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Hormone Receptor-Positive Breast Cancer Has a Worse Prognosis in Male Than in Female Patients
Original Study
Hormone Receptor-Positive Breast Cancer Has a Worse Prognosis in Male Than in Female Patients Xiaoxian Li,1 Jing Yang,2 Uma Krishnamurti,1 Lei Huo,3 Kevin C. Ward,2 Ruth O’Regan,4 Limin Peng2 Abstract Male breast carcinoma (MBC) has been thought to have similar survival as female breast carcinoma (FBC). We studies 172,847 FBC and 1442 MBC from the SEER data and found patients with MBC have worse survival than patients with FBC. Introduction: Male breast carcinoma (MBC) is treated similarly to female breast carcinoma (FBC), and similar survival rates for both have been assumed. We analyzed prognostic and clinicopathologic features of MBC to determine whether MBC subtypes differ from FBC subtypes. Patients and Methods: We reviewed data for 172,847 FBC and 1442 MBC patients from 2010 to 2012 from the National Cancer Institute Surveillance, Epidemiology, and End Results database. Carcinomas were subtyped according to hormone receptor (HR) and HER2 status as HR-positive (HRþ)/HER2, HRþ/ HER2þ, HR/HER2þ, and HR/HER2. Results: The overall incidence of MBC in all breast carcinoma cases was 0.8%. MBC was more frequently HRþ/HER2 than was FBC (78.3% vs. 67.4%) and less frequently HR/HER2 (2.1% vs. 10.9%). More MBC was staged as III or IV (24.9% vs. 17.2%). MBC had significantly worse overall survival (OS) than FBC (P < .0001). After adjustment for age, ethnicity, and tumor grade, stage I and II MBC had significantly worse OS time than stage-matched FBC (P ¼ .0011 for stage I, P ¼ .0229 for stage II). When stage- and subtype-matched patients were compared, MBC had significantly worse OS than FBC for stage I overall, for substages IA and IIB HRþ/HER2 carcinoma, and for stage III HRþ/HER2þ carcinoma. Furthermore, MBC patients with HRþ/HER2 T1aN0 carcinomas had worse OS than did FBC patients. Conclusion: Patients with MBC have worse survival than patients with FBC, especially for early-stage HRþ breast cancers. More studies are needed optimize treatment for MBC. Clinical Breast Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: Breast cancer prognosis, Breast cancer subtype, Male breast cancer, Matched stage and subtype, Prognosis
Introduction Unlike female breast carcinoma (FBC), the most common carcinoma in women, male breast carcinoma (MBC) is rare, comprising less than 1% of all breast carcinomas. However, the incidence of MBC has steadily increased. In 1991, it was estimated These data were presented, in part, at the United States and Canadian Academy of Pathology Annual Meeting, 2016, Seattle, WA. 1
Department of Department of Department of Houston, TX 4 Department of 2 3
Pathology and Laboratory Medicine Biostatistics and Bioinformatics, Emory University, Atlanta, GA Pathology, The University of Texas M.D. Anderson Cancer Center, Medicine, University of Wisconsin, Madison, WI
Submitted: Dec 2, 2016; Revised: Mar 2, 2017; Accepted: Mar 6, 2017 Address for correspondence: Xiaoxian Li, MD, PhD, Department of Pathology and Laboratory Medicine, Emory University, 1364 Clifton Rd, Suite H175, Atlanta, GA 30322 Fax: 404-727-3133; e-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2017.03.005
that 900 men in the United States had breast carcinoma; the number increased to 2240 by 2014.1,2 Risk factors associated with MBC include older patient age; a family history of breast cancer; the presence of breast cancer gene 2 mutations; exposure to hightemperature environments and exhaust fumes; and hyperestrogenism from Klinefelter syndrome, obesity, or excessive alcohol consumption.3-13 Factors associated with worse prognosis in MBC include axillary lymph node involvement, advanced stage, and long duration of symptoms.3-7,14-17 Recent research identified the prognostic potential of breast carcinoma subtypes and the differing biology and treatment responses among these subtypes. Molecular studies have classified breast carcinoma into luminal A, luminal B, HER2-enriched, basallike, and claudin-low subtypes.18,19 Clinical definitions of these subtypes are on the basis of the status of hormone receptors (HRs) and HER2: luminal A breast carcinoma is HR-positive (HRþ)/ HER2 with low Ki-67 score, luminal B is HRþ/HER2þ or HRþ
Clinical Breast Cancer Month 2017
-1
Male Breast Cancer with high Ki-67 score, HER2-enriched is HR/HER2þ, and basallike and claudin-low are HR/HER2. These subtypes differ in tumor biology and immunohistochemical profiles and in their responses to chemotherapy and targeted treatments.18-25 Most MBC is ductal type and estrogen receptor (ER)- and progesterone receptor-positive,4,6,9,26 and compared with FBC, MBC tends to have more lymph node involvement and to present at higher stages. However, the biology of MBC specifically has not been well studied, and the behavior of different subtypes in MBC is poorly understood. Overall, MBC is treated similarly to FBC, although a higher proportion of male than female patients tend to undergo total mastectomy.5,27 When adjusted for stage, MBC has been thought to have survival rates similar to FBC9,28,29; however, the rarity of MBC precludes large prospective clinical trials to compare survival rates and optimize therapy for MBC. To better characterize the biology and behavior of MBC, we analyzed prognostic and clinicopathologic features of MBC and compared the overall survival (OS) of patients with various MBC subtypes with the OS of patients with FBC subtypes. We used patient data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database and compared the clinical outcomes of FBC and MBC, matching characteristics such as tumor stage and subtype. Analysis indicated that some subtypes of MBC might carry a poorer prognosis than stage- and subtypematched FBC, suggesting that MBC might need to be treated differently than FBC.
Table 1 Clinicopathological Characteristics of SEER Database Male and Female Patients Diagnosed With Breast Carcinomas Between 2010 and 2012 Male (n [ 1442)
Characteristic Age at Diagnosis in Y
Female (n [ 172,847)
66.8 (12.8)
61.6 (13.7)
<50
152 (10.5)
35,535 (20.6)
50
1290 (89.5)
137,312 (79.4)
White
1155 (80.1)
138,065 (79.9)
Black
206 (14.3)
18,888 (10.9)
Others
74 (5.1)
14,804 (8.6)
Missing
7 (0.5)
1090 (0.6)
1
173 (12.0)
37,357 (21.6)
2
692 (48.0)
71,228 (41.2)
3
490 (34.0)
53,004 (30.7)
4
3 (0.2)
794 (0.5)
84 (5.8)
10,464 (6.0)
HRþ/HER2
1129 (78.3)
116,557 (67.4)
HRþ/HER2þ
134 (9.3)
16,040 (9.3)
Ethnicity
Tumor Grade
Missing Subtype
HR /HER2
þ
10 (0.7)
7119 (4.1)
31 (2.1)
18,905 (10.9)
138 (9.6)
14,226 (8.2)
524 (36.3)
87,906 (50.9)
481
83,902
HR/HER2 Missing Stage
Patients and Methods
I
Patient Information We searched the SEER database for all breast cancer patients diagnosed from 2010 to 2012 and identified 182,523 cases. Patients were excluded from our analysis if their disease was stage 0 or if information on stage was missing. Cases missing HR or HER2 status were included in the combined analysis of stages I to IV but excluded from analysis of subtypes. For cases that met our study criteria, we collected the following deidentified information: patient sex, age at diagnosis, ethnicity, and OS data; tumor Grade, HR and HER2 status; and staging on the basis of the Tumor, Node, Metastases and Roman Numeral staging system from the American Joint Committee on Cancer guidelines. We classified breast carcinomas according to HR and HER2 status into 4 subtypes: HRþ/HER2, HRþ/HER2þ, HR/ HER2þ, and HR/HER2. The follow-up time was up to 35 months with a median of 15 months for the entire cohort. For MBC cases, the mean follow-up time was 15.7 months with the median and interquantile range of 15 and 19 months, respectively. For the FBC cases, the mean follow-up time was 16 months with the median and interquantile range of 15 and 18 months, respectively.
IA IB
43
4004
560 (38.8)
55,203 (31.9)
IIA
368
36,819
IIB
192
18,384
III
253 (17.6)
19,684 (11.4)
IV
105 (7.3)
10,054 (5.8)
II
Age at diagnosis is presented as mean (SD), and other variables are presented as n (%). Each characteristic demonstrated statistically significant differences between breast cancer cases in male and female patients, showing P < .0001 in a 2-sample t test for age at diagnosis and c2 test for other characteristics. Cases missing characteristic data were not considered in analysis of that characteristic. Tumor Grade 1 was considered low grade and tumor Grades 2 to 4 were considered high grade; tumor Grade 4 was defined according to SEER as undifferentiated or anaplastic. Abbreviations: HR ¼ hormone receptor; SEER ¼ Surveillance, Epidemiology, and End Results.
Table 2 Univariate Analysis for Significant Predictors of Overall Survival in Breast Cancer Predictor
Hazard Ratio
95% CI
P
2.12
1.99-2.25
<.0001 <.0001
Age 50 vs. <50 Ethnicity
Statistical Analysis
2
-
Summary statistics were provided for demographic variables (patient age at diagnosis and ethnicity) and other potential predictors of survival (breast cancer stage, HR, and HER2 subtype, and tumor Grade) for male and female patients. Their differences between the male and female patient groups were assessed using the
Clinical Breast Cancer Month 2017
White vs. black
0.59
0.56-0.62
Others vs. black
0.38
0.35-0.42
2.18
2.04-2.33
Tumor Grade 2/3/4 vs. 1 P values were for log rank tests.
<.0001
Xiaoxian Li et al
1.00
Figure 1 Overall Survival of Male and Female Patients With Breast Cancer When All Cases Were Combined. Survival Probability With Male Breast Cancer Was Significantly Lower Than That With FBCs
0.90 0.85
Survival Probability
0.95
Log rank test: P < .0001
0.80
Male Female
0
5
10
15
20
25
30
35
Months
2-sample t test for continuous variables and the c2 test for categorical variables. All analyses were on the basis of available cases and performed using SAS version 9.4 software (SAS Institute, Inc, Cary, NC). The OS times of patients with MBC and FBC in all combined stages (I-IV), stage-matched subgroups, and subtype-matched subgroups were summarized using KaplaneMeier survival curves and compared using log rank tests. A univariate Cox proportional hazard model was conducted separately for sex, age, ethnicity, and tumor Grade. We further conducted multivariate Cox regression analyses to assess the effect of sex on OS while adjusting for the potential predictors including age, ethnicity, and tumor Grade for all patients or patient groups stratified according to disease stage and/or breast cancer subtype. HRs for the sex effect (MBC vs. FBC) and their associated 95% confidence intervals (CIs) were obtained from the Cox regression analysis. A P value below .05 was regarded as statistically significant. Patient age as well as tumor Grade were defined as binary variables: age as younger than 50 years (< 50) or 50 years or older ( 50), and tumor Grade as low (Grade 1) or high (Grade 2, 3, or 4; Grade 4 was defined according to SEER as undifferentiated or anaplastic carcinoma). For ethnicity, the categories American Indian/Alaska Native and Asian/Pacific Islander were combined as “others.” Because there were few HR/HER2þ and HR/HER2 MBC cases, detailed OS analysis at each stage was performed only
for HRþ/HER2þ and HRþ/HER2 carcinomas. Additionally, to examine whether at the lowest stage MBC had a worse prognosis than FBC, we compared OS times of stages T1aN0 and T1bN0 MBCs with those of FBCs. Only HRþ/HER2 carcinomas had sufficient data to enable this comparison.
Results Clinicopathological Characteristics of Patients Of the 182,523 cases originally identified from the SEER database search, cases of 172,847 FBCs and 1442 MBCs diagnosed from 2010 to 2012 met our study criteria, and these data were included in our analysis. Clinicopathologic information is summarized in Table 1. MBCs accounted for 0.8% of all breast carcinomas. Compared with FBC patients, MBC patients were significantly older (mean 66.8 vs. 61.6 years old; P < .0001), were more likely to be African-American (14.3% vs. 10.9%; P < .0001), had fewer Grade 1 carcinomas (12% vs. 21.6%; P < .0001), and had higher stage carcinoma (stages III and IV: 24.9% vs. 17.2%; P < .0001). MBC was more likely to be HRþ/HER2 than was FBC (78.3% vs. 67.4%; P < .0001) and less likely to be HR/ HER2 (2.1% vs. 10.9%; P < .0001). Log rank tests and a univariate Cox model showed that patient age, ethnicity, and tumor Grade significantly affected OS. Factors associated with a worse prognosis were age 50 years or older, African-American ethnicity, and high tumor Grade (Table 2).
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Male Breast Cancer Figure 2 Overall Survival of Male and Female Patients With Stage (A) I, (B) II, (C) III, and (D) IV Breast Cancer. The Difference in Overall Survival Between Male and Female Patients Was Significant in Stages I and II But Not in Stage III or IV
B
5
10
0.8
1.0 0
Male Female
0.4
Male Female
Log rank test: P = .0007
0.6
Survival Probability
0.8 0.6
Log rank test: P = .0004
0.4
Survival Probability
1.0
A
15
20
25
30
35
0
5
10
Months
30
35
30
35
1.0 5
10
15
20
25
30
35
Months
Male Breast Carcinoma Patients Had Worse OS Than FBC Patients Had in Stage I, Stage II, and All Stages of Disease Combined Of the 1442 MBC cases, 524 were stage I, 560 were stage II, 253 were stage III, and 105 were stage IV (Table 1). When cases in all stages were combined, MBC patients had a significantly worse OS than did FBC patients (P < .0001; Figure 1). The OS (95% CI) at 35 months was 0.82 (0.78-0.86) for MBC patients and 0.888 (0.88-0.89) for FBC. Comparing MBC with FBC at each stage, MBC had significantly worse OS in stage I (P ¼ .0004) and stage II (P ¼ .0007) but not in stages III and IV (Figure 2). After adjustment for age, ethnicity, and tumor Grade, MBC patients still had significantly worse OS than FBC patients for all stages combined (hazard ratio: 1.35; 95% CI, 1.11-1.64), for stage I (hazard ratio, 2.02; 95% CI, 1.33-3.08), and for stage II (hazard ratio, 1.47; 95% CI, 1.06-2.06), but not in stages III and IV (Table 3). This suggests that the observed worse OS in MBC is not fully explained by the older age at the time of diagnosis of MBC (compared with FBC), and sex has independent prognosis power on
Clinical Breast Cancer Month 2017
0.8
Male Female
0.4
Male Female
Log rank test: P = .22
0.6
Survival Probability
1.0 0.8 0.6
Log rank test: P = .71
0.4
Survival Probability
25
D
0
-
20
Months
C
4
15
0
5
10
15
20
25
Months
the OS of breast cancer. Detailed multivariate analysis is provided in Table 4.
Hormone Receptor-Positive/HER2 MBC Patients Had Worse OS in Stages I, IA, and IIB Than FBC Patients But Better OS in Stage IV Than FBC Patients
Within the HRþ/HER2 MBC subtype, 430 cases were stage I (390 stage IA, 40 stage IB), 440 stage II (296 stage IIA, 144 stage IIB), 199 stage III, and 60 stage IV (Table 5). Compared with FBC, the MBC HRþ/HER2 subtype had a significantly worse OS for stage I (P ¼ .0011) and stage II (P ¼ .0174) but not for stages III and IV (Figure 3). After adjustment for age, ethnicity, and tumor Grade, MBC patients had a worse OS for stage I compared with FBC patients, but MBC patients had a better OS for stage IV (Table 3). The HRþ/HER2 MBC subtype patients had significantly worse OS time than FBC patients had in stages IA (P ¼ .0003) and IIB (P < .0001) but not in stage IIA (P ¼ .95; Figure 4A-C). This trend was also true for patient survival after adjusting for age, ethnicity, and tumor Grade (Table 3).
Xiaoxian Li et al Table 3 Hazard Ratio of Overall Survival in MBC Compared With FBC According to Tumor Stage and Subtype, Adjusted for Age, Ethnicity, and Tumor Grade
T1bN0 stages. In these 2 tumor stages, only the HRþ/HER2 subtype had enough MBC cases for meaningful analysis. In the HRþ/HER2 subtype, MBC had 37 T1aN0 and 67 T1bN0 cases (Table 5). Compared with FBC, the MBC HRþ/HER2 subtype had significantly worse OS in the T1aN0 cases (P ¼ .0219) but not in the T1bN0 cases (P ¼ .76) (Figure 6). HRþ/HER2 T1aN0 MBC still had worse OS after adjusting for age, ethnicity, and tumor Grade (Table 3).
Hazard Ratio
95% CI
P
All Cases Combined
1.35
1.11-1.64
.0023a
Stage I
2.02
1.33-3.08
.0011a
Stage II
1.47
1.06-2.06
.0229a
Stage III
0.87
0.57-1.31
.50
Discussion
Stage IV
0.75
0.51-1.11
.16
Stage I
2.06
1.27-3.32
.0032a
Stage II
1.40
0.92-2.13
.12
Stage III
1.00
0.60-1.68
.99
Stage IV
0.50
0.27-0.93
.0290a
IA
2.24
1.39-3.62
.0010a
IB
e
e
e
IIA
0.89
0.46-1.71
.72
IIB
2.35
1.35-4.09
.0025a
T1aN0
5.04
1.24-20.49
.0239a
T1bN0
0.65
0.09-4.66
.67
Stage I
1.29
0.18-9.22
.80
Stage II
2.31
0.95-5.65
.0658
Stage III
3.48
1.60-7.54
.0016a
Stage IV
1.21
0.50-2.93
.68
IA
1.44
0.20-10.35
.72
IB
e
e
IIA
1.96
0.48-7.96
.35
IIB
2.90
0.90-9.41
.0756
To our knowledge, this is the first study to report that MBC has a worse prognosis than FBC for different subtypes and stages. Our analysis showed that compared with FBC, MBC was more frequently HRþ, more likely to be at a higher stage, and more likely to have significantly worse OS for all stages combined. After adjustment for age, ethnicity, and tumor grade, early stage MBC patients had significantly worse OS than stage-matched FBC patients. In a comparison of stage-matched and subtype-matched patients, MBC patients had significantly worse OS than FBC patients for multiple tumor subtypes and stages. Thus, some MBCs, particularly early stage HRþ MBC might have worse clinical outcomes than FBCs with the same stage. Male breast carcinoma has been considered similar to FBC, and MBC and FBC are currently treated similarly.3,5-8 Previously, reports of shorter OS in MBC attributed the change to older patient age and more advanced stages of disease.12,30,31 Miao et al reported that MBC had later onset of disease and more advanced disease than FBC. After adjustment for age, stage, and treatment, MBC patients had a significantly better relative survival rate than FBC patients with a relative excess risk of 0.78 (95% CI, 0.62-0.97).30 Giordano et al reported that men with breast cancer had a higher median age and more advanced stage at the time of diagnosis than women and that the MBC patients were more likely to be ERþ than were FBC patients. In multivariate analysis, these investigators reported that larger tumor size and lymph node involvement in MBC were associated with worse survival; that tumor Grade and HR status did not independently influence survival; and that within the same breast cancer stage, relative survival rates for men and women were similar.31 Greif et al also concluded that “breast cancer in men and women appears more alike than different.”32 Consistent with these studies, we found that MBC was diagnosed at an older age and at a higher stage than FBC. We found that compared with FBC, MBC had higher tumor Grade and was more frequently HRþ. In terms of OS in MBC versus FBC, our findings differed from those of the existing literature. The National Cancer Institute Physician Data Query noted that survival for men with breast cancer is similar to survival for women with breast cancer. Cutuli et al reported similar prognosis for male and FBC patients.6 In contrast to this report and other studies, we report herein that MBC had worse OS than FBC overall and within some stages and subtypes. Our study thoroughly compared the prognosis between MBC and FBC in matched stages, and we showed that patients with the HRþ/HER2 subtype of MBC had a worse OS time in early stages (stage IA and stage IIB), including for T1aN0 cancers, than female HRþ/HER2 breast cancers. For HRþ/HER2þ cancers, MBC had a worse OS for stage III cancer. It should be noted that although male patients were diagnosed with breast cancer at older age, such a
HRþ/HER2
HRþ/HER2þ
e
For HRþ/HER2 stage IB MBC patients, there were no death records and for HR2þ/HER2þ stage IB MBC patients, there were only 2 cases. Abbreviations: FBC ¼ female breast carcinoma; HR ¼ hormone receptor; MBC ¼ male breast cancer. a Statistically significant.
Hormone Receptor-Positive/HER2þ MBC Patients Had Worse OS in Stage III Than Did FBC Patients
Within the HRþ/HER2þ MBC subtype, 37 cases were stage I (35 stage IA, 2 stage IB), 52 stage II (27 stage IIA, 25 stage IIB), 27 stage III, and 18 stage IV (Table 5). Compared with FBC, the HRþ/HER2þ MBC subtype had significantly worse OS time for stages II (P ¼ .0098) and III (P < .0001) but not for stages I and IV (Figure 5). After adjustment for age, ethnicity, and tumor Grade, the HRþ/HER2þ MBC subtype had a significantly worse OS time than FBC for stage III carcinoma but stage II was no longer significant (Table 3). The HRþ/HER2þ MBC subtype had significantly worse OS time than FBC for stage IIB (P ¼ .0061) but not for stages IA and IIA (Figure 4D-F). This significance disappeared after adjustment for age, ethnicity, and tumor Grade (Table 3).
Male Breast Carcinoma Patients Had Worse OS in HRþ/ HER2 T1aN0 Carcinoma Than FBC Patients To examine whether MBC had a worse prognosis than FBC in the earliest stages, we compared MBC with FBC in T1aN0 and
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-5
6
Age (‡ 50 vs. < 50 Y)
MBC vs. FBC
All Cases Combined
Ethnicity (White vs. Black)
Ethnicity (Others vs. Black)
Tumor Grade (High vs. Low)
Hazard Ratio (95% CI)
P
Hazard Ratio (95% CI)
P
Hazard Ratio (95% CI)
P
Hazard Ratio (95% CI)
P
Hazard Ratio (95% CI)
P
1.35 (1.11-1.64)
.0023
2.16 (2.02-2.31)
<.0001
0.60 (0.57-0.64)
<.0001
0.41 (0.37-0.46)
<.0001
2.23 (2.09-2.38)
<.0001 <.0001
Stage I
2.02 (1.33-3.08)
.0011
4.81 (3.75-6.18)
<.0001
0.81 (0.69-0.94)
<.0001
0.50 (0.38-0.65)
<.0001
1.24 (1.11-1.38)
Stage II
1.47 (1.06-2.06)
.0229
3.09 (2.69-3.55)
<.0001
0.75 (0.67-0.84)
<.0001
0.45 (0.36-0.55)
<.0001
1.26 (1.11-1.42)
.0004
Stage III
0.87 (0.57-1.31)
.5
2.07 (1.82-2.36)
<.0001
0.64 (0.57-0.72)
<.0001
0.40 (0.31-0.51)
<.0001
1.83 (1.47-2.27)
<.0001
0.75 (0.51-1.11)
.16
1.88 (1.69-2.10)
<.0001
0.70 (0.64-0.77)
<.0001
0.63 (0.53-0.75)
<.0001
1.61 (1.37-1.90)
<.0001
Stage IV þ
HR /HER2 Stage I
2.06 (1.27-3.32)
.0032
6.70 (4.60-9.75)
<.0001
0.80 (0.65-0.98)
.03
0.56 (0.40-0.77)
.0005
1.12 (0.99-1.26)
.07
Stage II
1.4 (0.92-2.13)
.12
4.03 (3.21-5.06)
<.0001
0.80 (0.67-0.95)
.0102
0.45 (0.33-0.62)
<.0001
1.09 (0.95-1.27)
.22
Stage III
1.00 (0.60-1.68)
.99
2.50 (2.00-3.12)
<.0001
0.66 (0.55-0.81)
<.0001
0.40 (0.28-0.59)
<.0001
1.34 (1.05-1.71)
.02
Stage IV
0.50 (0.27-0.93)
.0290
2.10 (1.76-2.50)
<.0001
0.72 (0.62-0.83)
<.0001
0.57 (0.44-0.76)
<.0001
1.59 (1.30-1.95)
<.0001
.0001
1.12 (0.99-1.27)
.07
IA
2.24 (1.39-3.62)
.0010
6.98 (4.70-10.38)
<.0001
0.77 (0.62-0.95)
.014
0.51 (0.36-0.72)
IB
e
e
e
e
e
e
e
e
e
e
IIA
0.89 (0.46-1.71)
4.23 (3.14-5.70)
<.0001
0.80 (0.64-1.00)
0.55 (0.39-0.79)
.001
1.03 (0.87-1.22)
.76
<.0001
0.79 (0.59-1.04)
.1
0.27 (0.14-0.51)
<.0001
1.26 (0.94-1.68)
.12
.0009
0.60 (0.34-1.05)
.07
0.51 (0.21-1.21)
.13
1.05 (0.73-1.50)
.8
<.0001
0.72 (0.49-1.05)
.09
0.53 (0.29-0.97)
.0391
1.16 (0.09-4.66)
.19
.72
IIB
2.35 (1.35-4.09)
.0025
3.80 (2.68-5.41)
T1aN0
5.04 (1.24-20.49)
.0239
6.94 (2.21-21.86)
T1bN0
0.65 (0.09-4.66)
.67
4.55 (2.43-8.55)
.0548
HRþ/HER2þ Stage I
1.29 (0.18-9.22)
.8
8.65 (3.19-23.46)
<.0001
0.73 (0.43-1.24)
.24
0.48 (0.20-1.17)
.11
1.21 (0.68-2.16)
.52
Stage II
2.31 (0.95-5.65)
.07
9.65 (4.74-19.64)
<.0001
0.63 (0.42-0.94)
.0245
0.33 (0.16-0.70)
.037
0.65 (0.37-1.12)
.12
Stage III
3.48 (1.60-7.54)
.0016
2.33 (1.48-3.65)
.0002
0.85 (0.53-1.36)
.49
0.55 (0.23-1.31)
.18
0.72 (0.34-1.55)
.4
Stage IV
1.21 (0.50-2.93)
.68
2.23 (1.62-3.06)
<.0001
0.76 (0.57-1.03)
.07
0.87 (0.54-1.40)
.56
0.96 (0.45-2.03)
.91
IA
1.44 (0.20-10.35)
.72
7.99 (2.94-21.68)
<.0001
0.77 (0.44-1.35)
.35
0.54 (0.22-1.33)
.18
1.11 (0.62-1.99)
.72
IB
e
e
e
e
e
e
e
e
IIA
1.96 (0.48-7.96)
.35
e
9.83 (4.01-24.09)
<.0001
0.66 (0.40-1.10)
.11
0.26 (0.10-0.70)
.0075
0.68 (0.37-1.28)
.23
IIB
2.9 (0.90-9.41)
.08
9.02 (2.81-29.03)
.0002
0.54 (0.28-1.07)
.08
0.48 (0.15-1.53)
.22
0.64 (0.20-2.07)
.46
For each tumor stage and subtype, sex, age, ethnicity, and tumor grade were included in the multivariate model. Abbreviations: FBC ¼ female breast carcinoma; MBC ¼ male breast carcinoma.
e
Male Breast Cancer
Clinical Breast Cancer Month 2017
Table 4 Detailed Multivariate Analysis Results for Overall Survival According to Tumor Stage and Subtype
Xiaoxian Li et al Table 5 Number of Breast Carcinoma Cases in 4 Subtypes According to Stage and Sex Stage
HRD/HER2L
Sex
I
M F M F M F M F M F M F M F M F M F M F
IA IB II IIA IIB III IV T1aN0 T1bN0
430 64,926 390 61,847 40 3079 440 35,152 296 23,703 144 11,449 199 11,445 60 5034 37 9117 67 20,527
HRD/HER2D
(90.1) (80.4) (89.7) (80.4) (95.2) (82.0) (87.0) (68.4) (89.2) (69.1) (82.8) (67.1) (85.4) (62.5) (68.2) (61.4) (92.5) (77.7) (91.8) (84.4)
37 6426 35 6097 2 329 52 5839 27 3630 25 2209 27 2489 18 1286 1 1155 3 1554
HRL/HER2D
(7.8) (8.0) (8.0) (7.9) (4.8) (8.8) (10.3) (11.4) (8.1) (10.6) (14.4) (12.9) (11.6) (13.6) (20.1) (15.7) (2.5) (9.8) (4.1) (6.4)
1 2434 1 2320 0 114 4 2522 3 1558 1 964 2 1469 3 694 0 670 1 522
HRL/HER2L
(0.0) (3.0) (0.0) (3.0) (0.0) (3.0) (0.8) (4.9) (0.9) (4.5) (0.6) (5.6) (0.9) (8.0) (3.4) (8.5) (0.0) (5.7) (1.4) (2.1)
9 6938 9 6703 0 235 10 7863 6 5419 4 2444 5 2922 7 1182 2 796 2 1707
(1.9) (8.6) (2.1) (8.7) (0.0) (6.3) (2.0) (15.3) (1.8) (15.8) (2.3) (14.3) (2.1) (15.9) (8.0) (14.4) (5.0) (6.8) (2.7) (7.0)
Total 477 80,724 435 76,967 42 3757 506 51,376 332 34,310 174 17,066 233 18,325 88 8196 40 11,738 73 24,310
Data are expressed as absolute number (%). Abbreviations: F ¼ female; HR ¼ hormone receptor; M ¼ male.
0.6 0
5
10
Log rank test: P = .0174
Male Female
0.4
Male Female
0.8
Log rank test: P = .0011
0.6
Survival Probability
0.8
1.0
B
0.4
Survival Probability
A
1.0
Figure 3 Overall Survival of Male and Female Patients With Hormone Receptor-Positive and HER2L Breast Cancer in Stage (A) I, (B) II, (C) III, and (D) IV. This Subtype Showed a Significantly Worse Survival in Male Than in Female Patients in Stages I and II But Not in Stage III or IV
15
20
25
30
35
0
5
10
0.6
10
15
20
Months
35
Log rank test: P = .14
Male Female
0.4
Male Female
5
30
0.8
Log rank test: P = .40
0
25
0.6
Survival Probability
0.8
1.0
D
0.4
Survival Probability
C
20
Months
1.0
Months
15
25
30
35
0
5
10
15
20
25
30
35
Months
Clinical Breast Cancer Month 2017
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Male Breast Cancer Figure 4 Overall Survival of Male and Female Patients With (A-C) Hormone Receptor (HR)-Positive and HER2L Breast Cancer, and (D-F) HRD/HER2D Breast Cancer at Stages IA, IIA, and IIB. (A-C) Of Patients With HRD/HER2L Tumors, Overall Survival Was Significantly Worse in Male Than in Female Patients in Stages IA and IIB but not in Stage IIA. (D-F) Of Patients With HRD/ HER2D Tumors, Overall Survival Was Significantly Worse in Male Than Female Patients Only in Stage IIB
Male Female
0
5
1.0 0.6
0.8
Log rank test: P = .70
Male Female
0.4
0.85
Log rank test: P = .0003
Survival Probability
1.00
D
0.70
Survival Probability
A
10 15 20 25 30 35
0
5
10 15 20 25 30 35
Months
0.70
Male Female
0
5
1.0 0.6
0.8
Log rank test: P = .23
Male Female
0.4
1.00 0.85
Log rank test: P = .95
Survival Probability
E
B Survival Probability
Months
10 15 20 25 30 35
0
5
10 15 20 25 30 35
Months
0
5
10 15 20 25 30 35 Months
-
difference did not contribute to the worse OS in our multivariate analysis. These findings suggest that MBC and FBC might need to be treated differently in clinical settings and that early-stage HRþ MBCs in particular might require more aggressive treatment than has been typically recommended. Although treatment strategies for male patients with breast cancer are on the basis of predictive markers developed for FBC, our findings agree with other studies that MBC and FBC might have underlying differences in tumor biology. Some studies have reported genetic differences between MBC and FBC. When Johansson et al analyzed gene expression data and array comparative genomic hybridization data, they identified 30 driver genes in MBC and 67 in FBC. Among these driver genes, only 2 genes,
Clinical Breast Cancer Month 2017
1.0 0.8 0.6
Log rank test: P = .0061 Male Female
0.4
1.00 0.85
Male Female
0.70
Survival Probability
Log rank test: P < .0001
Survival Probability
F
C
8
Months
0
5
10 15 20 25 30 35 Months
TATA-box binding protein associated factor 4 and cluster of differentiation 164, were common in MBC and FBC.33 Gene microarray analysis of MBC revealed 2 unique subtypes, luminal M1 (approximately 70% of MBC) and luminal M2 (approximately 30% of MBC).34,35 These 2 subtypes are different from the intrinsic subtypes in FBC in terms of gene expression signature and methylation pattern, although there might be some overlap. The luminal M1 subtype showed a low score for the ER module, despite that most carcinomas in this subtype are ERþ in immunohistochemical study. This finding suggests that the ER pathway is less active in ERþ MBCs.34 In addition, studies have shown that microRNA expression profiles differ between MBC and FBC.36,37
Xiaoxian Li et al
0.6 0
5
10
Log rank test: P = .0098
Male Female
0.4
Male Female
0.8
Log rank test: P = .75
0.6
Survival Probability
0.8
1.0
B
0.4
Survival Probability
A
1.0
Figure 5 Overall Survival of Male and Female Patients With Hormone Receptor (HR)-Positive and HER2D Breast Cancer in Stages (A) I, (B) II, (C) III, and (D) IV. Male Breast Carcinoma Patients With This Subtype Experienced Significantly Worse Survival in Stages II and III Than Female Breast Carcinoma Patients
15
20
25
30
35
0
5
10
Months
20
25
30
35
Months
C
0.6 0
5
10
1.0
Male Female
0.4
Male Female
0.8
Log rank test: P < .0001
Log rank test: P = .30
0.6
Survival Probability
0.8
1.0
D
0.4
Survival Probability
15
15
20
25
30
35
0
5
Months
Among the studies that have proposed differences in the ER pathway of FBC and MBC, Shaaban et al reported that although ERa and the progesterone receptor clustered together in FBC, ERa clustered with ERb and the androgen receptor in MBCs.38 In other studies, androgen receptor positivity has been reported in 34% to 95% of MBCs.39-41 Taken together, although these data indicate that most MBCs are ERþ in immunohistochemistry, MBC might be only weakly driven by the ER pathway and more strongly driven by other pathways such as the androgen receptor pathway. It is possible that more HRþ MBC patients harbor intrinsic resistance to endocrine therapy, compared with HRþ FBC patients. Because we did not have access to Ki-67 score or the ability to do molecularly profiling, we were unable to definitively differentiate luminal A cancers, which are generally sensitive to endocrine therapy, from luminal B cancers in this study. However, a large international analysis showed that most MBCs are luminal A cancers.42 Additionally, one study showed similar Oncotype DX (Genomic Health, Redwood City, CA) recurrence score distribution in MBC compared to FBC.43 The main limitation of our study was the relatively short followup of patients’ clinical outcomes. ERþ breast cancers tend to recur
10
15
20
25
30
35
Months
and metastasize late. Longer follow-up is needed to draw conclusions about long-term survival. Nevertheless, our study did show at least worse short-term OS time in MBC than in FBC patients. Treatment information is not available from the SEER database. Although currently MBC patients are treated the same as FBC patients, missing the treatment information is another limitation of this study.
Conclusion To our knowledge, we are the first to report that HRþ MBC patients had a worse OS time than FBC patients in early stage cancers. The worse OS time was even seen in HRþ/HER2 T1aN0 cancers, which suggests that MBC needs more aggressive treatment in HRþ early stage breast cancers. MBC might be genetically different from FBC or might have an altered ER pathway that responds differently to hormone therapy than does FBC, which could at least partially explain the inferior prognosis of HRþ MBC. Therefore, treatment strategies for MBC should be tailored differently from treatment strategies for FBC. Further research is needed to understand the pathobiology of MBC to advance the development of optimal treatments.
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Male Breast Cancer Figure 6 Overall Survival of Male and Female Patients With Hormone Receptor (HR)-Positive and HER2L Breast Carcinoma in Stages (A) T1aN0 and (B) T1bN0. Only Within T1aN0 Cases Did Male Patients Have Significantly Worse Survival Than Female Patients
Survival Probability
Log rank test: P = .0219
Male Female
0
5
10
15
20
25
30
35
Months
Clinical Practice Points MBC has been thought to have similar survival as FBC. We studies 172,847 FBC and 1442 MBC from the SEER data
and found patients with MBC have worse survival than patients with FBC. Patients with MBC may need different treatments than patients with FBC.
Acknowledgments The authors thank Diane Hackett and Katelyn Werner (Scientific Publications, M.D. Anderson Cancer Center) for thorough editing of the manuscript.
Disclosure The authors have stated that they have no conflicts of interest.
References
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0.90 0.92 0.94 0.96 0.98 1.00
B 0.90 0.92 0.94 0.96 0.98 1.00
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A
Log rank test: P = .76
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12. Ravandi-Kashani F, Hayes TG. Male breast cancer: a review of the literature. Eur J Cancer 1998; 34:1341-7. 13. Thorlacius S, Tryggvadottir L, Olafsdottir GH, et al. Linkage to BRCA2 region in hereditary male breast cancer. Lancet 1995; 346:544-5. 14. Arnould N, Pouget O, Gharbi M, et al. Breast cancer in men: are there similarities with breast cancer in women? [in French]. Gynecol Obstet Fertil 2006; 34:413-9. 15. Carmalt HL, Mann LJ, Kennedy CW, et al. Carcinoma of the male breast: a review and recommendations for management. Aust N Z J Surg 1998; 68:712-5. 16. De los Santos JF, Buchholz TA. Carcinoma of the male breast. Curr Treat Options Oncol 2000; 1:221-7. 17. Fields EC, DeWitt P, Fisher CM, et al. Management of male breast cancer in the United States: a Surveillance, Epidemiology, and End Results analysis. Int J Radiat Oncol Biol Phys 2013; 87:747-52. 18. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000; 406:747-52. 19. Creighton CJ, Li X, Landis M, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A 2009; 106:13820-5. 20. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 2008; 100:672-9. 21. Davis DG, Siddiqui MT, Oprea-Ilies G, et al. GATA-3 and FOXA1 expression is useful to differentiate breast carcinoma from other carcinomas. Hum Pathol 2016; 47:26-31. 22. Li X, Wetherilt CS, Krishnamurti U, et al. Stromal PD-L1 expression is associated with better disease-free survival in triple-negative breast cancer. Am J Clin Pathol 2016; 146:496-502. 23. Li XB, Krishnamurti U, Bhattarai S, et al. Biomarkers predicting pathologic complete response to neoadjuvant chemotherapy in breast cancer. Am J Clin Pathol 2016; 145:871-8. 24. Li X, Yang J, Peng L, et al. Triple-negative breast cancer has worse overall survival and cause-specific survival than nonetriple-negative breast cancer. Breast Cancer Res Treat 2017; 161:279-87. 25. Dave B, Gonzalez DD, Liu ZB, et al. Role of RPL39 in metaplastic breast cancer. J Natl Cancer Inst 2016; 109:djw292. 26. Giordano SH. A review of the diagnosis and management of male breast cancer. Oncologist 2005; 10:471-9. 27. Cloyd JM, Hernandez-Boussard T, Wapnir IL. Outcomes of partial mastectomy in male breast cancer patients: analysis of SEER, 1983-2009. Ann Surg Oncol 2013; 20:1545-50. 28. Bender PF, de Oliveira LL, Costa CR, et al. Men and women show similar survival rates after breast cancer. J Cancer Res Clin Oncol 2017; 143:563-71. 29. Javidiparsijani S, Rosen LE, Gattuso P. Male breast carcinoma: a clinical and pathological review. Int J Surg Pathol 2017; 25:200-5. 30. Miao H, Verkooijen HM, Chia KS, et al. Incidence and outcome of male breast cancer: an international population-based study. J Clin Oncol 2011; 29:4381-6. 31. Giordano SH, Buzdar AU, Smith TL, et al. Is breast cancer survival improving? Cancer 2004; 100:44-52. 32. Greif JM, Pezzi CM, Klimberg VS, et al. Gender differences in breast cancer: analysis of 13,000 breast cancers in men from the National Cancer Data Base. Ann Surg Oncol 2012; 19:3199-204.
Xiaoxian Li et al 33. Johansson I, Ringner M, Hedenfalk I. The landscape of candidate driver genes differs between male and FBC. PLoS One 2013; 8:e78299. 34. Johansson I, Nilsson C, Berglund P, et al. Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker. Breast Cancer Res 2012; 14:R31. 35. Johansson I, Lauss M, Holm K, et al. Genome methylation patterns in male breast cancer - identification of an epitype with hypermethylation of polycomb target genes. Mol Oncol 2015; 9:1565-79. 36. Fassan M, Baffa R, Palazzo JP, et al. MicroRNA expression profiling of male breast cancer. Breast Cancer Res 2009; 11:R58. 37. Lehmann U, Streichert T, Otto B, et al. Identification of differentially expressed microRNAs in human male breast cancer. BMC Cancer 2010; 10:109. 38. Shaaban AM, Ball GR, Brannan RA, et al. A comparative biomarker study of 514 matched cases of male and FBC reveals gender-specific biological differences. Breast Cancer Res Treat 2012; 133:949-58.
39. 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. 40. Kidwai N, Gong Y, Sun X, et al. Expression of androgen receptor and prostate-specific antigen in male breast carcinoma. Breast Cancer Res 2004; 6: R18-23. 41. Murphy CE, Carder PJ, Lansdown MR, et al. Steroid hormone receptor expression in male breast cancer. Eur J Surg Oncol 2006; 32:44-7. 42. Cardoso F, Bartlett J, Slaets L, et al. Characterization of male breast cancer: first results of the EORTC10085/TBCRC/BIG/NABCG International Male BC Program. Presented at the 2014 San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2014. 43. Grenader T, Yerushalmi R, Tokar M, et al. The 21-gene recurrence score assay (Oncotype DX) in estrogen receptor-positive male breast cancer: experience in an Israeli cohort. Oncology 2014; 87:1-6.
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Hormone Receptor-Positive Breast Cancer Has a Worse Prognosis in Male Than in Female Patients Xiaoxian Li,1 Jing Yang,2 Uma Krishnamurti,1 Lei Huo,3 Kevin C. Ward,2 Ruth O’Regan,4 Limin Peng2 Abstract Male breast carcinoma (MBC) has been thought to have similar survival as female breast carcinoma (FBC). We studies 172,847 FBC and 1442 MBC from the SEER data and found patients with MBC have worse survival than patients with FBC. Introduction: Male breast carcinoma (MBC) is treated similarly to female breast carcinoma (FBC), and similar survival rates for both have been assumed. We analyzed prognostic and clinicopathologic features of MBC to determine whether MBC subtypes differ from FBC subtypes. Patients and Methods: We reviewed data for 172,847 FBC and 1442 MBC patients from 2010 to 2012 from the National Cancer Institute Surveillance, Epidemiology, and End Results database. Carcinomas were subtyped according to hormone receptor (HR) and HER2 status as HR-positive (HRþ)/HER2, HRþ/ HER2þ, HR/HER2þ, and HR/HER2. Results: The overall incidence of MBC in all breast carcinoma cases was 0.8%. MBC was more frequently HRþ/HER2 than was FBC (78.3% vs. 67.4%) and less frequently HR/HER2 (2.1% vs. 10.9%). More MBC was staged as III or IV (24.9% vs. 17.2%). MBC had significantly worse overall survival (OS) than FBC (P < .0001). After adjustment for age, ethnicity, and tumor grade, stage I and II MBC had significantly worse OS time than stage-matched FBC (P ¼ .0011 for stage I, P ¼ .0229 for stage II). When stage- and subtype-matched patients were compared, MBC had significantly worse OS than FBC for stage I overall, for substages IA and IIB HRþ/HER2 carcinoma, and for stage III HRþ/HER2þ carcinoma. Furthermore, MBC patients with HRþ/HER2 T1aN0 carcinomas had worse OS than did FBC patients. Conclusion: Patients with MBC have worse survival than patients with FBC, especially for early-stage HRþ breast cancers. More studies are needed optimize treatment for MBC. Clinical Breast Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: Breast cancer prognosis, Breast cancer subtype, Male breast cancer, Matched stage and subtype, Prognosis
Introduction Unlike female breast carcinoma (FBC), the most common carcinoma in women, male breast carcinoma (MBC) is rare, comprising less than 1% of all breast carcinomas. However, the incidence of MBC has steadily increased. In 1991, it was estimated These data were presented, in part, at the United States and Canadian Academy of Pathology Annual Meeting, 2016, Seattle, WA. 1
Department of Department of Department of Houston, TX 4 Department of 2 3
Pathology and Laboratory Medicine Biostatistics and Bioinformatics, Emory University, Atlanta, GA Pathology, The University of Texas M.D. Anderson Cancer Center, Medicine, University of Wisconsin, Madison, WI
Submitted: Dec 2, 2016; Revised: Mar 2, 2017; Accepted: Mar 6, 2017 Address for correspondence: Xiaoxian Li, MD, PhD, Department of Pathology and Laboratory Medicine, Emory University, 1364 Clifton Rd, Suite H175, Atlanta, GA 30322 Fax: 404-727-3133; e-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2017.03.005
that 900 men in the United States had breast carcinoma; the number increased to 2240 by 2014.1,2 Risk factors associated with MBC include older patient age; a family history of breast cancer; the presence of breast cancer gene 2 mutations; exposure to hightemperature environments and exhaust fumes; and hyperestrogenism from Klinefelter syndrome, obesity, or excessive alcohol consumption.3-13 Factors associated with worse prognosis in MBC include axillary lymph node involvement, advanced stage, and long duration of symptoms.3-7,14-17 Recent research identified the prognostic potential of breast carcinoma subtypes and the differing biology and treatment responses among these subtypes. Molecular studies have classified breast carcinoma into luminal A, luminal B, HER2-enriched, basallike, and claudin-low subtypes.18,19 Clinical definitions of these subtypes are on the basis of the status of hormone receptors (HRs) and HER2: luminal A breast carcinoma is HR-positive (HRþ)/ HER2 with low Ki-67 score, luminal B is HRþ/HER2þ or HRþ
Clinical Breast Cancer Month 2017
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Male Breast Cancer with high Ki-67 score, HER2-enriched is HR/HER2þ, and basallike and claudin-low are HR/HER2. These subtypes differ in tumor biology and immunohistochemical profiles and in their responses to chemotherapy and targeted treatments.18-25 Most MBC is ductal type and estrogen receptor (ER)- and progesterone receptor-positive,4,6,9,26 and compared with FBC, MBC tends to have more lymph node involvement and to present at higher stages. However, the biology of MBC specifically has not been well studied, and the behavior of different subtypes in MBC is poorly understood. Overall, MBC is treated similarly to FBC, although a higher proportion of male than female patients tend to undergo total mastectomy.5,27 When adjusted for stage, MBC has been thought to have survival rates similar to FBC9,28,29; however, the rarity of MBC precludes large prospective clinical trials to compare survival rates and optimize therapy for MBC. To better characterize the biology and behavior of MBC, we analyzed prognostic and clinicopathologic features of MBC and compared the overall survival (OS) of patients with various MBC subtypes with the OS of patients with FBC subtypes. We used patient data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database and compared the clinical outcomes of FBC and MBC, matching characteristics such as tumor stage and subtype. Analysis indicated that some subtypes of MBC might carry a poorer prognosis than stage- and subtypematched FBC, suggesting that MBC might need to be treated differently than FBC.
Table 1 Clinicopathological Characteristics of SEER Database Male and Female Patients Diagnosed With Breast Carcinomas Between 2010 and 2012 Male (n [ 1442)
Characteristic Age at Diagnosis in Y
Female (n [ 172,847)
66.8 (12.8)
61.6 (13.7)
<50
152 (10.5)
35,535 (20.6)
50
1290 (89.5)
137,312 (79.4)
White
1155 (80.1)
138,065 (79.9)
Black
206 (14.3)
18,888 (10.9)
Others
74 (5.1)
14,804 (8.6)
Missing
7 (0.5)
1090 (0.6)
1
173 (12.0)
37,357 (21.6)
2
692 (48.0)
71,228 (41.2)
3
490 (34.0)
53,004 (30.7)
4
3 (0.2)
794 (0.5)
84 (5.8)
10,464 (6.0)
HRþ/HER2
1129 (78.3)
116,557 (67.4)
HRþ/HER2þ
134 (9.3)
16,040 (9.3)
Ethnicity
Tumor Grade
Missing Subtype
HR /HER2
þ
10 (0.7)
7119 (4.1)
31 (2.1)
18,905 (10.9)
138 (9.6)
14,226 (8.2)
524 (36.3)
87,906 (50.9)
481
83,902
HR/HER2 Missing Stage
Patients and Methods
I
Patient Information We searched the SEER database for all breast cancer patients diagnosed from 2010 to 2012 and identified 182,523 cases. Patients were excluded from our analysis if their disease was stage 0 or if information on stage was missing. Cases missing HR or HER2 status were included in the combined analysis of stages I to IV but excluded from analysis of subtypes. For cases that met our study criteria, we collected the following deidentified information: patient sex, age at diagnosis, ethnicity, and OS data; tumor Grade, HR and HER2 status; and staging on the basis of the Tumor, Node, Metastases and Roman Numeral staging system from the American Joint Committee on Cancer guidelines. We classified breast carcinomas according to HR and HER2 status into 4 subtypes: HRþ/HER2, HRþ/HER2þ, HR/ HER2þ, and HR/HER2. The follow-up time was up to 35 months with a median of 15 months for the entire cohort. For MBC cases, the mean follow-up time was 15.7 months with the median and interquantile range of 15 and 19 months, respectively. For the FBC cases, the mean follow-up time was 16 months with the median and interquantile range of 15 and 18 months, respectively.
IA IB
43
4004
560 (38.8)
55,203 (31.9)
IIA
368
36,819
IIB
192
18,384
III
253 (17.6)
19,684 (11.4)
IV
105 (7.3)
10,054 (5.8)
II
Age at diagnosis is presented as mean (SD), and other variables are presented as n (%). Each characteristic demonstrated statistically significant differences between breast cancer cases in male and female patients, showing P < .0001 in a 2-sample t test for age at diagnosis and c2 test for other characteristics. Cases missing characteristic data were not considered in analysis of that characteristic. Tumor Grade 1 was considered low grade and tumor Grades 2 to 4 were considered high grade; tumor Grade 4 was defined according to SEER as undifferentiated or anaplastic. Abbreviations: HR ¼ hormone receptor; SEER ¼ Surveillance, Epidemiology, and End Results.
Table 2 Univariate Analysis for Significant Predictors of Overall Survival in Breast Cancer Predictor
Hazard Ratio
95% CI
P
2.12
1.99-2.25
<.0001 <.0001
Age 50 vs. <50 Ethnicity
Statistical Analysis
2
-
Summary statistics were provided for demographic variables (patient age at diagnosis and ethnicity) and other potential predictors of survival (breast cancer stage, HR, and HER2 subtype, and tumor Grade) for male and female patients. Their differences between the male and female patient groups were assessed using the
Clinical Breast Cancer Month 2017
White vs. black
0.59
0.56-0.62
Others vs. black
0.38
0.35-0.42
2.18
2.04-2.33
Tumor Grade 2/3/4 vs. 1 P values were for log rank tests.
<.0001
Xiaoxian Li et al
1.00
Figure 1 Overall Survival of Male and Female Patients With Breast Cancer When All Cases Were Combined. Survival Probability With Male Breast Cancer Was Significantly Lower Than That With FBCs
0.90 0.85
Survival Probability
0.95
Log rank test: P < .0001
0.80
Male Female
0
5
10
15
20
25
30
35
Months
2-sample t test for continuous variables and the c2 test for categorical variables. All analyses were on the basis of available cases and performed using SAS version 9.4 software (SAS Institute, Inc, Cary, NC). The OS times of patients with MBC and FBC in all combined stages (I-IV), stage-matched subgroups, and subtype-matched subgroups were summarized using KaplaneMeier survival curves and compared using log rank tests. A univariate Cox proportional hazard model was conducted separately for sex, age, ethnicity, and tumor Grade. We further conducted multivariate Cox regression analyses to assess the effect of sex on OS while adjusting for the potential predictors including age, ethnicity, and tumor Grade for all patients or patient groups stratified according to disease stage and/or breast cancer subtype. HRs for the sex effect (MBC vs. FBC) and their associated 95% confidence intervals (CIs) were obtained from the Cox regression analysis. A P value below .05 was regarded as statistically significant. Patient age as well as tumor Grade were defined as binary variables: age as younger than 50 years (< 50) or 50 years or older ( 50), and tumor Grade as low (Grade 1) or high (Grade 2, 3, or 4; Grade 4 was defined according to SEER as undifferentiated or anaplastic carcinoma). For ethnicity, the categories American Indian/Alaska Native and Asian/Pacific Islander were combined as “others.” Because there were few HR/HER2þ and HR/HER2 MBC cases, detailed OS analysis at each stage was performed only
for HRþ/HER2þ and HRþ/HER2 carcinomas. Additionally, to examine whether at the lowest stage MBC had a worse prognosis than FBC, we compared OS times of stages T1aN0 and T1bN0 MBCs with those of FBCs. Only HRþ/HER2 carcinomas had sufficient data to enable this comparison.
Results Clinicopathological Characteristics of Patients Of the 182,523 cases originally identified from the SEER database search, cases of 172,847 FBCs and 1442 MBCs diagnosed from 2010 to 2012 met our study criteria, and these data were included in our analysis. Clinicopathologic information is summarized in Table 1. MBCs accounted for 0.8% of all breast carcinomas. Compared with FBC patients, MBC patients were significantly older (mean 66.8 vs. 61.6 years old; P < .0001), were more likely to be African-American (14.3% vs. 10.9%; P < .0001), had fewer Grade 1 carcinomas (12% vs. 21.6%; P < .0001), and had higher stage carcinoma (stages III and IV: 24.9% vs. 17.2%; P < .0001). MBC was more likely to be HRþ/HER2 than was FBC (78.3% vs. 67.4%; P < .0001) and less likely to be HR/ HER2 (2.1% vs. 10.9%; P < .0001). Log rank tests and a univariate Cox model showed that patient age, ethnicity, and tumor Grade significantly affected OS. Factors associated with a worse prognosis were age 50 years or older, African-American ethnicity, and high tumor Grade (Table 2).
Clinical Breast Cancer Month 2017
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Male Breast Cancer Figure 2 Overall Survival of Male and Female Patients With Stage (A) I, (B) II, (C) III, and (D) IV Breast Cancer. The Difference in Overall Survival Between Male and Female Patients Was Significant in Stages I and II But Not in Stage III or IV
B
5
10
0.8
1.0 0
Male Female
0.4
Male Female
Log rank test: P = .0007
0.6
Survival Probability
0.8 0.6
Log rank test: P = .0004
0.4
Survival Probability
1.0
A
15
20
25
30
35
0
5
10
Months
30
35
30
35
1.0 5
10
15
20
25
30
35
Months
Male Breast Carcinoma Patients Had Worse OS Than FBC Patients Had in Stage I, Stage II, and All Stages of Disease Combined Of the 1442 MBC cases, 524 were stage I, 560 were stage II, 253 were stage III, and 105 were stage IV (Table 1). When cases in all stages were combined, MBC patients had a significantly worse OS than did FBC patients (P < .0001; Figure 1). The OS (95% CI) at 35 months was 0.82 (0.78-0.86) for MBC patients and 0.888 (0.88-0.89) for FBC. Comparing MBC with FBC at each stage, MBC had significantly worse OS in stage I (P ¼ .0004) and stage II (P ¼ .0007) but not in stages III and IV (Figure 2). After adjustment for age, ethnicity, and tumor Grade, MBC patients still had significantly worse OS than FBC patients for all stages combined (hazard ratio: 1.35; 95% CI, 1.11-1.64), for stage I (hazard ratio, 2.02; 95% CI, 1.33-3.08), and for stage II (hazard ratio, 1.47; 95% CI, 1.06-2.06), but not in stages III and IV (Table 3). This suggests that the observed worse OS in MBC is not fully explained by the older age at the time of diagnosis of MBC (compared with FBC), and sex has independent prognosis power on
Clinical Breast Cancer Month 2017
0.8
Male Female
0.4
Male Female
Log rank test: P = .22
0.6
Survival Probability
1.0 0.8 0.6
Log rank test: P = .71
0.4
Survival Probability
25
D
0
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20
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C
4
15
0
5
10
15
20
25
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the OS of breast cancer. Detailed multivariate analysis is provided in Table 4.
Hormone Receptor-Positive/HER2 MBC Patients Had Worse OS in Stages I, IA, and IIB Than FBC Patients But Better OS in Stage IV Than FBC Patients
Within the HRþ/HER2 MBC subtype, 430 cases were stage I (390 stage IA, 40 stage IB), 440 stage II (296 stage IIA, 144 stage IIB), 199 stage III, and 60 stage IV (Table 5). Compared with FBC, the MBC HRþ/HER2 subtype had a significantly worse OS for stage I (P ¼ .0011) and stage II (P ¼ .0174) but not for stages III and IV (Figure 3). After adjustment for age, ethnicity, and tumor Grade, MBC patients had a worse OS for stage I compared with FBC patients, but MBC patients had a better OS for stage IV (Table 3). The HRþ/HER2 MBC subtype patients had significantly worse OS time than FBC patients had in stages IA (P ¼ .0003) and IIB (P < .0001) but not in stage IIA (P ¼ .95; Figure 4A-C). This trend was also true for patient survival after adjusting for age, ethnicity, and tumor Grade (Table 3).
Xiaoxian Li et al Table 3 Hazard Ratio of Overall Survival in MBC Compared With FBC According to Tumor Stage and Subtype, Adjusted for Age, Ethnicity, and Tumor Grade
T1bN0 stages. In these 2 tumor stages, only the HRþ/HER2 subtype had enough MBC cases for meaningful analysis. In the HRþ/HER2 subtype, MBC had 37 T1aN0 and 67 T1bN0 cases (Table 5). Compared with FBC, the MBC HRþ/HER2 subtype had significantly worse OS in the T1aN0 cases (P ¼ .0219) but not in the T1bN0 cases (P ¼ .76) (Figure 6). HRþ/HER2 T1aN0 MBC still had worse OS after adjusting for age, ethnicity, and tumor Grade (Table 3).
Hazard Ratio
95% CI
P
All Cases Combined
1.35
1.11-1.64
.0023a
Stage I
2.02
1.33-3.08
.0011a
Stage II
1.47
1.06-2.06
.0229a
Stage III
0.87
0.57-1.31
.50
Discussion
Stage IV
0.75
0.51-1.11
.16
Stage I
2.06
1.27-3.32
.0032a
Stage II
1.40
0.92-2.13
.12
Stage III
1.00
0.60-1.68
.99
Stage IV
0.50
0.27-0.93
.0290a
IA
2.24
1.39-3.62
.0010a
IB
e
e
e
IIA
0.89
0.46-1.71
.72
IIB
2.35
1.35-4.09
.0025a
T1aN0
5.04
1.24-20.49
.0239a
T1bN0
0.65
0.09-4.66
.67
Stage I
1.29
0.18-9.22
.80
Stage II
2.31
0.95-5.65
.0658
Stage III
3.48
1.60-7.54
.0016a
Stage IV
1.21
0.50-2.93
.68
IA
1.44
0.20-10.35
.72
IB
e
e
IIA
1.96
0.48-7.96
.35
IIB
2.90
0.90-9.41
.0756
To our knowledge, this is the first study to report that MBC has a worse prognosis than FBC for different subtypes and stages. Our analysis showed that compared with FBC, MBC was more frequently HRþ, more likely to be at a higher stage, and more likely to have significantly worse OS for all stages combined. After adjustment for age, ethnicity, and tumor grade, early stage MBC patients had significantly worse OS than stage-matched FBC patients. In a comparison of stage-matched and subtype-matched patients, MBC patients had significantly worse OS than FBC patients for multiple tumor subtypes and stages. Thus, some MBCs, particularly early stage HRþ MBC might have worse clinical outcomes than FBCs with the same stage. Male breast carcinoma has been considered similar to FBC, and MBC and FBC are currently treated similarly.3,5-8 Previously, reports of shorter OS in MBC attributed the change to older patient age and more advanced stages of disease.12,30,31 Miao et al reported that MBC had later onset of disease and more advanced disease than FBC. After adjustment for age, stage, and treatment, MBC patients had a significantly better relative survival rate than FBC patients with a relative excess risk of 0.78 (95% CI, 0.62-0.97).30 Giordano et al reported that men with breast cancer had a higher median age and more advanced stage at the time of diagnosis than women and that the MBC patients were more likely to be ERþ than were FBC patients. In multivariate analysis, these investigators reported that larger tumor size and lymph node involvement in MBC were associated with worse survival; that tumor Grade and HR status did not independently influence survival; and that within the same breast cancer stage, relative survival rates for men and women were similar.31 Greif et al also concluded that “breast cancer in men and women appears more alike than different.”32 Consistent with these studies, we found that MBC was diagnosed at an older age and at a higher stage than FBC. We found that compared with FBC, MBC had higher tumor Grade and was more frequently HRþ. In terms of OS in MBC versus FBC, our findings differed from those of the existing literature. The National Cancer Institute Physician Data Query noted that survival for men with breast cancer is similar to survival for women with breast cancer. Cutuli et al reported similar prognosis for male and FBC patients.6 In contrast to this report and other studies, we report herein that MBC had worse OS than FBC overall and within some stages and subtypes. Our study thoroughly compared the prognosis between MBC and FBC in matched stages, and we showed that patients with the HRþ/HER2 subtype of MBC had a worse OS time in early stages (stage IA and stage IIB), including for T1aN0 cancers, than female HRþ/HER2 breast cancers. For HRþ/HER2þ cancers, MBC had a worse OS for stage III cancer. It should be noted that although male patients were diagnosed with breast cancer at older age, such a
HRþ/HER2
HRþ/HER2þ
e
For HRþ/HER2 stage IB MBC patients, there were no death records and for HR2þ/HER2þ stage IB MBC patients, there were only 2 cases. Abbreviations: FBC ¼ female breast carcinoma; HR ¼ hormone receptor; MBC ¼ male breast cancer. a Statistically significant.
Hormone Receptor-Positive/HER2þ MBC Patients Had Worse OS in Stage III Than Did FBC Patients
Within the HRþ/HER2þ MBC subtype, 37 cases were stage I (35 stage IA, 2 stage IB), 52 stage II (27 stage IIA, 25 stage IIB), 27 stage III, and 18 stage IV (Table 5). Compared with FBC, the HRþ/HER2þ MBC subtype had significantly worse OS time for stages II (P ¼ .0098) and III (P < .0001) but not for stages I and IV (Figure 5). After adjustment for age, ethnicity, and tumor Grade, the HRþ/HER2þ MBC subtype had a significantly worse OS time than FBC for stage III carcinoma but stage II was no longer significant (Table 3). The HRþ/HER2þ MBC subtype had significantly worse OS time than FBC for stage IIB (P ¼ .0061) but not for stages IA and IIA (Figure 4D-F). This significance disappeared after adjustment for age, ethnicity, and tumor Grade (Table 3).
Male Breast Carcinoma Patients Had Worse OS in HRþ/ HER2 T1aN0 Carcinoma Than FBC Patients To examine whether MBC had a worse prognosis than FBC in the earliest stages, we compared MBC with FBC in T1aN0 and
Clinical Breast Cancer Month 2017
-5
6
Age (‡ 50 vs. < 50 Y)
MBC vs. FBC
All Cases Combined
Ethnicity (White vs. Black)
Ethnicity (Others vs. Black)
Tumor Grade (High vs. Low)
Hazard Ratio (95% CI)
P
Hazard Ratio (95% CI)
P
Hazard Ratio (95% CI)
P
Hazard Ratio (95% CI)
P
Hazard Ratio (95% CI)
P
1.35 (1.11-1.64)
.0023
2.16 (2.02-2.31)
<.0001
0.60 (0.57-0.64)
<.0001
0.41 (0.37-0.46)
<.0001
2.23 (2.09-2.38)
<.0001 <.0001
Stage I
2.02 (1.33-3.08)
.0011
4.81 (3.75-6.18)
<.0001
0.81 (0.69-0.94)
<.0001
0.50 (0.38-0.65)
<.0001
1.24 (1.11-1.38)
Stage II
1.47 (1.06-2.06)
.0229
3.09 (2.69-3.55)
<.0001
0.75 (0.67-0.84)
<.0001
0.45 (0.36-0.55)
<.0001
1.26 (1.11-1.42)
.0004
Stage III
0.87 (0.57-1.31)
.5
2.07 (1.82-2.36)
<.0001
0.64 (0.57-0.72)
<.0001
0.40 (0.31-0.51)
<.0001
1.83 (1.47-2.27)
<.0001
0.75 (0.51-1.11)
.16
1.88 (1.69-2.10)
<.0001
0.70 (0.64-0.77)
<.0001
0.63 (0.53-0.75)
<.0001
1.61 (1.37-1.90)
<.0001
Stage IV þ
HR /HER2 Stage I
2.06 (1.27-3.32)
.0032
6.70 (4.60-9.75)
<.0001
0.80 (0.65-0.98)
.03
0.56 (0.40-0.77)
.0005
1.12 (0.99-1.26)
.07
Stage II
1.4 (0.92-2.13)
.12
4.03 (3.21-5.06)
<.0001
0.80 (0.67-0.95)
.0102
0.45 (0.33-0.62)
<.0001
1.09 (0.95-1.27)
.22
Stage III
1.00 (0.60-1.68)
.99
2.50 (2.00-3.12)
<.0001
0.66 (0.55-0.81)
<.0001
0.40 (0.28-0.59)
<.0001
1.34 (1.05-1.71)
.02
Stage IV
0.50 (0.27-0.93)
.0290
2.10 (1.76-2.50)
<.0001
0.72 (0.62-0.83)
<.0001
0.57 (0.44-0.76)
<.0001
1.59 (1.30-1.95)
<.0001
.0001
1.12 (0.99-1.27)
.07
IA
2.24 (1.39-3.62)
.0010
6.98 (4.70-10.38)
<.0001
0.77 (0.62-0.95)
.014
0.51 (0.36-0.72)
IB
e
e
e
e
e
e
e
e
e
e
IIA
0.89 (0.46-1.71)
4.23 (3.14-5.70)
<.0001
0.80 (0.64-1.00)
0.55 (0.39-0.79)
.001
1.03 (0.87-1.22)
.76
<.0001
0.79 (0.59-1.04)
.1
0.27 (0.14-0.51)
<.0001
1.26 (0.94-1.68)
.12
.0009
0.60 (0.34-1.05)
.07
0.51 (0.21-1.21)
.13
1.05 (0.73-1.50)
.8
<.0001
0.72 (0.49-1.05)
.09
0.53 (0.29-0.97)
.0391
1.16 (0.09-4.66)
.19
.72
IIB
2.35 (1.35-4.09)
.0025
3.80 (2.68-5.41)
T1aN0
5.04 (1.24-20.49)
.0239
6.94 (2.21-21.86)
T1bN0
0.65 (0.09-4.66)
.67
4.55 (2.43-8.55)
.0548
HRþ/HER2þ Stage I
1.29 (0.18-9.22)
.8
8.65 (3.19-23.46)
<.0001
0.73 (0.43-1.24)
.24
0.48 (0.20-1.17)
.11
1.21 (0.68-2.16)
.52
Stage II
2.31 (0.95-5.65)
.07
9.65 (4.74-19.64)
<.0001
0.63 (0.42-0.94)
.0245
0.33 (0.16-0.70)
.037
0.65 (0.37-1.12)
.12
Stage III
3.48 (1.60-7.54)
.0016
2.33 (1.48-3.65)
.0002
0.85 (0.53-1.36)
.49
0.55 (0.23-1.31)
.18
0.72 (0.34-1.55)
.4
Stage IV
1.21 (0.50-2.93)
.68
2.23 (1.62-3.06)
<.0001
0.76 (0.57-1.03)
.07
0.87 (0.54-1.40)
.56
0.96 (0.45-2.03)
.91
IA
1.44 (0.20-10.35)
.72
7.99 (2.94-21.68)
<.0001
0.77 (0.44-1.35)
.35
0.54 (0.22-1.33)
.18
1.11 (0.62-1.99)
.72
IB
e
e
e
e
e
e
e
e
IIA
1.96 (0.48-7.96)
.35
e
9.83 (4.01-24.09)
<.0001
0.66 (0.40-1.10)
.11
0.26 (0.10-0.70)
.0075
0.68 (0.37-1.28)
.23
IIB
2.9 (0.90-9.41)
.08
9.02 (2.81-29.03)
.0002
0.54 (0.28-1.07)
.08
0.48 (0.15-1.53)
.22
0.64 (0.20-2.07)
.46
For each tumor stage and subtype, sex, age, ethnicity, and tumor grade were included in the multivariate model. Abbreviations: FBC ¼ female breast carcinoma; MBC ¼ male breast carcinoma.
e
Male Breast Cancer
Clinical Breast Cancer Month 2017
Table 4 Detailed Multivariate Analysis Results for Overall Survival According to Tumor Stage and Subtype
Xiaoxian Li et al Table 5 Number of Breast Carcinoma Cases in 4 Subtypes According to Stage and Sex Stage
HRD/HER2L
Sex
I
M F M F M F M F M F M F M F M F M F M F
IA IB II IIA IIB III IV T1aN0 T1bN0
430 64,926 390 61,847 40 3079 440 35,152 296 23,703 144 11,449 199 11,445 60 5034 37 9117 67 20,527
HRD/HER2D
(90.1) (80.4) (89.7) (80.4) (95.2) (82.0) (87.0) (68.4) (89.2) (69.1) (82.8) (67.1) (85.4) (62.5) (68.2) (61.4) (92.5) (77.7) (91.8) (84.4)
37 6426 35 6097 2 329 52 5839 27 3630 25 2209 27 2489 18 1286 1 1155 3 1554
HRL/HER2D
(7.8) (8.0) (8.0) (7.9) (4.8) (8.8) (10.3) (11.4) (8.1) (10.6) (14.4) (12.9) (11.6) (13.6) (20.1) (15.7) (2.5) (9.8) (4.1) (6.4)
1 2434 1 2320 0 114 4 2522 3 1558 1 964 2 1469 3 694 0 670 1 522
HRL/HER2L
(0.0) (3.0) (0.0) (3.0) (0.0) (3.0) (0.8) (4.9) (0.9) (4.5) (0.6) (5.6) (0.9) (8.0) (3.4) (8.5) (0.0) (5.7) (1.4) (2.1)
9 6938 9 6703 0 235 10 7863 6 5419 4 2444 5 2922 7 1182 2 796 2 1707
(1.9) (8.6) (2.1) (8.7) (0.0) (6.3) (2.0) (15.3) (1.8) (15.8) (2.3) (14.3) (2.1) (15.9) (8.0) (14.4) (5.0) (6.8) (2.7) (7.0)
Total 477 80,724 435 76,967 42 3757 506 51,376 332 34,310 174 17,066 233 18,325 88 8196 40 11,738 73 24,310
Data are expressed as absolute number (%). Abbreviations: F ¼ female; HR ¼ hormone receptor; M ¼ male.
0.6 0
5
10
Log rank test: P = .0174
Male Female
0.4
Male Female
0.8
Log rank test: P = .0011
0.6
Survival Probability
0.8
1.0
B
0.4
Survival Probability
A
1.0
Figure 3 Overall Survival of Male and Female Patients With Hormone Receptor-Positive and HER2L Breast Cancer in Stage (A) I, (B) II, (C) III, and (D) IV. This Subtype Showed a Significantly Worse Survival in Male Than in Female Patients in Stages I and II But Not in Stage III or IV
15
20
25
30
35
0
5
10
0.6
10
15
20
Months
35
Log rank test: P = .14
Male Female
0.4
Male Female
5
30
0.8
Log rank test: P = .40
0
25
0.6
Survival Probability
0.8
1.0
D
0.4
Survival Probability
C
20
Months
1.0
Months
15
25
30
35
0
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10
15
20
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Clinical Breast Cancer Month 2017
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Male Breast Cancer Figure 4 Overall Survival of Male and Female Patients With (A-C) Hormone Receptor (HR)-Positive and HER2L Breast Cancer, and (D-F) HRD/HER2D Breast Cancer at Stages IA, IIA, and IIB. (A-C) Of Patients With HRD/HER2L Tumors, Overall Survival Was Significantly Worse in Male Than in Female Patients in Stages IA and IIB but not in Stage IIA. (D-F) Of Patients With HRD/ HER2D Tumors, Overall Survival Was Significantly Worse in Male Than Female Patients Only in Stage IIB
Male Female
0
5
1.0 0.6
0.8
Log rank test: P = .70
Male Female
0.4
0.85
Log rank test: P = .0003
Survival Probability
1.00
D
0.70
Survival Probability
A
10 15 20 25 30 35
0
5
10 15 20 25 30 35
Months
0.70
Male Female
0
5
1.0 0.6
0.8
Log rank test: P = .23
Male Female
0.4
1.00 0.85
Log rank test: P = .95
Survival Probability
E
B Survival Probability
Months
10 15 20 25 30 35
0
5
10 15 20 25 30 35
Months
0
5
10 15 20 25 30 35 Months
-
difference did not contribute to the worse OS in our multivariate analysis. These findings suggest that MBC and FBC might need to be treated differently in clinical settings and that early-stage HRþ MBCs in particular might require more aggressive treatment than has been typically recommended. Although treatment strategies for male patients with breast cancer are on the basis of predictive markers developed for FBC, our findings agree with other studies that MBC and FBC might have underlying differences in tumor biology. Some studies have reported genetic differences between MBC and FBC. When Johansson et al analyzed gene expression data and array comparative genomic hybridization data, they identified 30 driver genes in MBC and 67 in FBC. Among these driver genes, only 2 genes,
Clinical Breast Cancer Month 2017
1.0 0.8 0.6
Log rank test: P = .0061 Male Female
0.4
1.00 0.85
Male Female
0.70
Survival Probability
Log rank test: P < .0001
Survival Probability
F
C
8
Months
0
5
10 15 20 25 30 35 Months
TATA-box binding protein associated factor 4 and cluster of differentiation 164, were common in MBC and FBC.33 Gene microarray analysis of MBC revealed 2 unique subtypes, luminal M1 (approximately 70% of MBC) and luminal M2 (approximately 30% of MBC).34,35 These 2 subtypes are different from the intrinsic subtypes in FBC in terms of gene expression signature and methylation pattern, although there might be some overlap. The luminal M1 subtype showed a low score for the ER module, despite that most carcinomas in this subtype are ERþ in immunohistochemical study. This finding suggests that the ER pathway is less active in ERþ MBCs.34 In addition, studies have shown that microRNA expression profiles differ between MBC and FBC.36,37
Xiaoxian Li et al
0.6 0
5
10
Log rank test: P = .0098
Male Female
0.4
Male Female
0.8
Log rank test: P = .75
0.6
Survival Probability
0.8
1.0
B
0.4
Survival Probability
A
1.0
Figure 5 Overall Survival of Male and Female Patients With Hormone Receptor (HR)-Positive and HER2D Breast Cancer in Stages (A) I, (B) II, (C) III, and (D) IV. Male Breast Carcinoma Patients With This Subtype Experienced Significantly Worse Survival in Stages II and III Than Female Breast Carcinoma Patients
15
20
25
30
35
0
5
10
Months
20
25
30
35
Months
C
0.6 0
5
10
1.0
Male Female
0.4
Male Female
0.8
Log rank test: P < .0001
Log rank test: P = .30
0.6
Survival Probability
0.8
1.0
D
0.4
Survival Probability
15
15
20
25
30
35
0
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Among the studies that have proposed differences in the ER pathway of FBC and MBC, Shaaban et al reported that although ERa and the progesterone receptor clustered together in FBC, ERa clustered with ERb and the androgen receptor in MBCs.38 In other studies, androgen receptor positivity has been reported in 34% to 95% of MBCs.39-41 Taken together, although these data indicate that most MBCs are ERþ in immunohistochemistry, MBC might be only weakly driven by the ER pathway and more strongly driven by other pathways such as the androgen receptor pathway. It is possible that more HRþ MBC patients harbor intrinsic resistance to endocrine therapy, compared with HRþ FBC patients. Because we did not have access to Ki-67 score or the ability to do molecularly profiling, we were unable to definitively differentiate luminal A cancers, which are generally sensitive to endocrine therapy, from luminal B cancers in this study. However, a large international analysis showed that most MBCs are luminal A cancers.42 Additionally, one study showed similar Oncotype DX (Genomic Health, Redwood City, CA) recurrence score distribution in MBC compared to FBC.43 The main limitation of our study was the relatively short followup of patients’ clinical outcomes. ERþ breast cancers tend to recur
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and metastasize late. Longer follow-up is needed to draw conclusions about long-term survival. Nevertheless, our study did show at least worse short-term OS time in MBC than in FBC patients. Treatment information is not available from the SEER database. Although currently MBC patients are treated the same as FBC patients, missing the treatment information is another limitation of this study.
Conclusion To our knowledge, we are the first to report that HRþ MBC patients had a worse OS time than FBC patients in early stage cancers. The worse OS time was even seen in HRþ/HER2 T1aN0 cancers, which suggests that MBC needs more aggressive treatment in HRþ early stage breast cancers. MBC might be genetically different from FBC or might have an altered ER pathway that responds differently to hormone therapy than does FBC, which could at least partially explain the inferior prognosis of HRþ MBC. Therefore, treatment strategies for MBC should be tailored differently from treatment strategies for FBC. Further research is needed to understand the pathobiology of MBC to advance the development of optimal treatments.
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Male Breast Cancer Figure 6 Overall Survival of Male and Female Patients With Hormone Receptor (HR)-Positive and HER2L Breast Carcinoma in Stages (A) T1aN0 and (B) T1bN0. Only Within T1aN0 Cases Did Male Patients Have Significantly Worse Survival Than Female Patients
Survival Probability
Log rank test: P = .0219
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Clinical Practice Points MBC has been thought to have similar survival as FBC. We studies 172,847 FBC and 1442 MBC from the SEER data
and found patients with MBC have worse survival than patients with FBC. Patients with MBC may need different treatments than patients with FBC.
Acknowledgments The authors thank Diane Hackett and Katelyn Werner (Scientific Publications, M.D. Anderson Cancer Center) for thorough editing of the manuscript.
Disclosure The authors have stated that they have no conflicts of interest.
References
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B 0.90 0.92 0.94 0.96 0.98 1.00
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