42 Male C. Bernard-Marty, E. Azambuja, L. Dal Lago, M.J. Piccart, and F. Cardoso

42.1 Introduction

The earliest reference to (BC) in men dates from 3000–2500 BCE, on an Egyptian papyrus [11], and the first clinical report was described in the 14th cen- tury by John of Arderne [71]. Carcinoma of the male breast is a relatively rare disease that accounts for less than 1% of all cases of cancer in men. Therefore, BC in men has largely taken a back seat to the worldwide effort to control this disease in women. Similarly, the literature regarding male BC consists mainly of case-control and retrospective studies involv- ing small numbers of patients [28]. The statistical accuracy of the clinical character- istics of male BC is not fully established and knowledge relevant to specific aspects of the disease in men is still limited. Consequently, treatment strategies have been largely guided by extrapolation from experience in women. In this chapter, the available information on risk, prognostic factors, clinical fea- tures, and treatment modalities of male BC has been summarized. Tailored pro- spective clinical trials in this disease, through large Intergroup networks, should be initiated.

42.2 Incidence

According to the American Cancer Society, of the 212,600 new cases of BC diag- nosed in 2003, 1,300 (1%) were diagnosed in men and resulted in 400 deaths (30%) [39]. In contrast to the increasing incidence of BC in women, the incidence of BC in men has remained stable over the past 4 decades [47]. The median age of diag- nosis is 68 years (range: 5–93 years), approximately 5–10 years later than in women [28, 71]. The incidence increases with age and the bimodal age distribution seen in women is absent in men [28]. The incidence of male BC varies by geographical location, higher in the USA and UK, and is lower in Finland and Japan. In parts of Africa, the high incidence of male BC, which runs parallel to the high female cervical cancer rate, has led to the hy- pothesis of a relationship with sexually transmitted disease(s), or could be explained by an increased incidence of (a known risk factor for male BC) in these countries [91]. 904 Male Breast Cancer

42.3 Risk Factors

42.3.1 Hormonal Factors

A recent review of published literature by the MD Anderson Breast Cancer team has listed the main risk factors for male BC (Table 42.1) [28]. Many of them involve ab- normalities in and androgen balance (excess of estrogen and/or lack of an- drogen), which indicates that BC in men, as in women, may be hormonally driven [20, 28, 81]. An example of risk factors related to hormonal levels is , which causes increased peripheral aromatization of estrogen.

42.3.2 Testicular Abnormalities

An elevated risk of BC has been observed in patients with prior history of unde- scended testis, congenital inguinal hernia, orchidectomy, mumps orchitis, testicular injury, and infertility, although the association between these conditions and the development of BC in men remains unclear [91, 93]. The strongest known risk factor for male BC is Klinefelter’s syndrome, a con- dition that results from the inheritance of an additional X chromosome (47, XXY karyotype). These men have atrophic testis, , high levels of gonado-

Table 42.1 Risk factors for male breast cancer (BC) Testicular abnormalities Obesity Undescended testis Liver conditions Congenital inguinal hernia Cirrhosis Orchidectomy Orchitis Schistosomiasis Testicular injury Drugs Infertility Digoxin Klinefelter’s syndrome Thioridazine Familial history Marijuana Benign breast conditions Exogenous estrogen discharge Amphetamines Breast cysts Environmental factors Breast trauma Heat exposure Radiation exposure Head trauma Jewish ancestry Smoking Occupational exposure 42.3 Risk Factors 905 tropins, and low levels of testosterone. Their BC risk is up to 50-fold higher than in men with a normal genotype [37].

42.3.3 Benign Breast Conditions

An increased risk of BC in men has also been associated with nipple discharge, breast cysts, or history of breast trauma [92]. Gynecomastia is probably not a signifi- cant risk factor [28, 60, 102] since its incidence in male BC patients (6–38%) [104] is not higher than in the general population (35% of clinical and 40% of pathological gynecomastia) [10, 97].

42.3.4 Liver Conditions

Men with chronic liver disorders such as cirrhosis, chronic alcoholism, and schisto- somiasis are at increased risk of BC. The liver dysfunction means that they are unable to metabolize endogenous estrogen, resulting in a relative hyperestrogenism [88].

42.3.5 Drugs

Chronic use of drugs such as digoxin and thioridazine, chronic marijuana use, in- gestion of exogenous estrogen for treatment of prostate cancer [82], or hormonal replacement therapy in transsexuals [70] increases the risk of BC in men [71, 93].

42.3.6 Environmental Factors

The testicular function of workers in steel mills, blast furnaces, and rolling mills can be suppressed by chronic heat exposure [16]. Radiation exposure of men who work in electromagnetic fields or who are exposed to repeated fluoroscopy increases their risk of BC. Recently, a statistically significant association between and male BC incidence has been shown in a population of Japanese atomic bomb survivors [77]. Employers with more than 3 months exposure to gasoline and com- bustion products have an odds ratio for BC of 2.5 (1.3–5.4) [34].

42.3.7 Other Risk Factors

Other reported risk factors include head trauma through increased prolactin pro- duction and local chest trauma [61, 72]. A meta-analysis of seven case-controlled studies has revealed the characteristics of men “at high-risk” to be: never married, benign breast disease, Jewish ancestry, or history of BC in first-degree relatives [81]. 906 Male Breast Cancer

There is no evidence that male twins are at increased risk of BC when compared to the general population [96].

42.4 Genetics

Familial male BC was first described in 1889 [21, 44, 78, 98]. The genetic aberrations related to male and female BC are very similar.

42.4.1 BRCA1 and BRCA2

A positive family history is observed in 15–20% of male BC patients, compared to 7% of their female counterparts [28]. In women, mutations of the BRCA1 and BRCA2 genes are associated with a 50 and 80% risk of developing BC by the age of 60 years, respectively [101]. Numerous series of BRCA1 and BRCA2 mutations have been reported [12, 26, 35, 46, 62]. Male BC is a characteristic element of the BRCA2 phenotype. The lifetime risk of BC in male BRCA2 mutation carriers is approximately 80–100 times higher than in the general population, and BRCA2 mutations account for roughly 15% of all male BC [49]. Male BC is also reported in families with BRCA1 mutations, but the associ- ated risk seems to be lower [7]. Genetic testing criteria for men should perhaps be somewhat less strict than those for women, due to the rarity of the disease and the higher frequency of gene mutations. Men without cancer might be considered for testing if they have a fam- ily history of breast or ovarian cancer in a first- or second-degree relative, with BC diagnosed before age 50 years. Men with a diagnosis of BC should also be eligible for testing regardless of family history [49].

42.4.2 Other Alterations

Germline mutations in exons 2 and 3 encoding the DNA binding domain of the an- drogen receptor (AR) have been described (point mutation change Arg607 into Gln and Arg608 into Lys). These AR gene mutations suppress the activity of androgen in the breast cells, possibly leading to the development of BC as a result of loss of the protective effect of androgen [50]. A polymorphism of the CYP17 gene, a key regulator of the synthesis of andro- gens and , occurs significantly more frequently in male BC patients than in male controls (p = 0.038). The odds ratio for risk of developing BC in males with an allele C is 2.10 (95% confidence interval, CI = 1.04–4.27) [105]. However, no as- sociation has been described between this polymorphism of the CYP17 gene and BC in women. 42.5 Diagnosis 907

42.5 Diagnosis

42.5.1 Clinical Presentations

As reported above, the mean age of presentation of male BC is 68 years. Its most common presentation is a painless subareolar mass (50–97%), which is centrally located in 50–70% of cases, followed by the upper outer quadrant [33]. There is a slight predilection for the left breast (1.07:1) [28] and bilateral forms are rare (less than 2%) [13]. The median diameter of these masses is 3.0–3.5 cm (range: 0.5–12.5 cm) [71]. Others signs and symptoms are nipple retraction (10–51%), lo- cal pain (4–20%), nipple ulceration (4–17%), nipple discharge (1–12%), and nipple bleeding (2–9%) [28]. Edema and eczema can occur in 17–30% of cases, and Paget disease is present in 5%. Suspect axillary nodes are detected clinically in 40–55% of patients at the time of diagnosis [71]. The mean duration of symptoms before the diagnosis was 1–21 months in the earlier series, declining to 1–8 months in a more recent one [71]. A population-based analysis of 2,524 cases of male BC and 380,856 cases of fe- male BC showed that men were significantly older at diagnosis (p < 0.0001), more likely to present with later stage disease (p < 0.0001), had larger tumors (p < 0.0001), nodal involvement (p < 0.0001), ductal histology (p < 0.0001), and estrogen receptor (ER)-positive tumors (p < 0.0001) [29]. The distribution of the cases according to the disease stage at diagnosis has been described as follows: stage 0, 0–10%; stage I, 10–40; stage II, 15–45; stage III, 20–50; stage IV, 5–15% [104].

42.5.2 Mammographic Features

The main differential diagnoses in male BC are gynecomastia, breast abscess, metas- tases to the breast from other malignancies, and sarcoma not related to BC. Several characteristics could interfere with the mammographic diagnosis of BC: a diffuse increase in radiographic density in patients with gynecomastia can mask a carci- noma [33]. Moreover, there is a significant overlap in the mammographic appear- ances of benign nodular breast lesions and BC. Both may show either circumscribed or poorly defined margins. Coarse calcifications are seen in both benign and malig- nant masses [5]. Screening is not recommended for men because of the low incidence of BC among them [13]. To date, no data available are on the use of magnetic resonance imaging or 18fluorodeoxyglucose-positron emission tomog- raphy for male BC.

42.5.3 Prognostic Factors

As in women, axillary lymph node status, tumor size, histological grade and hor- mone receptor status have been shown to be significant prognostic factors in men with BC. 908 Male Breast Cancer

42.5.3.1 Node Status

Axillary lymph node involvement is the most important prognostic factor in male BC. In the literature, the 5-year survival for node-negative patients varies from 55 to 90%, versus 15–65% for node-positive patients [32, 36, 102, 104]. The rela- tive risk (RR) of death is over three times higher in node-positive patients com- pared to node-negative patients (p < 0.01) [36]. In a large retrospective review of 308 male BC patients, the disease-specific survival rate at 10 years for node-nega- tive and node-positive groups were 77% and 39%, respectively [19]. Intriguingly, survival was similar between 1,762 men without nodal involvement and 762 men with node-positive disease (median survival 139 months vs 136 months) in a recent retrospective study [29]. A possible reason for this outcome is that the majority of cases among men have a central location with a possible spread through the internal mammary chain.

42.5.3.2 Tumor Size

The 5-year survival rate is correlated with tumor size, with 83.3% for ≤ 30 mm ver- sus 15% for > 30 mm [104]. In a large retrospective review of 308 male BC patients, clinical tumor size and histological axillary status were the two major prognostic factors. The RR of death in node-negative patients was 1.0, 2.0, and 3.2 for T0–T1, T2, and T3–T4 groups, respectively. In node-positive patients, these RRs increased to 1.9, 3.9, and 6.0, respectively [19].

42.5.3.3 Grade

Tumor grade was also of prognostic importance, with 5-year survival rates of 76%, 66%, and 43% for disease grades 1, 2, and 3, respectively [75], and with 10-year survival rates of 93%, 66%, and 53% for disease grades 1, 2, and 3, respectively [29]. In a recent retrospective study, male BC presented a more aggressive clinical be- havior than female BC, related to higher grade at presentation, with 85% having grade 3 disease versus 50% in each stage-matched group of women [55]. In contrast, a study using data from the National Cancer Database, which includes more than 3,000 male BC cases, showed an almost identical distribution of grade and histo- logical type (with the exception of , which is extremely rare in men) [83].

42.5.3.4 Hormone Receptors

One major biological difference between male and female BC is the higher fre- quency of expression of ER and receptor (PR) in male BC: 81% and 42.6 Treatment of Localized Disease 909

74%, respectively [30]. In addition, ER positivity in men does not increase with age, as observed in women. Furthermore, the relationship between ER status and overall survival (OS) is uncertain, with some studies, showing a correlation between ER positivity and better survival [23, 29, 31]. The Surveillance Epidemiology, and End Results (SEER) database of 2,524 cases of male BC revealed that patients with PR- positive tumors had significantly better 10-year survival than those with PR-nega- tive disease (81% vs 71%) [29].

42.5.3.5 Age

In a Nordic study of 1,429 male BC patients, the relative survival rate, which is the ratio of observed/expected survival rates, varied between 47.7 and 63.3% at 5 years and between 41.7 and 53.2% at 10 years. A marked relationship was found between age at diagnosis and relative survival rate, with, surprisingly, the RR of dying from BC being lower in the young age group (RR = 0.39) than in the 40- to 49-year age group (RR = 0.63) [1]. This observation needs to be confirmed on a larger, indepen- dent data set.

42.5.4

The histological features of male BC are similar to those reported in women. The great majority of noninvasive tumors are (DCIS) [28], re- ported with a frequency of 0–17% in the literature. DCIS of the male breast differs from that of the female in that almost 75% of cases are low to intermediate grade [89]. The most frequent histopathological type of male BC is invasive ductal car- cinoma (70–90% of all patients) [13, 28, 71, 100]. Infrequent types are medullary, papillary, tubular, mucinous, and squamous carcinomas. Lobular carcinoma and lobular carcinoma in situ are very rare due to the absence of terminal lobules in the normal male breast [13]. The frequency of Paget disease and inflammatory carci- noma is the same as in women [89]. Sarcomas such as cystosarcoma phylloides, hemangiopericytomas, liposarcomas, and leiomyosarcoma have also been described [71]. Rare metastases from extrama- mmary tumors to the breast (0.5–3%) can arise in case of melanoma, lymphoma, lung, gastrointestinal, thyroid, and prostate carcinoma.

42.6 Treatment of Localized Disease

Due to the rarity of the disease, the optimal management of male BC is still un- known [8]. Treatment strategies are extrapolated from the female counterpart, with- out clear knowledge if they are indeed the best options. 910 Male Breast Cancer

42.6.1 Local Treatment

The main treatment for male BC is surgery. Primary standard treatment is a modi- fied with axillary dissection [13, 28, 71]. has a twofold decrease in local control rate, probably because of the limited amount of breast tissue and the central location of most tumors [19]. Conservative surgery may be used in selected cases, such as elderly patients or patients with concomitant comorbidities. In very small trials, the technique appears to confer the same advantages as in women [2, 69]. The recommended optimal treatment for DCIS is a simple mastectomy without axillary dissection, except if the lesion is of type or larger than 2.5 cm, since the risk of occult microinvasion is increased in these cases. The overall risk of recurrence of DCIS is around 20% at 5 and 10 years [18].

42.6.2 Adjuvant Radiotherapy

No prospective studies and only few retrospective studies have addressed the issue of postmastectomy radiation in male BC [24, 90]. Results are inconsistent due to the wide variation in indications and in radiation source, dose, and techniques. A recent large retrospective study reported local recurrence rates ranging from 3 to 20% [15]. In general, the recommendations for postmastectomy radiation are similar to those for female BC, and margin status, tumor size, and number of positive nodes should be taken in consideration when making a decision regarding adjuvant irradiation [68]. Since adjuvant treatment with radiotherapy is given primarily to decrease local recurrences, some authors recommend the treatment of small, node-negative, male BCs with modified radical mastectomy alone and to use adjuvant postmastectomy radiation to the chest wall and regional nodes in patients at high risk of local recur- rence (i.e., those with a large tumor, node positivity, or advanced-stage disease) [15]. Radiating internal mammary lymph nodes has been advocated on the basis of the central location of the large majority of primary tumors, but this recommendation is controversial [71].

42.6.3 Adjuvant

Since the majority of male BCs are ER-positive tumors, adjuvant tamoxifen therapy for 5 years is frequently recommended. The 5-year actuarial survival and disease- free survival (DFS) were statistically significantly improved in 39 patients treated with tamoxifen compared to a historical control group (61% vs 44%, and 56% vs 25%, respectively) [74]. Based on these data and the knowledge of the benefit of adjuvant tamoxifen in female BC patients, male patients with receptor-positive BC should receive tamoxifen for 5 years [28]. The most common side effects described with tamoxifen in men are decreased libido (29%), weight gain (25%), hot flashes 42.7 Metastatic Disease 911

(21%), mood alteration (21%), depression (17%), insomnia (12%), and thrombosis (4%) [4]. These side effects are severe enough to lead to treatment interruption in about 20% of cases. To date, no data are available regarding the use of aromatase inhibitors or gosere- lin (or any other hormonal treatment) in the adjuvant setting of male BC.

42.6.4 Adjuvant Chemotherapy

There are limited data about adjuvant chemotherapy in male BC. A National Can- cer Institute nonrandomized phase II study of 24 male BC patients treated with adjuvant , , and 5- (CMF) for up to 12 cycles has shown a 5-year survival rate of more than 80% [6]. An MD Anderson Cancer Center study of 11 men with BC, 10 of whom were treated with adjuvant chemotherapy of 5-fluorouracil, , and cyclophosphamide (FAC) and 1 with CMF, has demonstrated an estimated 5-year survival rate of 91% and a DFS of 63% [66]. Of note, no data with taxanes in male BC are available. One study has reviewed 13 male BC patients treated with high-dose chemotherapy and autologous hematopoietic stem-cell support and reported a toxicity and efficacy similar to those observed in female BC patients [54]. These data from a limited number of patients and nonrandomized studies sug- gest a reduction in the risk of recurrence and death with the use of adjuvant chemo- therapy. An ongoing adjuvant phase III trial (Southwestern Group, SWOG- S0221) is enrolling male and female BC, and compares four schedules of adjuvant anthracycline-based and taxane-based chemotherapy in patients with high-risk disease (node negative and tumor ≥ 2 cm or node positive). These patients will be randomized to one of four arms as follows: arm 1, doxorubicin 60 mg/m2 adminis- tered intravenously (IV), cyclophosphamide 600 mg/m2 IV, and pegfilgrastim 6 mg administered subcutaneously (SC) every 14 days for six courses followed by pacli- taxel 175 mg/m2 IV over 3 h and pegfilgrastim 6 mg SC every 14 days for 6 courses; arm 2, doxorubicin IV, oral cyclophosphamide on days 1–7, and filgrastim 5 µg/kg SC on days 2–7 every 7 days for 15 courses followed by paclitaxel as in arm 1; arm 3, doxorubicin, cyclophosphamide, and pegfilgrastim as in arm 1 followed by pacli- taxel 80 mg/m2 IV over 1 h every 7 days for 12 courses; arm 4, doxorubicin, cyclo- phosphamide, and pegfilgrastim as in arm 2 followed by paclitaxel IV as in arm 3 (http://www.swog.org).

42.7 Metastatic Disease

Of all treated male BC patients, 2–29% will have a local recurrence and 18–54% will eventually develop distant metastases. The median survival time after metastatic disease presentation is 26.5 months [80]. 912 Male Breast Cancer

42.7.1 Hormonal Therapy

The first treatment strategy for metastatic male BC described in 1942 was bilateral orchidectomy [25]. This procedure yielded objective response rates ranging from 31 to 67% [45, 57, 94] and mean remission duration varied between 17 and 30 months [41]. Other ablative therapies such as adrenalectomy and hypophysectomy were abandoned due to unacceptable toxicity despite their good response rates (80% and 56%, respectively) [42, 48, 94]. Additive hormonal therapies have shown activity in men with metastatic BC and less toxicity. Since the majority of BC in men expresses ER, tamoxifen is the endo- crine treatment of choice for metastatic disease, with response rates ranging from 32 to 81% [38, 67]. High response rates have also been reported with numerous other hormonal agents such as cyproterone acetate (43%) [38, 51], medroxyproges- terone (52%) [38, 64], androgens (75%), (57%), and aminoglutethi- mide (40%) [38]. A retrospective study of 55 patients treated with diethylstilboestrol (DES) has shown a response rate of 38%, mainly in patients with soft-tissue disease (33/55, 60%) and never in patients with bone metastases (8/55, 14%) [76]. The side effects of DES were rare. Used in ten men with recurrent or progressive BC, buserelin (a luteinizing hor- mone-releasing hormone, LHRH, analog) alone or in combination with the antian- drogen flutamide yielded nine partial responses, five as monotherapy and four as combination [22]. The side effects were mild hot flashes, decrease or loss of libido, transient increase in pain, and impotence. The combination of buserelin and cy- proterone acetate resulted in an objective response rate of 64% (7 out of 11 patients) with a median duration of 11.5 months [53]. To date, there are no data available on goserelin. A response rate of 19% has been reported with the use of aminogluthetimide in 21 male metastatic BC patients [51]. The MD Anderson Breast Cancer team has identified five male patients with metastatic disease treated with anastrozole: the best response was a stable disease in three cases [30]. A possible reason for this low response rate is that in men approximately 80% of estrogens derive from the aroma- tization of precursor androgens, whereas 20% are secreted directly from the testis and, therefore, are not blocked by aromatase inhibitors alone. This implies that the optimal way of administering an in men with BC is in combina- tion with an LHRH analog.

42.7.2 Chemotherapy

Chemotherapy for metastatic male BC has been used as second-line treatment after endocrine therapy failure, in ER-negative patients, or in the case of life-threaten- ing lesions. The majority of reports of metastatic BC in men treated with cytotoxic agents are case reports or small series. Objective responses have been described with single agents such as 5-fluorouracil, melphalan, chlorambucil, thiotepa, cyclophos- phamide, and methotrexate [52, 103]. Data from a retrospective study of 14 patients 42.8 Immunohistochemical Differences Between Male and Female BC 913 with recurrent or progressive male BC after endocrine therapy failure suggest that an anthracycline-based combination regimen could be better than the sequential single-agent approach [52], but the limited size of the patient population precludes any valid conclusion. Due to the lack of clinical trials, questions regarding the role of combination che- motherapy, optimal drugs, schedules, and duration of treatment remain unresolved. There is an urgent need for international, multicentric, well-designed clinical trials for both early and advanced male BC.

42.8 Immunohistochemical Differences Between Male and Female BC

Numerous retrospective studies have shown different immunohistochemical char- acteristics leading to the concept that BC in men and in women may not be com- pletely superimposable biological entities (see Table 42.2). As mentioned before, male BC differs from BC in women in that 81% are ER positive and 74% are PR positive [28]. Efforts have been directed at finding new prognostic factors.

42.8.1 HER-2 expression

The overexpression of HER-2 in male BC has been described in 0–45% of samples [40, 65, 73, 95, 100]. The first reports have possibly overestimated this number by

Table 42.2 Immunohistochemical features of male BC. OS Overall survival, RFS recurrence-free survival, MMP metalloproteinase Marker Comments Association with survival 81% positivity Progesterone receptor 74% positivity HER-2 0–45% positivity No association with OS p53 Lower expression than in females Association with OS (?) Bcl-2 Higher expression than in females No prognostic value Cyclin D1 50% positivity Inverse association with PFS c-myc 12–100% positivity No prognostic value p21waf1 and p27Kip1 Higher expression than in females Pepsinogen C 76% positivity No association with OS Lysozyme 40% positivity Shorter RFS. No difference in OS Apoliprotein D Association with longer RFS and OS in high levels MMP-2 and MMP-9 Higher expression than in females 914 Male Breast Cancer using immunohistochemistry (IHC), no standardized antibody preparations, and various definitions of positivity. The first study using fluorescence in situ hybridiza- tion (FISH) reported no gene amplification in the 58 tested samples [9]. A recent study of formalin-fixed, paraffin-embedded archival material from 99 primary male BC patients has evaluated HER-2 using both IHC and FISH [79]. The level of HER- 2 positivity in male BC was somewhat lower than that usually observed in women (15.1% by IHC and 11.1% by FISH). This low level of HER-2 positivity does not seem to be correlated with tumor stage, histological grade, ER/PR status, or lymph node status [79].

42.8.2 Cell-Cycle Regulatory Proteins

Mutations in the tumor suppressor gene p53 involved in cell-cycle blockage, apop- tosis, and cell differentiation have been reported to be lower or equivalent in men with BC as compared to women [28, 40, 55, 65, 73, 95, 99]. Some studies have asso- ciated p53 mutations with a poor outcome [28, 40, 100], while others have reported no association with specific survival probability [58, 73, 87]. The proto-oncogene Bcl-2, which inhibits apoptosis and promotes cell growth, was found to be signifi- cantly higher in male BC than in female BC patients [28, 55, 95]. This high rate of Bcl-2 positivity, however, was of no prognostic value [28, 55, 73, 95]. Cyclin D1, which is related to cell-cycle regulation, was overexpressed in approximately 50% of male BC cases, similar to the rate seen in women with BC [28, 73]. Low levels of cy- clin D1 have been associated with significantly decreased progression-free survival [28, 73]. In male BC, the reported frequency of c-myc overexpression, a cellular proliferative signal in breast tumorigenesis, has been extremely variable, ranging from 12 to 100%, and no association was found between this marker and specific survival probability [58]. Studies of p21waf1, a downstream effector of p53, have also led to conflicting data on its prognosis relevance. Upregulation of p21waf1 and of the cyclin-dependent kinase inhibitor p27Kip1 were more frequent in men than in women with BC [17]. There was a significant inverse correlation between p21waf1 and p27Kip1 overexpression and HER-2 positivity (64% and 82% of HER-2 negative respectively) [17]. A case report of karyotype alterations in male breast tumor cells has shown tri- somy of chromosomes 8 and 9, monosomy of chromosomes 12 and 17, and struc- tural rearrangement of chromosome 17, which contains several genes important to the development and progression of BC (p53, HER-2, and BRCA1) [14]. This overrepresentation of chromosome 17, already described in female BC, has been confirmed with a molecular technique [59].

4.8.3 Androgen-Regulated Proteins

Since the male sex hormones have been considered protective agents in the etio- pathogenesis of male BC, as suggested by an increased risk in patients with hypoan- 42.8 Immunohistochemical Differences Between Male and Female BC 915 drogenism, the prognostic role of ARs, and the expression of the androgen-regu- lated proteins have been studied. Contrary to female BC, in which the expression of ARs is associated with a longer DFS, due in part to their association with ERs, the relationship between ARs and ERs in male BC is variable: one study reported shorter survival correlated with the expression of ARs in tumor tissue (74% vs 33% for patients with AR-negative and AR-positive tumors, respectively, p = 0.029 for DFS; 71% vs 57%, p = 0.05 for OS) [46]; other studies have shown a positive associa- tion [63] or no association at all [43]. Production of prostate-specific antigen (PSA) is seen in some BC cell lines after treatment with androgens, suggesting an intact pathway. In a retrospective analy- sis of 26 patients a functional AR pathway in male BC was evaluated through the expression of androgen-regulated proteins, PSA, and prostate-specific acid phos- phatase (PSAP) [43]. AR expression was seen in 73% of cases. PSA expression was not correlated with AR expression, suggesting the existence of alternative pathways for the control of PSA expression, nor with classical prognosis factors such as ER, PR, and lymph node status. PSAP expression was not detected in any of the cases, suggesting that this marker might be useful for distinguishing primary BC from metastatic prostatic tumors. Few proteins are induced by androgens. Of these, pepsinogen C, a proteolytic enzyme, and apolipoprotein D (ApoD), a protein component of the human plasma lipid transport system, have been studied. Pepsinogen C is frequently expressed in male BC (76%) and is detected in all patients with gynecomastia [86]. Higher levels of pepsinogen C are found in well- and moderately differentiated tumors (grades 1 and 2) in comparison with poorly differentiated tumors (grade 3; p = 0.032), but this had no significant association with OS. ApoD is also expressed by a significant percentage of male BCs of favorable outcome [85]: high values of ApoD, present in 46% of patients, were associated with longer recurrence-free survival (RFS) and OS (p = 0.0003 and p = 0.04, respectively). In a multivariate analysis, ApoD values and node status were significant independent indicators of RFS. Of note, lysozyme, one of the major protein components of human milk, was expressed in 40% of male BC cases and was not detected in male patients with gynecomastia [84]. The RFS was shorter in lysozyme-positive tumors than in lysozyme-negative tumors (p < 0.05), although no impact on OS could be shown in this small, retrospective study involv- ing 60 patients.

42.8.4 Other Features

Increased matrix metalloprotease (MMP) activity could be responsible for the highly invasive tumor phenotype and for the occurrence of metastasis. The results of a ret- rospective study, which quantified the expression of MMP in male BC, suggested a stronger proteolytic activity in men compared to women with BC: proMMP-2, proMMP-9 concentrations, and active MMP-2 and MMP-9 tissue concentrations were higher, and MMP-2 and MMP-9 staining was more intense and diffuse in male patients [27]. 916 Male Breast Cancer

BRCA2 mutations had a significant association with histological grade (p = 0.02) and HER-2 positivity (p = 0.004) [62]. There were no differences between mutation carriers and noncarriers with respect to clinical stage and ER and PR status, but carriers tended to be younger at diagnosis [35]. In another study, patient carriers and noncarriers did not differ with respect to tumor size, lymph node involvement, histological grade, and ER, PR, and AR status [46]. However, the 5-year DFS and OS were significantly decreased in BRCA2-positive patients versus BRCA2-negative patients (p = 0.017 and p = 0.006, respectively). Unfortunately, all of these studies of new prognostic factors for male BC suffer from their small size, marked heterogeneity, lack of standardized methodology (use of different primary antibodies, and variations in tissue fixation and immunostain- ing techniques). Therefore, they can only be seen as hypothesis-generating studies.

42.9 Comparison of Outcome Between Male and Female BC

42.9.1 Is there a difference in prognosis?

Male BC has been considered a sufficiently different condition from its female coun- terpart to warrant exclusion from most BC trials. An online search of the National Cancer Institute’s clinical trial database revealed that only 4% of BC phase III trials are open to male patients [56]. However, it is unclear whether BC has a different prognosis and treatment responsiveness in males and females. In a male BC retrospective study, with 20 years of follow-up in the UK, 41 men with BC were compared to a group of women matched for the major prognostic factors and with an unmatched series of women treated over the same period [99]. Regarding DFS and OS, male and female BC showed a similar outcome when they were matched for the known prognostic factors. The worse overall outcome seen in the male group is probably due to a difference in the distribution of relevant prog- nostic factors, mainly the preponderance of grade 3 tumors. In a review of the literature, male BC patients have shown a less favorable out- come than women, probably as a result of the higher incidence of node-positive (60% in men versus 38% in women) and stage III disease (22% in men versus 6% in women), since no difference in survival was noted when men and women were age- and stage-matched [71]. To determine if male and female breast carcinogenesis is similar, a large analysis was performed using the SEER database. It compared 1,456 male BC patients with 50,730 female BC patients aged less than 50 years, and 165,334 female BC patients aged over 50 years. Favorable prognostic factors reflective of tumor biology (i.e., nuclear grade and hormone receptor expression) were more common in men and postmenopausal women, suggesting that male BC may be closer to postmenopausal BC [3] than to premenopausal BC. 42.9 Comparison of Outcome Between Male and Female BC 917

42.9.2 Potential Explanations

The higher frequency of node involvement and advanced stage would suggest a bio- logically aggressive tumor with poor histological differentiation and negative hor- mone receptor. However, this is not the case for the majority of male BC patients. A potential explanation for the higher stage in men is the delayed diagnosis and consequent larger tumor size at presentation. Active screening campaigns for early detection in women have been a major step forward in recent decades, but these ef- forts are lacking for male BC. Notwithstanding the fact that routine mammography is not used as a screening procedure in men, the diagnosis of palpable breast disease is anatomically easier in male patients. The aggressive behavior of male BC could also result from the anatomical difference between male and female , result- ing in a higher ability to spread to other tissues, reaching the subareolar and axillary lymph nodes and blood circulation more easily. Many studies have confirmed that male BC has a higher proportion of ER posi- tivity than female BC, although this finding does not correlate with a better progno- sis, as it does in women. One possibility is that hormone-receptor-positive are a consequence of aberrant steroid receptor upregulation, probably due to the low levels of circulating estrogens [55].

Fig. 42.1 Proposed algorithm for management of early male breast cancer. HR+ Hormone-recep- tor-positive, N– lymph-node negative, N+ lymph-node positive, CT chemotherapy, HT hormone therapy 918 Male Breast Cancer

New techniques, such as the use of DNA microarrays, might provide not only an improved biologic characterization of male BC, but also treatment tailoring based on distinct molecular profiles with a prognostic and/or predictive value. Large- scaled collaborative efforts are needed for this progress to materialize.

42.10 Conclusions

Our clinical understanding of BC in men comes largely from single-institution ret- rospective series, involving in general less than 100 patients diagnosed and treated over a period of 20–40 years. In addition, these studies often show conflicting data.

Fig. 42.2 Proposed algorithm for management of advanced male breast cancer. PD Progressive disease, CMF cyclophosphamide + methotrexate + 5-fluorouracil, A(E)C adriamycin (epirubicin) + cyclophosphamide, FE(A)C 5-fluorouracil + epirubicin (adriamycin) + cyclophosphamide, A+T anthracycline + taxane, +/– with or without References 919

BC in men and women differ with regard to age at diagnosis, frequency of the histological types, and frequency of expression of steroid hormone receptors and other molecular markers. Despite these biological differences, the clinical outcome for male BC seems to be similar to that of female BC when patients are matched for age, stage of cancer and treatment. The reasons for this paradox are unknown. In the near future, it is expected that a better understanding of the biology of BC, through the use of genomics/proteomics will allow us to dissect the similarities and the dif- ferences in breast tumors between men and women. Due to its rarity, absence of specific clinical trials, and exclusion of male patients from most of the existing BC trials, treatment of this disease is achieved by extrapo- lation from female BC management guidelines. However, as explained above, this approach is suboptimal. Well-designed, prospective, randomized trials are urgently needed. Moreover, only coordinated international collaboration will allow accrual in these trials if they are to be carried out within acceptable timeframes. Figures 42.1 and 42.2 depict proposed algorithms to manage early and metastatic male BC, re- spectively. These represent only the authors’ opinions, while waiting for the results of prospective randomized studies.

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