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A Review of the Diagnosis and Management of Male Breast Cancer

A Review of the Diagnosis and Management of Male Breast Cancer Male breast cancer is an uncommon disease although the cancer in men, but further work is clearly needed to bet- incidence has increased over the past 25 years. As with ter understand this disease. It shares many similarities many other rare “orphan” diseases, male breast can- with breast cancer in women; yet some clear differences cer is understudied. The rarity of the disease precludes have emerged. In this article, the latest information on prospective randomized clinical trials. In addition, few the epidemiology, biology, and treatment of male breast researchers and minimal funding have focused on breast cancer is reviewed. The Oncologist 2005;10:471–479 Introduction on the epidemiology, genetics, biologic characteristics, and Male breast cancer is an uncommon disease that has been clinical aspects of male breast cancer is covered. the focus of limited research. Because this disease is rare, no randomized trials have been possible, and only one pro- Epidemiology and Risk Factors spective therapeutic study has been published [1]. Most In 2005, an estimated 1,690 new cases of male breast can- information on breast cancer in men has been collected cer will be diagnosed in the U.S., and 460 men will die as a from retrospective studies spanning several decades, and result of breast cancer [3]. Male breast cancer accounts for treatment recommendations have been extrapolated from only 0.7% of all breast cancer diagnoses [4]. The mean age results of trials in female patients. Because the incidence of at diagnosis for men with breast cancer is 67 years, which is male breast cancer is rising [2], there has been an increasing 5 years older than the average age at diagnosis for women interest in this disease. In this article, the latest information [2]. However, breast cancer has been reported in male Correspondence: Sharon H. Giordano, M.D., M.P.H., Department of Breast Medical Oncology, The University of Texas M. D. Ander- son Cancer Center, 1515 Holcombe Boulevard, Box 424, Houston, Texas 77030, USA. Telephone: 713-792-2817; Fax: 713-794-4385; e-mail: sgiordan@mdanderson.org Received September 2, 2004; accepted for publication May 24, 2005. ©AlphaMed Press 1083- 7159/2005/$12.00/0 The Oncologist 2005;10:471–479 www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/10/7/471/6387469 by DeepDyve user on 31 January 2022 472 Male Breast Cancer patients ranging in age from 5–93 years [5]. The incidence reported to be mutation carriers in population-based series of male breast cancer increases with advancing patient age, [29–31]. The highest known prevalence is in Iceland, where climbing steadily until a plateau is reached around age 80 a founder mutation is present in 40% of men with breast can- [5, 6]. As in breast cancer in women, breast cancer in men cer [32]. Male breast cancer in patients with BRCA2 muta- has been increasing; the incidence has climbed 26% over tions tends to present at a younger age and may be associ- the past 25 years [2]. Yet the overall incidence in the U.S. ated with a poorer survival [33]. Because of the prevalence remains low: approximately one case per 100,000 popula- of these mutations in male breast cancer patients, genetic tion per year [7]. counseling and testing should be considered. The etiology of male breast cancer is unclear, but hor- Other genes have been investigated for a potential role monal levels may play a role in the development of this in the etiology of male breast cancer, but none has clearly disease. Testicular abnormalities such as undescended tes- been associated with an increased risk. Mutations in the tes, congenital inguinal hernia, orchiectomy, orchitis, and androgen receptor gene, PTEN (Cowden’s syndrome), and infertility have been consistently associated with elevations mismatch repair genes (hMLH1) have been reported in in breast cancer risk [8, 9]. Benign breast conditions, includ- male patients with breast cancer [34 –38]. However, none of ing history of breast trauma and nipple discharge, have these genes has been demonstrated to have a causal associa- also been reported to increase risk [8, 9]. Whether gyne- tion with male breast cancer. Further studies are needed to comastia is a risk factor for male breast cancer is unclear. elucidate their role. Gynecomastia has been reported in association with breast cancer in men [10, 11], but is also very common in healthy Pathologic Characteristics men [12]. Klinefelter’s syndrome, in which patients carry Ductal carcinoma in situ comprises approximately 10% of XXY chromosomes, may be present in 3% –7% of men with breast cancers in men [2, 39]. The most common growth breast cancer, giving males with Klinefelter’s syndrome a patterns are papillary and cribriform, and the majority of 50-fold greater risk over the general male population [13– these tumors are low grade [39, 40]. Lobular carcinoma in 15]. Men with a family history of breast cancer in a female situ is very rare because the male breast lacks terminal lob- relative have 2.5 times the odds of developing breast cancer ules, but has been reported in association with invasive lob- [16]. As in women, exposure to chest wall radiation, such ular carcinoma [41]. For invasive carcinomas, the ranges of as in patients previously treated with mantle radiation for histologic subtypes for female and male breast cancer are Hodgkin’s disease, increases the risk of a subsequent breast similar, but the relative distributions differ [2]. Data from cancer [8]. Alcohol use, liver disease, obesity, electromag- more than 2,000 male patients in the Surveillance, Epide- netic field radiation, and diet have all been proposed as risk factors, but findings have been inconsistent across studies [17–24]. Table 1. BRCA1 and BRCA2 mutations in male breast cancer Genetics BRCA1 BRCA2 mutations No. of mutations BRCA1 and BRCA2 are breast cancer susceptibility genes n (%) Study patients n (%) that are responsible for a proportion of cases of heritable Couch et al. [93] 50 – 7 (14) breast cancer. In women, mutations in these genes confer Thorlacius et al. 30 – 12 (40) a 40% –70% lifetime risk of breast cancer. Mutations in [32] BRCA1 and BRCA2 also increase the risk of affected men 54 0 2 (4) Friedman et al. developing breast cancer, although not to the same absolute [31] risk as in women (Table 1). BRCA1 mutations have been Ottini et al. [30] 25 1(4) 4 (16) reported in men with breast cancer, although they do not Haraldsson et al. 34 – 7 (21) appear to be a common cause of male breast cancer [25– [94] 30]. In series of high-risk families undergoing genetic Kwiatkowska et 37 – 4 (11) testing, 10% –16% of men with breast cancer have been al. [95] reported to have BRCA1 mutations [27, 28]. In population- Basham et al. 94 0 3 (8) [29] based series of men with breast cancer unselected by family history, BRCA1 mutations are much less common; 0% – 4% Sverdlov et al. 31 1 (3) 1 (3) [25] of men with breast cancer harbor this mutation [25, 29–31]. Frank et al. [28] 76 8 (11) 14 (18) Mutations in the BRCA2 gene are more frequent in males with breast cancer, with 4% –16% of men with breast cancer Population-based study. Downloaded from https://academic.oup.com/oncolo/article/10/7/471/6387469 by DeepDyve user on 31 January 2022 Giordano 473 miology, and End Results (SEER) cancer registry show that neu status should be evaluated in every patient, as these 93.7% of male breast cancers are ductal or unclassified car- may affect the clinical management. The extent of disease cinomas, 2.6% are papillary, 1.8% are mucinous, and only can be determined from laboratory evaluation, chest radi- 1.5% are lobular [2]. This distribution is in contrast to that ography, bone scan, and computed tomography scan of the seen in female breast cancer, in which almost 12% of can- abdomen, as clinically appropriate. Tumor stage is deter- cers are lobular carcinomas. mined using the American Joint Committee on Cancer Male breast cancers have high rates of hormone-recep- classification system, which considers tumor size, nodal tor expression. Approximately 90% of male breast cancers involvement, and distant metastases [58]. express the estrogen receptor, and 81% express the pro- Tumor size and lymph node involvement are two clear gesterone receptor [2]. Cancers of the male breast are sig- prognostic factors for male patients with breast cancer [2]. nificantly more likely than cancers of the female breast to Men with tumors measuring 2–5 cm have a 40% higher risk express hormone receptors, even after adjustment for tumor of death than men with tumors <2 cm in maximum diam- stage, grade, and patient age [2, 42– 44]. As in female breast eter [2]. Similarly, men with lymph node involvement have cancer, the rates of hormone-receptor positivity increase a 50% higher risk of death than those without lymph node with increasing patient age [2]. In contrast, the her2-neu involvement [2]. As in women, an increasing number of proto-oncogene is less likely to be overexpressed in can- involved axillary lymph nodes is associated with a poorer cers of the male breast [45, 46]. Early reports had suggested prognosis [59]. In univariate analyses, negative hormone- equivalent rates of her2-neu overexpression between male receptor status and high tumor grade were associated with and female breast cancers [47, 48]. However, those studies poorer survival, but these factors do not appear to have inde- were performed before improved standardization of meth- pendent prognostic value on multivariate analysis [2, 60 – odology and probably overestimated her2-neu overexpres- 62]. In general, the prognosis for male and female patients sion. A recent series of 75 patients found that only 5% of with breast cancer is similar [2, 54]. Overall survival rates male breast cancers overexpressed her2-neu [46]. Simi- are lower for men, but this is due to an older age at diagnosis larly, Bloom et al. found that only one of 58 male breast can- and more advanced disease at presentation [2]. When sur- cers overexpressed her2-neu and that zero of 58 had gene vival is adjusted for age at diagnosis and stage of disease, amplification [45]. The role of the androgen receptor in outcomes are comparable [2]. Disease-specific and over- male breast cancer is unclear. The reported rates of andro- all survival rates by stage of disease for male patients are gen-receptor expression have ranged from 34% –95%, but this receptor has not been associated with breast cancer prognosis [49–51]. Clinical Features The most common presenting symptoms in male breast cancer patients are a painless subareolar lump, nipple retraction, and bleeding from the nipple [10, 52, 53]. As in women, there is a slight preponderance of left-sided versus right-sided disease [54]. Usually the primary consider- ation in the differential diagnosis is gynecomastia, which affects approximately 30% of healthy men [55]. Mammog- raphy can be helpful in differentiating gynecomastia from malignant breast disease. An example of a mammogram performed in a male patient with an invasive ductal carci- noma is shown in Figure 1. Malignant breast tumors are more often eccentric and have irregular spiculated edges [56, 57]. The sensitivity and specificity of mammography for the diagnosis of male breast cancer have been reported to be 92% and 90%, respectively [56]. Ultrasonography can also be a useful adjunct and provide information regarding nodal involvement. After appropriate local imaging, any suspicious mass needs to be biopsied to confirm the diag- Figure 1. Mammogram of male patient with a 1.8-cm invasive ductal carcinoma in the right breast. nosis. Estrogen receptor, progesterone receptor, and her2- Downloaded from https://academic.oup.com/oncolo/article/10/7/471/6387469 by DeepDyve user on 31 January 2022 474 Male Breast Cancer shown in Table 2 and are illustrated in Figure 2 and Figure node dissection is clearly an important component of ther- 3. Disease-specific survival rates are notably higher than apy, because men who have nodal dissection omitted tend overall survival rates due to the older average age of this to have poorer outcomes [11, 67]. For instance, in a series population and deaths from other comorbid illnesses. of 397 patients with male breast cancer, 13% of patients without axillary dissection developed regional nodal recur- Treatment of Early-Stage Disease rence compared with 1.2% of patients who underwent axil- Local therapy for breast cancer is generally similar in men lary dissection [67]. Sentinel node biopsy has been recently and women. Most men are treated with modified radical evaluated in male patients (Table 3) [68–70]. Due to the rar- mastectomy with axillary lymph node dissection or senti- ity of this disease, large studies establishing the sensitivity nel node biopsy [54]. Historically, radical mastectomy was and specificity of sentinel node biopsy in male breast can- often performed, but retrospective studies indicate that the cer are not possible. However, several case series have been outcome for men is equally good when treated with less published that have established the feasibility of sentinel invasive surgery [63, 64]. Larger studies from female breast node biopsy in the male patient with breast cancer [68–72]. cancer patients also suppor t the use of modified radical mas- Among a total of 56 male patients combined from these tectomy over radical mastectomy [65, 66]. Axillary lymph reports, the sentinel node was successfully identified in all but one patient [68–72]. A combined total of 11 patients with a negative sentinel node biopsy underwent confirma- tory axillary dissection, and none had any additional nodes Table 2. Disease-specific and overall survival rates in male breast cancer among 1,986 male patients in the Surveillance, [68–72]. This procedure is now being increasingly used in Epidemiology, and End Results database, diagnosed in male patients who are clinically node-negative. 1988–2001 There are limited data regarding the indications for Survival rates (%) adjuvant radiation therapy in male patients, but generally Stage Stage Stage Stage similar guidelines are recommended in men as in women. I II III IV Men do tend to be treated with radiation therapy more Disease-specific often after mastectomy than women, perhaps because they survival are more likely to have nipple or skin involvement [54]. 3 years 99 93 83 39 Radiation therapy does appear to be effective in prevent- 5 years 96 88 60 23 ing local recurrences in male patients, but all studies have 10 years 93 74 44 21 been underpowered to address the question of a potential survival benefit [62, 67, 73, 74]. To determine which male Overall survival patients would derive benefit from adjuvant radiation, Per- 3 years 89 79 66 29 kins et al. studied a series of 142 male patients treated at The 5 years 78 66 39 14 University of Texas M. D. Anderson Cancer Center [75]. 10 years 55 39 21 5 Overall, 18% of patients experienced locoregional failure, Calculated from SEER database [7]. Figure 2. Kaplan-Meier curves for overall survival. This Figure 3. Kaplan-Meier curves for disease-specific survival. analysis includes 1,986 male breast cancer patients diagnosed This analysis includes 1,986 male breast cancer patients diag- in 1988–2001 in the Surveillance, Epidemiology, and End nosed in 1988–2001 in the Surveillance, Epidemiology, and Results cancer registry [7]. End Results cancer registry [7]. Downloaded from https://academic.oup.com/oncolo/article/10/7/471/6387469 by DeepDyve user on 31 January 2022 Giordano 475 Table 3. SLN biopsy in male breast cancer No. of patients Cimmino et al. [69] Port et al. [71] Goyal et al. [70] De Cicco et al. [72] Albo et al. [68] Total 6 16 9 18 7 SLN identified 6 15 9 18 7 Positive SLN 3 5 5 6 1 Completion ALND 3 4 4 6 1 Additional nodes 1 3 3 1 1 Negative SLN 3 10 4 12 6 Confirmatory ALND 1 6 1 0 3 Additional nodes 0 0 0 n/a 0 Abbreviations: ALND, axillary lymph node dissection; SLN, sentinel lymph node. with the most common sites of relapse being the chest wall ated the effectiveness of tamoxifen (Nolvadex ; AstraZen- and supraclavicular areas. Predictors of local regional fail- eca Pharmaceuticals, Wilmington, DE, http://www.astra- ure included margin status, tumor size, and the number of zeneca-us.com) in male breast cancer. In the metastatic involved axillary lymph nodes. Focal skin involvement was setting, tamoxifen clearly has activity against male breast not associated with a higher risk of local recurrence. cancer [52]. The retrospective series that have evaluated As for women with breast cancer, adjuvant chemo- tamoxifen in the adjuvant setting have shown a reduced risk therapy is used to treat male patients who have a substantial risk of recurrence and death from breast cancer. Whereas the data supporting adjuvant chemotherapy in women are strong [76], there is little information on the effectiveness of adjuvant chemotherapy in men. The limited data that have been published, however, do support a similar ben- efit in male and female patients. One prospective study of adjuvant chemotherapy in men has been published [1]. A series of 24 male patients with stage II breast cancer was treated at the National Cancer Institute with adjuvant CMF (cyclophosphamide, methotrexate, and f luorouracil). The projected 5-year survival rate was >80%, which was signif- icantly higher than a similar cohort of historical controls. Retrospective series have also suggested that adjuvant che- motherapy lowers the risk for recurrence in male patients [11, 77, 78]. Given the established benefit of chemotherapy in women and the suggestive evidence in men, most clini- cians use similar guidelines for adjuvant chemotherapy in male and female patients. For instance, at The University of Texas M. D. Anderson Cancer Center, chemotherapy is offered to those patients with breast tumors measuring >1 cm and to those patients with lymph node involvement. Anthracycline-based chemotherapy is offered to those patients without lymph node involvement, whereas both anthracyclines and taxanes are used for those patients with lymph node involvement. An algorithm for the treatment of male breast cancer is illustrated in Figure 4. Adjuvant hormonal therapy clearly has a role in male breast cancer patients with hormone receptor–positive tumors [10, 60, 79]. Many retrospective series have evalu- Figure 4. Treatment algorithm for male breast cancer. Downloaded from https://academic.oup.com/oncolo/article/10/7/471/6387469 by DeepDyve user on 31 January 2022 476 Male Breast Cancer of breast cancer recurrence and death [10, 60, 79, 80]. Given tins, androgens, steroids, aminoglutethamide, estrogens, that such a high proportion of males with breast cancer have and letrozole [84, 85, 87]. The role of fulvestrant (Faslo- tumors that express the estrogen or progesterone receptor, dex ; AstraZeneca Pharmaceuticals) remains unclear. For most male patients can benefit from adjuvant tamoxifen. male patients with hormone-refractory disease or rapidly The toxicities of tamoxifen in the male patient have not been progressing visceral metastases, chemotherapy can pro- extensively studied. One series reported that men had some vide significant palliation. Generally, a similar approach is difficulty tolerating this drug, and side effects, including used for chemotherapy in metastatic male breast cancer as deep-vein thrombosis, decreased libido, impotence, mood in female breast cancer. The effectiveness of trastuzumab alterations, and hot f lashes, have been noted [81]. (Herceptin ; Genentech, Inc., South San Francisco, CA, The role of aromatase inhibitors in the adjuvant setting http://www.gene.com) in her2-neu overexpressing male for male patients is limited. One case series of five patients breast cancer is unproven, but certainly seems reasonable with metastatic disease treated with aromatase inhibitors given the strong evidence in support of trastuzumab in has been published [82]. Of the five patients, three had a women with breast cancer. period of disease stability, but these patients had indolent disease prior to the addition of an aromatase inhibitor. No Second Primaries patients had objective responses. Anastrozole (Arimidex ; Male breast cancer survivors have an increased risk of AstraZeneca Pharmaceuticals) has been tested in healthy developing second primary cancers. Data from the Swed- male volunteers [83]. Men treated with anastrozole did not ish Family-Cancer Database indicate that men with breast appear to have as complete estrogen suppression as is seen cancer have a 93-fold greater risk of developing contralat- in women; a 50% decrease in estradiol concentrations was eral breast cancer than men with no history of breast cancer seen. In addition, therapy with anastrozole raised testoster- [91]. The absolute risk for an individual male patient devel- one levels by 58%. However, two recent case reports have oping contralateral breast cancer was 1.75%. Auvinen et al. described responses in male patients treated with letrozole reported similar findings from the SEER cancer registry (Femara ; Novartis Pharmaceuticals Corporation, East database; men with a history of breast cancer had a 30-fold Hanover, NJ, http://www.pharma.us.novartis.com) [84, greater risk of contralateral breast cancer [92]. The risk for 85]. Clearly, further investigation is needed to determine other cancers, including melanoma and prostate cancer, the efficacy of aromatase inhibitors in male patients. For may also be elevated in male breast cancer survivors, par- now, there are insufficient data to recommend an aromatase ticularly in mutation carriers [92]. inhibitor in the adjuvant setting for male patients. Conclusions Treatment of Metastatic Disease Male breast cancer remains a rare disease, although the inci- In general, the approach to the treatment of metastatic dence is increasing. While breast cancer in men is similar to breast cancer is similar in male and female patients with female breast cancer, there are distinct features that should breast cancer. Given that the vast majority of men have be appreciated. Risk factors include many conditions that estrogen receptor–positive tumors, hormonal therapy is could affect hormonal levels, a family history of breast can- often the first approach. Farrow and Adair reported on the cer, Klinefelter’s syndrome, and a prior history of radiation first male patient to respond to hor monal therapy [86]. They exposure. BRCA1 mutations are associated with some cases, described a male with metastatic breast cancer who had but the link between BRCA2 mutations and male breast tumor regression after orchiectomy. Although, histor ically, cancer is stronger. Men tend to be diagnosed at an older age surgical ablative therapies such as orchiectomy, adrenal- than women and with later stage disease. Most of the his- ectomy, and hypophysectomy have been used effectively tologic subtypes that are seen in women are also present in to control metastatic breast cancer in male patients, these men, except that lobular histology is much rarer. Tumors of surgical procedures are rarely used today and have been the male breast are more likely to express the estrogen and supplanted by additive hormonal therapies. Tamoxifen has progesterone receptors and less likely to overexpress her2- established efficacy in metastatic male breast cancer, with neu than breast cancers in women. Sentinel node biopsy an approximate 50% response rate, and is considered the appears feasible in male patients, but the data regarding this prefer red first-line approach [87]. Luteinizing hormone– procedure in the male breast are limited. Chemotherapy and releasing hormone agonists, with or without antiandro- adjuvant radiation should be offered in clinical situations gens, have also been reported to be effective in male breast in which these treatments would be deemed appropriate in cancer [88–90]. There have been case reports of responses women. Given the high prevalence of hormone receptor– to a wide variety of hormonal therapies including proges- positive disease, adjuvant hormonal therapy has an impor- Downloaded from https://academic.oup.com/oncolo/article/10/7/471/6387469 by DeepDyve user on 31 January 2022 Giordano 477 tant role in the treatment of the male patient. Tamoxifen Acknowledgments remains the gold standard of adjuvant hormonal therapies; Dr. Giordano is supported by NIH 1K07CA109064-01. the data on aromatase inhibitors are sparse, and these drugs should not currently be used in the adjuvant setting. 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[Complete remission obtained tions in male breast cancer cases and breast cancer families. Nat Genet with letrozole in a man with metastatic breast cancer]. Rev Med Inter ne 1996;13:123–125. 2004;25:323 –324. French. 94 Ha raldsson K, Loman N, Zhang QX et al. BRCA2 ger m-line mutations 86 Far row J, Adair F. Effect of Orchiectomy on skeletal metastases from can- are frequent in male breast cancer patients without a family histor y of the cer of the male breast. Science 1942;95:654. disease. Cancer Res 1998;58:1367–1371. 87 Jaiyesimi IA, Buzda r AU, Sahin AA et al. Ca rcinoma of the male breast. 95 Kwiatkowska E, Teresia k M, Lamperska K M et al. BRCA2 ger mline Ann Inter n Med 1992;117:771–777. mutations in male breast cancer patients in the Polish population. Hum 88 Labrie F, Dupont A, Belanger A et al. Complete response to combination Mutat 2001;17:73. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Oncologist Oxford University Press

A Review of the Diagnosis and Management of Male Breast Cancer

The Oncologist , Volume 10 (7) – Aug 1, 2005

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Abstract

Male breast cancer is an uncommon disease although the cancer in men, but further work is clearly needed to bet- incidence has increased over the past 25 years. As with ter understand this disease. It shares many similarities many other rare “orphan” diseases, male breast can- with breast cancer in women; yet some clear differences cer is understudied. The rarity of the disease precludes have emerged. In this article, the latest information on prospective randomized clinical trials. In addition, few the epidemiology, biology, and treatment of male breast researchers and minimal funding have focused on breast cancer is reviewed. The Oncologist 2005;10:471–479 Introduction on the epidemiology, genetics, biologic characteristics, and Male breast cancer is an uncommon disease that has been clinical aspects of male breast cancer is covered. the focus of limited research. Because this disease is rare, no randomized trials have been possible, and only one pro- Epidemiology and Risk Factors spective therapeutic study has been published [1]. Most In 2005, an estimated 1,690 new cases of male breast can- information on breast cancer in men has been collected cer will be diagnosed in the U.S., and 460 men will die as a from retrospective studies spanning several decades, and result of breast cancer [3]. Male breast cancer accounts for treatment recommendations have been extrapolated from only 0.7% of all breast cancer diagnoses [4]. The mean age results of trials in female patients. Because the incidence of at diagnosis for men with breast cancer is 67 years, which is male breast cancer is rising [2], there has been an increasing 5 years older than the average age at diagnosis for women interest in this disease. In this article, the latest information [2]. However, breast cancer has been reported in male Correspondence: Sharon H. Giordano, M.D., M.P.H., Department of Breast Medical Oncology, The University of Texas M. D. Ander- son Cancer Center, 1515 Holcombe Boulevard, Box 424, Houston, Texas 77030, USA. Telephone: 713-792-2817; Fax: 713-794-4385; e-mail: sgiordan@mdanderson.org Received September 2, 2004; accepted for publication May 24, 2005. ©AlphaMed Press 1083- 7159/2005/$12.00/0 The Oncologist 2005;10:471–479 www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/10/7/471/6387469 by DeepDyve user on 31 January 2022 472 Male Breast Cancer patients ranging in age from 5–93 years [5]. The incidence reported to be mutation carriers in population-based series of male breast cancer increases with advancing patient age, [29–31]. The highest known prevalence is in Iceland, where climbing steadily until a plateau is reached around age 80 a founder mutation is present in 40% of men with breast can- [5, 6]. As in breast cancer in women, breast cancer in men cer [32]. Male breast cancer in patients with BRCA2 muta- has been increasing; the incidence has climbed 26% over tions tends to present at a younger age and may be associ- the past 25 years [2]. Yet the overall incidence in the U.S. ated with a poorer survival [33]. Because of the prevalence remains low: approximately one case per 100,000 popula- of these mutations in male breast cancer patients, genetic tion per year [7]. counseling and testing should be considered. The etiology of male breast cancer is unclear, but hor- Other genes have been investigated for a potential role monal levels may play a role in the development of this in the etiology of male breast cancer, but none has clearly disease. Testicular abnormalities such as undescended tes- been associated with an increased risk. Mutations in the tes, congenital inguinal hernia, orchiectomy, orchitis, and androgen receptor gene, PTEN (Cowden’s syndrome), and infertility have been consistently associated with elevations mismatch repair genes (hMLH1) have been reported in in breast cancer risk [8, 9]. Benign breast conditions, includ- male patients with breast cancer [34 –38]. However, none of ing history of breast trauma and nipple discharge, have these genes has been demonstrated to have a causal associa- also been reported to increase risk [8, 9]. Whether gyne- tion with male breast cancer. Further studies are needed to comastia is a risk factor for male breast cancer is unclear. elucidate their role. Gynecomastia has been reported in association with breast cancer in men [10, 11], but is also very common in healthy Pathologic Characteristics men [12]. Klinefelter’s syndrome, in which patients carry Ductal carcinoma in situ comprises approximately 10% of XXY chromosomes, may be present in 3% –7% of men with breast cancers in men [2, 39]. The most common growth breast cancer, giving males with Klinefelter’s syndrome a patterns are papillary and cribriform, and the majority of 50-fold greater risk over the general male population [13– these tumors are low grade [39, 40]. Lobular carcinoma in 15]. Men with a family history of breast cancer in a female situ is very rare because the male breast lacks terminal lob- relative have 2.5 times the odds of developing breast cancer ules, but has been reported in association with invasive lob- [16]. As in women, exposure to chest wall radiation, such ular carcinoma [41]. For invasive carcinomas, the ranges of as in patients previously treated with mantle radiation for histologic subtypes for female and male breast cancer are Hodgkin’s disease, increases the risk of a subsequent breast similar, but the relative distributions differ [2]. Data from cancer [8]. Alcohol use, liver disease, obesity, electromag- more than 2,000 male patients in the Surveillance, Epide- netic field radiation, and diet have all been proposed as risk factors, but findings have been inconsistent across studies [17–24]. Table 1. BRCA1 and BRCA2 mutations in male breast cancer Genetics BRCA1 BRCA2 mutations No. of mutations BRCA1 and BRCA2 are breast cancer susceptibility genes n (%) Study patients n (%) that are responsible for a proportion of cases of heritable Couch et al. [93] 50 – 7 (14) breast cancer. In women, mutations in these genes confer Thorlacius et al. 30 – 12 (40) a 40% –70% lifetime risk of breast cancer. Mutations in [32] BRCA1 and BRCA2 also increase the risk of affected men 54 0 2 (4) Friedman et al. developing breast cancer, although not to the same absolute [31] risk as in women (Table 1). BRCA1 mutations have been Ottini et al. [30] 25 1(4) 4 (16) reported in men with breast cancer, although they do not Haraldsson et al. 34 – 7 (21) appear to be a common cause of male breast cancer [25– [94] 30]. In series of high-risk families undergoing genetic Kwiatkowska et 37 – 4 (11) testing, 10% –16% of men with breast cancer have been al. [95] reported to have BRCA1 mutations [27, 28]. In population- Basham et al. 94 0 3 (8) [29] based series of men with breast cancer unselected by family history, BRCA1 mutations are much less common; 0% – 4% Sverdlov et al. 31 1 (3) 1 (3) [25] of men with breast cancer harbor this mutation [25, 29–31]. Frank et al. [28] 76 8 (11) 14 (18) Mutations in the BRCA2 gene are more frequent in males with breast cancer, with 4% –16% of men with breast cancer Population-based study. Downloaded from https://academic.oup.com/oncolo/article/10/7/471/6387469 by DeepDyve user on 31 January 2022 Giordano 473 miology, and End Results (SEER) cancer registry show that neu status should be evaluated in every patient, as these 93.7% of male breast cancers are ductal or unclassified car- may affect the clinical management. The extent of disease cinomas, 2.6% are papillary, 1.8% are mucinous, and only can be determined from laboratory evaluation, chest radi- 1.5% are lobular [2]. This distribution is in contrast to that ography, bone scan, and computed tomography scan of the seen in female breast cancer, in which almost 12% of can- abdomen, as clinically appropriate. Tumor stage is deter- cers are lobular carcinomas. mined using the American Joint Committee on Cancer Male breast cancers have high rates of hormone-recep- classification system, which considers tumor size, nodal tor expression. Approximately 90% of male breast cancers involvement, and distant metastases [58]. express the estrogen receptor, and 81% express the pro- Tumor size and lymph node involvement are two clear gesterone receptor [2]. Cancers of the male breast are sig- prognostic factors for male patients with breast cancer [2]. nificantly more likely than cancers of the female breast to Men with tumors measuring 2–5 cm have a 40% higher risk express hormone receptors, even after adjustment for tumor of death than men with tumors <2 cm in maximum diam- stage, grade, and patient age [2, 42– 44]. As in female breast eter [2]. Similarly, men with lymph node involvement have cancer, the rates of hormone-receptor positivity increase a 50% higher risk of death than those without lymph node with increasing patient age [2]. In contrast, the her2-neu involvement [2]. As in women, an increasing number of proto-oncogene is less likely to be overexpressed in can- involved axillary lymph nodes is associated with a poorer cers of the male breast [45, 46]. Early reports had suggested prognosis [59]. In univariate analyses, negative hormone- equivalent rates of her2-neu overexpression between male receptor status and high tumor grade were associated with and female breast cancers [47, 48]. However, those studies poorer survival, but these factors do not appear to have inde- were performed before improved standardization of meth- pendent prognostic value on multivariate analysis [2, 60 – odology and probably overestimated her2-neu overexpres- 62]. In general, the prognosis for male and female patients sion. A recent series of 75 patients found that only 5% of with breast cancer is similar [2, 54]. Overall survival rates male breast cancers overexpressed her2-neu [46]. Simi- are lower for men, but this is due to an older age at diagnosis larly, Bloom et al. found that only one of 58 male breast can- and more advanced disease at presentation [2]. When sur- cers overexpressed her2-neu and that zero of 58 had gene vival is adjusted for age at diagnosis and stage of disease, amplification [45]. The role of the androgen receptor in outcomes are comparable [2]. Disease-specific and over- male breast cancer is unclear. The reported rates of andro- all survival rates by stage of disease for male patients are gen-receptor expression have ranged from 34% –95%, but this receptor has not been associated with breast cancer prognosis [49–51]. Clinical Features The most common presenting symptoms in male breast cancer patients are a painless subareolar lump, nipple retraction, and bleeding from the nipple [10, 52, 53]. As in women, there is a slight preponderance of left-sided versus right-sided disease [54]. Usually the primary consider- ation in the differential diagnosis is gynecomastia, which affects approximately 30% of healthy men [55]. Mammog- raphy can be helpful in differentiating gynecomastia from malignant breast disease. An example of a mammogram performed in a male patient with an invasive ductal carci- noma is shown in Figure 1. Malignant breast tumors are more often eccentric and have irregular spiculated edges [56, 57]. The sensitivity and specificity of mammography for the diagnosis of male breast cancer have been reported to be 92% and 90%, respectively [56]. Ultrasonography can also be a useful adjunct and provide information regarding nodal involvement. After appropriate local imaging, any suspicious mass needs to be biopsied to confirm the diag- Figure 1. Mammogram of male patient with a 1.8-cm invasive ductal carcinoma in the right breast. nosis. Estrogen receptor, progesterone receptor, and her2- Downloaded from https://academic.oup.com/oncolo/article/10/7/471/6387469 by DeepDyve user on 31 January 2022 474 Male Breast Cancer shown in Table 2 and are illustrated in Figure 2 and Figure node dissection is clearly an important component of ther- 3. Disease-specific survival rates are notably higher than apy, because men who have nodal dissection omitted tend overall survival rates due to the older average age of this to have poorer outcomes [11, 67]. For instance, in a series population and deaths from other comorbid illnesses. of 397 patients with male breast cancer, 13% of patients without axillary dissection developed regional nodal recur- Treatment of Early-Stage Disease rence compared with 1.2% of patients who underwent axil- Local therapy for breast cancer is generally similar in men lary dissection [67]. Sentinel node biopsy has been recently and women. Most men are treated with modified radical evaluated in male patients (Table 3) [68–70]. Due to the rar- mastectomy with axillary lymph node dissection or senti- ity of this disease, large studies establishing the sensitivity nel node biopsy [54]. Historically, radical mastectomy was and specificity of sentinel node biopsy in male breast can- often performed, but retrospective studies indicate that the cer are not possible. However, several case series have been outcome for men is equally good when treated with less published that have established the feasibility of sentinel invasive surgery [63, 64]. Larger studies from female breast node biopsy in the male patient with breast cancer [68–72]. cancer patients also suppor t the use of modified radical mas- Among a total of 56 male patients combined from these tectomy over radical mastectomy [65, 66]. Axillary lymph reports, the sentinel node was successfully identified in all but one patient [68–72]. A combined total of 11 patients with a negative sentinel node biopsy underwent confirma- tory axillary dissection, and none had any additional nodes Table 2. Disease-specific and overall survival rates in male breast cancer among 1,986 male patients in the Surveillance, [68–72]. This procedure is now being increasingly used in Epidemiology, and End Results database, diagnosed in male patients who are clinically node-negative. 1988–2001 There are limited data regarding the indications for Survival rates (%) adjuvant radiation therapy in male patients, but generally Stage Stage Stage Stage similar guidelines are recommended in men as in women. I II III IV Men do tend to be treated with radiation therapy more Disease-specific often after mastectomy than women, perhaps because they survival are more likely to have nipple or skin involvement [54]. 3 years 99 93 83 39 Radiation therapy does appear to be effective in prevent- 5 years 96 88 60 23 ing local recurrences in male patients, but all studies have 10 years 93 74 44 21 been underpowered to address the question of a potential survival benefit [62, 67, 73, 74]. To determine which male Overall survival patients would derive benefit from adjuvant radiation, Per- 3 years 89 79 66 29 kins et al. studied a series of 142 male patients treated at The 5 years 78 66 39 14 University of Texas M. D. Anderson Cancer Center [75]. 10 years 55 39 21 5 Overall, 18% of patients experienced locoregional failure, Calculated from SEER database [7]. Figure 2. Kaplan-Meier curves for overall survival. This Figure 3. Kaplan-Meier curves for disease-specific survival. analysis includes 1,986 male breast cancer patients diagnosed This analysis includes 1,986 male breast cancer patients diag- in 1988–2001 in the Surveillance, Epidemiology, and End nosed in 1988–2001 in the Surveillance, Epidemiology, and Results cancer registry [7]. End Results cancer registry [7]. Downloaded from https://academic.oup.com/oncolo/article/10/7/471/6387469 by DeepDyve user on 31 January 2022 Giordano 475 Table 3. SLN biopsy in male breast cancer No. of patients Cimmino et al. [69] Port et al. [71] Goyal et al. [70] De Cicco et al. [72] Albo et al. [68] Total 6 16 9 18 7 SLN identified 6 15 9 18 7 Positive SLN 3 5 5 6 1 Completion ALND 3 4 4 6 1 Additional nodes 1 3 3 1 1 Negative SLN 3 10 4 12 6 Confirmatory ALND 1 6 1 0 3 Additional nodes 0 0 0 n/a 0 Abbreviations: ALND, axillary lymph node dissection; SLN, sentinel lymph node. with the most common sites of relapse being the chest wall ated the effectiveness of tamoxifen (Nolvadex ; AstraZen- and supraclavicular areas. Predictors of local regional fail- eca Pharmaceuticals, Wilmington, DE, http://www.astra- ure included margin status, tumor size, and the number of zeneca-us.com) in male breast cancer. In the metastatic involved axillary lymph nodes. Focal skin involvement was setting, tamoxifen clearly has activity against male breast not associated with a higher risk of local recurrence. cancer [52]. The retrospective series that have evaluated As for women with breast cancer, adjuvant chemo- tamoxifen in the adjuvant setting have shown a reduced risk therapy is used to treat male patients who have a substantial risk of recurrence and death from breast cancer. Whereas the data supporting adjuvant chemotherapy in women are strong [76], there is little information on the effectiveness of adjuvant chemotherapy in men. The limited data that have been published, however, do support a similar ben- efit in male and female patients. One prospective study of adjuvant chemotherapy in men has been published [1]. A series of 24 male patients with stage II breast cancer was treated at the National Cancer Institute with adjuvant CMF (cyclophosphamide, methotrexate, and f luorouracil). The projected 5-year survival rate was >80%, which was signif- icantly higher than a similar cohort of historical controls. Retrospective series have also suggested that adjuvant che- motherapy lowers the risk for recurrence in male patients [11, 77, 78]. Given the established benefit of chemotherapy in women and the suggestive evidence in men, most clini- cians use similar guidelines for adjuvant chemotherapy in male and female patients. For instance, at The University of Texas M. D. Anderson Cancer Center, chemotherapy is offered to those patients with breast tumors measuring >1 cm and to those patients with lymph node involvement. Anthracycline-based chemotherapy is offered to those patients without lymph node involvement, whereas both anthracyclines and taxanes are used for those patients with lymph node involvement. An algorithm for the treatment of male breast cancer is illustrated in Figure 4. Adjuvant hormonal therapy clearly has a role in male breast cancer patients with hormone receptor–positive tumors [10, 60, 79]. Many retrospective series have evalu- Figure 4. Treatment algorithm for male breast cancer. Downloaded from https://academic.oup.com/oncolo/article/10/7/471/6387469 by DeepDyve user on 31 January 2022 476 Male Breast Cancer of breast cancer recurrence and death [10, 60, 79, 80]. Given tins, androgens, steroids, aminoglutethamide, estrogens, that such a high proportion of males with breast cancer have and letrozole [84, 85, 87]. The role of fulvestrant (Faslo- tumors that express the estrogen or progesterone receptor, dex ; AstraZeneca Pharmaceuticals) remains unclear. For most male patients can benefit from adjuvant tamoxifen. male patients with hormone-refractory disease or rapidly The toxicities of tamoxifen in the male patient have not been progressing visceral metastases, chemotherapy can pro- extensively studied. One series reported that men had some vide significant palliation. Generally, a similar approach is difficulty tolerating this drug, and side effects, including used for chemotherapy in metastatic male breast cancer as deep-vein thrombosis, decreased libido, impotence, mood in female breast cancer. The effectiveness of trastuzumab alterations, and hot f lashes, have been noted [81]. (Herceptin ; Genentech, Inc., South San Francisco, CA, The role of aromatase inhibitors in the adjuvant setting http://www.gene.com) in her2-neu overexpressing male for male patients is limited. One case series of five patients breast cancer is unproven, but certainly seems reasonable with metastatic disease treated with aromatase inhibitors given the strong evidence in support of trastuzumab in has been published [82]. Of the five patients, three had a women with breast cancer. period of disease stability, but these patients had indolent disease prior to the addition of an aromatase inhibitor. No Second Primaries patients had objective responses. Anastrozole (Arimidex ; Male breast cancer survivors have an increased risk of AstraZeneca Pharmaceuticals) has been tested in healthy developing second primary cancers. Data from the Swed- male volunteers [83]. Men treated with anastrozole did not ish Family-Cancer Database indicate that men with breast appear to have as complete estrogen suppression as is seen cancer have a 93-fold greater risk of developing contralat- in women; a 50% decrease in estradiol concentrations was eral breast cancer than men with no history of breast cancer seen. In addition, therapy with anastrozole raised testoster- [91]. The absolute risk for an individual male patient devel- one levels by 58%. However, two recent case reports have oping contralateral breast cancer was 1.75%. Auvinen et al. described responses in male patients treated with letrozole reported similar findings from the SEER cancer registry (Femara ; Novartis Pharmaceuticals Corporation, East database; men with a history of breast cancer had a 30-fold Hanover, NJ, http://www.pharma.us.novartis.com) [84, greater risk of contralateral breast cancer [92]. The risk for 85]. Clearly, further investigation is needed to determine other cancers, including melanoma and prostate cancer, the efficacy of aromatase inhibitors in male patients. For may also be elevated in male breast cancer survivors, par- now, there are insufficient data to recommend an aromatase ticularly in mutation carriers [92]. inhibitor in the adjuvant setting for male patients. Conclusions Treatment of Metastatic Disease Male breast cancer remains a rare disease, although the inci- In general, the approach to the treatment of metastatic dence is increasing. While breast cancer in men is similar to breast cancer is similar in male and female patients with female breast cancer, there are distinct features that should breast cancer. Given that the vast majority of men have be appreciated. Risk factors include many conditions that estrogen receptor–positive tumors, hormonal therapy is could affect hormonal levels, a family history of breast can- often the first approach. Farrow and Adair reported on the cer, Klinefelter’s syndrome, and a prior history of radiation first male patient to respond to hor monal therapy [86]. They exposure. BRCA1 mutations are associated with some cases, described a male with metastatic breast cancer who had but the link between BRCA2 mutations and male breast tumor regression after orchiectomy. Although, histor ically, cancer is stronger. Men tend to be diagnosed at an older age surgical ablative therapies such as orchiectomy, adrenal- than women and with later stage disease. Most of the his- ectomy, and hypophysectomy have been used effectively tologic subtypes that are seen in women are also present in to control metastatic breast cancer in male patients, these men, except that lobular histology is much rarer. Tumors of surgical procedures are rarely used today and have been the male breast are more likely to express the estrogen and supplanted by additive hormonal therapies. Tamoxifen has progesterone receptors and less likely to overexpress her2- established efficacy in metastatic male breast cancer, with neu than breast cancers in women. Sentinel node biopsy an approximate 50% response rate, and is considered the appears feasible in male patients, but the data regarding this prefer red first-line approach [87]. Luteinizing hormone– procedure in the male breast are limited. Chemotherapy and releasing hormone agonists, with or without antiandro- adjuvant radiation should be offered in clinical situations gens, have also been reported to be effective in male breast in which these treatments would be deemed appropriate in cancer [88–90]. There have been case reports of responses women. Given the high prevalence of hormone receptor– to a wide variety of hormonal therapies including proges- positive disease, adjuvant hormonal therapy has an impor- Downloaded from https://academic.oup.com/oncolo/article/10/7/471/6387469 by DeepDyve user on 31 January 2022 Giordano 477 tant role in the treatment of the male patient. Tamoxifen Acknowledgments remains the gold standard of adjuvant hormonal therapies; Dr. Giordano is supported by NIH 1K07CA109064-01. the data on aromatase inhibitors are sparse, and these drugs should not currently be used in the adjuvant setting. 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The OncologistOxford University Press

Published: Aug 1, 2005

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