poorer survival of male breast cancer compared with female breast cancer patients may be due to...

Original Articles

Poorer Survival of Male Breast Cancer Compared with Female BreastCancer Patients May Be Due to Biological Differences

Xingyu Chen1,2, Xiaodong Liu1,2, Li Zhang1,2, Shufen Li1,2, Yehui Shi1,2 and Zhongsheng Tong1,2,*

1Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Breast,Tianjin and 2Department of Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

*For reprints and all correspondence: Zhongsheng Tong, Department of Breast Oncology, Tianjin Medical UniversityCancer Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin 300060, China. E-mail: [email protected]

Received June 6, 2013; accepted July 21, 2013

Objective: The objective of the study was to compare disease-free survival and overall survivalin a group of matched males and females with breast cancer, and to analyze possible treat-ment- and gender-related differences.Methods: We retrospectively analyzed the data of 150 operable male breast cancer patientstreated in our hospital from December 1980 to June 2012. Each male breast cancer patientrecorded in the database was matched with two female breast cancer patients of equal stage.Prognosis in terms of disease-free survival and overall survival was evaluated.Results: The mean age at diagnosis was 58.6+9.7 years for males and 57.2+10.3 years forfemales. The median follow-up was 69 months for males and 81 months for females.Significant differences were identified for tumor location, hormone receptor status, molecularsubtypes and hormone therapy between the two groups. Monofactorial analysis demonstratedthat tumor size, lymph node state, American Joint Committee on Cancer stage, molecular sub-types and adjuvant chemotherapy treatment were prognostic factors in male breast cancerpatients. The 5- and 10-year disease-free survival rates were 65.6 and 40.1% for males, and74.9 and 51.5% for females, respectively. The 5- and 10-year overall survival rates were 72.9and 53.9% for males, and 83.2 and 68.5% for females, respectively. There was significantlydifference in disease-free survival and overall survival between the two matched groups(P ¼ 0.002).Conclusions: Male breast cancer patients had inferior outcome despite of equal stage in com-parison with matched female breast cancer patients, which demonstrates that biological differ-ences may contribute to the worse prognosis.

Key words: male breast cancer – female breast cancer – prognosis

INTRODUCTION

Male breast cancer (MBC) is a rare and often overlooked

disease accounting for ,1% of all breast cancer cases (1).

However, the incidence of MBC has been steadily increasing

along with the increasing incidence of female breast cancer

(FBC) over the past three decades (2). The reason for the in-

creasing incidence of MBC is likely due to several factors, in-

cluding longer lifespan, increased public awareness and rising

levels of obesity in the male population (3). This increasing

trend highlights the importance of understanding MBC and

whether it differs from FBC.

Because of its low incidence, MBC has not been studied as

extensively as FBC. Its rarity has precluded prospective rando-

mized controlled trials and only data from retrospective and

often small series are available. Few retrospective studies have

included more than 100 cases. Appropriate management

guidelines for MBC have not yet been clearly established, and

limited information is available regarding the epidemiology,

# The Author 2013. Published by Oxford University Press. All rights reserved.For Permissions, please email: [email protected]

Jpn J Clin Oncol 2013;43(10)954–963

doi:10.1093/jjco/hyt116

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treatment and prognosis of the disease (4). Therefore, despite

possible differences in pathogenesis, biology and genetics

between both the sexes, the treatment strategies for MBC have

been extrapolated from the data based on the FBC (5). As

more data on the tumor biology of MBC emerge, it is becom-

ing clear that MBC is a unique disease requiring its own trials

and treatment guidelines.

In the past two decades, several retrospective studies have

described the epidemiology and biological characteristics of

MBC and its prognosis compared with FBC, with inconsistent

results. It has been assumed that MBC carried a worse progno-

sis compared with FBC, which has mainly been attributed to

delays in diagnosis, more advanced stage at diagnosis, older

age at diagnosis and a higher incidence of lymph node metas-

tases in males with breast cancer (6 – 12). However, recent

studies revealed that MBC and FBC patients have a similar

prognosis (13–15). One study showed that although overall

survival (OS) was equivalent between both the sexes, disease-

specific survival was significantly better in MBC than in FBC

(16). Thus, there is no consensus on the relationship between

the patient’s sex and prognosis in breast cancer. Therefore, the

aim of the present study was to compare the survival in a

group of carefully matched males and females with breast

cancer, and to retrospectively analyze disease characteristics

of MBC in a Chinese population over the past 32 years. In this

regard, clinicopathological features, treatment patterns and

survival were investigated, and prognosis in terms of OS and

disease-free survival (DFS) was evaluated.

PATIENTS AND METHODS

PATIENT CHARACTERISTICS

We retrospectively reviewed the medical records of 150 MBC

patients who had been treated at the Cancer Institute and

Hospital of Tianjin Medical University, China, between

December 1980 and June 2012. To be included in this retro-

spective analysis, the following conditions had to be fulfilled:

all men had to suffer from invasive breast cancer curatively

treated with mastectomy, and had well-documented clinical

information and accurate TNM stage. Patients presenting with

metastatic lesions or second cancers at initial diagnosis were

excluded. Each male fulfilling the criteria was recorded in the

database and carefully matched with two females. Matching

criteria included the main potential prognostic factors such as

pathology of invasive ductal carcinoma in MBC and FBC, age

at diagnosis (+5 years), date of diagnosis (+5 years) (17)

and identical clinical stage of the primary cancer at diagnosis.

The females were selected from a total of 27 314 consecutive

patients whose data were recorded in the same database and

who underwent treatment at our institution during the same

period. When more than two females met the matching

criteria, the female patients whose date of diagnosis was

closer to the male patients were chosen (13). A total of 150

MBC patients and 300 matched FBC patients were enrolled in

the study.

The database was reviewed to obtain the demographic in-

formation, clinical history, tumor characteristics and treatment

characteristics. Follow-up information was obtained from the

database, the medical records and contact with the patients or

their family. Mortality due to breast cancer, second primary

cancer and other causes were the end points considered.

According to the standard of Perou (18) and Carey (19),

breast cancer molecular subtypes were classified according to

the immunohistochemical panel expression profile as follows:

ER positive and/or PR positive and HER2 negative for

Luminal A; ER positive and/or PR positive and HER2 positive

for Luminal B; ER and PR negative and HER2 positive for

HER2 over-expressed; ER, PR and HER2 all negative for

basal-like (triple negative).

STATISTICAL ANALYSES

We determined and compared the 5- and 10-year DFS time

and OS time for male- and female-matched groups. DFS was

defined as the time from the surgery until disease progression

or death by any cause on the date of the last follow-up. OS

was defined as the time from the surgery until death by any

cause. A statistical comparison of female-matched pair sur-

vival data was performed with the paired t-test. DFS and OS

were calculated using the Kaplan – Meier method from the

time of diagnosis (20). The log-rank test was used to assess

survival difference between the groups. Actuarial curves

were compared by the two-tailed log-rank test. The statistical

analysis was performed using SPSS software version 17.0.

A P value of , 0.05 was considered significant for both tests.

RESULTS

CLINICAL MATERIALS

The 150 cases of MBC patients were matched with 300 FBC

patients during the same period. Table 1 displays the matching

information and demographic data of the matched male and

female breast cancer (FBC) patients. The mean age at diagno-

sis was similar for the two matched groups: 58.6+ 9.7 years

(range, 26 – 83) for males and 57.2+ 10.3 years (range,

22–81) for females. The mean follow-up time for the 32-year

study period was 85.8+ 49.7 months (range, 9 – 298) for

males and was 90.2+ 49.2 months (range, 12 – 287) for

females. Invasive ductal carcinoma was the pathological type

of all cases.

The clinicopathological characteristics of both male and

female patients are described in Table 2. Significant differ-

ences were identified for tumor location (P , 0.01), hormone

receptor status (P , 0.01), molecular subtypes (P ¼ 0.005)

and hormone therapy between male and female patients.

Males were more likely to have an unknown hormone receptor

and HER2 status (20.7%, 35.3%) compared with females

(17.3%, 24.3%). 99 cases of MBC patients had positive ER/

PR and 26 cases had positive HER2 expression, and 147 cases

of FBC patients had positive ER/PR and 62 cases had positive

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HER2 expression. Among the patients who examined for

HER2 detection, the distribution of tumor molecular sub-

types was 59 (39.3%) Luminal A, 22 (14.7%) Luminal B, 4

(2.7%) HER2 over-expressed and 12 (8.0%) basal-like for

male patients, and 103 (34.3%) Luminal A, 42 (14.0%)

Luminal B, 20 (6.7%) HER2 over-expressed and 62

(20.7%) basal-like for female patients, respectively. A lower

number of male patients underwent endocrine therapy (58

cases, 38.7%) in comparison to female patients (146 cases,

48.7%) (P ¼ 0.045). Adjuvant endocrine therapy of men was

mainly performed with tamoxifen alone (n ¼ 47). Fewer

male patients received aromatase inhibitors (n ¼ 8) or a

switch from tamoxifen to an aromatase inhibitor (n ¼ 3) than

female patients (n ¼ 49 and 12). Stage-specific treatment

and use of multimodality therapy (surgery, chemotherapy

and radiotherapy) did not differ between the two matched

groups. There was no significant difference in chemotherapy

regimens between the two groups. Four different schedules

were administered: CMF (cyclophosphamide, methotrexate,

fluorouracil), CAF/CEF (cyclophosphamide, doxorubicin,

fluorouracil/cyclophosphamide, epirubicin, fluorouracil), AT

(paclitaxel and doxorubicin), TAC/TEC (docetaxel,

doxorubicin, cyclophosphamide/docetaxel, epirubicin and

cyclophosphamide).

MONOFACTORIAL ANALYSIS OF PROGNOSIS

To further investigate relevance of tumor- and treatment-

related factors of MBC on survival rate, the following subana-

lyses were performed. Univariate analysis revealed that

impact of tumor size, lymph node state, American Joint

Committee on Cancer (AJCC stage, molecular subtypes and

adjuvant chemotherapy treatment on OS rate were significant

for MBC and FBC (P , 0.05). Moreover, hormonal treatment

and adjuvant chemotherapy regimens were prognostic factors

of FBC, the impact of different chemotherapy regimens on

survival was not significant for MBC (Tables 3 and 4).

Estimated 5-year OS for male patients with tumor

size �5 cm and .5 cm were 81.8 and 33.3%, respectively

(P , 0.05, Fig. 1a). Presence of node-negative disease

resulted in an estimated 5-year OS of 84.7 versus 58.5% for

node-positive breast cancer (P ¼ 0.002, Fig. 1b). Due to the

very low incidence of HER2 over-expressed and basal-like

group, we only compared the 5-year OS of luminal A and

luminal B subtypes. There were no significant differences

between Luminal A and B groups by Kaplan–Meier survival

curves (5-year OS was 83.1 versus 78.9%, P ¼ 0.761,

Fig. 1c). Given chemotherapy was associated with 80.4%

5-year OS compared with 60.5% without chemotherapy reach-

ing a trend with P ¼ 0.041 (Fig. 1d). In contrast, administra-

tion of adjuvant hormonal treatment (AHT) had no impact on

5-year OS with 74.1 versus 62.0% (P ¼ 0.164, Fig. 1e).

SURVIVAL ANALYSIS AND COMPARISON OF MATCHED PAIRS

To evaluate whether MBC and FBC had a similar outcome,

matched pairs of males with females were generated. Five-

and 10-year DFS and OS of the two groups were calculated.

The Kaplan – Meier curves for DFS and OS (Figs. 2 and 3)

demonstrated significant difference between the male and the

matched female patients (P ¼ 0.006 and 0.002, log-rank test).

The 5- and 10-year DFS rates were 65.6 and 40.1% for males,

and 74.9 and 51.5% for females, respectively. The 5- and

10-year OS rates were 72.9 and 53.9% for males, and 83.2 and

68.5% for females, respectively.

DISCUSSION

The relationship between the patient’s sex and prognosis in

breast cancer is always controversial, since there are so many

differences between MBC and FBC (21). Some studies

observed similar predictors of outcome for men and women

with breast cancer, and suggested that the sex of the patient

did not influence mortality (22 – 24). Other studies showed

that the outcome of the present male cohort of breast cancer

patients was inferior to females (25), which was confirmed by

our matched pair analysis with females.

Table 1. Characteristics of patients

Characteristics Male (%) Female (%) P value

Sample size (n) 150 300

Age (years)

Mean+SD 58.6+9.7 57.2+10.3 0.107

Median (range) 59 (26–83) 57 (22–81)

Year of diagnosis (n)

1980–89 25 (16.6) 50 (16.6) 1.000

1990–99 43 (28.7) 86 (28.7)

2000–12 82 (54.7) 164 (54.7)

AJCC stage (n)

I 31 (20.7) 62 (20.7) 1.000

II 76 (50.7) 152 (50.7)

III 43 (28.6) 86 (28.6)

Follow-up time (months)

Mean+SD 85.8+49.7 90.2+49.2 0.372

Median (range) 69 (9–298) 81 (12–287)

Recurrence during follow-up (n)

No 63 (42.0) 136 (45.3) 0.502

Yes 87 (58.0) 164 (54.7)

Cause of mortality (n)

Breast cancer 39 (51.3) 91 (72.8) 0.002*

Second primary cancer 15 (19.7) 8 (6.4)

Other causes 22 (29.0) 26 (20.8)

SD, standard deviation; AJCC, American Joint Committee on Cancer.*P , 0.01.

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Table 2. Comparison of clinical and pathological characteristics between MBC and FBC patients

Characteristics Male, n ¼ 150 (%) Female, n ¼ 300 (%) x2 P value

Laterality

Right 78 (52.0) 148 (49.3) 0.733 0.392

Left 72 (48.0) 162 (50.7)

Tumor location

Central 46 (30.7) 16 (5.3) 54.734 0.000**

Peripheral quadrant 104 (69.3) 287 (94.7)

SBR tumor grade

1 34 (22.7) 75 (25.0) 0.306 0.858

2 98 (65.3) 191 (63.7)

3 18 (12.0) 34 (11.3)

Tumor size (cm)

�5 132 (88.0) 248 (82.7) 2.165 1.141

.5 18 (12.0) 52 (17.3)

Lymph node status

Negative 85 (56.7) 198 (66.0) 3.732 0.053

Positive 65 (43.3) 102 (34.0)

ER/PR status

Positive 99 (66.0) 147 (49.0) 21.265 0.000**

Negative 20 (13.3) 101 (33.7)

Unknown 31 (20.7) 52 (17.3)

HER2 status

Positive 26 (17.3) 62 (20.7) 6.010 0.050

Negative 71 (47.3) 165 (55.0)

Unknown 53 (35.3) 73 (24.3)

Molecular subtypes

Luminal A 59 (39.3) 103 (34.3) 14.796 0.005**

Luminal B 22 (14.7) 42 (14.0)

HER2 over-expressed 4 (2.7) 20 (6.7)

Basal-like 12 (8.0) 62 (20.7)

Unknown 53 (35.3) 73 (24.3)

Surgery of primary breast cancer

Simple mastectomy 21 (14.0) 52 (17.3) 0.818 0.366

Modified radical mastectomy 129 (86.0) 248 (82.7)

Adjuvant radiation treatment

No 88 (58.7) 177 (59.0) 0.005 0.946

Yes 62 (41.3) 123 (41.0)

Adjuvant chemotherapy treatment

No 38 (25.3) 64 (21.3) 0.913 0.339

Yes 112 (74.7) 236 (78.7)

CMF 27 (24.1) 82 (34.7) 6.125 0.190

CAF/CEF 22 (19.6) 48 (20.3)

AT 35 (31.3) 62 (26.3)

TAC/TEC 13 (11.6) 26 (11.0)

Other 15 (13.4) 18 (7.6)

Continued


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Following successful matching, we compared the survival

of MBC and FBC patients. Invasive ductal carcinoma is

the most frequent invasive carcinoma in men, accounting for

70 – 95% of MBC, and lobular carcinoma is rare (around 1%

of all cases) due to lack of terminal lobules in the male breast.

Thus, all patients selected for this study were affected with

invasive ductal carcinoma confirmed by pathology. We ana-

lyzed potential prognostic factors prior to prognosis analysis

and identified that the two groups were comparable.

Upon investigation of the characteristics of all patients, we

revealed that the tumor location, ER/PR expression, molecular

subtypes and endocrine therapy were different between males

and females. More male patients had centrally located tumors

(30.7 versus 5.3%) compared with female patients, and the

difference was significant (P , 0.001). Molecular subtype has

been proved to be an instinct characteristic of breast cancer

and has important value of predicting treatment effect. Most

studies indicated that the expressions of ER and PR were

higher in MBC than in FBC (8,26). In our study, the expres-

sions of ER and PR were significantly higher in MBC than in

FBC (P , 0.001). However, due to the long time span of this

study and the late development of HER2 detection methods, a

number of patients lacked immunohistochemical results of

ER, PR and HER2, which may affect their post-treatment and

data integrity. The patients with HER2 detection were not

much enough (97 MBC patients, 227 FBC patients). Among

the patients examined for HER2 detection, 26 male patients

(26 of 97, 17.3%) and 62 female patients (62 of 227, 20.7%)

had HER2 expression. HER2 expression levels were lower in

MBC than in FBC patients as previously reported in some lit-

erature data (27). The most common molecular subtypes of

MBC and FBC were Luminal A (59 of 97, 60.8 versus 103 of

227, 45.4%) followed by Luminal B (22 of 97, 22.7 versus 42

of 227, 18.5%). Ge et al. (28), in a retrospective study, also

obtained similar results, the proportion of Luminal A is as

high as 83%, followed by Luminal B (17%). However, the

HER2 over-expressed and basal-like group of FBC patients

are more common than those of MBC (6.7 and 20.7 versus

2.7% and 8.0%). The sex differences in epidemiologic risk

factors and tumor biology indicate that prognosis and treat-

ment, particularly endocrine and HER2/neu therapies, may

differ for MBC and FBCs. In this study, a lower number of

male patients underwent endocrine therapy (58 cases, 38.7%)

in comparison to female patients (146 cases, 48.7%) (P ¼

0.045). Since immunohistochemical markers identify distinct

subtypes of breast cancer with different clinical outcomes and

response to endocrine therapy and trastuzumab treatment (29),

we suggest that this may play a role in the difference in prog-

nosis between the two study groups.

According to the univariate survival analysis, tumor size,

lymph node state, AJCC stage, molecular subtypes and adju-

vant chemotherapy treatment were related to poor OS in MBC

and FBC (P , 0.05). The effect of tumor size on 5-year OS

was significant, and we also observed an inferior outcome for

node-positive men. In China, the subtypes of Luminals A and

B account for 97.5% in 40 cases of MBC. Some studies indi-

cated that Luminal A group had a better prognosis than other

types (30). In order to understand whether molecular subtypes

of MBC are associated with prognosis, we compared the

5-year OS of Luminal A and B subtypes and found no signifi-

cant differences between the two groups. Although adjuvant

chemotherapy and hormonal therapy have proven benefits for

a subgroup of FBC patients, their role in MBC is less clear

(31). Since MBC patients received adjuvant therapy following

similar guidelines that have been developed for women, the

most common adjuvant chemotherapy regimens were CMF,

CAF, AT and TAC. Due to the long time span of this study,

CMF was the most common regimen at the earlier stage.

Later, CAF, AT and TAC were widely used with an in-depth

understanding of anthracycline and taxane. Possibly due to

anatomical differences in men, larger tumors tend to metasta-

size more frequently by a hematogenic pathway (32). We

further emphasized the relevance of control of micrometas-

tases by the fact that the given chemotherapy was a positive

prognostic factor in this group. Tamoxifen is generally consid-

ered a standard adjuvant therapy. In several retrospective

studies, tamoxifen increased DFS and OS in MBC patients

(33). However, most studies suggested that male ER-positive

Table 2. Continued

Characteristics Male, n ¼ 150 (%) Female, n ¼ 300 (%) x2 P value

Hormonal treatment

No 92 (61.3) 154 (51.3) 4.035 0.045*

Yes 58 (38.7) 146 (48.7)

Tamoxifen 50 (81.0) 97 (58.2) 9.669 0.008**

Aromatase inhibitor 11 (13.8) 61 (33.6)

MBC, male breast cancer; FBC, female breast cancer; SBR, Scarff–Bloom–Richardson; ER, estrogen receptor; PR, progesterone receptor; HER2, humanepidermal growth factor receptor 2; CMF, cyclophosphamide, methotrexate and fluorouracil; CAF/CEF, cyclophosphamide, doxorubicin and fluorouracil/cyclophosphamide, epirubicin and fluorouracil; AT, paclitaxel and doxorubicin; TAC/TEC, docetaxel, doxorubicin and cyclophosphamide/docetaxel, epirubicinand cyclophosphamide.*P , 0.05.**P , 0.01.


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tumors do not respond to tamoxifen therapy in the same

manner as female ER-positive tumors do (34). Consequently,

hormone-receptor positivity does not translate into better

prognosis for ER-positive MBC (5). The role of aromatase

inhibitors in MBC is unclear, and some data suggested that

aromatase inhibitors may be less effective in men (35). Thus,

tamoxifen should be considered as the treatment of choice for

hormone-receptor-positive MBC. Consistent with previous

studies, we observed that hormonal treatment had no

statistically significant impact on 5-year DFS and OS of male

patients, which was different from female patients. Thus,

MBC, despite expression of similar biomarkers, may be dif-

ferent biologically in other, unmeasured ways.

The outcome of the present male cohort of breast cancer

patients in terms of DFS and OS was inferior to women as

expected from some literature data (25) and confirmed by our

matched pairs with women. A population-based comparison

of SEER data also demonstrated superior survival of 10% for

Table 3. Monofactorial analysis of prognosis in MBC patients

Characteristics n DFS OS

5-year % x2 P value 5-year % x2 P value

Age (years)

,60 80 66.3 0.188 0.665 78.8 0.711 0.399

�60 70 62.9 72.9

Tumor size (cm)

�5 132 69.7 27.660 0.000** 81.8 0.000**

.5 18 5.6 33.3 20.415

Lymph node status

Negative 85 74.1 10.994 0.001** 84.7 12.973 0.000**

Positive 65 47.7 58.5

AJCC stage

I þ II 107 82.2 72.820 0.000** 92.5 77.985 0.000**

III 43 7.0 20.9

Molecular subtypes

Luminal A 59 71.7 25.926 0.000** 83.1 25.476 0.000**

Luminal B 22 57.9 78.9

HER2 over-expressed 4 0.0 25.0

Basal-like 12 6.7 21.4


No 88 61.4 0.043 0.835 72.7 0.778 0.378

Yes 62 59.7 79.0


No 38 52.6 0.947 0.330 60.5 6.005 0.014*

Yes 112 61.6 80.4

CMF 27 51.9 7.774 0.100 77.8 0.900 0.925

CAF/CEF 22 59.1 81.8

AT 35 74.3 82.9

TAC/TEC 13 76.9 84.6

Other 15 40.0 73.3

Hormonal treatment

No 92 51.1 1.736 0.188 62.0 2.375 0.123

Yes 58 62.1 74.1

*P , 0.05.**P , 0.01.


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FBC compared with MBC patients (1). In our study, when

matched for age and stage, MBC patients had significantly

lower 5- and 10-year DFS and OS rates compared with FBC

patients (P , 0.05).

There are some possible explanations for this finding.

Higher rates of death from comorbid disease is a contributing

factor to clinical outcome in men with breast cancer (36).

Donegan et al. (8) reported that a major contributor to

the poor survival in MBC patients was from the high rate of

post-treatment mortality from comorbid disease. In this series,

the male patients were more likely to die of second primary

cancers and other causes than the female patients. The

second primary cancers resulting in mortality included pros-

tate, colon, lung and contralateral breast cancers (37).

Non-cancer-related causes of mortality were primarily related

to cardiac and vascular morbidities. Consequently, the impact

of comorbidities and second neoplasm is important and can

induce confusion in comparative results. Furthermore, the

Table 4. Monofactorial analysis of prognosis in FBC patients

Characteristics n DFS OS

5-year % x2 P value 5-year % x2 P value

Age (years)

,60 163 73.6 0.295 0.587 85.9 1.679 0.195

�60 137 70.8 80.3

Tumor size (cm)

�5 266 76.7 22.278 0.000** 88.0 36.329 0.000**

.5 34 38.2 47.1

Lymph node status

Negative 198 86.4 57.283 0.000** 93.4 42.781 0.000**

Positive 102 45.1 63.7

AJCC stage

I þ II 214 90.2 118.903 0.000** 96.3 89.837 0.000**

III 86 27.9 51.2

Molecular subtypes

Luminal A 103 82.5 56.076 0.000** 93.2 56.080 0.000**

Luminal B 42 69.0 81.0

HER2 over-expressed 20 15.0 40.0

Basal-like 62 35.5 46.8


No 177 69.5 1.742 0.187 81.1 1.215 0.270

Yes 123 76.4 86.2


No 64 53.1 14.999 0.000** 65.6 18.369 0.000**

Yes 236 77.5 88.1

CMF 82 70.7 9.073 0.059 81.7 9.709 0.046*

CAF/CEF 48 79.2 89.6

AT 62 85.5 95.2

TAC/TEC 26 88.5 96.2

Other 18 61.1 77.8

Hormonal treatment

No 154 63.0 13.813 0.000** 77.3 8.369 0.004**

Yes 146 82.2 89.7

*P , 0.05.**P , 0.01.


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Figure 1. Monofactorial analysis of tumor- and treatment-related factors on overall survival (OS) of male breast cancer (MBC). Five-year OS rates were estimated

using the Kaplan–Meier method. (a) Tumor size �5 cm was associated with superior survival (�5 cm: 81.8% versus .5 cm: 33.3%; P , 0.05). (b) Node nega-

tivity reached a trend to better survival outcome (pN0: 84.7 versus pNþ: 58.5%; P ¼ 0.002). (c) Luminal A and B subtypes had no significant differences in OS

with 83.1 versus 78.9% (P ¼ 0.761). (d) There was a trend to improved OS for adjuvant chemotherapy (80.4 versus 60.5%; P ¼ 0.041). (e) Adjuvant hormonal

treatment (AHT) had no impact on OS with 74.1 versus 62.0% (P ¼ 0.164).


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molecular biology and the response to traditional management

of the tumor may also be a contributor responsible for the sur-

vival disparities observed. Recent studies documented

improved survival rates over recent decades for both MBC

and FBC, but progress for males has lagged behind that for

females (1). In this series, the main reason for the same effect

could be the application of chemotherapy treatment which

was predominantly administered in the last decade. The

slower increase of survival rates in males probably attributed

to a limited benefit from hormonal treatment (38). It is uncer-

tain whether hormone-receptor positivity has the same prog-

nostic implication in male as in the female disease (39). In

turn, the main reason for treatment failure was distant metasta-

ses. Breast cancer-specific survival varies widely depending

on the site of metastasis. Perhaps, the progression and metasta-

sis of MBC are different from FBC. Some studies revealed

that MBC had a higher local recurrence rate compared with

FBC, which was the precondition for reduction of distant me-

tastases and long-term survival (40). These results suggest

that early detection, adequate treatment, close follow-up, pre-

vention and treatment of comorbid disease and second neo-

plasm would be the mainstay for improving survival of MBC

patients.

To the best of our knowledge, this is one of the first studies

of matched MBC and FBC patients and included relatively

large number of cases in China. It allowed the comparison of

breast cancer in a homogeneous population of patients, where

each male was carefully matched with two females.

Limitations include the retrospective design of the study and

the inclusion of a number of patients with unknown hormone

status.

In conclusion, after controlling for potential confounders of

survival in multivariate analyses, MBC patients had inferior 5-

and 10-year survival compared with our matched FBC patients,

which indicates that not only under-treatment, but also biologic-

al differences either of tumor or of population may contribute

to the worse prognosis. This assumption is supported by the

impact of tumor size and nodal stage on prognosis, and the

limited effect of adjuvant endocrine therapy. The clinicopatho-

logical features of MBC and potential lack of response to con-

ventional treatment do warrant further investigation. Therefore,

future studies should focus on the tumor biology and treatment-

and outcome-related investigations of MBC to determine

whether optimum treatment parallels that of FBC.

Acknowledgements

The authors greatly appreciate all the staff at the study centers

who had contributed to this study.

Funding

This study was supported by the Higher Education of Science

& Technology Development foundation Planning Projects

of Tianjin (No. 20100116), the Health Bureau Foundation of

Tianjin (No. 2010KZ76), the Anticancer Key Technologies

R & D Program of Tianjin (NO 12ZCDZSY16200) and WU

JIE PING Medical Foundation (NO 320.6700.1139).

Conflict of interest statement

None declared.

Figure 2. Kaplan–Meier curve for disease-free survival (DFS) of matched

MBC and female breast cancer (FBC) patients (P ¼ 0.006).

Figure 3. Kaplan–Meier curve for OS of matched MBC and FBC patients

(P ¼ 0.002).


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References

1. Anderson WF, Jatoi I, Tse J, et al. Male breast cancer: a population-basedcomparison with female breast cancer. J Clin Oncol 2010;28:232–9.

2. Contractor KB, Kaur K, Rodrigues GS, Kulkarni DM, Singhal H. Malebreast cancer: is the scenario changing. World J Surg Oncol 2008;6:58.

3. Speirs V, Shaaban AM. The rising incidence of male breast cancer.Breast Cancer Res Treat 2009;115:429–30.

4. Malani AK. Male breast cancer: a different disease than female breastcancer? South Med J 2007;100:197.

5. Wang-Rodriguez J, Cross K, Gallagher S, et al. Male breast carcinoma:correlation of ER, PR, Ki-67, Her2Neu, and p53 with treatment andsurvival, a study of 65 cases. Mod Pathol 2002;15:853–61.

6. Ciatto S, Iossa A, Bonardi R, Pacini P. Male breast carcinoma: review of amulticenter series of 150 cases. Coordinating Center and WritingCommittee of FONCAM (National Task Force for Breast Cancer), Italy.Tumori 1990;76:555–8.

7. Salvadori B, Saccozzi R, Manzari A, et al. Prognosis of breast cancer inmales: an analysis of 170 cases. Eur J Cancer 1994;30A930–5.

8. Donegan WL, Redlich PN, Lang PJ, Gall MT. Carcinoma of the breast inmales: a multiinstitutional survey. Cancer 1998;83:498–509.

9. Yildirim E, Berberoglu U. Male breast cancer: a 22-year experience. EurJ Surg Oncol 1998;24:548–52.

10. Tajima N, Tsukuma H, Oshima A. Descriptive epidemiology of malebreast cancer in Osaka, Japan. J Epidemiol 2001;11:1–7.

11. Sandler B, Carmen C, Perry RR. Cancer of the male breast. Am Surg1994;60:816–20.

12. Fentiman IS, Fourquet A, Hortobagyi GN. Male breast cancer. Lancet2006;367:595–604.

13. Marchal F, Salou M, Marchal C, et al. Men with breast cancer have samedisease-specific and event-free survival as women. Ann Surg Oncol2009;16:972–8.

14. Lynn K. Rare male breast cancer has similarities to female disease. MLOMed Lab Obs 2010;42:34–6.

15. Feifei Z, Rong H, Jun J, et al. A meta-analysis based on case-controlstudies shows the similar prognosis between male and female patientswith breast cancer. Chinese–German J Clin Oncol 2011;10:311–6.

16. El-Tamer MB, Komenaka IK, Troxel A, et al. Men with breast cancerhave better disease-specific survival than women. Arch Surg2004;139:1079–82.

17. Neumayer L, Schifftner TL, Henderson WG, et al. Breast cancer surgeryin veterans affairs and selected university medical centers: results of thepatient safety in surgery study. J Am Coll Surg 2007;204:1235–41.

18. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breasttumours. Nature 2000;406:747e52.

19. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, andsurvival in the Carolina Breast Cancer Study. JAMA 2006;295:2492e502.

20. Kaplan EL, Meier P. Nonparametric estimation from incompleteobservations. JASA 1958;53:457–81.

21. Zhou FF, Xia LP, Guo GF, et al. Changes in therapeutic strategies inChinese male patients with breast cancer: 40 years of experience in asingle institute. Breast 2010;19:450–55.

22. Giordano SH, Cohen DS, Buzdar AU, Perkins G, Hortobagyi GN. Breastcarcinoma in men: a population-based study. Cancer 2004;101:51–7.

23. Thalib L, Hall P. Survival of male breast cancer patients:population-based cohort study. Cancer Sci 2009;100:292–5.

24. Hill TD, Khamis HJ, Tyczynski JE, Berkel HJ. Comparison of male andfemale breast cancer incidence trends, tumor characteristics, and survival.Ann Epidemiol 2005;15:773–80.

25. Gnerlich JL, Deshpande AD, Jeffe DB, et al. Poorer survival outcomesfor male breast cancer compared with female breast cancer may beattributable to in-stage migration. Ann Surg Oncol 2011;18:1837–44.

26. Agrawal A, Ayantunde AA, Rampaul R, Robertson JF. Male breastcancer: a review of clinical management. Breast Cancer Res Treat

2007;103:11–21.27. Kornegoor R, Verschuur-Maes AH, Buerger H, et al. Molecular

subtyping of male breast cancer by immunohistochemistry. Mod Pathol

2012;25:398–404.28. Ge Y, Sneige N, Eltorky MA, et al. Immunohistochemical characterization

of subtypes of male breast carcinoma. Breast Cancer Res 2009;11:R28.

29. Tiezzi DG, Andrade JM, Ribeiro-Silva A, et al. HER2, p53, p21 andhormonal receptors proteins expression as predictive factors of responseand prognosis in locally advanced breast cancer treated with neoadjuvantdocetaxel plus epirubicin combination. BMC Cancer 2007;7:36.

30. Yu X-F, Feng W-L, Miao L-L, Chen B, Yang H-J. The prognosticsignificance of molecular subtype for male breast cancer: a 10-yearretrospective study. Breast 2013;14:36–2.

31. Giordano SH, Buzdar AU, Hortobagyi GN. Breast cancer in men. Ann

Intern Med 2002;137:678–87.32. Joshi MG, Lee AK, Loda M, et al. Male breast carcinoma: an evaluation

of prognostic factors contributing to a poorer outcome. Cancer

1996;77:490–8.

33. Ribeiro GG, Swindell R, Harris M, Banerjee SS, Cramer A. A review ofthe management of the male breast carcinoma based on an analysis of420 treated cases. Breast 1996;5:141–6.

34. Giordano SH, Perkins GH, Broglio K, et al. Adjuvant systemic therapyfor male breast carcinoma. Cancer 2005;104:2359–64.

35. Eggemann H, Ignatov A, Smith BJ, et al. Adjuvant therapy withtamoxifen compared to aromatase inhibitors for 257 male breast cancerpatients. Breast Cancer Res Treat 2013;137:465–70.

36. Giordano SH. A review of the diagnosis and management of male breastcancer. Oncologist 2005;10:471–9.

37. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J

Clin 2004;54:8–29.38. Pich A, Margaria E, Chiusa L, et al. Androgen receptor expression in

male breast carcinoma: lack of clinicopathological association. Br J

Cancer 1999;79:959–64.39. Nahleh ZA. Hormonal therapy for male breast cancer: a different

approach for a different disease. Cancer Treat Rev 2006;32:101–5.40. Muller AC, Gani C, Rehm HME, et al. Are there biologic differences

between male and female breast cancer explaining inferior outcomeof men despite equal stage and treatment? Strahlenther Onkol

2012;188:782–7.


at Belgorod State U


Dow

nloaded from



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