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Clinicopathological characteristics and survival outcomes of male breast cancer according to race: A SEER population-based study

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Oncotarget. 2017; 8:69680-69690. https://doi.org/10.18632/oncotarget.18265

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He-Fen Sun, Yang Zhao, Shui-Ping Gao, Liang-Dong Li, Wen-Yan Fu, Hong-Lin Jiang, Meng-Ting Chen, Li-Peng Yang and Wei Jin _

Abstract

He-Fen Sun1,2, Yang Zhao1,2, Shui-Ping Gao1,2, Liang-Dong Li1,2, Wen-Yan Fu1,2, Hong-lin Jiang3, Meng-Ting Chen1,2, Li-Peng Yang4 and Wei Jin1,2

1Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Collaborative Innovation Center of Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200030, China

2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200030, China

3Division of Molecular Medicine and Genetic, Department of Internal Medicine and Life Sciences Insititute, University of Michigan, Ann Abor, Michgan 48109, USA

4Department of pathology, School of Basic Medical Sciences, Fudan University, Shanghai, 200030, China

Correspondence to:

Wei Jin, email: [email protected]

Keywords: male breast cancer, race, overall survival, SEER

Received: December 30, 2016     Accepted: May 15, 2017     Published: May 26, 2017

ABSTRACT

To investigate the clinicopathological characteristics and survival outcomes of breast cancer in the male population, 8,607 cases of patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database, including white males (n = 7122), black males (n = 1111), and other males (American Indian/AK Native, Asian/Pacific Islander) (n = 374). Black male breast cancer patients were more likely to be in stages II–IV and have more advanced tumors. The rate of lymph node (LN) involvement at diagnosis was higher in black men than in whites and others. The ER- and PR-positive rates were lower in black men than in whites and others. The distant metastasis rate was higher in blacks than in whites and others. Furthermore, the overall survival (OR) rates and breast cancer-specific survival rates were significantly poorer in blacks than in whites and others (χ2 = 29.974, P < 0.001; χ2 = 7.285, P = 0.026, respectively). In a multivariate analysis, the results showed that race could also be a prognostic indicator (P < 0.001). Moreover, significant differences were also observed in OS among 1:1:1 matched white, black, and other groups (P < 0.001). Differences in outcomes may be partially explained by differences in tumor grades, LN status, and ER and PR status between the 3 groups. This study might provide insights into a better understanding of male breast cancer.


INTRODUCTION

Male breast carcinoma (MBC) is a rare disease with steady incidence rates; it comprises about 1% of all cancers in men in Western countries [12]. Although rare, breast cancer (BC) affects men’s health and quality of life. The present study showed that the mean age of MBC patients was about 60–65 years old. However, this disease may develop in a wide range of ages. For example, the youngest MBC patient was 9 years old and the oldest was above 90 years [3].

As a result of the absence of screening programs in men, MBCs are usually diagnosed at a more advanced age. In the SEER data, the median ages at diagnosis of breast cancer were 67 and 62 years in males and females, respectively [4]. MBC patients are also diagnosed with a more severe clinical manifestation with relatively larger tumor sizes and more frequent lymph node involvement than female breast cancer (FBC) patients [5]. Moreover, male breast cancer also develops with a much higher proportion of positive tumor hormone receptors, a significantly prolonged treatment delay, and a more advanced tumor, node, and metastasis (TNM) stage of the disease at the time of diagnosis than FBC [6]. There are some differences in clinical and biological characteristics between FBC and MBC. However, the treatment of MBC is currently based on FBC due to the inadequate characterization [78].

Although the incidence of MBC is lower than that of FBC, a substantial variable may exist between different countries. The incidence of MBC in Thailand (0.14 per 100 000 man-years) was significantly lower than that in Israel (1.08 per 100 000 man-years). The variability in rates may be due to population-specific factors [9].

In specific population groups, cancer disparities exist in the incidence, prevalence, mortality, and burden of cancer and related adverse health conditions [10]. Of all the disparities, the differences in cancer related to race and ethnicity have been well described and are major public health concerns. For example, black men have higher incidence and death rates than white men when considering all cancer sites combined; black women also have higher death rates than white women [1113]. These disparities apply to much of the United States, where whites and blacks are the predominant racial groups. However, a majority of studies ignore other races, including American Indians, AK Natives, Asians, and Pacific Islanders. Therefore, we wanted to know whether there was also some variability in male breast cancer in different races. Therefore, the aim of this study is to report clinicopathological characteristics and outcomes of a series of MBCs in different races.

RESULTS

Clinical characteristics of the study population

Overall, 8,607 patients with male breast cancer were enrolled, including 7,122 white patients, 1,111 black patients, and 374 patients of other races (including American Indians/AK Natives and Asian/Pacific Islanders). Their characteristics were analyzed and the results are summarized in Table 1. There were significant differences in clinical characteristics, including the year of diagnosis, age, tumor size, LN status, AJCC stage, ER status, PR status, and HER2 status. Among the 3 populations, white patients presented with an older age (50–85 years: 91.2% vs. 85.0% and 86.6%, respectively; P < 0.001). Furthermore, black MBC patients were more likely to be stages II-IV (9.7% vs. 8.3% and 6.7% in stage II, 4.7% vs. 3.3% and 3.2% in stage III, 3.4% vs. 1.5% and 1.9% in stage IV, respectively; P < 0.001) and to have more advanced tumors (2 cm < tumor size ≤ 5 cm: 23.0% vs. 20.8% and 19.5%, tumor size > 5 cm: 11.2% vs. 6.2% and 7.2%, respectively; P < 0.001). In addition, the rate of LN involvement at diagnosis was higher in blacks than in whites and others (29.6% vs. 22.9% and 23.3%, respectively; P < 0.001). An ER-positive rate was detected in 66.6% of the whites, 65.7% of the blacks, and 70.3% of the others (P < 0.001). Similarly, PR was expressed as 58.9%, 54.4%, and 66% of the whites, blacks, and others, respectively (P < 0.001). HER2 positivity was higher in the blacks than in the others and the whites (3.4% vs 2.1% and 2.1%, respectively; P = 0.002). The incidence of distant metastasis was higher in blacks than in the whites and others (bone metastasis: 2.3% vs 1.0 vs 1.1, P < 0.001; brain metastasis: 0.2 vs 0.1 vs 0, P = 0.010; liver metastasis: 0.5 vs 0.2 vs 0.3, P = 0.002; lung metastasis; 1.5 vs 0.6 vs 1.1, P < 0.001).

Table 1: Patient characteristics in white patients compared to blacks and others

Variables

White

Black

othera

total

n = 7122

n = 1111

n = 374

n = 8607

No.

%

No.

%

No.

%

No.

%

p

Median follow-up (months) (IQR)

115 (111–119)

105 (93–116)

91 (78–103)

Year of diagnosis

1973–1993

1553

21.8

189

17.0

65

17.4

1807

21.0

< 0.001

1994–2013

5569

78.2

922

83.0

309

82.6

6800

79.0

age (years)

10–49

630

8.8

167

15.0

50

13.4

847

9.8

< 0.001

50–85

6492

91.2

944

85.0

324

86.6

7760

90.2

Laterality

right

3375

47.4

540

48.6

178

47.6

4093

47.6

0.346

left

3640

51.1

560

50.4

187

50.0

4387

51.0

bilateral

107

1.5

11

1.0

9

2.4

127

1.5

Grade

I

703

9.9

106

9.5

34

9.1

843

9.8

0.385

II

2795

39.2

414

37.3

148

39.6

3357

39.0

III

1966

27.6

337

30.3

107

28.6

2410

28.0

IV

109

1.5

13

1.2

10

2.7

132

1.5

unknown

1549

21.7

241

21.7

75

20.1

1865

21.7

AJCC stage

I

532

7.5

85

7.7

29

7.8

646

7.5

< 0.001

II

592

8.3

108

9.7

25

6.7

725

8.4

III

238

3.3

52

4.7

12

3.2

302

3.5

IV

108

1.5

38

3.4

7

1.9

153

1.8

unknown

5652

79.4

828

74.5

301

80.5

6781

78.8

Tumor size (cm)

≤ 2

1656

23.3

224

20.2

105

28.1

1985

23.1

< 0.001

> 2 and ≤ 5

1484

20.8

255

23.0

73

19.5

1812

21.1

> 5

441

6.2

124

11.2

27

7.2

592

6.9

unknown

3541

49.7

508

45.7

169

45.2

4218

49

LN status

Negative

1952

27.4

274

24.7

118

31.6

2344

27.2

< 0.001

Positive

1629

22.9

329

29.6

87

23.3

2045

23.8

To be continued

unknown

3541

49.7

508

45.7

169

45.2

4218

49.0

ER

Negative

233

3.3

62

5.6

21

5.6

316

3.7

< 0.001

Positive

4745

66.6

730

65.7

263

70.3

5738

66.7

unknown

2144

30.1

319

28.7

90

24.1

2553

29.7

PR

Negative

678

9.5

172

15.5

32

8.6

882

10.2

< 0.001

Positive

4192

58.9

604

54.4

247

66

5043

58.6

unknown

2252

31.6

335

30.2

95

25.4

2682

31.2

HER2

Negative

1219

17.1

227

20.4

61

16.3

1507

17.5

0.002

Positive

147

2.1

38

3.4

8

2.1

193

2.2

unknown

5756

80.8

846

76.1

305

81.6

6907

80.2

Radiation

Yes

1612

22.6

268

24.1

75

20.1

1955

22.7

0.195

No

5424

76.2

835

75.2

292

78.1

6551

76.1

unknown

86

1.2

8

0.7

7

0.1

101

1.2

Bone metastasis

No

1434

20.1

264

23.8

72

19.3

1770

20.6

< 0.001

yes

74

1.0

25

2.3

4

1.1

103

1.2

unknown

5614

78.8

822

74.0

298

79.7

6734

78.2

Brain metastasis

No

1497

21.0

285

25.7

76

20.3

1858

21.6

0.010

Yes

10

0.1

2

0.2

0

0

12

0.1

unknown

5615

78.8

824

74.2

298

79.7

6737

78.3

Liver metastasis

No

1493

21.0

283

25.5

75

20.1

1851

21.5

0.002

Yes

14

0.2

6

0.5

1

0.3

21

0.2

unknown

5615

78.8

822

74.0

298

79.7

6735

78.3

Lung metastasis

No

1462

20.5

271

24.4

72

19.3

1805

21.0

< 0.001

Yes

42

0.6

17

1.5

4

1.1

63

0.7

unknown

5618

78.9

823

74.1

298

79.7

6739

78.3

P-value was calculated among all groups by the Chi-square test, and a bold type indicates significance. a: Including American Indian/Alaskan native, Asian/Pacific Islander and others-unspecified.

Comparison of MBC survival among whites, blacks, and other races

As shown in Kaplan-Meier plots, 30-year overall survival (OS) was better in other patients than in the white and black populations (χ 2 = 29.974, P < 0.001, Figure 1A). We also analyzed the breast cancer-specific survival (BCSS) and slightly significant differences were observed (χ 2 = 7.285, P = 0.026, Figure 1B). The median survival time was 102 months (95% CI: 98–1105), 80 months (95% CI: 72–88), and 133 months (95% CI: 108–157) in the white, black, and other patients, respectively. The 30-year OS likely represents mortality from other causes; we capped it at 15 years, and it showed similar results in the Supplementary Figure 1. Furthermore, we used the Cox proportional hazards model to investigate the effects of the clinical characteristics on OS (Table 2). Many prognostic indicators were also found to be significantly associated with OS in the univariate analysis, including the year of diagnosis, laterality, tumor grade, tumor size, age, LN status, ER status, PR status, HER2 status, and radiation (Table 2). The results showed that race could also be a prognostic indicator. Taking the white race as the reference, we found that the white race could be a protective factor when compared to the black race (HR = 1.208, 95% CI: 1.107–1.319, P < 0.001), but could also be a risk factor when compared to the others (HR = 0.775, 95% CI: 0.659–0.911, P = 0.002). All the variables were included in the multivariate analysis to estimate the prognostic factors that were identified in the univariate analysis (Table 2). Race was also an independent prognostic factor in the multivariate analysis after adding the other prognostic factors. When we adjusted for white patients as a control group, the white race could also be an independent protective factor when compared to the black race (HR = 1.208, 95% CI: 1.106–1.320, P < 0.001), while it was a risk factor when compared with the other races (HR = 0.801, 95% CI: 0.681–0.942, P = 0.007).

The overall survival and breast cancer specific survival of White, Black and other patients.

Figure 1: The overall survival and breast cancer specific survival of White, Black and other patients. Kaplan meier test for overall survival (χ2 = 29.974, P < 0.001) (Figure 1A) and breast cancer specific survival (χ2 = 7.285, P = 0.026, Figure 1B) to compare White patients to Blacks and others.

Table 2: Univariate and multivariate analysis of overall survival (OS)

Variables

Univariate analysis

Multivariate analysis

HR (95% CI)

P–Value

HR (95% CI)

P–Value

Year of diagnosis

1973–1993

reference

reference

1994–2013

0.861 (0.087–0.920)

< 0.001

1.002 (0.917–1.095)

0.963

age (years)

10–49

reference

reference

50–85

2.373 (2.105–2.676)

< 0.001

2.494 (2.211–2.814)

< 0.001

Laterality

right

reference

reference

left

1.004 (0.946–1.066)

0.885

1.000 (0.942–1.061)

1.000

bilateral

0.448 (0.353–0.568)

< 0.001

1.620 (1.262–2.079)

0.001

Grade

I

reference

reference

II

1.313 (1.159–1.487)

< 0.001

1.267 (1.118–1.436)

< 0.001

III

1.712 (1.508–1.943)

< 0.001

1.559 (1.372–1.772)

< 0.001

IV

1.988 (1.585–2.494))

< 0.001

1.759 (1.399–2.211)

< 0.001

unknown

1.736 (1.555–1.999)

< 0.001

1.478 (1.293–1.690)

< 0.001

AJCC stage

I

reference

reference

II

1.735 (1.195–2.520)

0.004

0.940 (0.636–1.389)

0.755

III

2.361 (1.561–3.570)

< 0.001

1.070 (0.694–1.650)

0.758

IV

8.156 (5.489–12.119)

< 0.001

2.840 (1.863–4.329)

< 0.001

unknown

2.562 (1.892–3.469)

< 0.001

0.791 (0.524–1.192)

0.262

Tumor size (cm)

≤ 2

reference

reference

> 2 and ≤ 5

1.995 (1.756–2.266)

< 0.001

1.802 (1.574–2.063)

< 0.001

> 5

3.334 (2.850–3.899)

< 0.001

2.519 (2.132–2.977)

< 0.001

unknown

1.779 (1.595–1.984)

< 0.001

1.630 (1.432–1.856)

< 0.001

LN status

Negative

reference

reference

Positive

1.584 (1.417–1.770)

< 0.001

1.261 (1.122–1.418)

< 0.001

unknown

1.371 (1.249–1.506)

< 0.001

ER

Negative

reference

reference

Positive

0.684 (0.587–0.796)

< 0.001

0.800 (0.675–0.964)

0.010

unknown

0.892 (0.765–1.040)

0.144

1.211 (0.912–1.608)

0.186

Continued

PR

Negative

reference

reference

To be continued

Positive

0.763 (0.689–0.845)

< 0.001

0.861 (0.768–0.964)

0.010

unknown

0.988 (0.891–1.095)

0.813

0.675 (0.524–0.870)

0.002

Her2

Negative

reference

reference

Positive

1.698 (1.166–2.473)

0.006

1.305 (0.894–1.905)

0.168

unknown

1.606 (1.361–1.894)

< 0.001

2.059 (1.484–2.855)

< 0.001

Radiation

Yes

reference

No

0.950 (0.884–1.019)

0.154

unknown

1.397 (0.977–1.998)

0.067

Race

White

reference

reference

Black

1.208 (1.107–1.319)

< 0.001

1.208 (1.106–1.320)

< 0.001

Othera

0.775 (0.659–0.911)

0.002

0.801 (0.681–0.942)

0.007

The CI and P-value was calculated by Cox proportional hazards model and the bold type indicates significance. a:Including American Indian/Alaskan native, Asian/Pacific Islander and others-unspecified.

Survival analysis in matched groups

There was a large difference among the 3 races. To ensure that the outcomes were not based on the differences of patient quantity of the groups, we performed a 1:1:1 (white: black: other) matched case control analysis using the propensity score matching method. We finally focused on a group of 1122 patients, including 374 patients in each racial type (Table 3). Compared to the results in Table 1, similar results are shown in Table 3. There were also significant differences in the clinical characteristics, including tumor size, LN status, AJCC stage, ER status, and PR status, except in age and laterality. Furthermore, we also found that the black race was associated with a poorer prognosis in OS, similar to the total group (χ2 = 26.811, P < 0.001, Figure 2).

Table 3: Patient Characteristics in the 1:1 matched groups

Variables

white

black

othera

total

n = 374

n = 374

n = 374

n = 1122

No.

%

No.

%

No.

%

No.

%

p

Median follow-up (months) (IQR)

290(255–324)

148(128–167)

91(78–103)

Year of diagnosis

1973-1993

263

70.3

141

37.7

65

17.4

469

41.8

< 0.001

1994-2013

111

29.7

233

62.3

309

82.6

653

58.2

age (years)

10-49

37

9.9

51

13.6

50

13.4

138

12.3

0.22

50-85

337

90.1

323

86.4

324

86.6

984

87.7

Laterality

right

189

50.5

182

48.7

178

47.6

549

48.9

0.373

left

174

46.5

188

50.3

187

50.0

549

48.9

bilateral

11

1

4

0.4

9

0.8

24

2.1

Grade

I

36

9.6

19

5.1

34

9.1

89

7.9

< 0.001

II

95

25.4

101

27.0

148

39.6

344

30.7

III

70

18.7

120

32.1

107

28.6

297

26.5

IV

3

0.8

4

1.1

10

2.7

17

1.5

unknown

170

45.5

130

34.8

75

20.1

375

33.4

AJCC stage

I

1

0.3

21

5.6

29

7.8

51

4.5

< 0.001

II

2

0.5

27

7.2

25

6.7

54

4.8

III

0

0

10

2.7

12

3.2

22

2

IV

1

0.5

12

3.2

7

1.9

20

1.8

unknown

370

98.9

304

81.3

301

80.5

975

86.9

Tumor size (cm)

≤ 2

9

2.4

43

11.5

105

28.1

157

14

< 0.001

> 2 and ≤ 5

9

2.4

58

15.5

73

19.5

140

12.5

> 5

1

0.3

29

7.8

27

7.2

57

5.1

unknown

355

94.9

244

65.2

169

45.2

768

68.4

LN status

To be continued

Negative

12

3.2

54

14.4

118

31.6

184

16.4

< 0.001

Positive

7

1.9

76

20.3

87

23.3

170

15.2

unknown

355

94.9

244

65.2

169

45.2

768

68.4

ER

Negative

8

2.1

19

5.1

21

5.6

48

4.3

< 0.001

Positive

129

34.5

192

51.3

263

70.3

584

52.0

unknown

237

63.4

163

43.6

90

24.1

490

43.7

PR

Negative

20

5.3

52

13.9

32

8.6

104

9.3

< 0.001

Positive

112

29.9

156

41.7

247

66.0

515

45.9

unknown

242

64.7

166

44.4

95

25.4

503

44.8

Her2

Negative

3

0.8

55

14.7

61

16.3

119

10.6

< 0.001

Positive

1

0.3

10

2.7

8

2.1

19

1.7

unknown

370

98.9

309

82.6

305

81.6

984

87.7

Radiation

Yes

92

24.6

88

23.5

75

20.1

255

22.7

0.03

No

282

75.4

284

75.9

292

78.1

858

76.5

unknown

0

0

2

0.5

7

1.9

9

0.8

P-value was calculated among all groups by the Chi-square test, and the bold type indicates significance. a: Including American Indian/Alaskan native, Asian/Pacific Islander and others-unspecified.

The overall survival of 1:1:1 matched groups of White, Black and other patients.

Figure 2: The overall survival of 1:1:1 matched groups of White, Black and other patients. Kaplan meier test for overall survival of 1:1:1 matched groups to compare to compare white patients to Blacks and others (χ2 = 26.811, P < 0.001).

We also used the Cox proportional hazards model to investigate the effects of the clinical characteristics on OS in the matched group (Table 4). The univariate analysis results showed results similar to Table 2. In the multivariate analysis, white race could also be an independent protective factor when compared to the black race (HR = 1.153, 95% CI: 0.936–1.419, P = 0.001) and other races (HR = 1.447, 95% CI: 1.169–1.793, P = 0.003) (Table 4).

Table 4: Univariate and multivariate analysis of overall survival in the 1:1 matched groups

Variables

Univariate analysis

Multivariate analysis

HR (95% CI)

P-Value

HR (95% CI)

P-Value

Year of diagnosis

1973–1993

reference

reference

1994–2013

0.867 (0.740–1.015)

0.075

-

-

age (years)

10–49

reference

reference

50–85

2.619 (1.976–3.472)

< 0.001

2.741 (2.066–3.635)

< 0.001

Laterality

right

reference

reference

left

0.971 (0.836–1.128)

0.701

-

-

bilateral

1.220 (0.749–1.987)

0.425

-

-

Grade

I

reference

reference

II

1.183 (0.840–1.666)

0.336

1.300 (0.922–1.835)

0.135

III

1.740 (1.237–2.446)

0.001

1.687 (1.196–2.381)

0.003

IV

1.902 (1.037–3.491)

0.038

1.692 (0.911–3.142)

0.096

unknown

1.634 (1.179–2.266)

0.003

1.416 (1.008–1.988)

0.045

Tumor size (cm)

≤ 2

reference

reference

> 2 and ≤ 5

2.101 (1.305–3.383)

0.002

1.804 (1.118–2.912)

0.016

> 5

4.026 (2.346–6.909)

< 0.001

3.653 (2.112–6.318)

0.003

unknown

2.116 (1.441–3.109)

< 0.001

1.624 (1.084–2.434)

0.019

LN status

Negative

reference

reference

Positive

1.351 (0.904–2.018)

0.142

-

-

unknown

1.408 (1.029–1.926)

0.033

-

-

ER

Negative

reference

reference

Positive

0.865 (0.573–1.304)

0.488

4.006 (1.462–10.980)

0.007

unknown

1.204 (0.803–1.804)

0.369

3.244 (1.328–7.926)

0.01

PR

Negative

reference

reference

Positive

0.656 (0.498–0.866)

0.003

1.512 (0.630–3.627)

0.355

unknown

0.977 (0.752–1.269)

0.859

1.505 (0.668–3.390)

0.324

Race

White

reference

reference

Black

1.310 (1.105–1.552)

0.002

1.153 (0.936–1.419)

0.001

Otherb

0.770 (0.632–0.937)

0.009

1.447 (1.169–1.793)

0.003

a: The total CI and P-value using Cox proportional hazards model and a bold type indicates significance. b: Including American Indian/Alaskan native, Asian/Pacific Islander.

Stratification analysis with molecular subtype

To further investigate the effects of molecular subtypes on breast cancer outcomes between different races of patients, we stratified all the cases according to molecular subtype. In our study, only 1,796 cases had the definite subtype categorization when we eliminated all cases recorded before 2010. Hence, we attempted to conduct a subgroup analysis based on ER/PR/HER2 status. The results showed that 1,976 cases were included (1,748 cases of luminal, 15 cases of HER2+, and 33 cases of basal type). The subgroup distribution among whites, blacks, and others showed no significant difference (P = 0.475) (Table 5). We further performed the multivariate analysis, stratifying according to molecular subtype. However, all cases included were still alive during the follow-up period. Hence, we could not obtain more useful information for the subtype in the 3 races with MBC.

Table 5: Characteristics of patients with different ER/PR status

subtype

White(n = 1543)

Black (n = 293)

othera

total

No.

%

No.

%

No.

%

No.

%

P

Her+ 3

11

0.7

2

0.7

1

1.3

14

0.7

0.475

Luminal 1

1411

91.4

268

91.5

70

88.6

1749

91.3

Basal 0

22

1.4

8

2.7

3

3.8

33

1.7

Unknown 4

99

6.4

15

5.1

5

6.3

119

6.2

P-value was calculated among all groups by the Chi-square test. a: Including American Indian/Alaskan native, Asian/Pacific Islander.

DISCUSSION

Because of the delay in the diagnosis and loss of the social male-specific information, an increased trend in male breast cancer mortality rates has emerged. However, the relatively lower incidence of MBC than that of FBC has not aroused the same attention for improving research and prevention. At the present time, the management and treatment of MBC is based on guidelines developed for women [14]. It is known that FBC and MBC differ biologically. For example, the levels of hormone receptors in malignant tumors of the male mammary gland are higher than in malignant female breast tumors on average. The presence of receptor-positive tumors in men does not increase with the age, as is observed in FBC [1517]. It is necessary to use optimized therapeutic approaches for the treatment of breast cancer in both sexes. Therefore, research on male breast cancer is needed to further promote treatment and prevention.

Because male breast cancer is a relatively rare disease, there is only limited data in the published literature regarding race as a risk factor in male breast cancer patients. For example, one report in 2011 showed the age-adjusted incidence rates overall and for white, black, and Hispanic males were 1.4, 1.3, 1.9, and 0.8 per 100,000, respectively [9, 18]. Crew et al. found that there was an association of black race with increased male breast cancer-specific mortality after adjustment for known clinical, demographic, and treatment factors using the SEER-Medicare database to identify men 65 years of age or older diagnosed with stage I-III breast cancer from 1991 to 2002 [19]. In our study, we obtained 8,607 cases from the current SEER database, and this study is currently the largest analysis of MBC in different races. The results provided evidence that white male breast cancer patients have a particular distribution of clinical characteristics. We summarized the clinicopathological characteristics of the 3 races with MBC and found that white patients presented with an older age, more were unmarried, they had smaller tumors, and they were more likely to be in stage I. Our study also indicated that the hormonal receptor-positive rate including ER, PR, and HER2 were higher in whites than in the blacks and others. Our study enrolled more cases of MBC from 1973 to 2013, and we analyzed more factors with racial disparities than Crew et al.

Common FBC risk factors such as the environment, genetics, hormones, smoking, and alcohol are also involved in the pathogenesis of male breast cancer [20]. For instance, one study found that MBC survival differences were observed between metropolitan and nonmetropolitan regions and an interaction between nonmetropolitan area and regional stage MBC was a significant predictor of poorer survival [21]. However, regional differences in tumor grade size and stage at diagnosis were not statistically significant. Only a small study analyzed those disparities in male breast cancer patients of different races. For example, Monederol et al. reported that smokers with male breast cancer had a significantly decreased survival rate [18].

This study provided some detailed relationships of these risk factors to race. The results showed that white and black male breast cancer patients have a poorer OS and BCSS than others. There were significant differences among whites, blacks, and others, such as the age of diagnosis (P < 0.001) and the hormone receptor status (ER, PR, and HER2, P < 0.001), which may be the main risk factors among whites, blacks and others.

Other factors might participate in the poorer OS of white and black patients than others. As a multifactorial disease, MBC requires a precise and comprehensive knowledge of the risk factors such as family history, genetic susceptibility, and predisposition for useful and effective treatment. In other words, male breast cancer can be affected by genetics, epigenetics, and ethical aspects [14]. In this study, we focused on the genetic and ethical factors to clarify the difference in clinical characteristics among the 3 groups. These might provide insights into a better understanding of MBC.

Our study has several limitations. FBC is categorized into different subtypes that have important prognostic implications, and clear racial/ethnic differences exist in the distribution of tumor subtypes [2223]. However, it is not clear whether subtypes in MBC are associated with the same prognostic factors. It was reported that non-Hispanic blacks have more than triple the number of receptor-negative tumors and are more likely to have ER+/PR tumors than non-Hispanic black patients.[24] In our study, with the incomplete subtype data, we could not obtain more useful information for the subtype in the 3 races with MBC.

In conclusion, this study explored the clinicopathological characteristics and survival in white, black, and other races with male breast cancer, including American Indians, AK Natives, Asians, and Pacific Islanders. The white and black MBC patients have poorer OS and BCSS than the others. Race could also be a prognostic indicator. Differences in outcomes may be partially explained by the differences in tumor grade, LN status, and ER and PR status between the 3 groups. Our study might provide insights into a better understanding of MBC and further promote its treatment and prevention.

MATERIALS AND METHODS

Ethics statement

We obtained the SEER research data using the reference number 11443-Nov2015, and the data in the SEER database do not require informed patient consent. Our study was approved by the Ethical Committee and Institutional Review Board of Fudan University Shanghai Cancer Center (FDUSCC). The methods were performed in accordance with the approved guidelines.

patients

The case listing in this study was generated by SEER *Stat version 8.3.2, which included data from 18 population-based registries (1973–2013) and covered approximately 28% of the United States. We choose 8,607 cases of patients according to the following criteria: male; known age; year of diagnosis before 2013; known race; unilateral breast cancer; pathologically confirmed breast cancer and breast cancer as the first and only malignant cancer diagnosis; known ER, PR, and HER2 status; and American Joint Committee on Cancer (AJCC) stages I-IV.

Patients were categorized according to the year of diagnosis (1973–2008 and 2009–2013), their ages (10–49 and 50–58 years), laterality (left or right or paired site), tumor size (tumor size ≤ 2 cm, tumor size 2–5 cm, or tumor size > 5 cm), LN, ER, PR, and HER2 status (negative, positive, and unknown), and radiation (yes, no, or unknown).

Statistical analysis

The clinical characteristics of all selected cases were compared between different racial groups using the χ2 test. We used the Kaplan-Meier method to generate the survival curves, and the log-rank test was performed to compare the OS of white, black, and other (including American Indians, AK Natives, Asians, and Pacific Islanders) patients. OS was defined as the time from the date of diagnosis to the date of death due to all causes (including breast cancer) or the last follow-up. BCSS was measured from the date of diagnosis to the date of breast cancer death. Adjusted HRs with 95% CIs were calculated using Cox proportional hazard regression models to estimate the prognostic factors. These statistical analyses were performed utilizing SPSS software version 22.0. In addition, we matched white, black, and other male patients 1:1:1 on the following predetermined factors: age, AJCC stage, grade, breast subtype, utilizing psmatch 3.04 in SPSS designed for propensity score matching methods. In detail: binary treatment indicator: race; covariates: AJCC stage, grade, tumor size, LN status, AJCC stage, ER status, PR status, and HER2 status; matching algorithm: nearest neighbor matching; discard units outside of common support: none (always used by optimal matching); estimation algorithm: logistic regression; caliper: no caliper. A two-sided P value < 0.05 was considered statistically significant.

Abbreviations

MBC: male breast cancer, FBC: female breast cancer; OS: overall survival; BCSS: breast cancer specific survival; CI: confidence interval; ER: oestrogen receptor; PR: progesterone receptor; HER2: human epidermal growth factor receptor 2; HR: hazard ratio; LN: lymph nodes.

Author contributions

W.J. and H.-F.S. conceived and designed the study. H.-F.S., S.-P.G., L.-D.L, W.-Y.F. performed the analysis, Y.-Z., M.-T.-C., H.-L.J. and P.-L.Y. prepared the figures, H.-F.S. prepared tables and wrote the main manuscript. All of the authors reviewed the manuscript.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

FUNDING

This work was supported by grants from National Natural Science Foundation of China (81302299, 81472669).

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