Male Breast Cancer: What Do We Know About This Rare Disease?

Laura Steponavičienė¹˒², Austė Steponavičiūtė³

¹National Cancer Institute Cancer Epidemiology Laboratory
²National Cancer Institute Consultation Polyclinic Department
³Vilnius University Faculty of Medicine

Introduction

Male breast cancer (MBC) is a very rare disease, accounting for less than 1% of all diagnosed cases of breast cancer (BC) worldwide (1). It is most commonly diagnosed at an advanced stage. The aim of this article is to briefly review the main risk factors, clinical features, diagnostic methods, and treatment options for this disease.

Epidemiology

As mentioned, MBC accounts for less than 1% of all BC cases. Both MBC and female BC are most frequently reported in North America and Europe and least frequently in Asian countries (2). In Africa, higher-than-average rates are reported in Uganda (5%) and Zambia (15%) due to endemic infectious liver diseases associated with hyperestrogenism (3).

Unlike female BC, MBC occurs at an older age (mean age in men – 67 years; in women – 61 years) (4, 5). Some authors suggest that the incidence of MBC is increasing, but these results should be interpreted cautiously because of the small number of cases. The increase in incidence may be related to increasing average life expectancy (6).

In Lithuania, breast cancer is diagnosed in only a few men each year (0.6–1.2 cases per 100,000 population). The number of MBC cases and deaths from the disease varies from year to year, with no established trends. According to the latest Cancer Registry data, 16 new cases of MBC were diagnosed in Lithuania in 2012, and 2 individuals died from the disease (7).

Risk Factors

MBC is closely associated with genetic changes. It has been found that men diagnosed with Klinefelter syndrome have a 20–50 times higher risk of developing BC than men with a normal karyotype. It has been estimated that 3–7.5% of men with BC have this syndrome (8).

Family history is an important factor. Approximately 15–20% of MBC cases are reported to have a family history of breast or ovarian cancer (9). These data were confirmed in a cohort study conducted at the National Institutes of Health in the United States (10).

It has been found that 10% of men with BC have a BRCA2 gene mutation (11). A BRCA1 gene mutation is less common but also occurs. Moreover, BRCA2 mutations are also associated with prostate and pancreatic cancer and have an impact on gallbladder and stomach cancer and melanoma. ASCO (American Society of Clinical Oncology) recommends that men with BC be offered genetic testing for possible mutations and that men with BRCA1 or BRCA2 mutations be taught to perform periodic breast self-examinations (12). It has been found that these mutations are inherited in 4–40% of cases (13).

Another important risk factor is the endocrine system. An increased risk of BC is associated with higher estrogen and lower androgen levels in the male body. Cases of MBC associated with excess estrogen have been described in men treated for prostate cancer and in transgender individuals taking estrogen supplements (14). Men with liver disease are also at risk because the adrenal glands secrete more androstenedione, which is converted in the body to estrone and ultimately to estradiol.

Obesity is one of the most common causes of hyperestrogenism in men and may therefore be associated with the risk of MBC. D'Avanzo and colleagues showed that the risk of MBC in obese men was halved compared with non-obese men (15).

Undescended testicles, congenital inguinal hernia, orchidectomy, acute testicular inflammation caused by mumps in individuals over 20 years of age, testicular trauma, and infertility are also indicated as risk factors for MBC (15). This may be related to decreased testosterone levels in the body. However, there are no reliable data on the impact of decreased testosterone levels.

Studies show that individuals of non-white races have a higher risk of developing BC (1.8 cases per 100,000 population) than individuals of Caucasian descent. They also have larger tumors, greater lymph node involvement, and more cases of advanced-stage disease (16). A higher incidence of MBC has been found among Jews, regardless of their place of residence (2.3 cases per 100,000 population) (14).

The risk of MBC is also associated with ionizing radiation. A cohort study indicated a higher risk of BC (1.8 cases per 100,000 population) among men who survived an atomic bomb explosion (17).

Alcohol consumption is a risk factor for the development of BC in both women and men. A case-control study conducted in Europe showed an association between MBC and alcohol consumption: consuming 10 g of alcohol per day increases the risk of MBC by 16% (18).

Clinical Features

The most common symptom of MBC, occurring in 75% of cases, is a painless breast mass that can be detected by palpation. Pain associated with a breast mass is rare, occurring in 5% of cases. Other possible symptoms include nipple retraction (9%), nipple discharge (6%), and changes in the nipple or surrounding skin (6%).

Because MBC is rare, neither men nor some physicians immediately suspect cancer, resulting in approximately 40% of cases being diagnosed at advanced stages (III or IV) (19). The distribution of MBC stages at diagnosis worldwide is presented in Table 1. According to data from the Cancer Registry of Lithuania, MBC is most commonly diagnosed at stage II (37%) and stage III (25%).

Table 1. Distribution of MBC Stages at Diagnosis Worldwide (23)

Histopathological Features

The most common morphological form of MBC, accounting for 90% of all cases, is invasive ductal carcinoma, with 55% of cases being moderately differentiated (G2). A less common form is ductal carcinoma in situ (10%), while papillary, medullary, mucinous, and lobular carcinomas are extremely rare, accounting for less than 2% (Table 2) (19).

Positive estrogen receptors are detected in 90% of MBC cases and positive progesterone receptors in 92–96%, while androgen receptor expression varies more widely, from 39% to 95% (20). Estrogen receptor positivity is higher than in female BC, and overall, the histopathological characteristics are similar to those of breast tumors diagnosed in postmenopausal women.

Data on increased HER-2 receptor expression are inconsistent because of insufficient research. According to different authors, increased expression of this receptor is detected in 1.7–34% of all MBC cases (19).

Table 2. Frequency of MBC Morphological Forms (19)

Diagnosis

The diagnosis is usually established using three methods: clinical evaluation, mammography and/or ultrasonography, and fine- or core-needle biopsy. The sensitivity and specificity of mammography reach 90–92% (21). In many cases, definite signs of a tumor are visible on mammograms and sonograms. Unlike in female BC, microcalcifications are less common.

A visible breast mass often needs to be differentiated from gynecomastia, with the differences being readily distinguishable on mammography, as well as from breast abscesses and metastases to breast tissue. Core-needle biopsy allows more reliable identification of invasive MBC and determination of histopathological features, which are essential when selecting further treatment strategies (22).

Treatment

Because of the lack of comprehensive studies evaluating the advantages and disadvantages of available treatments for MBC, treatment recommendations are based on guidelines for the treatment of female BC. Based on current epidemiological and histopathological research data, MBC is similar to hormone receptor-positive BC in postmenopausal women.

Since MBC is a rare disease, the available data are inconclusive. Some researchers and physicians do not support treating men in the same way as women and argue that the goal should be to treat male BC based not on its similarities to female BC but on its differences (12).

Surgical Treatment

For most men with BC in the 20th century, the standard surgical treatment for locally advanced disease was radical mastectomy, which has now been replaced by less invasive techniques, including modified radical or simple mastectomy (23). It is important to emphasize that these changes have not resulted in decreased survival rates.

Currently, the most common surgical treatment is modified radical mastectomy. According to the literature, this method is used in approximately 70% of patients, radical mastectomy in 8–30% of patients, and lumpectomy with or without radiation therapy in 1–13% of patients (24). Radical mastectomy is most beneficial in cases of extensive involvement of the chest wall muscles, although systemic neoadjuvant therapy is a better option in such cases (12).

Breast-conserving surgery is less commonly selected for men with early-stage disease because of the limited amount of breast tissue and the location of most tumors in the central portion of the breast. In invasive BC, axillary lymph node dissection is usually performed. Metastases in the axillary lymph nodes are found in approximately 50% of men with BC, and in 40% of cases, more than 3 lymph nodes are involved (24, 25).

Several cases have been described in which only sentinel lymph node dissection was performed in BC (26, 27). This procedure is associated with lower mortality. More information is available on sentinel lymph node biopsy. This procedure is considered safe in cases of BC in which there is no clinical suspicion of metastases to the axillary lymph nodes.

Radiation Therapy

Because of the lack of research, the indications for adjuvant radiation therapy in male BC are the same as those in women with BC (24). Adjuvant radiation therapy is used more frequently in male BC than in female BC because more advanced stages of the disease are often diagnosed (28).

Postoperative radiation therapy is recommended in cases of large tumor size, tumor spread to the skin, areolar region, or major chest muscle, metastases to the axillary lymph nodes, or the presence of tumor cells at the resection margin. Radiation therapy should also be considered in cases of multicentric tumors, a high proliferation index, or intravascular tumor spread (29).

When administering radiation therapy, attention should be paid to the risk of congestive heart failure. It has been reported that after a 20-year follow-up period, this risk reaches 20% in women who received chemotherapy and radiation therapy (30). In recent years, with advances in radiation therapy technologies, this risk has decreased (31), but it remains relevant in male BC because the disease is more commonly diagnosed in older men, who already have a higher prevalence of cardiovascular pathology.

Systemic Therapy

Systemic therapy includes chemotherapy, hormone therapy, and biological therapy.

Chemotherapy. Data on adjuvant chemotherapy in male BC have been obtained from small, non-randomized studies. All of these studies have demonstrated a lower risk of cancer recurrence and death. Therefore, this treatment is recommended for men with intermediate- or high-risk BC, particularly when hormone receptors are negative. In most cases, the same regimens are used as in women with BC (14).

Chemotherapy is most commonly administered using CMF or FAC regimens, while data on the use of taxanes are very limited. When deciding whether to administer chemotherapy to men with BC, the decision is usually based on existing data regarding the benefits of chemotherapy in women. The lack of data is mainly due to the fact that men with BC are not included in clinical trials, which provide the most accurate and reliable data.

Hormone Therapy. Tamoxifen is the most extensively studied and widely used medication recommended for adjuvant therapy in hormone receptor-positive cases and is prescribed for 5 years (32). In a study conducted at MDACC (M.D. Anderson Cancer Center), tamoxifen was prescribed to 92% of patients, and its use was associated with a lower risk of disease recurrence and improved overall survival (RR=0.45; p=0.01) (33).

Smaller studies have also demonstrated the benefit of tamoxifen, even when the medication was prescribed for less than 2 years (34, 23). Data on tamoxifen tolerability are inconsistent across studies. Some researchers report that tamoxifen is well tolerated (35), while other authors indicate that men discontinue treatment more frequently because of adverse effects. The most commonly reported adverse effects are decreased libido (29%), weight gain (25%), hot flashes (21%), mood changes (21%), depression (17%), insomnia (12%), and thrombosis (4%) (36).

The benefit of aromatase inhibitors for the adjuvant treatment of male BC has not been established. Until reliable data are available, they should not be prescribed.

Biological Therapy. There are no data on the benefit of adjuvant treatment with trastuzumab in male BC. Since the benefit of trastuzumab has been demonstrated in women with HER2-positive BC (37), and there are no biological reasons why trastuzumab would act differently in the male body, this treatment may be prescribed to men with HER2-positive BC.

Prognosis

It has been estimated that the overall survival of men with breast cancer (BC) increased between 1975 and 2005. The 5-year survival rate ranges from 36% to 66% (34). This wide range is reported because survival depends on the stage of cancer and the treatment methods selected. Poor survival rates are most often associated with delayed diagnosis.

According to the literature, local disease recurrence is diagnosed in 2–29% of BC cases, while distant metastases develop in 18–54% of cases. After the detection of metastases, the average survival duration is 26.5 months (38).

In addition, men with BC have an increased risk of secondary tumors. According to data from the Surveillance, Epidemiology and End Results (SEER) database, among 4,873 men diagnosed with breast cancer, 1.9% experienced breast cancer recurrence, while 21% were diagnosed with secondary tumors outside the breast. The most common secondary tumors involved the prostate, colon, and genitourinary system (39).

Specific Aspects

Because BC is uncommon in men, most are unaware that they may develop the disease. As a result, the disease is often diagnosed late, which can lead to psychological problems. After diagnosis, men gradually realize that they have a very rare disease, that most specialists have not encountered cases of male BC, and that the treatment they receive is based on general guidelines for the treatment of female BC. This may cause not only stress but also more profound psychological problems.

Many patients feel that their masculinity is compromised because breast cancer is perceived as a women's disease (40). Therefore, psychological support for men with BC is particularly important.

Recently, considerable attention has been devoted to developing clear, research-based recommendations for the treatment of BC in men. Therefore, it has been suggested that as much data as possible should be collected on the characteristics of BC to facilitate the planning of clinical trials specifically for men (12).

Efforts are being made to establish an international BC program with objectives that include conducting a retrospective analysis of available clinical and pathological data and creating an international BC registry to collect data from all patients. These data would facilitate better planning of randomized clinical trials (12).

Summary

Despite recent advances, many unanswered questions regarding BC in men remain. It is evident that understanding this disease, like many other rare diseases, requires the accumulation of data from various sources. International collaboration is essential to improve the understanding of BC in men.

Current efforts to collect epidemiological data, clinical information, and tumor samples will improve understanding of the etiology of the disease. International collaboration will also facilitate the planning of successful clinical trials to address key issues in BC treatment.

It is essential to educate both patients and healthcare professionals involved in the diagnostic and treatment processes to increase awareness of BC and ensure evidence-based treatment decisions, as well as to encourage participation in future clinical and biological studies aimed at optimizing the management of this rare disease.

Publication "Internistas" No. 1, 2020.

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