Male breast cancer: do we know everything about this rare disease?

Laura Steponavičienė^{1, 2}, Austė Steponavičiūtė³

1 National Cancer Institute Cancer Epidemiology Laboratory

2 National Cancer Institute Consultation Polyclinic Department

3 Vilnius 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 aspects, diagnostic, and treatment options of this disease.

Epidemiology

As mentioned, MBC accounts for less than 1% of all BC cases. Both MBC and female BC cases are most frequently reported in North America and Europe, and least in Asian countries (2). In Africa, more than average cases 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 (average age of men - 67 years; women - 61 years) (4, 5). Some authors claim that the incidence of MBC is increasing, but results need to be interpreted cautiously due to the small number of cases. The increase in incidence may be related to the increasing average lifespan (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 this disease varies each 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 this disease (7).

Risk Factors

Male breast cancer (MBC) is closely related to several genetic, hormonal, and lifestyle factors. Understanding these risk factors can help with early detection and management.

Genetic Factors

1. Klinefelter Syndrome: Men diagnosed with Klinefelter syndrome have a 20-50 times higher risk of developing breast cancer compared to men with a normal karyotype. It is estimated that 3-7.5% of men with BC have this syndrome (8).

2. Family History: A family history of breast or ovarian cancer significantly increases the risk. Approximately 15-20% of MBC cases have a familial background. This was confirmed in a cohort study at the National Institutes of Health in the United States (9, 10).

3. BRCA Mutations: About 10% of men with BC have a BRCA2 gene mutation, and, though rarer, mutations in BRCA1 also occur. BRCA2 mutations are linked not only to breast cancer but also to prostate, pancreatic cancers, gallbladder, stomach cancer, and melanoma. ASCO (American Society of Clinical Oncology) recommends genetic testing for men with BC and suggests that men with BRCA1 or BRCA2 mutations perform regular self-examinations (11, 12). These mutations are inherited in 4-40% of cases (13).

Hormonal Factors

The endocrine system plays a crucial role in the risk of MBC:

• Higher levels of estrogen and lower levels of androgens are associated with an increased risk.
• Men treated for prostate cancer or transgender individuals taking estrogen supplements are at higher risk due to excess estrogen (14).
• Liver diseases can increase the risk as adrenal glands secrete more androstenedione, which is converted to estrone and then to estradiol in the body.

Lifestyle and Physical Factors

1. Obesity: Obesity is a common cause of hyperestrogenism in men, which can lead to a higher risk of MBC. D'Avanzo and colleagues found that the risk of MBC in obese men is halved compared to non-obese men (15).

2. Testicular Conditions: Conditions like undescended testicles, congenital inguinal hernia, orchidectomy, testicular trauma, acute mumps-induced testicular inflammation (in individuals over 20 years of age), and infertility also increase the risk of MBC. These may relate to decreased testosterone levels, though there's no reliable data on the impact of decreased testosterone levels (15).

Racial and Ethnic Factors

Studies indicate:

• Non-white individuals have a higher risk of developing BC (1.8 cases per 100,000 population) compared to Caucasians. They also present with larger tumors, higher lymph node involvement and more advanced stage disease (16).
• Jews, regardless of their living location, show a higher incidence of MBC (2.3 cases per 100,000 population) (14).

Environmental and Lifestyle Factors

1. Ionizing Radiation: Exposure to ionizing radiation significantly increases the risk. A cohort study indicated a higher BC risk (1.8 cases per 100,000 population) in men who survived an atomic bomb explosion (17).

2. Alcohol Consumption: Alcohol consumption is a known risk factor. A European case-control study showed that consuming 10 g of alcohol per day increases the risk of MBC by 16% (18).

Clinical Features

The most common symptom of Male Breast Cancer (MBC) (75% of cases) is a painless mass in the breast that can be felt on palpation. Pain associated with a breast mass is rare, occurring in 5% of cases. Other possible symptoms include nipple retraction (9%), nipple discharge (6%), or changes in the nipple or surrounding skin (6%). Since MBC is rare, neither men nor some doctors immediately suspect cancer, resulting in about 40% of cases being diagnosed at advanced stages (III or IV) (19). The distribution of MBC stages upon 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 upon diagnosis worldwide (23)

Stage	Frequency
I	37%
II	21%
III	33%
IV	9%

Histopathological Features

The most common morphological form of MBC (90% of all cases) is invasive ductal carcinoma, with 55% of cases being moderately differentiated (G2). A rarer form is ductal carcinoma in situ (10%), while papillary, medullary, mucinous, lobular carcinoma are extremely rare (less than 2%) (Table 2) (19). Positive estrogen receptors are detected in 90% of MBC cases, positive progesterone receptors in 92-96%, while androgen receptor expression varies more widely, from 39-95% (20). Positive estrogen indicators are higher than in female Breast Cancer cases, and overall all histopathological indicators are similar to breast tumors diagnosed in women after menopause. Data on increased HER-2 receptor expression are inconsistent due to insufficient studies. 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)

Morphological Form of Breast Cancer	Frequency
Invasive ductal carcinoma G1 G2 G3	90% 20% 55% 25%
Ductal carcinoma in situ	10%
Papillary carcinoma	2%
Medullary carcinoma	2%
Mucinous carcinoma	1%
Paget's disease of the breast	1%
Lobular carcinoma	1%

Diagnosis

The diagnosis is usually made using three methods - clinical evaluation, mammography and/or ultrasound examination, and biopsy with a thin or thick needle. The sensitivity and specificity of mammographic examination reach 90-92% (21). In many cases, definite signs of a tumor are visible on mammograms and sonograms, unlike in female Breast Cancer cases where microcalcifications are less common. The visible mass in the breast often needs to be differentiated from gynecomastia (differences are easily distinguished on mammograms), breast abscess, and metastases in breast tissue. Biopsy using a thick needle allows for a more reliable determination of invasive MBC and identification of histopathological features, which are essential in selecting further treatment tactics (22).

Treatment

Due to a lack of comprehensive studies evaluating the advantages and disadvantages of possible treatments for MBC, treatment recommendations are based on guidelines for treating female Breast Cancer. Based on current epidemiological and histopathological research data, MBC is similar to postmenopausal female Breast Cancer with positive hormone receptors. Since MBC is a rare disease, the available data are not conclusive. Some scientists and doctors do not support the idea of treating men the same as women and argue that the goal should be to treat men for Breast Cancer based not on similarities with female Breast Cancer but on 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 - modified radical or simple mastectomy (23). It is important to emphasize that these changes have not led to a decrease in survival rates. Currently, the most common surgical treatment is modified radical mastectomy. According to literature data, this method is used in about 70% of patients, radical mastectomy in 8-30% of patients, and lumpectomy with or without radiation therapy is chosen by 1-13% of patients (24). Radical mastectomy is most beneficial in cases of extensive involvement of the chest wall muscles, but in such cases, a better choice is systemic neoadjuvant therapy (12). Breast-conserving surgery is less commonly chosen for men in early stages of the disease due to the lack of breast tissue and the location of most tumors in the central portion. In invasive BC, axillary lymph node dissection is usually performed. Metastases in axillary lymph nodes are found in about 50% of men with BC, and in 40% of cases, more than 3 lymph nodes are affected (24, 25). Several cases have been described where 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. It is believed that this procedure is safe in cases of BC where there is no clinical suspicion of metastases in the axillary lymph nodes.

Radiation Therapy

Due to a lack of research, the indications for adjuvant radiation therapy in BC are the same as in women with BC (24). Adjuvant radiation therapy is more commonly chosen in BC compared to women with BC, as more advanced stages of the disease are often diagnosed (28). Postoperative radiation therapy is recommended in cases of: large tumor size; tumor spread in the skin, areola area, or major chest muscle; metastases in axillary lymph nodes; presence of tumor cells at the resection margin. Radiation therapy should also be considered in cases of multicentric tumors, high proliferation index, or intravascular tumor spread (29). When administering radiation therapy, attention must be paid to the risk of congestive heart failure. It is reported that after a 20-year follow-up period, this risk reaches 20% for women who received chemotherapy and radiation therapy (30). In recent years, with the advancement of radiation therapy technologies, this risk is lower (31), but it remains relevant in BC cases, as the disease is more often diagnosed in older men, who already have a higher incidence of cardiovascular pathology.

Systemic Therapy

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

Chemotherapy

Small non-randomized studies have provided data on adjuvant chemotherapy in breast cancer (BC). All of these studies show a lower risk of cancer recurrence and death. Therefore, doctors recommend this treatment for men with intermediate or high-risk BC, especially when hormone receptors are negative. In most cases, doctors use the same regimens as in women with BC (14). The most common regimens are CMF (Cyclophosphamide, Methotrexate, and Fluorouracil) or FAC (Fluorouracil, Adriamycin, and Cyclophosphamide), with very limited data on taxane group drugs. When deciding on chemotherapy for men with BC, physicians often rely on existing data on the benefits of chemotherapy for women. The lack of specific data results from the exclusion of men with BC from clinical trials, which provide the most accurate and reliable data.

Hormone Therapy

Tamoxifen stands as the most studied and widely used drug for adjuvant therapy in cases of positive hormone receptors. Doctors typically prescribe it for 5 years (32). In a study at MDACC (M.D. Anderson Cancer Center), doctors prescribed tamoxifen to 92% of patients, associating its use 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 prescribed for less than 2 years (34, 23).

Data on tamoxifen tolerance vary across studies. Some researchers claim tamoxifen is well tolerated (35), while others report that men often discontinue this treatment due to side effects. The most commonly reported side effects include decreased libido (29%), weight gain (25%), hot flashes (21%), mood changes (21%), depression (17%), insomnia (12%), and thrombosis (4%) (36). Researchers have not proven the benefit of aromatase inhibitors for adjuvant BC treatment. Until researchers obtain reliable data, doctors should not prescribe them.

Biological Therapy

Researchers have no data on the benefit of adjuvant treatment with trastuzumab in BC. However, since the treatment has proven beneficial in HER2-positive BC in women (37) and there are no biological reasons for a different response in male bodies, doctors can prescribe trastuzumab to men with HER2-positive BC.

Prognosis

It has been calculated that the overall survival of men with Breast Cancer (BC) increased from 1975 to 2005. The 5-year survival rate ranges from 36% to 66% (34). Such a wide interval is indicated because survival depends on the stage of cancer and the chosen treatment methods. Poor survival rates are most often due to delayed diagnosis. According to the literature, 2-29% of BC cases are diagnosed with local disease recurrence, while 18-54% of cases develop distant metastases. Upon detecting metastases, the average survival duration reaches 26.5 months (38). Additionally, men with BC have an increased risk of secondary tumors.According to data from the Surveillance, Epidemiology and End Results (SEER) database, out of 4,873 men diagnosed with breast cancer, 1.9% experienced a breast cancer recurrence, and 21% were diagnosed with secondary tumors not in the breast. The most common secondary tumors were in the prostate, colon, and genitourinary system (39).

Specific Aspects

Since BC is not common, most men are unaware that they may face such a problem. Therefore, the disease is often diagnosed late, leading to psychological issues. After diagnosis, men gradually realize they have a very rare disease, most specialists have not encountered BC cases, and the treatment they receive follows general guidelines for female BC treatment. This not only causes stress but also deeper psychological problems. Most 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 crucial. Recently, much attention has been given to creating clear, research-based recommendations for BC treatment. Therefore, it is suggested to gather as much data as possible about BC characteristics to plan clinical trials specifically for men (12). Efforts are being made to establish an international BC program with tasks such as 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 advancements, many unanswered questions remain regarding BC. It is evident that understanding the disease, like many other rare diseases, requires data accumulation from various sources. International collaboration is essential to better comprehend BC. Current efforts in collecting epidemiological data, clinical information, and tumor samples will enhance the understanding of the disease's etiology. International collaboration will also facilitate the planning of successful clinical trials to address key BC treatment issues. It is essential to educate both patients and healthcare providers involved in the diagnostic and treatment processes to increase awareness of BC and ensure evidence-based treatment decisions, as well as 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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