecular events that occur in postmenopausal female breast cancers may be similar in male breast cancers, including intratumoral enzyme systems that produce bioactive estrogens in situ. Over-expression of aromatase occurs in male breast cancers, and is likely to contribute to the intratumoral production of estrogen, and may provide a selection advantage for ER-positive tumors. Essentially, the significance and function of both estrogen and progesterone receptors in men remains unclear. HER-2/neu The HER-2/neu proto-oncogene, on chromosome 17q, has been found to be both a prognostic and predictive factor in female breast cancer. It is seen in up to 25% of female breast cancers, but appears to be less common in male breast cancers. Early studies indicated higher rates of HER-2/neu positivity; but possibly due to changed and improved laboratory techniques, more recent studies do not support this. 57 One retrospective examination of 58 male breast cancers showed only one (1.7%) stained 3+ (maximum staining) on immunohistochemical analysis, and none showed HER-2 gene amplification using fluorescent in-situ hybridization (FISH). 26 of these patients had been evaluated in a previous study and 35% had been deemed HER-2/neu overexpressing. 58 Another study examining immunohistochemistry in 75 cancer cases found only a 5% incidence of HER-2 overexpression. 59 A further analysis of 128 breast tumors in men found HER-2 amplification in only 1 2% of tumors. 60 However, rates differ between publications a retrospective review of 77 cases of male breast cancer from the Mayo Clinic found HER-2/neu positivity (on immunohistochemistry) in 29% (22 cases) although the degree of staining was not reported and FISH testing was not carried out. 54 Thus the true rate of HER-2 overexpression in male breast cancers remains to be determined. Other molecular markers Markers which are not routinely tested in Australia, but differ in expression between male and female breast cancer include bcl-2 and p53. Bcl-2, an inhibitor of apoptosis, governs mitochondrial outer membrane permeabilization and is a target for estrogen. The rate of expression of Bcl-2 is higher in male than in female breast cancers; up to 94% in some series. 54,59 One theory for this difference is that up-regulation of estrogen receptors in a low-estrogen environment (the male body) causes an increased response of estrogen targets such as Bcl P53 is a tumor suppressor gene and is less likely to be expressed in male breast cancer (10 20%) than in female breast cancer (approx. 30%). 54,61 However, the reported rates of expression differ between series in and another publication suggests similar rates of p53 expression between males and females. 62 In one retrospective series of 77 patients, androgen receptor expression was reported at 95%. 54 This would suggest that antiandrogen therapy may be of benefit. Currently, routine testing and management decisions based on expression of these and other markers are not used in clinical practice. Thus, there do appear to be differences in the rates of expression of various molecular markers in male breast cancers when compared to females, highlighting potential problems when using data from female-only trials and extrapolating the data to treat male patients. STAGING INVESTIGATIONS There is little published evidence for staging investigations specific for males with breast cancer, therefore the recommended staging investigations are adopted from those established in female breast cancer. According to the Practice Guideline Report from Ontario, intraductal and pathological stage I patients do not require any additional staging tests, bone scans are recommended in stage II patients, with lung/liver imaging in those with

5 10 KM Field et al. >3 positive lymph nodes, and bone, liver and chest imaging for those with stage III tumors. 63 PROGNOSTIC FACTORS AND PROGNOSIS Male breast cancer has a worse overall prognosis than female breast cancer, with an overall 5-year survival rate of 40 65% as compared to 85% in women. 64 However, when matched for stage, age and prognostic factors, the prognosis is similar. 47,51,64 The inferior outcome in men is primarily due to the presence of more advanced disease at diagnosis. Gender itself is not a prognostic factor. 65 In male breast cancer, the reported 5-year survival rates stage-by-stage are: % stage I, 50 80% stage II, and 30 60% stage III. 64 Patients with distant metastatic disease (stage IV) have a poor prognosis, with a 5- year survival rate of <20% and median survival of 15 months. 7,51 The most important prognostic factors in male breast cancer are stage, nodal status, tumor size, histologic grade and hormone receptor status. 51 In a retrospective review Wang-Rodriguez et al. found that clinical stage (irrespective of nodal status or tumor size) was the single most significant prognostic factor. 66 Nodal involvement is common, found in up to 60% of patients. The overall survival at 5 years for node-negative male breast cancer is 85%, compared to 57% for node-positive patients. 47 With regard to hormone receptor status, ER-positive male breast cancer patients are thought to have a better survival than ER-negative patients, 66 although this is controversial, with other series suggesting that ER positivity has no significant effect on survival. 7,67 Assessment of genetic expression may also be useful for classification of risk groups. HER-2/neu positivity and p53 mutations are associated with shorter diseasefree survival, 66 and have been shown to be prognostic in retrospective series of male breast cancer. 66 Male breast cancer with overexpression of both HER-2/neu and p53 has an additive deleterious effect on survival, and represents a high risk patient group. 68 There is an emerging understanding of breast tumor subtypes (e.g. luminal A/B, basal-like, HER-2) and the concept that breast cancer is a range of diseases rather than a single disease entity. 69 Molecular profiling may lead to more accurate prognostication, and the ability to tailor treatment approaches. The first immunophenotypic profile data in male breast cancer was presented in 2007 with a case series of 9 patients phenotypically five were luminal A and four were luminal B. 70 More data is awaited before information on tumor subtypes can be used to guide treatment decisions for male breast cancer. TREATMENT Local therapy Surgery Surgical treatment of male breast cancer follows the same principles as for females. Modified radical mastectomy is generally the recommended approach as breast conservation is rarely feasible because of small breast size and the generally high ratio of tumor-to-breast size. In male patients with loco-regionally advanced disease, modified radical mastectomy may be considered after neo-adjuvant chemotherapy given with the aim to down-size the tumor and improve resectability, or to render inoperable tumors operable; this practice is an extrapolation from studies performed in female breast cancer patients. Sentinel lymph node (SLN) biopsy has not been as extensively investigated in male breast cancer patients as in their female counterparts. However, there is no reason to suggest that it would be less effective in male patients, and SLN biopsy is becoming more widely practiced in men who are clinically node-negative. SLN biopsy has been shown to be feasible and accurate in small, single institutional series Radiation Most male breast cancer patients present with locoregionally advanced disease, and postmastectomy radiotherapy (PMRT) is commonly employed to reduce the risk of loco-regional relapse. Due to the low incidence of male breast cancer, there is a paucity of prospective evidence regarding radiotherapy. However, single institutional retrospective series support the use of PMRT in men. 74 One series confirmed similar patterns of failure between the genders, providing a valid rationale to use the same indications for PMRT that apply to female breast cancer. 75 Treatment indications, techniques and doses are extrapolated from female breast cancer. These indications are primary size >5 cm, chest wall or pectoral muscle invasion, skin involvement or 4 positive axillary lymph nodes. 76,77 Published clinical practice guidelines recommend that PMRT should encompass the chest wall and the supraclavicular, infraclavicular and axillary apical lymph node areas. 76 A standard radiation dose for PMRT is 50Gy in 25 fractions at five fractions

6 Review of treatment for male breast cancer 11 per week, over 5 weeks; 52 there is insufficient evidence to support one fractionation schedule over another. 76 Systemic therapy Generally, male patients are treated in the same way, stage for stage, as female patients. Individual therapies will be discussed below; studies, although generally small, do demonstrate survival advantages for systemic therapies. A review from the MD Anderson Cancer Center examined the treatment of 135 men in the adjuvant setting between 1944 and Of these, 32 received chemotherapy and 38 received endocrine therapy (19 received both). An overall survival benefit was seen for those receiving systemic therapy compared with those who did not (HR 0.57, 95% CI ). 78 This is one of the largest reports of adjuvant systemic therapies in males with breast cancer. Another retrospective review of 50 patients supported the use of adjuvant therapies, with favorable survival benefits. 79 Yet the apparent beneficial effects of chemotherapy and endocrine therapy are controversial. A 2002 retrospective review of 65 cases from a US registry found no survival differences in male patients comparing those who underwent surgery alone to those who had surgery combined with adjuvant treatments (including tamoxifen, chemotherapy and radiotherapy). This conflicting finding may be contributed to by small sample size and the lack of consistent treatment regimens being employed. 66 Goss et al. published a retrospective review of 229 patients treated between 1955 and 1996 and found that adjuvant chemotherapy was associated with a shorter disease-free and overall survival, although patients were more likely to have chemotherapy if they had node positive (and thus poorer prognosis) disease. Adjuvant hormone treatment, conversely, had a significantly positive influence on DFS and OS. 67 Again, this may be reflective of hormone receptor expression being a positive prognostic factor. Endocrine therapy The majority of male breast cancers are hormone receptor positive. Thus, endocrine therapy is an important component of systemic management of breast cancer in the male population, both in the adjuvant and metastatic settings. Tamoxifen has been the primary endocrine therapy for male breast cancer. While there are no randomised studies in the adjuvant setting, retrospective studies show improved disease-free and overall survival. 67,80 One of the most quoted papers is a prospective study beginning in the 1970s in which males with stage II and III breast cancer, all with axillary lymph node involvement, were given adjuvant tamoxifen for one or two years after surgery. Disease-free and overall survival benefits for 39 patients were compared with historical controls. Overall survival of the tamoxifen treated patients was 61% at 5 years compared to 44% for historical controls (P = 0.006). Disease-free survival was 56% versus 28% at 5 years (P = 0.005). 80 In the metastatic setting, response rates of up to 25 80% have been documented in various publications. 81,82 Data supporting 5 years of adjuvant tamoxifen for females are assumed to be relevant for males. 11,83 The potential side-effects of tamoxifen can occur in males, for example, decreased libido, weight gain, mood alterations, deep vein thrombosis and hot flushes, and it has been suggested that cessation of therapy due to sideeffects is more common in the male population than in females. 84 Aromatase inhibitors and their effectiveness are less well understood in males. While most male estrogen is derived from peripheral aromatization of androgens, approximately 20% of estrogen is produced by the testes and is thus independent of aromatase. 59 Although multiple phase III trials are available for female patients, results of these trials cannot be directly extrapolated to fit the male counterpart. As such, the role of aromatase inhibitors in the male remains unclear and to date, only case reports in metastatic disease are available in the literature (Table 3). Preclinical data on male rats found increases in follicle stimulating hormone (FSH) and testosterone when chronically administering aromatase inhibitors, with no change in estradiol levels. 85 An analysis of the effect of anastrozole on hormone suppression in a small number of healthy male volunteers found that estrogen concentration decreased by only 48%, in contrast to the near-complete estrogen suppression in females given aromatase inhibitors; in addition, serum testosterone increased. 86 Letrozole has also been tested in healthy males. With higher doses (over 2.5 mg), estrogen was suppressed by 75 90% from baseline; similar to the anastrazole studies, serum testosterone increased by %. 87,88 There have been varying responses to aromatase inhibitors in the handful of case reports published on this topic. A 2002 review of male patients with metastatic breast cancer at the MD Anderson Cancer Center discussed five cases (over a 10-year period) of males treated with anastrozole. Although no patients had objective responses, anastrozole did stabilise disease in three. 89 Two other single patient case reports have shown a response to aromatase inhibitors; both of these

7 12 KM Field et al. Table 3 Evidence for use of endocrine agents other than tamoxifen in advanced male breast cancer Author Agent Patient no. Result Response duration Giordano et al. 89 Anastrazole 5 3 = stable disease 9 months 2 = disease progression 8 months 4 months 3 months 2 months Italiano et al. 91 Letrozole 1 Disease response Not given Zabolotny et al. 90 Letrozole 1 Disease response 12 months (at time of publication) Giordano et al. 92 Letrozole/leuprolide 1 Disease response 22 weeks Anastrazole/leuprolide 1 Disease response 6 months Agrawal 95 Fulvestrant 2 1 = partial response 22.5 months 1 = stable disease 14 months used letrozole: one patient had metastatic disease which had progressed on tamoxifen and the other had locally advanced disease and was treated de novo. 90,91 In addition to suppressing the aromatase enzyme, it would make sense to decrease serum testosterone, given the increased serum testosterone levels documented in the phase I trials described above. Luteinizing-hormonereleasing hormone (LHRH) agonists can inhibit the feedback loop to the hypothalamic-pituitary axis and thus further decrease the production of testosterone and estrogen. A recent publication described two patients with metastatic disease treated with leuprolide acetate (a LHRH agonist) plus an aromatase inhibitor, with excellent disease response; one patient s disease having previously progressed on an aromatase inhibitor alone. 92 A prospective Phase II study is underway in the USA, combining anastrazole and goserelin (an LHRH analog) in males with hormone-receptor-positive metastatic breast cancer. 93 The use of aromatase inhibitors as single agents remains controversial biochemically, and recommendations against their use as single agents for male breast cancer have been made. 94 Thus, tamoxifen remains the standard first-line endocrine therapy for males with hormone-receptor positive breast cancer in both the adjuvant and metastatic settings. Nevertheless, with tamoxifen being replaced by the aromatase inhibitors in the setting of female breast cancer, there is increasing interest in the use of aromatase inhibitors in males. Questions such as whether aromatase inhibitors should be used as adjuvant treatment in males with a contra-indication to tamoxifen (e.g. history of deep vein thrombosis), or who are intolerant to tamoxifen, have arisen. There is no evidence and no data to support their use in the adjuvant setting, either upfront or in sequence from tamoxifen. The main concern with respect to use of aromatase inhibitors in Table 4 cancer Line of therapy First line Second line Third line Fourth line Other options Endocrine therapy options for advanced male breast Hormonal agent Tamoxifen Aromatase inhibitor (anastrazole or letrozole) Aromatase inhibitor plus LHRH agonist Fulvestrant Orchidectomy, aminoglutethimide, medroxyprogesterone acetate, cyproterone acetate the adjuvant setting is the aromatase-independent testicular production of estrogen. Combining aromatase inhibitors with a LHRH analog may prove useful to overcome this and is a strategy that should be examined in the future, after results from the phase II study in metastatic disease, described above, become available. The potential side-effects of LHRH agonists, including loss of virility, may be more of an issue in the adjuvant setting than for patients with metastatic disease. Fulvestrant, an estrogen receptor antagonist, may potentially be of use in the treatment of male breast cancer. A recent publication described two male patients, one with metastatic disease and one with locally advanced tumor, both of whom derived clinical benefit (stable disease and partial response, respectively) 95 (Table 3). Table 4 outlines options for endocrine therapy in metastatic male breast cancer. Ablative therapies for metastatic disease such as orchidectomy, adrenalectomy and hypophysectomy have been utilized. In the 1940s, orchidectomy was the standard method of treatment for metastatic male breast

8 Review of treatment for male breast cancer 13 cancer when its efficacy was established. 96 Response rates of 30 50% were reported. 94 Other ablative therapies were explored after disease progression following orchidectomy. In one review response rates were 80% for adrenalectomy and 56% for hypophysectomy. 81 The benefits of these approaches in the adjuvant settings are unknown. As surgical techniques have potential complications, use of these therapies has diminished with the development of drug-based hormonal therapies. Other systemic hormonal treatments for metastatic disease have included corticosteroids, antiandrogens, aminoglutethimide, medroxyprogesterone acetate and LHRH agonists, with varying response rates ranging from 30 to 75% in small numbers of patients. 81,90,97 Chemotherapy The use of chemotherapy in males with breast cancer is largely extrapolated from randomised controlled trials in women. Due to the small numbers, there is a paucity of direct evidence to guide decision making with respect to chemotherapy. A prospective trial beginning in 1974 used CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy in 24 male patients with node-positive breast cancer and demonstrated a 5-year survival rate of greater than 80%. 98 Although not randomized, comparison with contemporary data indicated that without chemotherapy the 5-year male survival rates were less than 30%. Another small study of 11 male patients with stage II or III breast cancer given FAC (5-fluorouracil, adriamycin and cyclophosphamide), also found a 5-year survival rate of greater than 80%. 99 Larger retrospective surveys also recommend the use of chemotherapy in the adjuvant setting. 100,101 Examining over 50 years of data from the MD Anderson Cancer Center (32 men receiving chemotherapy), it was found that for lymph node positive disease, adjuvant chemotherapy was associated with a lower risk of death (hazard ratio = 0.78), although the P-value was not significant. Using the evidence for chemotherapy in females, similar guidelines are used by clinicians to recommend adjuvant chemotherapy to male patients. In the metastatic setting, as with other modalities of treatment, there is little data regarding chemotherapy regimens and outcomes. There is even less regarding impact on quality of life and patient perceptions. Chemotherapy in the metastatic setting has been generally reserved for after failure of hormonal therapies. The agents and regimens used are similar to those used in females. Jaiyesimi et al. published a review of all articles pertaining to male breast cancer from 1942 to 2002, suggesting that the overall response rate for chemotherapy in males with metastatic disease is around 40%. This figure is calculated using data from small series (largest n = 21) where a variety of regimens including CMF, FAC, doxorubicin/vincristine, and cyclophosphamide alone have been used. This response rate is similar, the paper suggests, to that observed in females with metastatic disease treated with CMF. 81 Trastuzumab In males trastuzumab in both the high-risk adjuvant and metastatic settings should be as beneficial as seen in the female population. However, reports indicate that HER-2 gene amplification is rare. Initial publications had suggested a high rate of HER-2 positivity in male breast cancers, but more recent data suggest that the incidence of HER-2 overexpressing tumors is less than in females. There is little evidence to support use of trastuzumab in males with breast cancer other than isolated case reports. 102 Nevertheless, in those males whose tumors do overexpress HER-2, there is no indication that trastuzumab would not be of benefit. In Australia, there are no prescribing restrictions to using trastuzumab in male patients in either the adjuvant or metastatic disease setting, as the gender of the patient is not specified. The use of trastuzumab in the adjuvant setting has not been studied, and given the small numbers there is unlikely to ever be level one evidence to support its use. However, in men with high risk HER-2 positive breast cancer, trastuzumab should be recommended in a similar fashion to females, given that they are likely to derive clinical benefit. PSYCHOSOCIAL CONSEQUENCES Breast cancer has become an important issue in the community with significant government and media focus. There are numerous support and advocacy groups. Quite rightly, the primary focus of this attention is on females. In general there is minimal awareness in the community that breast cancer can also affect men. This concept that breast cancer is a female disease is a difficult issue for men with breast cancer to cope with. Male breast cancer patients therefore face a struggle not just with a diagnosis of cancer, but also a potential attack on their sense of masculinity and sexuality. There are both psychological and physical affronts to being male with breast cancer. A recent UK study surveyed 161 men with breast cancer, as part of the Men s Attitude towards Cancer and Health (MATCH) project. 103,104 This found that

9 14 KM Field et al. nearly 25% of men experienced traumatic stress symptoms related to breast cancer. Altered body image was the strongest factor associated with depression in statistical analyzes. Correlates of higher distress levels included avoidance techniques such as denial and substance use. Gender-specific information needs in the above survey also contributed to the experience of distress. Another UK publication, gathering information from focus groups, questionnaires and interviews, reported that over 50% of males wanted much more information about male breast cancer than was available to them; information that was provided was felt to be inappropriate as it was directed at women. 105 A publication following an exploratory focus group study in the UK found all participating men felt it would be useful to be able to speak with other male patients, but not with female patients, about their diagnosis. 106 To begin to address the issue of gender-specific information and support, an Australian website for males with breast cancer was established in July 2006 by the National Breast Cancer Center. 107 This provides links to written information specifically designed for men covering etiology, diagnosis and treatment. This is a positive initial step in widening the awareness and support for males diagnosed with breast cancer. CONCLUSION There remains much to learn about breast cancer in men, and there is a relative lack of evidence to help guide management decisions. Given the later presentation of male breast cancer with subsequent poorer prognosis, improved education for males stressing the reality of this disease, and encouragement for men to be aware and to present early following the discovery of a breast lump, may best change the overall outcomes for men who are diagnosed with breast cancer. Surgery, radiotherapy, chemotherapy and endocrine therapy are all believed to play just as important a role in the management of this condition as in females with breast cancer; and given the evidence available, management stage-for-stage is comparable. An understanding of some differences between male and female breast cancer is emerging, particularly in respect to HER-2 status, which will have implications for its management in both the adjuvant and metastatic settings. The role of aromatase inhibitors, well established in the management of female breast cancer, continues to be explored. Although there have been scant resources directed to address the psychosocial aspects of being diagnosed with male breast cancer, this appears to be slowly changing. However, it is only with international collaboration that necessary research and trials can be initiated which will allow a clearer understanding to emerge of the differences between breast cancer in men and women, and how best to manage this difference. REFERENCES 1 Ries LAG, Melbert D, Krapcho M, Mariotto A, Miller BA, Feuer EJ, Clegg L, Horner MJ, Howlader N, Eisner MP, Reichman M, Edwards BK (eds). SEER Cancer Statistics Review, [Cited April 2007]. Available from: 2 Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB (eds). Cancer Incidence in Five Continents, Vol. VIII. International Agency for Research in Cancer Scientific Publication No. 155, Lyon France Bhagwandeen SB. Carcinoma of the male breast in Zambia. East Afr Med J 1972; 49: Amir H, Makwaya CK, Moshiro C, Kwesigabo G. Carcinoma of the male breast: a sexually transmitted disease? East Afr Med J 1996; 73: Mabuchi K, Bross DS, Kessler II. Risk factors for male breast cancer. J Natl Cancer Inst 1985; 74: Australian Institute of Health and Welfare. Australian Cancer Incidence Data [Cited April 2007] Available from: 7 Giordano SH, Cohen DS, Buzdar AU, Perkins G, Hortobagyi GN. Breast carcinoma in men: a populationbased study. Cancer 2004; 101: La Vecchia, Levi CF, Lucchini F. Descriptive epidemiology of male breast cancer in Europe. Int J Cancer 1992; 51: La Vecchia C, Lucchini F, Negri E, Boyle P, Maisonneuve P, Levi F. Trends of cancer mortality in Europe, : III, breast and genital sites. Eur J Cancer 1992; 28A: Anderson WF, Althuis MD, Brinton LA, Devesa SS. Is male breast cancer similar or different than female breast cancer? Breast Cancer Res Treat 2004; 83: Giordano SH, Buzdar AU, Hortobagyi GN. Breast cancer in men. Ann Intern Med 2002; 137: Fentiman IS, Fourquet A, Hortobagyi GN. Male breast cancer. Lancet 2006; 367: Thorlacius S, Olafsdottir G, Tryggvadottir L et al. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 1998; 352: Struewing JP, Coriaty ZM, Ron E et al. Founder BRCA1/2 mutations among male patients with breast cancer in Israel. Am J Hum Genet 1999; 65: Thorlacius S, Olafsdottir G, Tryggvadottir L et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 1996; 13:

10 Review of treatment for male breast cancer Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 2004; 22: Thompson D, Easton D. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 2001; 68: Ford D, Easton DF, Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The breast cancer linkage consortium. Am J Hum Genet 1998; 62: Basham VM, Lipscombe JM, Ward JM et al. BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res 2002; 4: R2. 20 Fackenthal JD, Marsh DJ, Richardson AL et al. Male breast cancer in Cowden syndrome patients with germline PTEN mutations. J Med Genet 2001; 38: Ottini L, Masala G, D Amico C et al. BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. Cancer Res 2003; 63: Frank TS, Deffenbaugh AM, Reid JE et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of individuals. J Clin Oncol 2002; 20: Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 2002; 94: Harnden DG, Maclean N, Langlands AO. Carcinoma of the breast and Klinefelter s syndrome. J Med Genet 1971; 8: Hultborn R, Hanson C, Köpf I, Verbiené I, Warnhammar E, Weimarck A. Prevalence of Klinefelter s syndrome in male breast cancer patients. Anticancer Res 1997; 17: Meijers-Heijboer H, van den Ouweland A, Klijn J et al. Low-penetrance susceptibility to breast cancer due to CHEK2 (*) 1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 2002; 31: Syrjäkoski K, Kuukasjärvi T, Auvinen A, Kallioniemi OP. CHEK2 1100delC is not a risk factor for male breast cancer population. Int J Cancer 2004; 108: Ohayon T, Gal I, Baruch RG, Szabo C, Friedman E. CHEK2*1100delC and male breast cancer risk in Israel. Int J Cancer 2004; 108: McClure JA, Higgins CC. Bilateral carcinoma of male breast after estrogen therapy. J Am Med Assoc 1951; 146: Symmers WS. Carcinoma of breast in trans-sexual individuals after surgical and hormonal interference with the primary and secondary sex characteristics. Br Med J 1968; 2: Karlsson CT, Malmer B, Wiklund F, Grönberg H. Breast cancer as a second primary in patients with prostate cancer estrogen treatment or association with family history of cancer? J Urol 2006; 176: Ganly I, Taylor EW. Breast cancer in a trans-sexual man receiving hormone replacement therapy. Br J Surg 1995; 82: Pritchard TJ, Pankowsky DA, Crowe JP, Abdul-Karim FW. Breast cancer in a male-to-female transsexual. A case report. JAMA 1988; 259: El-Gazayerli MM, Abdel-Aziz AS. On bilharziasis and male breast cancer in Egypt: a preliminary report and review of the literature. Br J Cancer 1963; 17: Guénel P, Cyr D, Sabroe S et al. Alcohol drinking may increase risk of breast cancer in men: a European population-based case-control study. Cancer Causes Control 2004; 15: Sørensen HT, Friis S, Olsen JH et al. Risk of breast cancer in men with liver cirrhosis. Am J Gastroenterol 1998; 93: Weiderpass E, Ye W, Adami HO, Vainio H, Trichopoulos D, Nyrén O. Breast cancer risk in male alcoholics in Sweden. Cancer Causes Control 2001; 12: Griffin JE, Wilson JD. Disorders of the testes and the male reproductive tract. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds). Textbook of Endocrinology, 9th Edition, WB Saunders, Philadelphia, 1998; Ewertz M, Holmberg L, Tretli S, Pedersen BV, Kristensen A. Risk factors for male breast cancer a case-control study from Scandinavia. Acta Oncol 2001; 40: Johnson KC, Pan S, Mao Y. Risk factors for male breast cancer in Canada, Eur J Cancer Prev 2002; 11: D Avanzo B, La Vecchia C. Risk factors for male breast cancer. Br J Cancer 1995; 71: Hsing AW, McLaughlin JK, Cocco P, Co Chien HT, Fraumeni JF Jr. Risk factors for male breast cancer (United States). Cancer Causes Control 1998; 9: Thomas DB, Jimenez LM, McTiernan A et al. Breast cancer in men: risk factors with hormonal implications. Am J Epidemiol 1992; 135: Sasco AJ, Lowenfels AB, Pasker-de Jong P. Review article: epidemiology of male breast cancer. A meta-analysis of published case-control studies and discussion of selected aetiological factors. Int J Cancer 1993; 53: Ron E, Ikeda T, Preston DL, Tokuoka S. Male breast cancer incidence among atomic bomb survivors. Male breast cancer incidence among atomic bomb survivors. J Natl Cancer Inst 2005; 97: McLaughlin JK, Malker HS, Blot WJ, Weiner JA, Ericsson JL, Fraumeni JF Jr. Occupational risks for male breast cancer in Sweden. Br J Ind Med 1988; 45: Meguerditchian AN, Falardeau M, Martin G. Male breast carcinoma. Can J Surg 2002; 45: Ozet A, Yavuz AA, Kömürcü S et al. Bilateral male breast cancer and prostate cancer: a case report. Jpn J Clin Oncol 2000; 30:

11 16 KM Field et al. 49 Dong C, Hemminki K. Second primary breast cancer in men. Breast Cancer Res Treat 2001; 66: Auvinen A, Curtis RE, Ron E. Risk of subsequent cancer following breast cancer in men. J Natl Cancer Inst 2002; 94: Giordano SH, Buzdar A, Hortobagyi GN. Breast cancer in men. Ann Intern Med 2002; 137: Fentiman I, Fourquet A, Hortobagyi AN. Male breast cancer. Lancet 2006; 367: Murphy CE, Carderb P, Lansdown MRJ, Speirs V. Steroid hormone receptor expression in male breast cancer. EJSO 2006; 32: Rayson D, Erlichman C, Suman VJ et al. Molecular markers in male breast carcinoma. Cancer 1998; 83: Meijer-van Gelder ME, Look MP, Bolt-de Vries J, Peters HA, Klijn JG, Foekens JA. Clinical relevance of biologic factors in male breast cancer. Breast Cancer Res Treat 2001; 68: Speirs V, Carder P, Lane S. Oestrogen receptor a: what it means for patients with breast cancer. Lancet Oncol 2004; 5: Blin N, Kardaś I, Welter C et al. Expression of the c-erbb2 proto-oncogene in male breast carcinoma: lack of prognostic significance. Oncology 1993; 50: Bloom KJ, Govil H, Gattuso P, Reddy V, Francescatti D. Status of HER-2 in male and female breast carcinoma. Am J Surg 2001; 182: Muir D, Kanthan R, Kanthan SC. Male versus female breast cancers. A population-based comparative immunohistochemical analysis. Arch Pathol Lab Med 2003; 127: Bärlund M, Kuukasjärvi T, Syrjäkoski K, Auvinen A, Kallioniemi A. Frequent amplification and overexpression of CCND1 in male breast cancer. Int J Cancer 2004; 111: Nahleh Z, Girnius S. Male breast cancer: a gender issue. Nat Clin Pract Oncol 2006; 3: Anelli A, Anelli TF, Youngson B, Rosen PP, Borgen PI. Mutations of the p53 gene in male breast cancer. Cancer 1995; 75: Members of the Breast Cancer Disease Site Group, C.C.O.Baseline Staging Tests in Primary Breast Cancer Practice Guideline Report # [Cited April 2007.] Available from: 64 Hinrichs CS, Watroba NL, Rezaishiraz H et al. Lymphedema secondary to postmastectomy radiation: incidence and risk factors. Ann Surg Oncol 2004; 11: Macdonald G, Paltiel C, Olivotto IA, Tyldesley S. A comparative analysis of radiotherapy use and patient outcome in males and females with breast cancer. Ann Oncol 2005; 16: Wang-Rodriguez J, Cross K. Gallagher S et al. Male breast carcinoma: correlation of ER, PR, Ki-67, Her2- Neu, and p53 with treatment and survival, a study of 65 cases. Mod Pathol 2002; 15: Goss PE, Reid C, Pintilie M, Lim R, Miller N. Male breast carcinoma: a review of 229 patients who presented to the Princess Margaret Hospital during 40 years: Cancer 1999; 85: Pich A, Margaria E, Chiusa L. Oncogenes and male breast carcinoma: c-erbb-2 and p53 coexpression predicts a poor survival. J Clin Oncol 2000; 18: Sorlie T. Molecular portraits of breast cancer: tumour subtypes as distinct disease entities. Eur J Cancer 2004; 40: Martin Gomez T, Torio B, Ruiz I, Arranz F, Arizcun A. Immunophenotypic profiles of male breast cancer. Abstract # Journal of Clinical Oncology, ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), Boughey JC, Bedrosian I, Meric-Bernstam F et al. Comparative analysis of sentinel lymph node operation in male and female breast cancer patients. J Am Coll Surg 2006; 203: Albo D, Ames FC, Hunt KK, Ross MI, Singletary SE, Kuerer HM. Evaluation of lymph node status in male breast cancer patients: a role for sentinel lymph node biopsy. Breast Cancer Res Treat 2003; 77: Goyal A, Horgan K, Kissin M et al. Sentinel lymph node biopsy in male breast cancer patients. Eur J Surg Oncol 2004; 30: Schuchardt U, Seegenschmiedt MH, Kirschner MJ, Renner H, Sauer R. Adjuvant radiotherapy for breast carcinoma in men: a 20-year clinical experience. Am J Clin Oncol 1996; 19: Chakravarthy A, Kim CR. Post-mastectomy radiation in male breast cancer. Radiother Oncol 2002; 65: Truong PT, Olivotto I, Whelan TJ, Levine M. Steering committee on clinical practice guidelines for the care and treatment of breast cancer, clinical practice guidelines for the care and treatment of breast cancer: 16. Locoregional post-mastectomy radiotherapy. CMAJ 2005; 170: Recht A, Edge S, Solin LJ et al.; American Society of Clinical Oncology. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001; 19: Giordano SH, Perkins GH, Broglio K et al. Adjuvant systemic therapy for male breast carcinoma. Cancer 2005; 104: Margaria E, Chiusa L, Ferrari L, Dal Canton O, Pich A. Therapy and survival in male breast carcinoma: a retrospective analysis of 50 cases. Oncol Rep 2000; 7: Ribeiro G, Swindell R. Adjuvant tamoxifen for male breast cancer (MBC). Br J Cancer 1992; 65: Jaiyesimi IA, Buzdar AU, Sahin AA, Ross MA. Carcinoma of the male breast. Ann Intern Med 1992; 117:

12 Review of treatment for male breast cancer Patterson JS, Battersby LA, Bach BK. Use of tamoxifen in advanced male breast cancer. Cancer Treat Rep 1980; 64: Gennari R, Curigliano G, Jereczek-Fossa BA et al. Male breast cancer: a special therapeutic problem. Anything new? (Review) Int J Oncol 2004; 24: Anelli TF, Anelli A, Tran KN, Lebwohl DE, Borgen PI. Tamoxifen administration is associated with a high rate of treatment-limiting symptoms in male breast cancer patients. Cancer 1994; 74: Turner KJ, Morley M, Atanassova N, Swanston ID, Sharpe RM. Effect of chronic administration of an aromatase inhibitor to adult male rats on pituitary and testicular function and fertility. J Endocrinol 2000; 164: Mauras N, O Brien KO, Klein KO, Hayes V. Estrogen suppression in males: metabolic effects. J Clin Endocrinol Metab 2000; 85: Trunet PF, Mueller P, Bhatnagar AS, Dickes I, Monnet G, White G. Open dose-finding study of a new potent and selective nonsteroidal aromatase inhibitor, CGS 20, 267, in healthy male subjects. J Clin Endocrinol Metab 1993; 77: Bhatnagar AS, Müller P, Schenkel L, Trunet PF, Beh I, Schieweck K. Inhibition of estrogen biosynthesis and its consequences on gonadotrophin secretion in the male. J Steroid Biochem Mol Biol 1992; 41: Giordano SH, Valero V, Buzdar AU, Hortobagyi GN. Efficacy of anastrozole in male breast cancer. Am J Clin Oncol 2002; 25: Zabolotny BP, Zalai CV, Meterissian SH. Successful use of letrozole in male breast cancer: a case report and review of hormonal therapy for male breast cancer. J Surg Oncol 2005; 90: Italiano A, Largillier R, Marcy PY. [Complete remission obtained with letrozole in a man with metastatic breast cancer]. Rev Med Interne 2004; 25: Giordano SH, Hortobagyi GN. Leuprolide acetate plus aromatase inhibition for male breast cancer. J Clin Oncol 2006; 24: e National Cancer Institute Clinical Trials: Phase II Study of Goserelin and Anastrozole in Men With Estrogen Receptor- or Progesterone Receptor-Positive Recurrent or Metastatic Breast Cancer. Protocol ID: SWOG-S0511 NCT Cited April Available from: Nahleh ZA. Hormonal therapy for male breast cancer: a different approach for a different disease. Cancer Treat Rev 2006; 32: Agrawal A, Cheung KL, Robertson JF. Fulvestrant in advanced male breast cancer. Breast Cancer Res Treat 2007; 101: Farrell J. Effect of orchiectomy on skeletal metastases from carcinoma of the male breast. Science 1941; 95: Kantarjian H, Yap HY, Hortobagyi G, Buzdar A, Blumenschein G. Hormonal therapy for metastatic male breast cancer. Arch Intern Med 1983; 143: Bagley CS, Wesley MN, Young RC, Lippman ME. Adjuvant chemotherapy in males with cancer of the breast. Am J Clin Oncol 1987; 10: Patel HZ 2nd, Buzdar AU, Hortobagyi GN. Role of adjuvant chemotherapy in male breast cancer. Cancer 1989; 64: Donegan WL, Redlich PN, Lang PJ, Gall MT. Carcinoma of the breast in males: a multiinstitutional survey. Cancer 1998; 83: Yildirim E, Berberoglu U. Male breast cancer: a 22-year experience. Eur J Surg Oncol 1998; 24: Rudlowski C, Rath W, Becker AJ, Wiestler OD, Buttner R. Trastuzumab and breast cancer. N Engl J Med 2001; 345: Brain K, Williams B, Iredale R, France L, Gray J. Psychological distress in men with breast cancer. J Clin Oncol 2006; 24: Iredale R, Williams B, Brain K, France E. Breast cancer in men: group is exploring issues for men with breast cancer across the United Kingdom. BMJ 2003; 327: Iredale R, Brain K, Williams B, France E, Gray J. The experiences of men with breast cancer in the United Kingdom. Eur J Cancer 2006; 42: Williams BG, Iredale R, Brain K, France E, Barrett-Lee P, Gray J. Experiences of men with breast cancer: an exploratory focus group study. Br J Cancer 2003; 89: National Breast Cancer Centre.Breast Cancer in Men [Cited April 2007.] Available from: breasthealth.com.au/men.