Introduction

Breast cancer in men, though exceptionally rare, presents a multifaceted medical challenge, and a complete understanding of its intricacies and associated risk factors continues to elude the medical community. The incidence rate of male breast cancer (MBC) is a mere 1 in 100,000 in Europe, contributing just 1% to the total breast cancer cases globally, and representing a mere 0.3% of all cancers diagnosed in men [1]. What sets MBC apart is its heightened mortality rate when compared to its female counterpart, underscoring the urgent need for increased awareness and exploration of this relatively neglected condition [2].

The challenges intertwined with MBC, including delayed diagnosis due to its later onset and limited awareness leading to fewer screenings, pose significant threats to the survival outcomes of affected individuals. Despite these formidable obstacles, an array of studies suggests that male breast neoplasia is intricately linked to distinct risk factors and biological foundations. Recognizing and disseminating knowledge about this disease is paramount, as it plays a pivotal role in improving prognosis through timely and appropriate management.

Against this backdrop, the principal objective of the present study is to conduct a thorough retrospective analysis, delving into various facets of MBC. This comprehensive exploration encompasses modes of presentation and diagnosis, identifiable risk factors, essential biological characteristics, major treatment modalities, and survival rates among male breast cancer patients. The overarching goal is to offer valuable insights that can illuminate medical professionals, researchers, and the general public about the nuanced dimensions of MBC, thereby contributing to a deeper understanding, early detection, and improved outcomes for those grappling with this exceedingly rare form of cancer. As we embark on this investigative journey, our commitment is to provide a wealth of information that transcends the statistical rarity of MBC, fostering a collective awareness that can drive advancements in research, medical practice, and public consciousness, ultimately leading to more effective strategies for the prevention, diagnosis, and treatment of male breast cancer.

Methods

This is a multicenter retrospective observational cohort study conducted by The Italian Society of Surgical Oncology (SICO) Breast Oncoteam, encompassing patients treated in 12 Italian breast units (the list of participating centers is provided in the Appendix). The study received notification to the Ethics Committee and obtained approval from the Institutional Review Board. The database included male patients, 18 years of age or older, diagnosed with breast cancer (invasive or in situ) from January 1975 to December 2019. However, due to limitations in available data or follow-up, only patients who underwent surgery between 1992 and 2019 were included in this analysis.

Data were collected regarding clinical information and radiological examinations conducted for diagnosis by the surgeons at each involved center. Patient characteristics encompassed age at surgery, family history of cancer(s), and prostate-specific antigen (PSA). Clinical characteristics comprised tumor size, nodal status, TNM stage according to the American Joint Committee on Cancer (AJCC), WHO histologic type, Nottingham combined histologic grade, estrogen receptor (ER) status, progesterone receptor (PR) status, proliferative index Ki67, human epidermal growth factor receptor 2 (HER2) status, and type of surgery performed. Postoperative adjuvant treatments (including chemotherapy, hormone therapy, and radiotherapy) were also documented. ER, PR, and HER2 expressions were determined through immunohistochemistry testing. In equivocal HER2 cases, data from fluorescent in-situ hybridization assay records were utilized for molecular stratification. Invasive breast cancer subtypes were categorized into the following groups according to St. Gallen 2013 [3]: luminal A cases (ER+ /PR+ /HER2− , Ki67 < 20%), luminal B cases (luminal B HER2− : HER+ /HER2− and at least one of Ki67 ≥ 20% or PR− , luminal B HER2+ : ER+ /HER2+ /any Ki67/any PR), HER2 + (ER− /PR− /HER2 +), and triple-negative breast cancers (ER− /PR− /HER2−). Data of molecular subtypes were collected in alignment with the TNM classification of the eighth edition of the American Joint Commission [4].

Follow-up data were also collected. Statistical analysis presented continuous variables as medians with interquartile ranges (IQR) and dichotomous variables as counts and percentages. Endpoints evaluated were disease-free survival (DFS) and overall survival (OS). DFS was defined as the time (years) from surgery until local recurrence, metastasis, other primary carcinoma, or death, whichever occurred first. OS was defined as the time (years) from surgery until death (from any cause). Kaplan–Meier method was used to estimate the OS and DFS functions. Clinically relevant variables, such as grade, tumor size, nodal status, and subtype were analyzed with univariable and multivariable Cox regression models to quantify their impact on OS and DFS for patients with invasive breast cancer. Variables of adjuvant treatments (chemotherapy, hormone therapy, and radiotherapy) were not considered in the univariable and multivariable analysis due to their high correlation with tumor characteristics and subtype. All reported p-values are two-sided. Statistical analyses were conducted using SAS statistical software version 9.4 (SAS Institute, Inc., Cary, NC, USA).

Results

On a series of 671 male patients with breast cancer assessed for eligibility, 268 were excluded from our analyses for one or more of the following reasons: metastatic cancer at diagnosis, previous cancer(s), neoadjuvant treatment received, incomplete data on (neo) adjuvant treatment(s), and/or follow-up data. Four hundred-three patients (28 with ductal carcinoma in situ, DCIS, and 375 with invasive neoplasm) were included in the analyses (Fig. 1). All included patients underwent surgery during the period spanning from 1992 to 2019. Overall, the median age at surgery was 63.8 years (IQR 56.1–72.1) [64.3 years (IQR 56.3–72.6) in patients with invasive tumors, 60.5 years (IQR 47.4–66.1) in those with DCIS].

Fig. 1
figure 1

Flowchart for patient’s selection. DCIS ductal carcinoma in situ aUrinary and genital (N = 38), digestive system (N = 22), multiple sites (N = 20), skin (N = 15), hematopoietic and lymphoid tissues (N = 10), breast (N = 4), soft tissue and bone (N = 4), endocrine organs (N = 3), head and neck (N = 3), thoracic (N = 3), not specified (N = 4). bOnly chemotherapy (N = 8), only hormone therapy (N = 11), both chemotherapy and hormone therapy (N = 3).

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Table 1 shows the distribution of patient characteristics and preoperative diagnostic examinations. The vast majority of our patients were of Caucasian ethnicity (99.5%). In 31.3% of cases, familiarity with cancer was reported. Only 16.9% of patients had genetic testing, with a mutation found in 27.9% of cases. Most of the patients had a preoperative radiological diagnostic examination: 68% had at least an echography, and 55.1% had at least a mammography. In 10.7% of cases, patients had breast magnetic resonance imaging (MRI) with contrast. In 36.2% of cases, patients had preoperative needle biopsy or fine needle aspiration cytology (FNAC), respectively, while only 4.2% had both (Table 1).

Table 1 Distribution of patient characteristics and preoperative diagnostic examinations
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The distribution of tumor stage and lymph node surgical procedures is summarized in Table 2. Most of the tumors presented with G2 grading (51.4%) and pT1 (58.6%). In 51.4% of cases, patients underwent axillary dissection (Table 2).

Table 2 Distribution of tumor stage and lymph nodes surgical procedures
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Table 3 shows the distribution of tumor characteristics and treatments. Most of the patients were ER and PR positive (63.8%) and HER2 negative (80.4%). Most of the neoplasms had high (≥ 20%) Ki67 values (61.3%) and luminal B subtype (51.1%). The main histological subtype was ductal carcinoma (87.8%). Most of the patients underwent hormone therapy (HT) with (31.8%) or without (52.4%) chemotherapy (CT) and did not undergo radiotherapy (RT, 56.8%; Table 3).

Table 3 Distribution of tumor characteristics and treatments
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After a median follow-up of 7.5 years (IQR 3.9–12.3), 85 MBC patients died (21.1%), 3 with DCIS and 82 with invasive BC. The 10-year OS was 74.9% (95% CI 68.7–80.1) overall, 73.6% (95% CI 67.0–79.1) for invasive BC, and 90% (95% CI 65.6–97.4) for DCIS (Table 4 and Fig. 2A). One hundred twenty-nine patients experienced disease recurrence or death (DFS events). The most common event was distant recurrence (35.7%). The 10-year DFS was 61.1% (95% CI 54.5–67.0) overall, 59.9% (95% CI 53.0–66.0) for invasive BC, and 75.6% (95% CI 44.8–90.7) for DCIS (Table 4 and Fig. 2B).

Table 4 Overall survival and disease-free survival
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Fig. 2
figure 2

Kaplan–Meier curves for overall survival (OS; panel A) and disease-free survival (DFS; panel B) according to tumor invasion

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Tables 5 and 6 show the univariable and multivariable Cox regression models for OS and DFS, respectively, in the subgroup of patients with invasive BC (N = 375). In univariable analysis, having a G3 tumor (vs. G1), pT2/3/4 (vs. pT1), pN2/3 (vs. pN0), luminal B subtype with Ki67 ≥ 20% (vs. Luminal A) were significantly associated with a higher risk of death (Table 5).

Table 5 Univariable and multivariable Cox regression model for overall survival (OS) in patients with invasive breast cancer (N = 375)
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Table 6 Univariable and multivariable Cox regression model for disease-free survival (DFS) in patients with invasive breast cancer (N = 375)
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In the multivariable analysis, having a HER2 positive or a triple-negative subtype (vs. Luminal A) was also significantly associated with a higher risk of mortality (HR 4.76, 95% CI 1.26–18.1; Table 5).

Similar results were found for DFS. In univariable analysis, having a G3 tumor (vs. G1), pT2/3/4 (vs. pT1), pN2/3 (vs. pN0), luminal B subtype with Ki67 ≥ 20% or HER2 positive or triple-negative disease (vs. Luminal A), and having received radiotherapy were significantly associated with a higher risk of recurrence or death (Table 6). In multivariable analyses, pT, pN, and subtype remained significantly associated with a higher risk of recurrence or death: pT2/3/4 vs. pT1 HR 1.57 (95% CI 1.04–2.38), pN2/3 vs. pN0 HR 1.99 (95% CI 1.18–3.36), HER2 positive or triple-negative subtype vs. Luminal A subtype HR 5.25 (95% CI 1.69–16.3; Table 6).

Discussion

Most of the knowledge regarding MBC treatment is derived from therapeutic strategies for female BC, despite significant differences between these two entities. Therefore, we conducted a multicenter study focusing on male patients with BC treated in 12 Italian breast units, providing an analysis of characteristics and survival rates at a national level. To our knowledge, this is the largest published series in our country, encompassing 403 patients.

BC incidence rates steadily increase with age in men, mirroring trends observed in women [5]. In our case series, the median age at surgery (63.8 years) is similar but slightly higher compared to that reported in the literature for women (62 years). This may reflect two distinct aspects: firstly, male breast cancer is often accompanied by less awareness, and secondly, men are not included in screening policies due to the very low incidence of MBC.

Several risk factors causing breast cancer in men have been identified, including general and genetic factors. Among genetic risk factors, radiation exposure, age, and obesity are the most common. High estrogen levels are also associated with MBC, often caused by chromosomal disorders such as Klinefelter syndrome [6]. From our retrospective cohort, we observe a significant proportion of patients with mutations (27.9%) or a family history (31.3%) of malignancy. However, analyses of potential genetic mutations or associated syndromes (such as Klinefelter syndrome and obesity) have rarely been performed. This highlights the need for increased awareness and a standardized approach to this rare but important disease.

Approximately 1 in 5 men who develop breast cancer have a family history of the disease, and we found that 31.5% of all patients have a family history of malignancy in general. Therefore, the American Society of Clinical Oncology (ASCO) guidelines recommend offering genetic counseling to all men diagnosed with breast cancer. Interestingly, as reported by Yadav et al. [7], almost 20% of MBC patients are diagnosed after another tumor diagnosis, with prostate, colon, and genitourinary cancers being the most common. Among our 671 patients, 126 (18.9%) had a previous tumor (mainly genitourinary), and they were excluded from the analysis. MBC can present in several ways, with a palpable breast mass being the most common presentation. Almost 90% of patients in our series were diagnosed with early-stage disease, considering the thinness of the male mammary gland and the rapid clinical detection of palpable masses [8]. Most patients (90.9%) in our series were pT1 or pT2, confirming this observation. Additionally, half of the patients had disease without nodal involvement.

In suspected cases, men should be referred for standard imaging, often consisting of ultrasound rather than mammography, as seen in our series where breast ultrasound was performed in 68% of cases. All suspicious lesions should undergo biopsy, with core needle biopsy being the preferred method. However, cytology can provide a satisfactory specimen and could be considered a reasonable option, especially considering the low breast thickness [9]. In our cohort, both methods were performed in similar proportions.

In female BC, invasive ductal carcinoma is the most common tumor histology [10], and invasive lobular carcinoma is very infrequent, comprising less than 2% of total cases [11]. Our cohort confirms this observation, with 86.9% of cases being invasive ductal carcinoma and 1.5% invasive lobular carcinoma. This could be partially explained by the occasional formation of terminal lobules in male breast tissues, associated with estrogen exposure in females [12]. The main reason for the majority of MBC being invasive (over 90% in our series) is the lack of substantial evidence supporting screening mammograms in the general male population. As widely reported in published data, the majority of male breast cancers are grade 2 [13, 14]. Most of them are ER and PR receptor positive and HER2 negative [7, 15]. Our series confirms this, with G2 neoplasia reported in 51.4% of cases and high expression of ER and PR in 63.8% of cases. In more than 80% of cases, we had HER2-negative cancers.

In a large international MBC program consortium, Cardoso F et al. [16] retrospectively evaluated 1483 patients from 1990 to 2010 and found that 99% of patients were ER+ , 82% PR+ , 8.7% HER2 negative, and only 0.3% triple-negative.

Triple-negative cancers were extremely rare in our series, occurring in only 3 cases. The majority of patients showed a high rate of Ki67 (61.3%), considering the cut-off of 20% as established by the 2013 St. Gallen consensus guidelines [17]. Currently, the treatment of MBC is based on standard care developed for female breast cancer, with no prospective randomized studies available to date for the management of MBC.

Surgical treatment is usually the first therapeutic approach, and mastectomy is the intervention of choice [18]. One of the most important effects of non-special type (NST) regards the downstaging of tumor size, allowing for breast conservative surgery with aesthetic and functional advantages. However, this objective is less relevant in MBC patients, as more than two-thirds of them underwent mastectomy, considering different goals in cosmetic outcomes. Additionally, due to anatomical conditions (the male areola almost totally corresponds to the glandular residue), modest aesthetic value, and poor psychosocial implications, mastectomy is the most frequently performed surgery [18]. Despite this evidence, some authors [19, 20] suggest considering less aggressive approaches in the future, such as BCS or different conservative mastectomies.

Although no randomized clinical trial has been conducted on the use of sentinel lymph node biopsy (SLNB), this procedure can be applied with the same indications and technique as axilla management in female BC [21]. We performed SLNB in almost half of our patients and axillary dissection in 51.4%. As in women, the standard treatment option for men with early-stage breast cancer is surgery followed by adjuvant hormone therapy (HT), chemotherapy (CT), or radiation therapy (RT), depending on surgical outcomes, hormone receptor status, and prognostic factors [18].

No prospective data about adjuvant CT in males are available, but several observational studies showed better outcomes in terms of mortality rates and recurrence in men treated with adjuvant CT, especially in those with nodal involvement disease [18].

The impact of adjuvant RT on overall survival in MBC is greater than in females [22, 23]. The indications for RT come from the guidelines for females, and all men with BCS should undergo adjuvant RT [22]. Post-mastectomy radiation is more controversial in MBC, but several retrospective analyses showed improved outcomes in terms of local recurrence in post-mastectomy RT, particularly in node-positive disease [23].

The 10-year overall survival (OS) for the entire cohort stood at 74.9%. Mortality risk showed a significant increase in patients with G3 tumor grade, pT2/3/4, pN2/3, and Luminal B with Ki67 ≥ 20%. These findings align with results from other published studies [24].

The risk of recurrence can be quantified by gene recurrence scores such as Oncotype DX and MammaPrint, widely used in female breast cancer treatment [25]. The most used chemotherapeutic schemes are usually CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) and FAC (anthracycline, 5-fluorouracil, and methotrexate).

Early diagnosis is particularly crucial, especially in patients with a family history and genetic predisposition. For those with a high genetic and familial predisposition, it is recommended to consider at least an annual breast ultrasound [26, 27].

Our study is constrained by its retrospective design, which prevented the collection of comprehensive data for all patients, such as information on risk factors and mutations.

One of the primary limitations of the study is the extended observation period of the involved patients, which needs to be juxtaposed with the diagnostic and therapeutic changes that have transpired over the years (1999–2019).

However, to our knowledge, this is the largest cohort ever analyzed in our country. Future studies should prospectively assess the role of neoadjuvant and adjuvant treatments and consider secondary aspects such as emotional consequences, sexual dysfunction, or fertility preservation strategies.

Conclusion

Male breast cancer is a rare disease, and a better understanding is essential for a more effective diagnostic and therapeutic approach. Our study, with its extensive cohort, can contribute to enhancing the management of patients with male breast carcinoma.