Breast Cancer in Men

What is the problem and what is known about it so far? Men can get breast cancer, but it is much less common in men than in women. Because breast cancer in men is rare, we know little about the factors that make men susceptible to the disease and how to treat it. Why did the authors do this review? The authors published a review of breast cancer in men in 1992. The purpose of the current review is to see whether material published in the past 10 years helps us reach new conclusions about breast cancer in men. How did the authors do this review? The authors searched computerized databases of medical articles on breast cancer in men that were published between 1942 and 2000. They focused on information published since 1990. What did the authors find? About 1500 cases of breast cancer and 400 breast cancer deaths occur in men each year in the United States. Men with a history of testicular or breast disease, a family history of breast cancer in women, or Jewish ancestry have a higher-than-average risk for developing breast cancer. Men with a genetic condition called Klinefelter syndrome have a much higher risk for breast cancer than do men without this condition. Abnormalities in the BRCA2 gene, which greatly increase the risk for breast cancer in women, seem to also increase the risk in men. In contrast, abnormalities in the BRCA1 gene, another gene related to breast cancer in women, do not seem to be associated with breast cancer in men. Breast enlargement in men (gynecomastia) does not seem to be a risk factor for breast cancer. In general, men develop the same kinds of breast cancer as do women. However, breast cancer in men is more likely than breast cancer in women to be hormone receptor positive. This means that the cancer cells depend on the hormones estrogen or progesterone for growth. Molecular markers of breast cancer (proteins that appear in abnormal forms or at higher levels in cancer cells) seem to be similar in women and in men. Men are more likely to have a delay between onset of symptoms and diagnosis, probably because many are unaware that breast cancer can occur in men. The existing evidence suggests that men with breast cancer should get the same treatments as do women. However, given the large proportion of hormone receptorpositive tumors in men, hormone-related treatments may prove to be particularly useful. What are the implications of the review? Men should be aware that they can get breast cancer. They should see a doctor promptly if they develop a breast lump, breast pain, a sore or dimpling of the nipple, or nipple discharge or bleeding. However, screening for breast cancer in men with no symptoms is not recommended because the disease is so uncommon.


Introduction
Breast cancer in men accounts for approximately 1% of all breast cancers diagnosed in the United States each year 1 . In Ghana, it accounts for about 2.9% of all breast cancers seen, consistent with the slightly higher rates reported in other parts of Sub-Saharan Africa with most patients presenting with advanced disease 2 . To date there are no randomized trials or large databases to validate current treatment strategies. Most of the information on breast cancer in men is derived from retrospective studies spanning several decades, and treatment recommendations are extrapolated from results of trials in female patients. Male breast cancer behaves like postmenopausal women with breast cancer. However, compared to all female breast cancers, it has poorer outcomes attributed to advanced stage at diagnosis and less aggressive management practices 3 .

Epidemiology and Risk Factors
Male breast cancer usually occurs in the 7 th decade, a decade later than occurs in females, with younger male patients more likely to have inherited genetic mutation 4 . Several risk factors are associated with higher incidence. These include Klinefelter syndrome, a family history of breast cancer, increased estrogen levels as occurs in conditions such as testicular disorders (e.g., cryptorchidism, mumps orchitis, and orchiectomy, use of finasteride and other hormonal ablation therapies used to manage prostate cancer , previous radiation exposure , gynecomastia, thyroid diseases, occupational and environmental exposures such as thermal heat, electromagnetic fields, polycyclic aromatic hydrocarbons, and dietary factors) 5-7. Male breast cancer seems to have a higher male to female ratio in blacks compared to whites 8 . The Surveillance, Epidemiology, and End Results( SEER) database form the united states records on breast cancer from 1976 -2005 shows that improvement in overall breast cancer cause specific death rates is less pronounced in males compared with females (28% versus 42% respectively) 9 .
A meta-analysis of male breast cancer in 27 African countries suggests more late presentation , younger age (54.7years), higher incidence rates compared to developed countries, with Zambia reporting rates as high as 15% 10. Higher incidence rates in the sub region could be attributed to high estrogen levels following endemic infectious and other chronic liver disease processes 6,11 . Cirrhosis of the liver results in hyperestrogenism in men secondary to increased binding of androgens to increased sex tubulins 12 . This has been reported as a causative association and could be a result of gynecomastia predisposing to cancer. Genetics BRCA1 and BRCA2 autosomal dominant genes are the major breast cancer susceptibility genes associated with a significant proportion of heritable breast cancer cases 13 . Mutation of these DNA repair genes in women confer a 40%-70% lifetime risk of breast cancer. There is a greater representation of BRCA2 tumors (41.7% vs 8.3%, p=0.0008) and under representation of BRCA1 tumors in men compared to women (5.0% vs 14.4%, p=0.0001) 14 . Male patients with BRCA2 mutations tend to present at a younger age and associated with a poorer survival 14 . Mutations in other genes may be implicated in the etiology of male breast cancer but are yet to be confirmed. BRCA2 is associated with aggressive prostate cancer and few reports indicate a higher incidence of breast cancer in males with this genetic mutation, and therefore it is recommended they undergo screening for both prostate and breast cancer 15 .
Androgen suppression therapy for the management of prostate cancer may be associated with increased breast cancer risk secondary to altered androgen to estrogen ratio or may be related to inherited genetic mutations conferring a higher risk 16 . On the other hand transgender males who received androgen suppression therapy so far have not demonstrated an increased risk of breast cancer 17 .

Screening for Male Breast Cancer
Current recommendations for screening are based on guidelines developed for females with BRCA mutations. All males with a family or personal history of breast cancer should undergo screening: monthly self breast examination, semi annual clinical breast examination and yearly mammograms for those found to have gynecomastia on the baseline mammogram 18 . The standard of choice remains mammography which has a sensitivity and specificity value of 92 and 90% respectively and a positive and negative predictive value of 99 and 55% respectively 19 . Mammograms are reliable for distinguishing gynecomastia from malignancy; the two could coexist in the same breast. Sonography by itself has a high false positivity rate but is valuable for evaluating complex masses, whereas Magnetic resonance imaging is currently recommended in males who require further evaluation of a highly suspicious mass 20 .

Pathology
Data from the SEER cancer registry show that 93.7% of male breast cancers are ductal carcinomas, 2.6% papillary, 1.8% mucinous, and 1.5% are lobular carcinoma 21 . Ductal carcinoma in situ (DCIS) occurs in about 10% of male breast cancers with the most common growth patterns being papillary and cribriform. Lobular carcinoma in situ is very rare because the male breast lacks terminal lobules 21 . Approximately 80-90% of male breast cancers are estrogen receptor positive, and 65-90% are progesterone receptor positive 4 . The her2-neu proto-oncogene is less likely to be overexpressed in male breast cancer. A large Italian study by Ottini et al identified 382 MBC with her2-neu positivity of 2.1%, and triple negative tumors as 3.7 %. Also, BRCA2 mutation was associated with family history, high grade, hormone receptor negative disease and resulted in poorer outcomes 22 . The hormone positivity rate for male breast cancer is expected to be lower in Africa following similar patterns as female breast cancer , therefore receptor testing is highly recommended to individualize treatment 23 .

Clinical Features
The most common presenting symptoms in male breast cancer are painless sub-areolar lump, nipple retraction, and bleeding from the nipple [24][25][26] . Men with a previous history of breast cancer have a greater risk of developing contralateral breast cancer and a few present with de novo metastatic disease 27 . Based on the American College of Radiology of Appropriateness criteria, males younger than 25 years with a breast mass have lower chances of harboring a malignancy and therefore should have initial ultrasonography complemented by mammography if suspicious, whereas males older than 25 years should have bilateral mammography with ultrasonography, and biopsy for a breast mass 28 . Mammographic findings are abnormal in up to 90% of male breast malignancy and often depict eccentric masses with irregular spiculated edges 29 .
Significant prognostic factors are tumor size and lymph node involvement. Tumors measuring 2-5 cm have a 40% higher risk of death than men with tumors <2 cm in maximum diameter 4 . Similarly, lymph node involvement is associated with a 50% higher risk of death compared to those without lymph node involvement 6 . Other identified prognostic features associated with better survival are ER+/PR+, Androgen Receptor negative, her 2 neu negative and ki67/p53 low group (median: 11.5 years; 95%CI: 6.2-16.8 years) and worst in PR-group (median:4.5 years; 95%CI: 1.6-7.8 years) 30 .

Management of Early Disease
Generally follows the same management strategies as in females as no prospective randomized trials have been conducted to establish treatment protocols in men 31 . Trucut biopsies are preferable to ensure enough tissue is obtained for further mandatory immunohistochemistry testing.
Even though several small studies have reported the successful use of sentinel node biopsy in males, randomized studies establishing the sensitivity and specificity of sentinel node biopsy in male breast cancer have not been possible 32 . Breast conservation in males may be a challenge due to difficulties in obtaining negative margins resulting in a high rate of upfront radical mastectomies performed 33 . As pertains in females, a minimum of ten axillary lymph nodes should be dissected to obtain adequate prognostic and therapeutic information 34 .
The indications for adjuvant radiation therapy in male breast cancer patients' follows same recommendations as in women, which includes breast conservation, T3/T4 tumors and positive axillary nodes. Following mastectomy, lesions greater than 5 cm with persistently positive surgical margins, lymph node positive disease, lympho-vascular space invasion, peri-neural invasion should be referred for radiation therapy 35 . Predictors of local regional failure included margin status, tumor size, and the number of involved axillary lymph nodes, lympho-vascular and peri-neural invasion 35 .
Adjuvant chemotherapy is recommended in all breast cancer patients who have a substantial risk of recurrence. Whereas the data supporting adjuvant chemotherapy in women are strong, there are few studies with low numbers on the effectiveness of adjuvant chemotherapy in men. A prospective study conducted by the National Cancer Institute (NCI) in USA in which 24 male patients with stage II breast cancer were treated with adjuvant CMF (cyclophosphamide, methotrexate, and fluorouracil) showed a projected 5-year survival rate of more than 80%, significantly higher than a similar cohort of historical controls 36 . Retrospective series have suggested adjuvant chemotherapy lowers the risk for recurrence in male patients 37 . Given the established benefit of chemotherapy in women and the suggestive evidence in men, most clinicians use similar guidelines for adjuvant chemotherapy as in female patients.
Tamoxifen is the recommended choice for positive hormone receptor staining in men 37 . Aromatase inhibitors are considered contraindicated because at least 20% of circulating estrogen in males is independent of aromatase and therefore indicated only in circumstances when tamoxifen is contraindicated or fails to control disease 38

Management of Locally Advanced Disease
Neoadjuvant chemotherapy should be considered for localized unresectable disease to improve resectability followed by radiotherapy to control local symptoms 40 . For patients with persistently unresectable disease, radiation therapy should be offered. Hormonal therapy has a role in receptors-positive disease most often following chemotherapy. Neoadjuvant hormonal therapy may be an option when there are contraindications to chemotherapy. However more than six months of treatment is required to achieve adequate shrinkage of disease and complete responses are rare with tamoxifen even in females 41 . Maximal tumor reduction with systemic therapies should be achieved prior to surgical intervention and this may require administering several cycles of chemotherapy and switching protocols. Positive surgical margins directly correlate with poor outcome and should be avoided 42 .

Management of Recurrent Disease
Poorly managed local recurrence may result in early distant disease. A disease free interval of greater than one year has a better prognosis compared with less than 6 months 43 . All patients should be evaluated for metastatic disease including radiological assessment of the lungs and liver. Bone scans and brain imaging are only indicated when there is high suspicion of disease involvement. Plain X-ray of the involved bone is recommended where bone scintigraphy is unavailable. The latter is preferred because bone scintigraphy completely assesses the skeletal system for evidence of osteoblastic bony involvement.
Second line treatment depends on previous therapies received, response achieved and disease extent. Surgery is an option for resectable lesions and clear surgical margins must be achievable. Patients who did not receive prior radiotherapy should be offered chest wall radiation. Anthracycline chemotherapy is associated with cardiotoxicity and lifetime maximal doses should not be exceeded 44 . The role of hormone and Her2 neu therapies are dependent on receptor status obtained for new lesions 45 .

Management of Metastatic Male Breast Cancer
The general approach to the treatment of metastatic male breast cancer is similar to that in female breast cancer. Hormonal therapy is often the first approach in men with estrogen and/ or progesterone receptor positive tumors in the absence of a visceral crisis. Tamoxifen has established efficacy in the metastatic setting with an approximate 50% response rate and is currently the preferred first-line approach for receptor positive male breast cancer 36 . Surgical ablative therapies such as orchiectomy, adrenalectomy, hypophysectomy and chemical castration using luteinizing hormonereleasing hormone agonists, with or without antiandrogens are reported to be effective in metastatic male breast cancer following tamoxifen failures 46 .
Men with hormone receptor negative, hormonerefractory disease or rapidly progressing visceral metastases should be managed with chemotherapy using the same protocols established for women 47 . The tole of Trastuzumab in managing Her2-neu overexpressing metastatic male breast cancer is however currently under debate as response rates are considered suboptimal 39 .

Survival Patterns for Male Breast Cancer
Several studies have demonstrated similar survival rates for both sexes with breast cancer after correcting for age, stage, molecular subtyping and other prognostic indicators 48 . Male breast cancer patients are less likely to receive post lumpectomy radiation and adjuvant chemotherapy compared to their female counterparts and these poor management practices could account for poorer outcomes 49 . BRCA2 mutations are associated with significantly lower survival compared to normal males (p=0.04) 50 In a series of 137 male patients, adjuvant chemotherapy was beneficial in node positive disease  51 . Several reports indicate worse prognosis in black compared to white patients with breast cancer specific mortality hazard ratio in black males is at least double compared to white 49 . A small study from Nigeria reports a 5 year overall survival for 57 men following adequate surgery to be less than 25% compared to 47.6 % in a study of survival for female breast cancer patients from Ghana (11,53) . This poor outcome may be attributed to general lack of hormone receptor testing for male breast cancer patients in the sub region. A recent publication from the USA comparing outcomes for black versus white male breast cancer patients revealed a worse outcome in younger black males which became non-significant when corrected for covariates such as income and insurance i.e. access to care 53 . In the latter study, there were no differences observed for males older than 65 years and could be explained by improved access to Medicare facilities above age 65 years.

Conclusion
In spite of the rising incidence, male breast cancer is still considered rare. Many present with advanced disease resulting in poor control in spite of better prognostic features compared to female counterparts. Tumors of the male breast are more likely to express estrogen and progesterone receptors and less likely to overexpress Her 2 neu compared to women and therefore receptor staining is pivotal in the management of male breast cancer. A multidisciplinary approach is recommended with decisions based broadly on principles established for female breast cancer. Education of patients, families and health providers will increase awareness of male breast cancer, ensuring early presentation, prompt referral for early diagnosis, treatment and improved survival. Large randomized trials in male breast cancer are encouraged to direct evidence based therapies in Africa as conclusions from small studies may be biased.