Retrospective Male Breast Cancer study in the Czech Republic: Treatment and Prognosis Experience Over 11 Years in 256 Cases

doi:10.21203/rs.3.rs-2748844/v1

Purpose

To analyze clinicopathologic characteristics, treatment procedures, and prognosis of men with breast cancer (MBC) in the Czech Republic and compare them with international data.

Methods

Men diagnosed with breast cancer in 2007–2017 were retrospectively identified from the databases of Complex Oncological Centers in the Czech Republic, and subsequently clinical, histopathological, and molecular-genetic characteristics, treatment procedures, and long-term treatment outcomes were evaluated. Prognostic factors of survival outcomes (overall survival, relapse-free survival, and breast cancer-specific mortality) were analyzed using Cox and the competing risks model.

Results

In this study, data from 256 patients with MBC at a median age of 66 years were analyzed. Of 201 patients with primary non-metastatic (M0) radically treated MBC, 6% were younger than 40 years, 29% had stage I, 55% were node-negative (cN0), and 54% were indicated to genetic testing. Estrogen receptor (ER) expression over 10% had 97% of tumors, 61% had high mitotic activity (Ki67), 40% high grade (G3), and 68% Luminal B-like (HER2- negative) subtype. Regarding the therapy, 97% of men underwent mastectomy (ME), 34% sentinel lymph node biopsy (SLNB), 48% adjuvant radiotherapy (RT), 13% neoadjuvant therapy, 44% adjuvant chemotherapy (CT), 90% adjuvant endocrine therapy (ET), of which 74% adjuvant tamoxifen (TMX). Patients treated with aromatase inhibitor (AI) alone had significantly shortened RFS (p < 0.001). There were also associations between OS/RFS/BCSM and disease stage, T, N, progesterone receptor (PR) expression, G and Ki67. Median OS reached 122 months in curatively treated M0 patients, 42 months in the de novo metastatic (M1) group (N = 30), and 39 months in the group of M0/X patients treated with palliative intention (N = 25).

Conclusion

Although the number of MBC cases with unfavorable features (young age, M1 cases, predominant Luminal B-like tumors) was higher in the Czech dataset compared to international studies, the prognosis of men remains consistent with the real-world published data.

Male

male breast cancer

MBC

epidemiology

genetic testing

prognosis

treatment

retrospective study

On the background of frequent breast cancer (BC) in women (FBC, female breast cancer), male breast cancer (MBC) is a rare disease. However, the incidence of MBC has been increasing in recent years [1, 2, 3]. Incidence data of MBC in the Czech Republic are in line with worldwide. The number of new MBC cases was 1.33 per 100,000 between 2016 and 2020, up 6.4% from the period 2011–2015 and nearly doubling over the past 30 years (0.7 per 100,000 in 1991–1995) (see Additional file 1: Table S1). In the period evaluated in our study (2007–2017), approximately 580 cases of MBC were diagnosed, corresponding to about 45–65 cases of newly diagnosed patients per year.

As with other rare diagnoses, even MBC patients suffer from poorer prognosis, mainly compared to women, despite the increasing number of BC clinical trials enrolling men [4, 5].

MBC is typically endocrine sensitive [5, 6, 7, 8], centrally localized [5], affecting older men (68 vs 62 years) [9], and diagnosed in more advanced stages [5] compared to FBC. Of the mutations that are the cause of hereditary BC, BRCA2 mutation is the most frequent in MBC [10].

Therapy of MBC is overwhelmingly extrapolated from FBC [11]. In the adjuvant setting, men contraindicated to tamoxifen (TMX), the strongly preferred endocrine therapy (ET) option, may be treated with an aromatase inhibitor (AI) combined with a luteinizing hormone-releasing hormone (LHRH) agonist [12]. According to international guidelines, all MBC patients should be referred for genetic testing [11, 12, 13, 14].

Centralization of care may contribute to improving the prognosis of MBC and other rare diseases. Complex Oncological Centers (COC) in the Czech Republic enable access to targeted therapy and clinical trials. The aim of this study was to evaluate the prognosis of MBC in the Czech Republic by merging retrospective record MBC cases from COC and/or associated regional centers. Nine out of fifteen COC joined the cooperation to map the MBC cases over an eleven-year period and compare it with international data.

Data from MBC patients diagnosed between 2007 and 2017 were obtained from databases of participating COC and subsequently centralized, retrospectively evaluated, and statistically processed at Masaryk Memorial Cancer Institute, Brno, Czech Republic (MMCI). Inclusion criteria included the year of diagnosis (determined from the date of tumor biopsy), histological examination, and at least partially available data on the treatment of MBC. Patients with incomplete treatment data but available histological examination were included in the study. Nine out of fifteen COC across the Czech Republic (three in Prague, one in each of followed towns: Hradec Kralove, Liberec, Usti nad Labem, Plzen, Brno, and Zlin) joined the study. The study was approved by the Institutional Ethical Committee of MMCI, protocol code 2023/825/MOU.

The register included pseudonymized data of the date of diagnosis and last visit of follow-up or death, stage of the disease, age of patients at the time of diagnosis, main histological characteristics of MBC, i.e., histological type, tumor grade (G), Ki67 proliferation index, expression levels of estrogen receptors (ER), progesterone receptors (PR) and receptor type 2 for human epidermal growth factor (HER2), date and type of surgery, type of radiotherapy (RT), genetic testing information and results, length, and type of adjuvant and/or neoadjuvant therapy if indicated and type of maximally three lines of palliative treatment in metastatic or relapsed patients. Histological characteristics were obtained from original pathological reports, including standard immunohistochemical (IHC) evaluations of ER, PR, and HER2 and/or in situ hybridization of HER2 in indicated samples (standardly all with the result evaluated as 2 + by IHC). Sanger sequencing was used for BRCA1/2 mutation testing since 2007. Next-generation sequencing (NGS) methods for BRCA1/2 mutation identification have been used since 2014 (information about the methodology of the genetic testing was not obtained). According to the histopathological results, subtypes of BC were classified as follows: Luminal A-like (ER-positive, PR > 10%, Ki67 < 15%), Luminal B-like, HER2-negative (ER-positive, HER2-negative, PR < 10% or Ki67 > 20%), Luminal B-like, HER2-positive (ER-positive, HER2-positive, any PR, any Ki67), HER2-positive, non-luminal (ER and PR-negative, HER2-positive, any Ki67) or Triple-negative (ER, PR and HER2-negative, any Ki67). Cases with incomplete subtype parameters are described below in the appropriate table.

The study's main aim was to evaluate patients and disease characteristics, treatment, availability of genetic testing, and long-term outcomes in the whole group and separately in de novo M1, M0 patients who underwent surgery, and patients with an unknown stage (MX) or M0 but treated with palliative intention.

Long-Term Outcomes and Statistical Analysis

Long-term outcomes were considered in terms of relapse-free survival (RFS), breast cancer-specific mortality (BCSM), and overall survival (OS). RFS was determined as the time from the date of surgery to the locoregional or distant relapse in the M0 group. OS was defined as the time from the date of diagnosis to the date of death from any cause. Patients without the observed event or lost from follow-up were censored at the date of the last appropriate visit. BCSM was considered the time from the date of diagnosis to the date of death from disease relapse/progression. Other deaths were considered competing events.

Patient and treatment characteristics were described using standard summary statistics, i.e., median and interquartile range (IQR) and mean with standard deviation (SD) for continuous variables and frequencies and proportions for categorical variables. For OS and RFS, survival functions were calculated using the Kaplan–Meier method and compared using the log-rank test. The marginal probability of death from BC was estimated by cumulative incidence function and compared using Gray's test. Cox proportional hazard model for OS and RFS and the Fine and Gray subdistribution hazard model for BCSM were used to perform the univariable analysis and to calculate hazard ratios (HR). The follow-up was determined using the reverse Kaplan–Meier method. All statistical analyses were performed employing R version 4.2.2 [15] and a common significance level of 0.05.

In this multicentric retrospective analysis, we evaluated 256 cases of MBC diagnosed between 2007 and 2017 in the Czech Republic. Enrolled patients were divided into three groups according to disease stage and treatment intention (Fig. 1); patients with M0 disease treated with curative intention (N=201; 78%), patients with primary M0 or MX disease treated with palliative intention (N=25; 10%) and patients with de novo M1 disease (N=30; 12%).

Patient and disease characteristics

The median age at diagnosis of all men was 66 years. Sixteen (6.2%) men were younger than 40, and 52 (20%) were older than 75. In the group of M0/X patients treated with palliative intention, the median age was higher compared to M0 curatively treated and de novo M1 patients (73 vs. 65 vs. 66 years).

The majority of patients were diagnosed as stage II or III (37% and 26%, respectively). The typical MBC location was the central part of the breast (C50.1 according to ICD-10 classification in 46% of patients). Genetic testing was indicated in 127 (51%) patients, and 94 (76%) of examined men were non-mutated. Some germline mutation was found in 30 (24%) patients, most often BRCA2 (12%). Patient and disease characteristics are summarized in Table 1.

Table 1 Patient and tumor characteristics

	Overall N = 256	Primary M0 N = 201	de novo M1 N = 30	M0/X treated with palliative intention N = 25
Period of diagnosis
2007–2010	62 (24%)	52 (26%)	5 (17%)	5 (20%)
2011–2014	91 (36%)	69 (34%)	15 (50%)	7 (28%)
2015–2017	103 (40%)	80 (40%)	10 (33%)	13 (52%)
Age at diagnosis
Mean (SD)	64 (13)	63 (13)	65 (13)	71 (12)
Median (IQR)	66 (58, 73)	65 (57, 72)	66 (62, 73)	73 (61, 80)
Range	20, 90	20, 89	32, 85	36, 90
≤40	16 (6.2%)	12 (6.0%)	3 (10%)	1 (4.0%)
41–50	21 (8.2%)	20 (10.0%)	1 (3.3%)	0 (0%)
51–60	45 (18%)	38 (19%)	3 (10%)	4 (16%)
61–65	43 (17%)	35 (17%)	5 (17%)	3 (12%)
66–70	50 (20%)	38 (19%)	9 (30%)	3 (12%)
71–75	29 (11%)	22 (11%)	3 (10%)	4 (16%)
>75	52 (20%)	36 (18%)	6 (20%)	10 (40%)
Genetic testing indicated	127 (51%)	106 (54%)	10 (37%)	11 (44%)
Missing	7	4	3	0
Genetic testing results
Non-mutated	94 (76%)	80 (78%)	7 (70%)	7 (64%)
BRCA1	7 (5.6%)	5 (4.9%)	1 (10%)	1 (9.1%)
BRCA2	15 (12%)	12 (12%)	0 (0%)	3 (27%)
CHEK2	4 (3.2%)	3 (2.9%)	1 (10%)	0 (0%)
Other	4 (3.2%)	3 (2.9%)	1 (10%)	0 (0%)
Missing	3	3	0	0
Location^*
C50.0	7 (2.7%)	7 (3.5%)	0 (0%)	0 (0%)
C50.1	117 (46%)	93 (46%)	13 (43%)	11 (44%)
C50.2	7 (2.7%)	7 (3.5%)	0 (0%)	0 (0%)
C50.3	5 (2.0%)	5 (2.5%)	0 (0%)	0 (0%)
C50.4	76 (30%)	58 (29%)	11 (37%)	7 (28%)
C50.5	6 (2.3%)	5 (2.5%)	0 (0%)	1 (4.0%)
C50.8	10 (3.9%)	5 (2.5%)	3 (10%)	2 (8.0%)
C50.9	28 (11%)	21 (10%)	3 (10%)	4 (16%)
Stage
0 (DCIS)	4 (1.6%)	4 (2.0%)	0 (0%)	0 (0%)
I	59 (24%)	57 (29%)	0 (0%)	2 (9.1%)
II	93 (37%)	87 (44%)	0 (0%)	6 (27%)
III	65 (26%)	51 (26%)	0 (0%)	14 (64%)
IV	30 (12%)	0 (0%)	30 (100%)	0 (0%)
Missing	5	2	0	3
cT
Tis	4 (1.6%)	4 (2.1%)	0 (0%)	0 (0%)
1	92 (38%)	84 (44%)	3 (11%)	5 (21%)
2	85 (35%)	74 (38%)	6 (21%)	5 (21%)
3	7 (2.9%)	3 (1.6%)	3 (11%)	1 (4.2%)
4	57 (23%)	28 (15%)	16 (57%)	13 (54%)
Missing	11	8	2	1
cN
0	117 (51%)	100 (55%)	4 (15%)	13 (57%)
1	85 (37%)	68 (38%)	11 (42%)	6 (26%)
2	16 (7.0%)	9 (5.0%)	5 (19%)	2 (8.7%)
3	12 (5.2%)	4 (2.2%)	6 (23%)	2 (8.7%)
Unknown	26	20	4	2
Site of relapse or metastasis
None	129 (60%)	129 (73%)	0 (0%)	0 (0%)
Locoregional	23 (11%)	13 (7.4%)	3 (10%)	7 (70%)
Bone	20 (9.3%)	11 (6.2%)	8 (27%)	1 (10%)
Visceral	14 (6.1%)	14 (7.4%)	0 (0%)	0 (0%)
Combination	44 (20%)	23 (13%)	19 (63%)	2 (20%)
Unknown	26	11	0	15

*According to International Classification of Diseases, Tenth Revision.

Abbreviations: DCIS Ductal Carcinoma In Situ, M0 primary non-metastatic disease, M1 de novo metastatic disease, MX breast cancer with unknown M stage, cT clinical T stage, cN clinical N stage, Tis carcinoma in situ

Among M0 patients treated with curative intention (N=201), only 29% were diagnosed as stage I, although 46% of tumors were under 2 cm (T1), and 52% of patients were N0. The most common histological subtype was invasive ductal (NST) carcinoma (N=177; 88%). Only 9.8% of tumors were G1, and 23% had low proliferation marker Ki67. Vice versa, aggressive features with G3 and Ki67 > 20% were present in 40% and 61% of M0 patients, respectively. Almost all men (N=171; 87%) had endocrine sensitive HER2 negative MBC and 84% had high ER expression but only 18% of tumors were classified as Luminal A-like. The predominant subtype was Luminal B-like, HER2 negative in 68% of MBC. Detailed tumor characteristics are described in Table 2.

Table 2 Pathological characteristics

	Overall N = 256	Primary M0 N = 201	de novo M1 N = 30	M0/X treated with palliative intention N = 25
Histological subtype
DCIS	4 (1.6%)	4 (2.0%)	0 (0%)	0 (0%)
IDC (NST)	223 (87%)	177 (88%)	25 (83%)	21 (84%)
IDC+ILC	3 (1.2%)	2 (1.0%)	0 (0%)	1 (4.0%)
Mucinous	3 (1.2%)	3 (1.5%)	0 (0%)	0 (0%)
Invasive papillary	15 (5.9%)	10 (5.0%)	3 (10%)	2 (8.0%)
Other	8 (3.1%)	5 (2.5%)	2 (6.7%)	1 (4.0%)
Grade
1	28 (11%)	19 (9.8%)	3 (10%)	6 (26%)
2	123 (50%)	96 (50%)	16 (53%)	11 (48%)
3	95 (39%)	78 (40%)	11 (37%)	6 (26%)
Missing	10	8	0	2
Ki67 (%)
1-14	54 (22%)	45 (23%)	5 (19%)	4 (18%)
15-20	38 (16%)	31 (16%)	3 (11%)	4 (18%)
>20	151 (62%)	118 (61%)	19 (70%)	14 (64%)
Missing	13	7	3	3
ER (%)
<10	10 (4.0%)	5 (2.5%)	3 (10%)	2 (8.7%)
10-79	26 (10%)	26 (13%)	0 (0%)	0 (0%)
80-100	216 (86%)	169 (84%)	26 (90%)	21 (91%)
Missing	4	1	1	2
PR (%)
<10	36 (14%)	27 (14%)	8 (28%)	1 (4.3%)
10-79	88 (35%)	69 (35%)	11 (38%)	8 (35%)
80-100	128 (51%)	104 (52%)	10 (34%)	14 (61%)
Missing	4	1	1	2
HER2
Negative	217 (88%)	171 (87%)	25 (86%)	21 (91%)
Positive	31 (12%)	25 (13%)	4 (14%)	2 (8.7%)
Missing	8	5	1	2
Clinico-pathological subtypes*
Luminal A-like, HER2-	41 (17%)	35 (18%)	2 (6.9%)	4 (19%)
Luminal B-like, HER2-	167 (68%)	132 (68%)	21 (72%)	14 (67%)
Luminal B-like, HER2+	29 (12%)	24 (12%)	3 (10%)	2 (9.5%)
HER2+ (non-luminal)	2 (0.8%)	1 (0.5%)	1 (3.4%)	0 (0%)
TNBC	6 (2.4%)	3 (1.5%)	2 (6.9%)	1 (4.8%)
Unknown	11	6**	1	4
pT
0	1 (0.5%)	1 (0.5%)	0 (0%)	0 (0%)
Tis	6 (2.8%)	5 (2.5%)	0 (0%)	1 (11%)
1	98 (46%)	92 (46%)	3 (43%)	3 (33%)
2	89 (42%)	84 (42%)	3 (43%)	2 (22%)
3	4 (1.9%)	3 (1.5%)	1 (14%)	0 (0%)
4	16 (7.5%)	13 (6.6%)	0 (0%)	3 (33%)
Unknown	42	3	23	16
pN
0	107 (51%)	105 (52%)	2 (29%)	0 (0%)
ITC	3 (1.4%)	2 (1.0%)	1 (14%)	0 (0%)
1mi	4 (1.9%)	4 (2.0%)	0 (0%)	0 (0%)
1	59 (28%)	58 (29%)	1 (14%)	0 (0%)
2	25 (12%)	23 (12%)	2 (29%)	0 (0%)
3	10 (4.8%)	8 (4.0%)	1 (14%)	1 (100%)
Unknown	48	1	23	24

Abbreviations: DCIS Ductal Carcinoma In Situ, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma, Ki67 mitotic activity marker, ER estrogen receptor, PR progesterone receptor, HER2 receptor type 2 for human epidermal growth factor, TNBC triple-negative breast cancer, T size and/or extent of the main tumor, N lymph node(s) involvement, pT pathological T stage, pN pathological N stage, Tis carcinoma in situ, M0 primary non-metastatic disease, N1mi micrometastasis present in lymph node, ITC isolated tumor cells, M1 de novo metastatic disease, MX breast cancer with unknown M stage

* Ki67 was unknown in 9 HER2 negative cases; 1/9 with G1 were classified as Luminal A-like, 2/9 with G3 as Luminal B-like, 4/9 with G2 and PR=0-79 as Luminal B-like and 2/9 cases remain unknown

**5/6 were hormone receptor-positive patients (4 with unknown HER2 and one HER2 negative), 1/6 had unknown ER, PR, HER2, and Ki67

Eight (27%) out of 30 patients with de novo M1 disease had bone-only metastatic disease, three (10%) had locoregional disease only, and the remaining 19 (63%) patients had combined metastatic disease. For more clinico-pathological details, see Table 1 and 2.

Treatment

An overview of therapy in curatively treated M0 patients is in Table 3. Only seven (3.5%) men underwent breast-conserving surgery (BCS), although four patients had DCIS and 84 (44%) patients had small T1 tumors. On the contrary, modified radical ME remains the standard surgery recorded in 194 (97%) patients. A total of 69 (34%) patients underwent SLNB, with approximately half among N0 patients.

Table 3 Treatment characteristics for primary M0 patients

	N = 201
Neoadjuvant therapy	27 (13%)
Anthracycline	2 (7.4%)
Anthracyclines and taxanes	16 (59%)
Taxanes	1 (3.7%)
Endocrine therapy	6 (22%)
Chemotherapy and endocrine therapy	2 (7.4%)
Anti-HER2 in neoadjuvant therapy	1/6 (17%)
Breast surgery
BCS	7 (3.5%)
ME	194 (97%)
Nodal surgery
SLNB	69 (34%)
Axilla exenteration	132 (66%)
Adjuvant chemotherapy	87 (44%)
Unknown	1
Adjuvant chemotherapy regimen
Anthracycline	51 (59%)
Anthracyclines and taxanes	32 (37%)
Taxanes	3 (3.4%)
Capecitabine	1 (1.1%)
Endocrine therapy	180 (90%)
Unknown	1
Endocrine therapy type
Tamoxifen	134 (74%)
Aromatase inhibitor (AI)	28 (16%)
Tamoxifen followed by AI	18 (10%)
Castration therapy	17 (9.2%)
Missing	16
Anti-HER2 in adjuvant therapy	22/25 (88%)
Radiotherapy	96 (48%)
Unknown	1
Target regions of radiotherapy
Breast/Chest wall	7 (7.3%)
Breast/Chest wall and regional nodes	88 (92%)
Regional nodes	1 (1.0%)

Abbreviations: BCS breast-conserving surgery, ME radical mastectomy, SLNB sentinel lymph node biopsy, AI aromatase inhibitor

Adjuvant RT was indicated in 96 (48%) men. Among patients after radical ME (N=194) only four (2%) patients underwent isolated RT of the chest wall and 86 (44%) RT of the chest wall and lymph nodes area. Of seven patients with BCS, five were irradiated after surgery.

Neoadjuvant systemic therapy was indicated in 27 (13%) patients. The median age of neoadjuvant-treated men was 61 years, 77% of them had stage III and 23% had stage II. Nineteen (73%) patients were treated by CT, six (22%) by ET, and two men (7%) with combined ET and CT.

Adjuvant ET was recorded in 180 (90%) cases. Of hormone receptor-positive patients (N=196), 15 (7.7%) patients remained untreated. TMX was the standard indicated ET type used in 152 (84%) patients. Among 46 (26%) men treated with an AI, only 11 of them (24%) received luteinizing hormone-releasing hormone (LHRH) analogs (see Additional File 1: Table S2). Totally 17 (9.2%) patients were treated by castration therapy.

Adjuvant CT was administered to 87 (44%) patients. The most common regimens were anthracyclines based in 51 (59%) patients and a combination of anthracyclines and taxanes in 32 (37%) patients. Among 25 HER2-positive patients, 22 (88%) were treated with anti-HER2 therapy, of which 16 combined targeted therapy with CT and 6 with ET or were treated with anti-HER2 therapy only.

In the group of de novo M1 patients, ME underwent eight (27%) out of 30 men. Fourteen (47%) men were irradiated; locoregional RT was indicated in eight patients, and palliative RT of metastases in six men. First-line palliative systemic therapy was administered to 29 (97%) patients. Out of luminal HER2 negative tumors (N=23) thirteen (57%) patients were treated with ET, two (9%) with CT, seven (30%) patients received both CT and maintenance ET and therapy of the remaining one patient is unknown.

In the group of M0/X patients treated with palliative intention (N=25), twelve (48%) patients were not operated on, and 13 (52%) underwent inadequate surgery. The most common was withholding surgery in the axilla in 21 (84%) men. Twelve (48%) men underwent RT, five (42%) of them were irradiated to the chest wall and axilla, one (8%) to the breast, and six (50%) to the breast and axilla. Totally, 22 (88%) patients were treated with ET and 5 (21%) with CT in the first-line of palliative setting.

Overall outcomes

During a median follow-up period of 90 months (95% CI 82–98), 116 (45%) deaths were observed. The rate of death was as follows: 76/201 (38%) of M0 curatively treated patients, 15/25 (60%) of palliatively treated M0/X men, and 25/30 (83%) of de novo M1 patients died. The association of death with the cause summarizes in Additional File 1: Table S3.

Median OS reached 122 months in curatively treated M0 patients, 42 months in the de novo M1 group, and 39 months in the group of M0/X patients treated with palliative intention (Fig. 2A, and Additional File 1: Table S4). Five-years OS data were 80%, 36%, and 48% for primary M0, de novo M1, and palliatively treated M0/X patients, respectively. In the subgroup of N0M0 patients, the median OS was not reached, and for N+M0 men was 101 months (see Additional File 1: Table S4).

In the curatively treated M0 group, 61 relapses (32%) were observed during follow-up. Median RFS was not reached in the whole M0 group nor among N0 patients. Median RFS in N+ patients reached 108 months (Fig. 2B, and Additional File 1: Table S4).

The 5-year BCSM rates were 9.5% for curatively treated M0 patients and 50% for de novo M1 patients. In the subgroup of N0M0 patients, the 5-year BCSM rate was 2.2%, and for N+M0 men was 18% (Fig. 2C, and Additional File 1: Table S4).

The prognostic effect of clinical and pathological characteristics for M0 curatively treated patients was investigated using univariable analyses (Table 4). The prognostic value of age was observed in relation to OS (p<0.002) but not to BC outcomes (RFS and BCSM). Disease stage, T, and N status were associated with all observed survival endpoints, particularly BC outcomes. Grade was prognostic for RFS (p=0.004, Fig. 3A) and BSCM (p=0.023, Fig. 3B). From biological markers, only PR and Ki67 were associated with survival outcomes. Regarding PR, the worst outcomes were observed in the subgroup of patients with PR 10-79%, significantly for OS (p=0.008) and BSCM (p=0.043, Fig. 3C) and borderline significant for RFS (p=0.052, Fig. 3D). The proliferation rate expressed as an index Ki67 was directly related to prognosis (p=0.034 for OS, p<0.001 for RFS, Fig. 3E, and p=0.018 for BSCM, Fig. 3F).

Table 4 Univariable analysis of clinical and pathological characteristics for overall survival, relapse-free survival, and breast cancer-specific mortality

		OS				RFS				BSCM
Characteristic	N	HR	95% CI	Median (months)	p¹	HR	95% CI	Median (months)	p¹	HR	95% CI	p²
Age at diagnosis					0.002				0.279			0.321
≤40	68	Ref		NR		Ref		108		Ref
61–70	72	2.01	1.06, 3.81	119		0.71	0.40, 1.26	NR		1.10	0.50, 2.42
>70	56	3.02	1.59, 5.74	78		0.62	0.32, 1.20	130		0.50	0.17, 1.46
Stage					0.076				<0.001			0.002
I	54	Ref		170		Ref		NR		Ref
II	87	1.47	0.80, 2.71	164		1.98	0.92, 4.24	NR		2.59	0.74, 9.04
III	49	2.10	1.09, 4.03	101		4.40	2.07, 9.35	61		6.52	1.95, 21.8
pT					0.055				0.012			<0.001
0, Tis	6	0.64	0.09, 4.69	NR		NS		NR		NS
1	88	Ref		170		Ref		NR		Ref
2	83	1.27	0.76, 2.12	164		1.64	0.94, 2.84	NR		2.45	1.02, 5.87
3-4	16	2.61	1.26, 5.40	101		3.11	1.38, 7.00	46		7.32	2.49, 21.5
pN					0.070				<0.001			<0.001
0, ITC	104	Ref		164		Ref		NR		Ref
1mi,1	62	1.47	0.88, 2.47	102		1.64	0.91, 2.96	NR		2.63	1.07, 6.41
2-3	29	2.04	1.07, 3.91	80		3.59	1.91, 6.74	53		5.95	2.37, 14.9
Grade					0.198				0.004			<0.001
1	19	0.48	0.17, 1.35	170		0.16	0.02, 1.15	NR		NS
2	93	Ref		119		Ref		NR		Ref
3	77	1.19	0.74, 1.94	150		1.70	1.00, 2.86	93		1.91	0.93, 3.95
Clinico-pathological subtypes					0.474				0.012			<0.001
HER2+	24	Ref		164		Ref		NR		Ref
Luminal A-like	34	1.41	0.53, 3.77	122		0.18	0.05, 0.67	NR		0.31	0.06, 1.66
Luminal B-like	131	1.85	0.79, 4.31	103		0.96	0.49, 1.91	108		1.09	0.38, 3.13
TNBC	3	NS		NR		NS		NR		NS
ER (%)					0.588				0.755			0.832
<10	5	Ref		NR		Ref		NR		Ref
10-79	23	1.08	0.24, 4.85	106		0.63	0.13, 2.98	NR		0.57	0.06, 5.83
80-100	167	0.79	0.19, 3.24	150		0.59	0.14, 2.43	NR		0.80	0.10, 6.35
PR (%)					0.008				0.052			0.045
<10	27	Ref		NR		Ref		NR		Ref
10-79	66	2.89	1.21, 6.91	85		2.77	1.06, 7.24	88		2.41	0.68, 8.52
80-100	102	1.57	0.65, 3.76	NR		1.75	0.68, 4.53	130		0.97	0.26, 3.58
HER2					0.198				0.393			0.814
Negative	169	Ref		106		Ref		NR		Ref
Positive	24	0.58	0.25, 1.34	164		1.34	0.68, 2.65	NR		1.13	0.40, 3.25
Ki67 (%)					0.034				<0.001			0.033
1-14	43	Ref		122		Ref		NR		Ref
15-20	31	0.67	0.25, 1.77	NR		3.26	1.00, 10.6	130		2.30	0.40, 13.4
>20	115	1.69	0.91, 3.12	102		5.60	2.01, 15.6	96		5.35	1.27, 22.5

¹p-value for score (log-rank) test for Cox model, ²p-value for Fine and Gray model

Abbreviations: OS overall survival, RFS relapse-free survival, BSCM breast cancer-specific mortality, HR hazard ratio, CI confidence interval, NR not reached, Ref Reference category, NS not specified due to limited number of events

The effects of treatment modalities on survival outcomes were investigated using univariable analyses adjusted for clinical and tumor characteristics (age, T, N, G, PR, HER2, and Ki67) in the subgroup of hormone receptor-positive patients with M0 invasive tumors (N=192). A significant effect was observed especially for ET on RFS (p<0.001, Table 5). Men treated with TMX or a sequence of TMX and AI relapsed less often than patients treated with AI alone or without ET (Fig. 4). On the other hand, this effect was not reflected in BCSM.

Table 5 Clinical and tumor characteristics adjusted univariable analyses of treatment characteristics overall survival, relapse-free survival, and breast cancer-specific mortality in the subgroup of hormone receptor-positive patients with primary M0 invasive tumor

		OS			RFS			BSCM
Characteristic	N	HR	95% CI	p¹	HR	95% CI	p¹	HR	95% CI	p²
Nodal surgery				0.178			0.044			0.100
SLNB	59	—	—		—	—		—	—
Axilla exenteration	113	1.58	0.80, 3.10		2.30	0.98, 5.39		3.33	0.80, 14.0
Adjuvant chemotherapy				0.233			0.087			0.205
No	92	—	—		—	—		—	—
Yes	80	0.67	0.35, 1.29		0.58	0.31, 1.08		0.54	0.20, 1.41
Endocrine therapy (ET)				<0.001			<0.001			0.733
Tamoxifen	125	—	—		—	—		—	—
Aromatase inhibitor (AI)	14	0.76	0.26, 2.24		1.52	0.46, 4.98		0.55	0.08, 3.55
Tamoxifen followed by AI	23	1.89	0.92, 3.89		4.53	2.01, 10.2		1.36	0.42, 4.41
No ET	10	10.5	4.01, 27.4		15.4	4.17, 56.8		2.13	0.31, 14.5
Radiotherapy				0.348			0.143			0.374
no	89	—	—		—	—		—	—
yes	83	0.74	0.39, 1.39		1.70	0.83, 3.48		1.62	0.56, 4.66

¹p-value for Cox model, ²p-value for Fine and Gray model

Abbreviations: OS overall survival, RFS relapse-free survival, BSCM breast cancer-specific mortality, HR hazard ratio, CI confidence interval, AI aromatase inhibitor, SLNB sentinel lymphatic node biopsy

In this first Czech retrospective multicentric study, we evaluated data from 256 MBC patients diagnosed and treated in COC between 2007 and 2017 in the Czech Republic. As the average number of new cases per year was about 45-65 in this period, we recorded nearly half of MBC cases in the Czech Republic.

Patients with MBC are typically around 65 years old; Yao published mean age of 63 years in MBC [5], Konduri 65 [1], and Cardoso and Gucalp median of 68 years [6,7]. Cardoso published only 1.6% of MBC cases under 40 and 29.3% over 75 [6]. In our dataset, the median age was 66, and the distribution of MBC cases in age subgroups under 40 and over 75 was 6.2% and 20%, respectively. The only group of patients with higher median age (73 years) were men with M0/MX disease treated with palliative intention. This subgroup contains more locally advanced MBC cases compared to the M0 subgroup treated curatively. Age and associated comorbidities could be a reason for late diagnosis and less aggressive treatment with palliative intention. The reason for the relatively high percentage of young MBC cases in our study is not entirely clear. A possible explanation is the biased effect of centralized oncological care in COC, which may be sought after by younger patients in comparison to older men treated probably more often in regional centers. The prognostic impact of age in relation to breast cancer-specific outcomes (RFS and BCSM) was not confirmed.

All men with MBC should be offered genetic counseling and testing, although it depends on the possibilities of the workplace. In our study, 51% of men underwent genetic testing, and 12% of them had germline BRCA2 mutation, which is known to be the most common type [7,10]. We had no information about the compliance of men enrolled in our study with genetic testing. Though, we found significant differences among examined patients among COC ranging from 3.2% to 85%.

More than 80% of MBC are invasive ductal carcinomas, according to published data [5,6,7,8]. The percentage of N1 disease is around 30% [1,6], N2/3 around 5-9% [1,5,6], and M1 disease around 5% [5,6,7]. Luminal B-like subtypes are more common than Luminal A-like [16], but molecular subtyping is rare compared to immunohistochemical. Between a quarter and a third of patients have aggressive properties of the disease, such as high Ki67 or G3 [5,6]. In our dataset, some disease characteristics were more aggressive compared to published data; we recorded a higher percentage of de novo M1 patients (12%), and among M0 curatively treated MBC cases, a higher percentage of stage III (26%) and pN2/3 stage (16%), G3 (40%), high Ki67 (61%) and Luminal B-like subtype (68%).

The high proportion of de novo M1 patients in our dataset is similar to Brazil data (11.48%) [17] or results of mainly European men published by Giordano (12%) [18]. Semedo identified 8.9% of men with stage IV MBC diagnosed in 2011-2016 in SEER (Surveillance, Epidemiology, and End Results) database [19]. We assumed younger patients with probably more aggressive disease among M1 cases, but the median age in this group was similar to M0 curatively treated men (66 vs 65 years). A delay in diagnosis may explain a high percentage of stage IV.

The rate of T and N stage among all men was similar to data published by Yao [5], but the rate of stage III was higher (26% vs. 14%) compared to Wang data [4]. We also recorded more pN2/3 cases in M0 curatively treated patients compared to data published by Cardoso (16% vs. 7.8%) [6]. Concerning other disease characteristics in M0 patients, G3 was 30-35% in published articles [1,5,6] and 40% in our dataset. Ki67 is generally rarely examined in clinical practice but is frequently established in the Czech Republic. In the dataset of Cardoso, 61% of MBC had low Ki67 (range 1-14%) and 25% high Ki67 (over 20%), contrary to our result where 23% of MBC had low and 61% high mitotic activity [6]. Since only 14% of patients had low PR expression, the high number of Luminal B- like tumors (68%) is due to cases with high Ki67. We confirmed the prognostic significance of Ki67 (and G) both on RFS and BCSM. Both parameters could be crucial for indicating adjuvant CT, mainly in patients with N0 MBC.

Among M0 hormone receptor-positive patients (N=196), 31% of men with N0 disease (N=103) were indicated to CT and 92% to adjuvant ET. The total number of cases (N=201) treated with neo-/adjuvant CT in our dataset was 106 (53%). This number is in correlation with the number of MBC with risk characteristics. According to data published by Cardoso neo-/adjuvant CT was indicated in only 29.8% of patients, although 48.6% of cases were Luminal B-like, 24.7% highly proliferated (with Ki67 > 20%), and 27% with G3 [6]. The evaluated period was longer, and the authors discussed that a trend of increased indication of CT was seen in time.

In total, adjuvant ET was indicated in 90% of hormone receptor-positive patients (N=201). This number is very high, contrary to some researchers who report that only 57.9% [4,20], 67.3% [21], and 76.8% [6] of men with hormone receptor-positive MBC were treated with ET. We assumed that, in addition to the region, this also depends on organization and/or quality of care.

Hormone receptor positive patients with primary M0 invasive tumor treated with TMX (N=133) had favorable prognosis compared to patients treated with AI alone (N=28) in our study, which is in correlation with a mechanism of action of AI in men [22,23]. Out of 18 men treated with a sequence of TMX and AI, seven (39%) combined AI with castration therapy. Vice versa, only four (14%) patients treated with AI underwent castration therapy. Both factors, TMX prior to AI therapy in the sequence and the absence of castration therapy in men treated with AI alone, could affect the significant difference in RFS and OS in these subgroups. The number of inadequately treated men was low but deserves attention. We found no other significant differences in the treatment of Czech men with MBC and published data.

According to our results, the overall prognosis depends on the disease stage, consistent with international data. Cardoso published OS of 10.4 and 8.4 years in N0M0 and N+M0 subgroups and 2.6 years in M1 patients, respectively [6]. The five-year OS rate was 80% for M0 and 36% for M1 patients in our study. Similarly, the 5-year OS rate of more than 2000 men with primary MBC diagnosed in 2005-2010 reached 82.8% by Liu [24]. On the dataset of 16.000 men with MBC diagnosed between 2004 and 2014, the 5-year OS rate was 77.6% irrespective of disease stage and 21.4% in patients in stage IV [4].

Among disease characteristics connected to prognosis, we evaluated a significant effect of PR expression on OS (p=0.008) and BCSM (p=0.045) and borderline significant on RFS (p=0.052). Interlaboratory variability in pathological examination of PR may also help explain the mentioned phenomenon. Though, this result remains provocative. Cardoso published a significant influence of ER, PR, and androgen receptor (AR) expression on OS [6]. It must be said that the results of receptor expressions were re-tested centrally in EORTC/TBCRC/BIG/NABCG trial [6]. Contrary, pathologic information was collected from minimally fourteen hospitals in our study. Several data also show that PR status did not influence OS survival in MBC patients [25,26].

The strength of our study is the quantity of relevant information recorded. We recorded a minimal number of cases with massively incomplete data. On the contrary, we analyzed disease stage and simultaneously T and N stages, data about the tumor location within the breast, the availability of genetic testing, or Ki67 status, which have been rarely focused on. We are aware of the study limitations, especially the relatively large number of involved centers, which can be a source of differences, particularly in histological examination. COC are specialized centers generally concentrating on worse patients (younger and/or more advanced and/or requiring targeted therapy). On the other hand, the number of patients treated with certain therapy may be higher compared to regional centers.

In this multicentric retrospective study, we evaluated data about 256 patients with MBC diagnosed and treated between 2007 and 2017 in the Czech Republic. We showed a high number of M0 patients indicated to CT consistent with the percentage of patients with Luminal B-like tumors and/or risk factors of MBC. We also showed that almost all patients with hormone receptor-positive MBC were treated with ET, an indirect sign of availability and quality of care in the Czech Republic. We have shown that prognosis of men with hormone receptor- positive MBC can be negatively affected by AI monotherapy without castration therapy. Finally, although the number of de novo M1 patients was higher in our dataset, we have shown their better prognosis compared to published data.

BC: breast cancer, MBC: male breast cancer, FBC: female breast cancer, OS: overall survival, BCSM: breast cancer specific mortality, RFS: relapse-free survival, CT: chemotherapy, ET: endocrine therapy, RT: radiotherapy, SLNB: sentinel lymph node biopsy, EA: axilla exenteration, IHC: immunohistochemistry, ER: estrogen receptor, PR: progesterone receptor, HER2: receptor type 2 for human epidermal growth factor, G: grade, Ki67: mitotic activity, T: size and/or extent of the main tumor, N0: no involved axillary lymph node(s), N+: lymph node(s) involved, AI: aromatase inhibitor, TMX: tamoxifen, LHRH: luteinizing hormone-releasing hormone, M1: metastatic disease, M0: non-metastatic disease at the time of diagnosis, MX: unknown M stage, COC: complex oncological centers

Ethics approval and consent to participate: The study was approved by the Institutional Ethical Committee of MMCI, protocol code 2023/825/MOU.

Consent for publication: Not applicable.

Availability of data and materials: The data underlying this article cannot be shared publicly due to individuals' privacy that participated in the study. The data will be shared on a reasonable request to the corresponding author.

Competing interests: The authors declare that they have no competing interests.

Funding: This research was supported by the Ministry of Health of the Czech Republic–conceptual development of research organization (VFN, 00064165 and MMCI, 00209805). APC was paid with the aid of Open Access Fund (OAF) of the General University Hospital in Prague, Czech Republic.

Authors' contributions: Conceptualization, Z.B.; Data curation, Z.B., M.H., I.S.; Formal analysis, M.H., I.S.; Funding acquisition, Z.B., M.H.; Investigation, Z.B., M.H., O.S., I.K., R.S., J.P., L.R., V.C., L.L., M.Z., M.Ch., L.J., L.L., K.K., D.P.; Methodology, Z.B., M.H., I.S.; Project administration, Z.B.; Software, I.S.; Validation, Z.B., M.H., I.S.; Visualization, I.S.; Writing-original draft, Z.B.; Writing-review and editing, M.H., I.S. All authors contributed to the interpretation of the data, read and edited manuscript and accepted responsibility to submit it for publication.

Acknowledgements: We thank all patients who participated in this study and Prof. RNDr. Ladislav Dušek, Ph.D. for epidemiologic data extracted from The National Health Information System of the Czech Republic.

Authors' information: Zuzana Bielcikova, Milos Holanek, and Iveta Selingerova contributed equally to this work

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No competing interests reported.

Additionalfile1.pdf
Additional file 1 (PDF format) Table S1. Main epidemiologic characteristics of MBC in the Czech Republic. Table S2. Association of castration and endocrine therapy in primary M0 patients. Description: Regarding the castration therapy, 17 (8.5%) out of 201 men underwent, 168 (84%) didn’t undergo castration therapy (luteinizing hormone-releasing hormone analogs or orchiectomy), and there is no information in the remaining 16 (8%) patients. Regarding the type of castration therapy, goserelin was applied to 14 (88%) patients, one patient underwent orchiectomy (OE), and one started with goserelin and later underwent OE. Regarding the type of endocrine therapy combined with castration therapy, six (4.5%) patients took tamoxifen (TMX) and eleven patients took aromatase inhibitor (AI). Table S3. Death rate and cause of death among enrolled patients. Table S4. Survival characteristics of OS, RFS, and BCSM for subgroups of patients.

Retrospective Male Breast Cancer study in the Czech Republic: Treatment and Prognosis Experience Over 11 Years in 256 Cases

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