- Email: [email protected]
Treatment Outcomes and Prognostic Factors in Male Patients With Stage IV Breast Cancer: A Population-based Study
Original Study
Treatment Outcomes and Prognostic Factors in Male Patients With Stage IV Breast Cancer: A Population-based Study Wei Chen,1,2 Ying Huang,2,3 Gary D. Lewis,2,4 Sean S. Szeja,2,4 Sandra S. Hatch,4 Andrew Farach,2 Darlene Miltenburg,5 E. Brian Butler,2 Jenny C. Chang,6 Bin S. Teh2 Abstract Male breast cancer is a rare disease, and limited data exists regarding metastatic male breast cancer. To better characterize this population, we used the Surveillance, Epidemiology, and End Results database to examine prognostic factors that affected survival outcomes. On multivariate analysis, patients with progesterone receptor-positive disease, younger age (£ 65 years), tumor size £ 2 cm, or who had undergone surgery of the primary tumor had better overall survival and cause-specific survival. Purpose: Male breast cancer (MBC) represents < 1% of breast cancer patients, and limited data exists regarding metastatic MBC. To better characterize this patient subset, we performed a population-based study examining prognostic factors among patients with stage IV MBC. Methods: Patients with stage IV MBC diagnosed between 1988 and 2012 were selected from the Surveillance, Epidemiology, and End Results database. Prognostic factors for overall survival (OS) and cause-specific survival (CSS) were evaluated. Results: Overall, 394 patients had metastatic disease meeting inclusion criteria. The median follow-up was 21 months. The 5-year OS and CSS rates were 21.1% and 38.3%, respectively. Of those with known progesterone receptor (PR) status, 52% were PR-positive, which was associated with better OS (P < .001) and CSS (P ¼ .003). Overall, 197 patients (50%) received surgery for the primary tumor, and 197 (50%) did not. Patients undergoing surgery had longer median CSS than those who did not (36 vs. 21 months; P < .001). Additional factors that correlated with prolonged OS and CSS were smaller tumor size ( 2 cm; P < .05) and younger age ( 65 years; P < .05). In multivariate analysis, smaller tumor size, PR-positivity, younger age, and resection of the primary tumor were associated with longer OS and CSS (P < .05). Conclusions: Although stage IV MBC has poor OS and CSS, patients with PR-positive disease, younger age ( 65 years), tumor size 2 cm, or who undergo surgery of the primary tumor have better OS and CSS. This is the largest study of stage IV MBC to date, and these findings address some of the questions regarding this rare presentation of breast cancer. Clinical Breast Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: Male breast cancer, Metastatic, Prognosis, SEER, Surgery
Introduction Male breast cancer (MBC) represents < 1% of all patients with breast cancer, with an estimated incidence of 2600 cases a year.1 Although MBC shares some features with female breast cancer,
W.C. and Y.H. contributed equally to this work as first authors.
there are significant differences in the presentation, epidemiology, and prognosis between the 2 disease entities. Several studies have suggested that men with breast cancer have a worse prognosis compared with women with breast cancer,2 possibly because of
5
Department of Surgery, Texas Women’s Comprehensive Breast Center, Houston, TX Department of Medicine, Houston Methodist Hospital, Houston, TX
6
1
Department of General Surgery, Guangdong General Hospital, Guangzhou, China Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China 4 Department of Radiation Oncology, University of Texas Medical Branch Galveston, Galveston, TX 2
Submitted: Apr 2, 2017; Revised: Jun 15, 2017; Accepted: Jul 9, 2017
3
1526-8209/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2017.07.005
Address for correspondence: Bin S. Teh, MD, Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX 77030 E-mail contact: [email protected]
Clinical Breast Cancer Month 2017
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Treatment Outcomes in Stage IV Male Breast Cancer delayed diagnosis,3 differences in age and stage at diagnosis,4-7 or even differences in cancer cell biology.8,9 However, further attempts to characterize and describe MBC in the context of female breast cancer are limited by the rarity of the disease. National database and institutional-based data suggest that MBC patients with older age, higher grade disease, advanced stage, lack of estrogen receptor (ER)/progesterone receptor (PR) positivity, and BRCA mutation have a worse prognosis.7,10,11 In addition, men with breast cancer who do receive therapies standard in women (ie, mastectomy, radiotherapy, endocrine therapy, or antieHer2neu therapy) have better outcomes.11 However, there is limited data on patients with stage IV MBC. This is a small subset of a rare disease, and only single-institution studies with low patient numbers describe this population.12,13 In order to better characterize this disease, we performed a population-based study examining prognostic factors for patients with stage IV MBC.
Methods Patient Selection Data was obtained from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, using the 18 registry (1973-2012) database. SEER currently collects and publishes cancer incidence and survival data from populationbased cancer registries covering approximately 28% of the United States population. Data on tumor location, grade, and histology were recorded according to the International Classification of Diseases for Oncology Version 3. Male patients with stage IV breast cancer diagnosed between 1988 and 2012 were selected from the SEER database. Patient characteristics that were retrieved and recorded included race, age at diagnosis, and year of diagnosis. Tumor characteristics that were retrieved and recorded included laterality, histologic grade, tumor size, regional lymph node status, American Joint Committee on Cancer stage, ER status, PR status, and human epidermal growth factor receptor 2 (Her2) status. The SEER program began collecting data on ER and PR status in 1990 and started collecting HER2-neu data in 2010. The inclusion criteria used in the final analysis included male gender, unilateral breast cancer, invasive breast cancer (International Classification of Diseases for Oncology Version 3 site code C50.0-C50.9) as the first cancer diagnosis, diagnosis not obtained from a death certificate or autopsy, only 1 primary site, American Joint Committee on Cancer stage IV, known survival in months, and vital status.
receptor status. All tests were 2-sided; P < .05 was considered significant.
Results Patient Characteristics From 1988 to 2012, 8292 men with stage IV invasive breast cancer were recorded. Of these, 394 met inclusion criteria (Figure 1). The majority (71.8%) of patients were of Caucasian descent. The largest percentage (38.6%) of patients had grade III disease. In addition to distant metastatic disease, 62.5% of patients had nodal involvement. Overall, 66.8% had ER-positive (ERþ) disease and 52% had PR-positive (PRþ) disease. Unfortunately, Her2-neu status was unavailable in the majority of patients (82.2%) as SEER began collecting this data in 2010. Of the 70 patients with known Her2 status, only 14 were Her2 positive (Her2þ). Full patient characteristics are summarized in Table 1. In terms of type of surgery performed, modified radical mastectomy was performed the most (47.2% of patients). The frequencies of different surgery types are included in Table 2.
Survival Outcomes The median follow-up was 21 months (range, 1-170 months). Over the study period, 311 deaths occurred, 243 deaths of which were owing to breast cancer. Median OS was 21 months. The 5-year OS and CSS for stage IV MBC patients was 21.1% and 38.3%, respectively. The 5-year OS and CSS for patients who were ERþ/PRþ was 22.4% and 26.4%, respectively. The 5-year OS and CSS for ERþ/PR-negative (PR) patients was 12.4% and 13.8%, respectively. There was not sufficient data to determine the OS or CSS for patients who were ER-negative (ER)/PR and Her2þ or for patients with triple-negative disease.
Prognostic Factors
Of those with known PR status, 52% were PRþ, which was associated with better OS (P < .001) and CSS (P ¼ .003)
Figure 1 Diagram of Analytic Cohort for Survival Analysis
Statistical Analyses
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All statistical calculations were performed using PASW Statistics 22.0 (SPSS, Chicago, IL) and STATA (version 12.0, College Station, TX). Survival rates were estimated using the Kaplan-Meier method, and significance was determined using the log-rank test (P < .05).14 Multivariate analysis with the Cox proportional hazards model was performed to determine prognostic factors for overall survival (OS) and cause-specific survival (CSS).15 OS was defined as the time from breast cancer diagnosis to the time of death or last follow-up. CSS was measured from the date of diagnosis to either the date of death owing to breast cancer or the date of last contact. Factors analyzed in the multivariable analysis included age at diagnosis, ethnicity, grade, stage, surgery, tumor size, and hormone
Clinical Breast Cancer Month 2017
Abbreviation: SEER ¼ Surveillance, Epidemiology, and End Results.
Wei Chen et al Table 1 Patient Characteristics Patient Characteristics
Table 2 Extent of Surgery Performed in Patients With Stage IV MBC No. Patients (%) Surgery Type on Primary Site
Age, y Median (range)
43 (30-93)
Ethnicity White
283 (71.8)
Black
89 (22.6)
Other
22 (5.6) 12 (3)
II
116 (29.4)
III
152 (38.6)
IV Unknown
7 (1.8) 107 (27.2)
T status T1
27 (6.9)
T2
76 (19.3)
T3
22 (5.6)
T4
74 (18.8)
Unknown
195 (49.5)
N status N0
73 (18.5)
N1
115 (29.2)
N2
44 (11.2)
N3
87 (22.1)
Unknown
75 (19)
ER status Positive
263 (66.8)
Negative
42 (10.7)
Unknown
89 (22.6)
PR status Positive
No. Patients
%
46 54 93 3 1
23.4 27.5 47.2 1.5 0.5
Abbreviation: MBC ¼ male breast cancer.
Grade I
Partial mastectomy Total (simple) mastectomy Modified radical mastectomy Radical mastectomy Subcutaneous mastectomy
205 (52)
age (HR, 1.46; 95% CI, 1.05-2.01), and surgery of primary tumor (HR, 0.51; 95% CI, 0.37-0.70) were associated with longer CSS, whereas, the factors of smaller tumor size (P ¼ .013), PRþ disease (P ¼ .01), younger age (P ¼ .006), and surgery of primary tumor (P ¼ .023) predicted for better OS. Results of the univariate and multivariate analysis are included in Tables 3 and 4. Because patients undergoing surgery may have been subject to a selection bias (ie, patients may have been younger, had a better performance status, or had a smaller disease burden), a propensitymatched cohort was created to determine if these factors were responsible for the benefit seen with surgery. The characteristics of the original, unmatched cohort and the propensity-matched cohort are included in Table 5. For the unmatched cohort, there were statistically significant differences in ethnicity and N status between the patients who did not undergo surgery and those who did. However, even with propensity matching, there was still a statistically significant benefit in terms of CSS and OS with surgery using stratified log-rank tests with matched pairs (Figure 8). Multivariate analysis with the Cox proportional hazards model was performed on the propensity-matched cohort, confirming a CSS and OS benefit with surgery. In addition, smaller tumor size and PRþ disease were also associated with a CSS and OS benefit for this cohort, whereas younger age was only associated with a CSS benefit. These findings are summarized in Table 6.
Negative
94 (23.9)
Unknown
95 (24.1)
Discussion
14 (3.6)
MBC is an understudied disease process compared with female breast cancer owing to its rarity. Optimal treatment guidelines and
HER2 status Positive Negative
56 (14.2)
Unknown
324 (82.2)
Initial surgery to primary tumor Yes
197 (50)
No
197 (50)
Figure 2 Overall Survival Stratified by PR Status
Abbreviations: ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; PR ¼ progesterone receptor.
(Figures 2 and 3). Of the 394 patients, 197 (50%) received surgery of the primary tumor, and 197 (50%) did not. Those undergoing primary tumor surgery had longer median OS and CSS than those who did not (P < .001 for both) (Figures 4 and 5). Additional clinical factors that correlated with prolonged CSS and OS were age less than 65 years and smaller tumor size (P ¼ .009 and P ¼ .005, respectively) (Figures 6 and 7). After multivariate analysis, smaller tumor size (hazard ratio [HR], 1.93; 95% confidence interval [CI], 1.20-3.10), PRþ disease (HR, 1.67; 95% CI, 1.20-2.31), younger
Abbreviation: PR ¼ progesterone receptor.
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Treatment Outcomes in Stage IV Male Breast Cancer Figure 3 Cause-Specific Survival Stratified by PR Status
Figure 5 Cause-Specific Survival Stratified by Surgery Status
Abbreviation: PR ¼ progesterone receptor.
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predictive factors are unclear, as therapy strategies have been modeled after female breast cancer. Stage IV MBC is even more difficult to manage, as it represents a segment of an already small patient population. Therefore, our goal for this population-based study was to better characterize prognostic factors for this disease entity in order to potentially suggest improved treatment strategies. The OS for metastatic MBC was 21.1% at 5 years, which is consistent with findings from previous studies. Patients with luminal A disease (ERþ/PRþ) had better OS and CSS rates compared with patients with luminal B disease (ERþ/PR). This was confirmed on multivariate analysis as PRþ disease was associated with better CSS. Previous studies of MBC as a whole have analyzed the prognostic role of molecular subtype and have found conflicting results. A SEER analysis by Leone et al11 and a large multicenter study by Cardoso et al16 found that patients with ERþ disease have a better prognosis but other, smaller studies did not.4,17,18 A separate SEER analysis by Leone et al19 found that Her2þ and triple-negative disease were associated with worse OS; the first study to report a negative effect of these subtypes. It is difficult to parse through these inconsistent findings. Our understanding of breast cancer in women suggests that molecular subtype does play a role in disease outcomes,
but the rarity of the disease in men likely prevents researchers from making definitive conclusions. One interesting finding from our analysis is that surgical resection of the primary tumor was a positive prognostic factor associated with prolonged survival. Our study is the first to report of a potential benefit of surgical resection of the primary tumor in stage IV MBC. In female breast cancer, the role of surgery in patients with metastatic disease is a topic of growing debate.20,21 Surgical resection of the primary tumor has always been an option for palliation of local symptoms such as pain, ulceration, and lymphedema. However, there is some thought that surgical excision of the primary tumor may also improve disease outcomes. Removal of the primary tumor may lower the number of circulating tumor cells, reduce cancer cell seeding, and remove areas of disease that are not susceptible/accessible to systemic therapy.20 Our finding that patients with smaller tumor size had a better prognosis would fit into this principle. On the other hand, surgery may delay the patient from receiving the benefit of upfront systemic therapy. Some observational studies, retrospective reports, institutional data, meta-analyses, and national registry data suggest a survival benefit for surgery in females with stage IV breast cancer.21-27 However, there are also institutional and national database studies on female breast cancer that found no benefit to surgical resection of the primary in the setting of metastatic disease.22,28 Unfortunately,
Figure 4 Overall Survival Stratified by Surgery Status
Figure 6 Overall Survival Stratified by Tumor Size
Clinical Breast Cancer Month 2017
Wei Chen et al comparing surgery followed by systemic therapy versus systemic therapy alone in 274 newly-diagnosed, stage IV, female patients with breast cancer who were treatment-naive.29 There was no improvement in 36-month survival in the surgical arm. However, longer follow-up revealed statistically significant improvement in median survival (46 months vs. 37 months) with surgery at median follow-up of 40 months. Patients with what they deemed a more indolent form of metastatic breast cancer (ERþ, HER2-neu, solitary bone metastasis, age less than 55 years) had a significant survival benefit with initial surgery. In contrast, Badwe et al reported results of an open-label randomized controlled trial.30 Patients with resectable primaries were randomized upfront to locoregional treatment (surgery plus radiation) or no locoregional treatment. Patients with unresectable disease were treated with chemotherapy: those with objective tumor response after 6 to 8 cycles of chemotherapy were randomized. Overall, 350 patients were randomized, and there was no difference in median OS at a median follow-up of 23 months. King et al also presented preliminary data on a multicenter prospective registry study that examined the role of surgery in female patients with stage IV breast cancer who responded to upfront systemic therapy.31 Patients who
Figure 7 Cause-Specific Survival Stratified by Tumor Size
there are limitations and inherent biases when using retrospective data to formulate treatment strategies. Three prospective trials in female patients with stage IV breast cancer were performed to better answer this question. Soren et al presented preliminary data from a multicenter phase III trial
Table 3 Univariate Analysis on Overall Survival and Cause-Specific Survival Overall Survival Mean Survivals, mo
5-Year Survival, %
Age <65
29
24.9
Age 65
17
9.3
White
21
15.6
Black
19
19.3
Other
34
25.7
I-II
29
20.6
III-IV
21
16.3
2
34
34.9
>2
23
14.8
Positive
28
20.7
Negative
6
8.3
Positive
34
22.2
Negative
14
9.9
16
37.0b
24
b
57.1
Yes
21
23.6
No
13
10.0
Variable
Cause-specific Survival P
Mean Survivals, mo
5-Year Survival, %
33
30.3
26
15.1
33
21.7
25
26.0
48
20.3
36
24.0
28
22.3
51
42.7
29
18.6
P
Age, y .001
.021
Ethnicity .642
.458
Grade .08
.154
Tumor size, cm .009
.005
ER status <.001
34
24.0
21
14.6
.06
PR status <.001
37
26.0
20
15.8
18
44.4b
26
70.9b
.003
HER2 status Positive Negative
.077
.099
Surgerya <.001
36
29.6
21
15.6
<.001
Abbreviations: ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; PR ¼ progesterone receptor. a According to initial surgery to primary tumor. b Three-year survival (%), according to HER2 result achieved from 2010.
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Treatment Outcomes in Stage IV Male Breast Cancer Table 4 Multivariate Cox Regression Analysis on Overall Survival and Cause-Specific Survival Overall Survival Variable
Cause-Specific Survival P
HR (95% CI)
Age, y (65 vs. <65) Tumor size, cm (>2 vs. 2) PR status (positive vs. negative) Surgerya (yes vs. no)
1.87 2.34 1.80 0.73
(1.20-2.93) (1.20-4.57) (1.15-2.80) (0.56-0.96)
P
HR (95% CI)
.006 .013 .01 .023
1.46 1.93 1.67 0.51
(1.05-2.01) (1.20-3.10) (1.20-2.31) (0.37-0.70)
.023 .007 .002 <.001
Abbreviations: CI ¼ confidence interval; ER ¼ estrogen receptor; HR ¼ hazard ratio; PR ¼ progesterone receptor. a According to initial surgery to primary tumor.
Table 5 Baseline Characteristics of Patients Treated With Surgery or Without Surgery Original, Unmatched Cohort No Surgery No.
%
Surgery No.
No Surgery %
Age, y
No.
%
No.
%
28
14.2
22
11.2
21
16.2
18
13.8
50-65
69
35
82
41.6
46
35.4
52
40.0
65
100
50.8
93
47.2
63
48.5
60
46.2
.016
1.000
130
66.0
153
77.7
99
76.2
99
76.2
Black
51
25.9
38
19.3
27
20.8
27
20.8
Other
16
8.1
6
3.0
4
3.1
4
3.1
1988-1998
76
38.6
85
43.1
45
34.6
56
43.1
1999-2012
121
61.4
112
56.9
85
65.4
74
56.9
Year of diagnosis
.356
Grade
.162
.130
.029
I þ II
58
50.0
70
40.9
44
56.4
46
40.4
III þ IV
58
50.0
101
59.1
34
43.6
68
59.6
2
21
15.6
31
17.7
13
13.8
21
17.1
>2
114
84.4
144
82.3
81
86.2
102
82.9
Tumor size, cm
.614
T status
.515
.667
.441
T1
12
12.9
15
14.2
9
13.8
12
16.9
T2
32
34.4
44
41.5
26
40.0
35
49.3
T3
12
12.9
10
9.4
4
6.2
5
7.0
T4
37
39.8
37
34.9
26
40.0
19
26.8
N0
37
24.3
36
21.6
36
27.7
36
27.7
N1
61
40.1
54
32.3
47
36.2
47
36.2
N2
10
6.6
34
20.4
10
7.7
10
7.7
N3
44
28.9
43
25.7
37
28.5
37
28.5
Positive
121
86.4
142
86.1
85
88.5
96
84.2
Negative
19
13.6
23
13.9
11
11.5
18
15.8
N status
.005
ER status
1.000
.926
PR status
.365
.951
.162
Positive
93
68.4
112
68.7
67
72.0
71
62.8
Negative
43
31.6
51
31.3
26
28.0
42
37.2
Positive
9
25.0
5
14.7
6
23.1
3
18.8
Negative
27
75.0
29
85.3
20
76.9
13
81.3
HER2 status
.282
.529
Abbreviations: ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; PR ¼ progesterone receptor.
Clinical Breast Cancer Month 2017
P .715
<50
White
-
P
Surgery
.351
Ethnicity
6
Propensity-Matched Cohort
Wei Chen et al Figure 8 Kaplan-Meier Survival Curves for Treated With Surgery Arm and Without Surgery Arm in the Propensity-Matched Cohort of 260 Patients. A, Overall Survival; B, Cause-Specific Survival; P Values Were Calculated Using Stratified Log-Rank Test by Matched Pairs
had partial response, complete response, or stable disease after upfront systemic therapy were referred to discuss elective surgery. Thirty-nine patients of the 94 responder patients in the cohort underwent surgery. There was no difference in survival with surgery.
These initial results illustrate the ongoing controversy surrounding the role of surgical resection of the primary in female patients with stage IV breast cancer. However, the role of surgical resection of the primary tumor in men is not clear. Many treatment principles from female patients with breast cancer have been
Clinical Breast Cancer Month 2017
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Treatment Outcomes in Stage IV Male Breast Cancer Table 6 Multivariable Cox Regression Analysis on Overall Survival and Cause-Specific Survival in a Propensity-Matched Cohort Overall Survival Variable Age, y (65 vs. <65) Tumor size, cm (>2 vs. 2) PR status (positive vs. negative) Surgerya (yes vs. no)
Cause-Specific Survival P
HR (95% CI) 1.36 2.08 2.08 0.58
(1.06-1.74) (1.24-3.50) (1.24-3.50) (0.40-0.81)
.017 .006 .009 .001
HR (95% CI) 1.25 2.29 1.60 0.51
(0.96-1.64) (1.30-4.05) (1.10-2.32) (0.35-0.74)
P .096 .004 .013 <.001
Abbreviations: CI ¼ confidence interval; HR ¼ hazard ratio; PR ¼ progesterone receptor. a According to initial surgery to primary tumor.
extrapolated to MBC as the rarity of the disease limits the possibility of randomized controlled trials. The question is whether MBC behaves biologically similar to female breast cancer. The existing literature suggests that it does. Risk factors such as higher grade disease, advanced stage, lack of estrogen/progesterone receptor positivity, and BRCA mutation are adverse prognostic factors in men, just as they are in women.7,10,11,19 Modeling MBC after female breast cancer may just be the necessary consequence of the rarity of cases. Another point to consider is that, if there is a role for the local therapy of surgery in the setting of metastatic disease, there may be a role for other local therapies, such as radiotherapy. Radiotherapy can also be used to palliate local symptoms including pain and ulceration. In addition, radiotherapy can induce cell death, which may result in decreased circulating tumor cells and cancer cell seeding, just like with surgery. Radiotherapy may be combined with surgery as consolidation, just like with localized breast cancer. However, radiotherapy does have issues similar to systemic therapy, as relatively avascular/hypoxic areas are less susceptible to treatment; a problem that is circumvented with surgical removal. One study found radiotherapy alone was comparable with the combination of surgery and radiation to the primary in stage IV disease.32 Clearly, further study and randomized trials must be performed before any recommendations can be made. Our study has several limitations. First, we must acknowledge the retrospective design of this study and all the inherent biases associated. In addition, there are also limitations related to the weaknesses of the SEER database. Chemotherapy or systemic therapy use is not recorded in SEER, so it is unknown if this may contribute to some of the differences in survival based on observed prognostic factors. This is particularly important given the prominent role of systemic therapy in the treatment of stage IV disease. In addition, molecular and genetic factors of interest, including BRCA1/2 status and androgen receptor positivity, are not recorded. Furthermore, because Her2 status was only reported from 2010 onwards, the majority of patients did not have this information available. Finally, we must recognize the possibility of miscoded information in the SEER database, which has been previously discussed in regards to breast cancer.33
Conclusion
8
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To date, this is the largest analysis of stage IV MBC. OS and CSS at 5 years remains low. Consistent with previous analyses, hormone receptor-negative disease is a poor prognostic factor for this population. On the other hand, younger age, smaller tumor size, and
Clinical Breast Cancer Month 2017
surgical resection of the primary tumor were associated with improved OS and CSS, adding to the growing debate about the role of local therapy and surgery in the setting of metastatic disease. More definitive answers will likely be obtained after results from randomized trials and prospective studies in women are published.
Clinical Practice Points MBC represents < 1% of all patients with breast cancer.
Although MBC shares some features with female breast cancer, there are significant differences in the presentation, epidemiology, and prognosis between the 2 disease entities. National database and institutional-based data suggest that MBC patients with older age, higher grade disease, advanced stage, lack of estrogen/progesterone receptor positivity, and BRCA mutation have a worse prognosis. In addition, men with breast cancer who do receive therapies standard in women (ie, mastectomy, radiotherapy, endocrine therapy, or anti-Her2-neu therapy) have better outcomes. However, there is limited data on patients with stage IV MBC. This is a small subset of a rare disease, and only single-institution studies with low patient numbers describe this population. Our study is the largest analysis of stage IV MBC to date. Consistent with previous analyses, hormone receptor-negative disease is a poor prognostic factor for this population. On the other hand, younger age, smaller tumor size, and surgical resection of the primary tumor were associated with improved OS and CSS. Although there is some preliminary evidence supporting the use of primary surgical resection in stage IV disease, our findings only add to the growing debate about the role of local therapy in the setting of metastatic disease. More definitive answers will likely be obtained after results from randomized trials and prospective studies are published.
Acknowledgment This work was supported by Grants from the Natural Science Foundation of China (81402244).
Disclosure The authors have stated that they have no conflicts of interest.
References 1. American Cancer Society. What are the key statistics about breast cancer in men? Atlanta: American Cancer Society; 2016.
Wei Chen et al 2. Iorfida M, Bagnardi V, Rotmensz N, et al. Outcome of male breast cancer: a matched single-institution series. Clin Breast Cancer 2014; 14:371-7. 3. Henriques Abreu M, Henriques Abreu P, Afonso N, Pereira D, Henrique R, Lopes C. Patterns of recurrence and treatment in male breast cancer: a clue to prognosis? Int J Cancer 2016; 139:1715-20. 4. Giordano SH, Cohen DS, Buzdar AU, Perkins G, Hortobagyi GN. Breast carcinoma in men. Cancer 2004; 101:51-7. 5. Miao H, Verkooijen HM, Chia K-S, et al. Incidence and outcome of male breast cancer: an international population-based study. J Clin Oncol 2011; 29:4381-6. 6. Moten A, Obirieze A, Wilson LL. Characterizing lobular carcinoma of the male breast using the SEER database. J Surg Res 2013; 185:e71-6. 7. Anders CK, Johnson R, Litton J, Phillips M, Bleyer A. Breast cancer before age 40 years. Semin Oncol 2009; 36:237-49. 8. Chen X, Liu X, Zhang L, Li S, Shi Y, Tong Z. Poorer survival of male breast cancer compared with female breast cancer patients may be due to biological differences. Jpn J Clin Oncol 2013; 43:954-63. 9. Abreu MH, Afonso N, Abreu PH, et al. Male breast cancer: looking for better prognostic subgroups. Breast 2016; 26:18-24. 10. Gargiulo P, Pensabene M, Milano M, et al. Long-term survival and BRCA status in male breast cancer: a retrospective single-center analysis. BMC Cancer 2016; 16: 375. 11. Leone JP, Zwenger AO, Iturbe J, et al. Prognostic factors in male breast cancer: a population-based study. Breast Cancer Res Treat 2016; 156:539-48. 12. Di Lauro L, Pizzuti L, Barba M, et al. Efficacy of chemotherapy in metastatic male breast cancer patients: a retrospective study. J Exp Clin Cancer Res 2015; 34:26. 13. Foerster R, Schroeder L, Foerster F, et al. Metastatic male breast cancer: a retrospective cohort analysis. Breast Care 2014; 9:267-71. 14. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81. 15. Cox DR. Regression models and life-tables. J R Stat Soc B 1972; 34:187-220. 16. 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. Cancer Res 2015; 75 (abstract S6-05). 17. Arslan ÜY, Öksüzoglu B, Özdemir N, et al. Outcome of non-metastatic male breast cancer: 118 patients. Med Oncol 2012; 29:554-60. 18. Selcukbiricik F, Tural D, Aydogan F, Bes¸e N, Büyükünal E, Serdengeçti S. Male breast cancer: 37-year data study at a single experience center in Turkey. J Breast Cancer 2013; 16:60-5. 19. Leone JP, Leone J, Zwenger AO, Iturbe J, Vallejo CT, Leone BA. Prognostic significance of tumor subtypes in male breast cancer: a population-based study. Breast Cancer Res Treat 2015; 152:601-9.
20. Nguyen DH, Truong PT. A debate on locoregional treatment of the primary tumor in patients presenting with stage IV breast cancer. Expert Rev Anticancer Ther 2011; 11:1913-22. 21. Nguyen DHA, Truong PT, Alexander C, et al. Can locoregional treatment of the primary tumor improve outcomes for women with stage IV breast cancer at diagnosis? Int J Radiat Oncol Biol Phys 2012; 84:39-45. 22. AlJohani B, AlMalik O, Anwar E, et al. Impact of surgery on survival in stage IV breast cancer. Breast J 2016; 22:678-82. 23. Rapiti E, Verkooijen HM, Vlastos G, et al. Complete excision of primary breast tumor improves survival of patients with metastatic breast cancer at diagnosis. J Clin Oncol 2006; 24:2743-9. 24. Gnerlich J, Jeffe DB, Deshpande AD, Beers C, Zander C, Margenthaler JA. Surgical removal of the primary tumor increases overall survival in patients with metastatic breast cancer: analysis of the 1988e2003 SEER data. Ann Surg Oncol 2007; 14:2187-94. 25. Babiera GV, Rao R, Feng L, et al. Effect of primary tumor extirpation in breast cancer patients who present with stage IV disease and an intact primary tumor. Ann Surg Oncol 2006; 13:776-82. 26. Thomas A, Khan SA, Chrischilles EA, Schroeder MC. Initial surgery and survival in stage IV breast cancer in the United States, 1988-2011. JAMA Surg 2016; 151: 424-31. 27. Harris E, Barry M, Kell MR. Meta-analysis to determine if surgical resection of the primary tumour in the setting of stage IV breast cancer impacts on survival. Ann Surg Oncol 2013; 20:2828-34. 28. Dominici L, Najita J, Hughes M, et al. Surgery of the primary tumor does not improve survival in stage IV breast cancer. Breast Cancer Res Treat 2011; 129: 459-65. 29. Soran A, Ozmen V, Ozbas S, et al. A randomized controlled trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer: Turkish Study (Protocol MF07-01). J Clin Oncol 2016; 34:1005. 30. Badwe R, Hawaldar R, Nair N, et al. Locoregional treatment versus no treatment of the primary tumour in metastatic breast cancer: an open-label randomised controlled trial. Lancet Oncol 2015; 16:1380-8. 31. King TA, Lyman J, Gonen M. A prospective analysis of surgery and survival in stage IV breast cancer (TBCRC 013). J Clin Oncol 2016; 34:1006. 32. Bourgier C, Khodari W, Vataire A-L, et al. Breast radiotherapy as part of locoregional treatments in stage IV breast cancer patients with oligometastatic disease. Radiother Oncol 2010; 96:199-203. 33. Walker GV, Giordano SH, Williams M, et al. Muddy water? variation in reporting receipt of breast cancer radiation therapy by population-based tumor registries. Int J Radiat Oncol Biol Phys 2013; 86:686-93.
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Treatment Outcomes and Prognostic Factors in Male Patients With Stage IV Breast Cancer: A Population-based Study Wei Chen,1,2 Ying Huang,2,3 Gary D. Lewis,2,4 Sean S. Szeja,2,4 Sandra S. Hatch,4 Andrew Farach,2 Darlene Miltenburg,5 E. Brian Butler,2 Jenny C. Chang,6 Bin S. Teh2 Abstract Male breast cancer is a rare disease, and limited data exists regarding metastatic male breast cancer. To better characterize this population, we used the Surveillance, Epidemiology, and End Results database to examine prognostic factors that affected survival outcomes. On multivariate analysis, patients with progesterone receptor-positive disease, younger age (£ 65 years), tumor size £ 2 cm, or who had undergone surgery of the primary tumor had better overall survival and cause-specific survival. Purpose: Male breast cancer (MBC) represents < 1% of breast cancer patients, and limited data exists regarding metastatic MBC. To better characterize this patient subset, we performed a population-based study examining prognostic factors among patients with stage IV MBC. Methods: Patients with stage IV MBC diagnosed between 1988 and 2012 were selected from the Surveillance, Epidemiology, and End Results database. Prognostic factors for overall survival (OS) and cause-specific survival (CSS) were evaluated. Results: Overall, 394 patients had metastatic disease meeting inclusion criteria. The median follow-up was 21 months. The 5-year OS and CSS rates were 21.1% and 38.3%, respectively. Of those with known progesterone receptor (PR) status, 52% were PR-positive, which was associated with better OS (P < .001) and CSS (P ¼ .003). Overall, 197 patients (50%) received surgery for the primary tumor, and 197 (50%) did not. Patients undergoing surgery had longer median CSS than those who did not (36 vs. 21 months; P < .001). Additional factors that correlated with prolonged OS and CSS were smaller tumor size ( 2 cm; P < .05) and younger age ( 65 years; P < .05). In multivariate analysis, smaller tumor size, PR-positivity, younger age, and resection of the primary tumor were associated with longer OS and CSS (P < .05). Conclusions: Although stage IV MBC has poor OS and CSS, patients with PR-positive disease, younger age ( 65 years), tumor size 2 cm, or who undergo surgery of the primary tumor have better OS and CSS. This is the largest study of stage IV MBC to date, and these findings address some of the questions regarding this rare presentation of breast cancer. Clinical Breast Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: Male breast cancer, Metastatic, Prognosis, SEER, Surgery
Introduction Male breast cancer (MBC) represents < 1% of all patients with breast cancer, with an estimated incidence of 2600 cases a year.1 Although MBC shares some features with female breast cancer,
W.C. and Y.H. contributed equally to this work as first authors.
there are significant differences in the presentation, epidemiology, and prognosis between the 2 disease entities. Several studies have suggested that men with breast cancer have a worse prognosis compared with women with breast cancer,2 possibly because of
5
Department of Surgery, Texas Women’s Comprehensive Breast Center, Houston, TX Department of Medicine, Houston Methodist Hospital, Houston, TX
6
1
Department of General Surgery, Guangdong General Hospital, Guangzhou, China Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China 4 Department of Radiation Oncology, University of Texas Medical Branch Galveston, Galveston, TX 2
Submitted: Apr 2, 2017; Revised: Jun 15, 2017; Accepted: Jul 9, 2017
3
1526-8209/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2017.07.005
Address for correspondence: Bin S. Teh, MD, Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX 77030 E-mail contact: [email protected]
Clinical Breast Cancer Month 2017
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Treatment Outcomes in Stage IV Male Breast Cancer delayed diagnosis,3 differences in age and stage at diagnosis,4-7 or even differences in cancer cell biology.8,9 However, further attempts to characterize and describe MBC in the context of female breast cancer are limited by the rarity of the disease. National database and institutional-based data suggest that MBC patients with older age, higher grade disease, advanced stage, lack of estrogen receptor (ER)/progesterone receptor (PR) positivity, and BRCA mutation have a worse prognosis.7,10,11 In addition, men with breast cancer who do receive therapies standard in women (ie, mastectomy, radiotherapy, endocrine therapy, or antieHer2neu therapy) have better outcomes.11 However, there is limited data on patients with stage IV MBC. This is a small subset of a rare disease, and only single-institution studies with low patient numbers describe this population.12,13 In order to better characterize this disease, we performed a population-based study examining prognostic factors for patients with stage IV MBC.
Methods Patient Selection Data was obtained from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, using the 18 registry (1973-2012) database. SEER currently collects and publishes cancer incidence and survival data from populationbased cancer registries covering approximately 28% of the United States population. Data on tumor location, grade, and histology were recorded according to the International Classification of Diseases for Oncology Version 3. Male patients with stage IV breast cancer diagnosed between 1988 and 2012 were selected from the SEER database. Patient characteristics that were retrieved and recorded included race, age at diagnosis, and year of diagnosis. Tumor characteristics that were retrieved and recorded included laterality, histologic grade, tumor size, regional lymph node status, American Joint Committee on Cancer stage, ER status, PR status, and human epidermal growth factor receptor 2 (Her2) status. The SEER program began collecting data on ER and PR status in 1990 and started collecting HER2-neu data in 2010. The inclusion criteria used in the final analysis included male gender, unilateral breast cancer, invasive breast cancer (International Classification of Diseases for Oncology Version 3 site code C50.0-C50.9) as the first cancer diagnosis, diagnosis not obtained from a death certificate or autopsy, only 1 primary site, American Joint Committee on Cancer stage IV, known survival in months, and vital status.
receptor status. All tests were 2-sided; P < .05 was considered significant.
Results Patient Characteristics From 1988 to 2012, 8292 men with stage IV invasive breast cancer were recorded. Of these, 394 met inclusion criteria (Figure 1). The majority (71.8%) of patients were of Caucasian descent. The largest percentage (38.6%) of patients had grade III disease. In addition to distant metastatic disease, 62.5% of patients had nodal involvement. Overall, 66.8% had ER-positive (ERþ) disease and 52% had PR-positive (PRþ) disease. Unfortunately, Her2-neu status was unavailable in the majority of patients (82.2%) as SEER began collecting this data in 2010. Of the 70 patients with known Her2 status, only 14 were Her2 positive (Her2þ). Full patient characteristics are summarized in Table 1. In terms of type of surgery performed, modified radical mastectomy was performed the most (47.2% of patients). The frequencies of different surgery types are included in Table 2.
Survival Outcomes The median follow-up was 21 months (range, 1-170 months). Over the study period, 311 deaths occurred, 243 deaths of which were owing to breast cancer. Median OS was 21 months. The 5-year OS and CSS for stage IV MBC patients was 21.1% and 38.3%, respectively. The 5-year OS and CSS for patients who were ERþ/PRþ was 22.4% and 26.4%, respectively. The 5-year OS and CSS for ERþ/PR-negative (PR) patients was 12.4% and 13.8%, respectively. There was not sufficient data to determine the OS or CSS for patients who were ER-negative (ER)/PR and Her2þ or for patients with triple-negative disease.
Prognostic Factors
Of those with known PR status, 52% were PRþ, which was associated with better OS (P < .001) and CSS (P ¼ .003)
Figure 1 Diagram of Analytic Cohort for Survival Analysis
Statistical Analyses
2
-
All statistical calculations were performed using PASW Statistics 22.0 (SPSS, Chicago, IL) and STATA (version 12.0, College Station, TX). Survival rates were estimated using the Kaplan-Meier method, and significance was determined using the log-rank test (P < .05).14 Multivariate analysis with the Cox proportional hazards model was performed to determine prognostic factors for overall survival (OS) and cause-specific survival (CSS).15 OS was defined as the time from breast cancer diagnosis to the time of death or last follow-up. CSS was measured from the date of diagnosis to either the date of death owing to breast cancer or the date of last contact. Factors analyzed in the multivariable analysis included age at diagnosis, ethnicity, grade, stage, surgery, tumor size, and hormone
Clinical Breast Cancer Month 2017
Abbreviation: SEER ¼ Surveillance, Epidemiology, and End Results.
Wei Chen et al Table 1 Patient Characteristics Patient Characteristics
Table 2 Extent of Surgery Performed in Patients With Stage IV MBC No. Patients (%) Surgery Type on Primary Site
Age, y Median (range)
43 (30-93)
Ethnicity White
283 (71.8)
Black
89 (22.6)
Other
22 (5.6) 12 (3)
II
116 (29.4)
III
152 (38.6)
IV Unknown
7 (1.8) 107 (27.2)
T status T1
27 (6.9)
T2
76 (19.3)
T3
22 (5.6)
T4
74 (18.8)
Unknown
195 (49.5)
N status N0
73 (18.5)
N1
115 (29.2)
N2
44 (11.2)
N3
87 (22.1)
Unknown
75 (19)
ER status Positive
263 (66.8)
Negative
42 (10.7)
Unknown
89 (22.6)
PR status Positive
No. Patients
%
46 54 93 3 1
23.4 27.5 47.2 1.5 0.5
Abbreviation: MBC ¼ male breast cancer.
Grade I
Partial mastectomy Total (simple) mastectomy Modified radical mastectomy Radical mastectomy Subcutaneous mastectomy
205 (52)
age (HR, 1.46; 95% CI, 1.05-2.01), and surgery of primary tumor (HR, 0.51; 95% CI, 0.37-0.70) were associated with longer CSS, whereas, the factors of smaller tumor size (P ¼ .013), PRþ disease (P ¼ .01), younger age (P ¼ .006), and surgery of primary tumor (P ¼ .023) predicted for better OS. Results of the univariate and multivariate analysis are included in Tables 3 and 4. Because patients undergoing surgery may have been subject to a selection bias (ie, patients may have been younger, had a better performance status, or had a smaller disease burden), a propensitymatched cohort was created to determine if these factors were responsible for the benefit seen with surgery. The characteristics of the original, unmatched cohort and the propensity-matched cohort are included in Table 5. For the unmatched cohort, there were statistically significant differences in ethnicity and N status between the patients who did not undergo surgery and those who did. However, even with propensity matching, there was still a statistically significant benefit in terms of CSS and OS with surgery using stratified log-rank tests with matched pairs (Figure 8). Multivariate analysis with the Cox proportional hazards model was performed on the propensity-matched cohort, confirming a CSS and OS benefit with surgery. In addition, smaller tumor size and PRþ disease were also associated with a CSS and OS benefit for this cohort, whereas younger age was only associated with a CSS benefit. These findings are summarized in Table 6.
Negative
94 (23.9)
Unknown
95 (24.1)
Discussion
14 (3.6)
MBC is an understudied disease process compared with female breast cancer owing to its rarity. Optimal treatment guidelines and
HER2 status Positive Negative
56 (14.2)
Unknown
324 (82.2)
Initial surgery to primary tumor Yes
197 (50)
No
197 (50)
Figure 2 Overall Survival Stratified by PR Status
Abbreviations: ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; PR ¼ progesterone receptor.
(Figures 2 and 3). Of the 394 patients, 197 (50%) received surgery of the primary tumor, and 197 (50%) did not. Those undergoing primary tumor surgery had longer median OS and CSS than those who did not (P < .001 for both) (Figures 4 and 5). Additional clinical factors that correlated with prolonged CSS and OS were age less than 65 years and smaller tumor size (P ¼ .009 and P ¼ .005, respectively) (Figures 6 and 7). After multivariate analysis, smaller tumor size (hazard ratio [HR], 1.93; 95% confidence interval [CI], 1.20-3.10), PRþ disease (HR, 1.67; 95% CI, 1.20-2.31), younger
Abbreviation: PR ¼ progesterone receptor.
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Treatment Outcomes in Stage IV Male Breast Cancer Figure 3 Cause-Specific Survival Stratified by PR Status
Figure 5 Cause-Specific Survival Stratified by Surgery Status
Abbreviation: PR ¼ progesterone receptor.
4
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predictive factors are unclear, as therapy strategies have been modeled after female breast cancer. Stage IV MBC is even more difficult to manage, as it represents a segment of an already small patient population. Therefore, our goal for this population-based study was to better characterize prognostic factors for this disease entity in order to potentially suggest improved treatment strategies. The OS for metastatic MBC was 21.1% at 5 years, which is consistent with findings from previous studies. Patients with luminal A disease (ERþ/PRþ) had better OS and CSS rates compared with patients with luminal B disease (ERþ/PR). This was confirmed on multivariate analysis as PRþ disease was associated with better CSS. Previous studies of MBC as a whole have analyzed the prognostic role of molecular subtype and have found conflicting results. A SEER analysis by Leone et al11 and a large multicenter study by Cardoso et al16 found that patients with ERþ disease have a better prognosis but other, smaller studies did not.4,17,18 A separate SEER analysis by Leone et al19 found that Her2þ and triple-negative disease were associated with worse OS; the first study to report a negative effect of these subtypes. It is difficult to parse through these inconsistent findings. Our understanding of breast cancer in women suggests that molecular subtype does play a role in disease outcomes,
but the rarity of the disease in men likely prevents researchers from making definitive conclusions. One interesting finding from our analysis is that surgical resection of the primary tumor was a positive prognostic factor associated with prolonged survival. Our study is the first to report of a potential benefit of surgical resection of the primary tumor in stage IV MBC. In female breast cancer, the role of surgery in patients with metastatic disease is a topic of growing debate.20,21 Surgical resection of the primary tumor has always been an option for palliation of local symptoms such as pain, ulceration, and lymphedema. However, there is some thought that surgical excision of the primary tumor may also improve disease outcomes. Removal of the primary tumor may lower the number of circulating tumor cells, reduce cancer cell seeding, and remove areas of disease that are not susceptible/accessible to systemic therapy.20 Our finding that patients with smaller tumor size had a better prognosis would fit into this principle. On the other hand, surgery may delay the patient from receiving the benefit of upfront systemic therapy. Some observational studies, retrospective reports, institutional data, meta-analyses, and national registry data suggest a survival benefit for surgery in females with stage IV breast cancer.21-27 However, there are also institutional and national database studies on female breast cancer that found no benefit to surgical resection of the primary in the setting of metastatic disease.22,28 Unfortunately,
Figure 4 Overall Survival Stratified by Surgery Status
Figure 6 Overall Survival Stratified by Tumor Size
Clinical Breast Cancer Month 2017
Wei Chen et al comparing surgery followed by systemic therapy versus systemic therapy alone in 274 newly-diagnosed, stage IV, female patients with breast cancer who were treatment-naive.29 There was no improvement in 36-month survival in the surgical arm. However, longer follow-up revealed statistically significant improvement in median survival (46 months vs. 37 months) with surgery at median follow-up of 40 months. Patients with what they deemed a more indolent form of metastatic breast cancer (ERþ, HER2-neu, solitary bone metastasis, age less than 55 years) had a significant survival benefit with initial surgery. In contrast, Badwe et al reported results of an open-label randomized controlled trial.30 Patients with resectable primaries were randomized upfront to locoregional treatment (surgery plus radiation) or no locoregional treatment. Patients with unresectable disease were treated with chemotherapy: those with objective tumor response after 6 to 8 cycles of chemotherapy were randomized. Overall, 350 patients were randomized, and there was no difference in median OS at a median follow-up of 23 months. King et al also presented preliminary data on a multicenter prospective registry study that examined the role of surgery in female patients with stage IV breast cancer who responded to upfront systemic therapy.31 Patients who
Figure 7 Cause-Specific Survival Stratified by Tumor Size
there are limitations and inherent biases when using retrospective data to formulate treatment strategies. Three prospective trials in female patients with stage IV breast cancer were performed to better answer this question. Soren et al presented preliminary data from a multicenter phase III trial
Table 3 Univariate Analysis on Overall Survival and Cause-Specific Survival Overall Survival Mean Survivals, mo
5-Year Survival, %
Age <65
29
24.9
Age 65
17
9.3
White
21
15.6
Black
19
19.3
Other
34
25.7
I-II
29
20.6
III-IV
21
16.3
2
34
34.9
>2
23
14.8
Positive
28
20.7
Negative
6
8.3
Positive
34
22.2
Negative
14
9.9
16
37.0b
24
b
57.1
Yes
21
23.6
No
13
10.0
Variable
Cause-specific Survival P
Mean Survivals, mo
5-Year Survival, %
33
30.3
26
15.1
33
21.7
25
26.0
48
20.3
36
24.0
28
22.3
51
42.7
29
18.6
P
Age, y .001
.021
Ethnicity .642
.458
Grade .08
.154
Tumor size, cm .009
.005
ER status <.001
34
24.0
21
14.6
.06
PR status <.001
37
26.0
20
15.8
18
44.4b
26
70.9b
.003
HER2 status Positive Negative
.077
.099
Surgerya <.001
36
29.6
21
15.6
<.001
Abbreviations: ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; PR ¼ progesterone receptor. a According to initial surgery to primary tumor. b Three-year survival (%), according to HER2 result achieved from 2010.
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Treatment Outcomes in Stage IV Male Breast Cancer Table 4 Multivariate Cox Regression Analysis on Overall Survival and Cause-Specific Survival Overall Survival Variable
Cause-Specific Survival P
HR (95% CI)
Age, y (65 vs. <65) Tumor size, cm (>2 vs. 2) PR status (positive vs. negative) Surgerya (yes vs. no)
1.87 2.34 1.80 0.73
(1.20-2.93) (1.20-4.57) (1.15-2.80) (0.56-0.96)
P
HR (95% CI)
.006 .013 .01 .023
1.46 1.93 1.67 0.51
(1.05-2.01) (1.20-3.10) (1.20-2.31) (0.37-0.70)
.023 .007 .002 <.001
Abbreviations: CI ¼ confidence interval; ER ¼ estrogen receptor; HR ¼ hazard ratio; PR ¼ progesterone receptor. a According to initial surgery to primary tumor.
Table 5 Baseline Characteristics of Patients Treated With Surgery or Without Surgery Original, Unmatched Cohort No Surgery No.
%
Surgery No.
No Surgery %
Age, y
No.
%
No.
%
28
14.2
22
11.2
21
16.2
18
13.8
50-65
69
35
82
41.6
46
35.4
52
40.0
65
100
50.8
93
47.2
63
48.5
60
46.2
.016
1.000
130
66.0
153
77.7
99
76.2
99
76.2
Black
51
25.9
38
19.3
27
20.8
27
20.8
Other
16
8.1
6
3.0
4
3.1
4
3.1
1988-1998
76
38.6
85
43.1
45
34.6
56
43.1
1999-2012
121
61.4
112
56.9
85
65.4
74
56.9
Year of diagnosis
.356
Grade
.162
.130
.029
I þ II
58
50.0
70
40.9
44
56.4
46
40.4
III þ IV
58
50.0
101
59.1
34
43.6
68
59.6
2
21
15.6
31
17.7
13
13.8
21
17.1
>2
114
84.4
144
82.3
81
86.2
102
82.9
Tumor size, cm
.614
T status
.515
.667
.441
T1
12
12.9
15
14.2
9
13.8
12
16.9
T2
32
34.4
44
41.5
26
40.0
35
49.3
T3
12
12.9
10
9.4
4
6.2
5
7.0
T4
37
39.8
37
34.9
26
40.0
19
26.8
N0
37
24.3
36
21.6
36
27.7
36
27.7
N1
61
40.1
54
32.3
47
36.2
47
36.2
N2
10
6.6
34
20.4
10
7.7
10
7.7
N3
44
28.9
43
25.7
37
28.5
37
28.5
Positive
121
86.4
142
86.1
85
88.5
96
84.2
Negative
19
13.6
23
13.9
11
11.5
18
15.8
N status
.005
ER status
1.000
.926
PR status
.365
.951
.162
Positive
93
68.4
112
68.7
67
72.0
71
62.8
Negative
43
31.6
51
31.3
26
28.0
42
37.2
Positive
9
25.0
5
14.7
6
23.1
3
18.8
Negative
27
75.0
29
85.3
20
76.9
13
81.3
HER2 status
.282
.529
Abbreviations: ER ¼ estrogen receptor; HER2 ¼ human epidermal growth factor receptor 2; PR ¼ progesterone receptor.
Clinical Breast Cancer Month 2017
P .715
<50
White
-
P
Surgery
.351
Ethnicity
6
Propensity-Matched Cohort
Wei Chen et al Figure 8 Kaplan-Meier Survival Curves for Treated With Surgery Arm and Without Surgery Arm in the Propensity-Matched Cohort of 260 Patients. A, Overall Survival; B, Cause-Specific Survival; P Values Were Calculated Using Stratified Log-Rank Test by Matched Pairs
had partial response, complete response, or stable disease after upfront systemic therapy were referred to discuss elective surgery. Thirty-nine patients of the 94 responder patients in the cohort underwent surgery. There was no difference in survival with surgery.
These initial results illustrate the ongoing controversy surrounding the role of surgical resection of the primary in female patients with stage IV breast cancer. However, the role of surgical resection of the primary tumor in men is not clear. Many treatment principles from female patients with breast cancer have been
Clinical Breast Cancer Month 2017
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Treatment Outcomes in Stage IV Male Breast Cancer Table 6 Multivariable Cox Regression Analysis on Overall Survival and Cause-Specific Survival in a Propensity-Matched Cohort Overall Survival Variable Age, y (65 vs. <65) Tumor size, cm (>2 vs. 2) PR status (positive vs. negative) Surgerya (yes vs. no)
Cause-Specific Survival P
HR (95% CI) 1.36 2.08 2.08 0.58
(1.06-1.74) (1.24-3.50) (1.24-3.50) (0.40-0.81)
.017 .006 .009 .001
HR (95% CI) 1.25 2.29 1.60 0.51
(0.96-1.64) (1.30-4.05) (1.10-2.32) (0.35-0.74)
P .096 .004 .013 <.001
Abbreviations: CI ¼ confidence interval; HR ¼ hazard ratio; PR ¼ progesterone receptor. a According to initial surgery to primary tumor.
extrapolated to MBC as the rarity of the disease limits the possibility of randomized controlled trials. The question is whether MBC behaves biologically similar to female breast cancer. The existing literature suggests that it does. Risk factors such as higher grade disease, advanced stage, lack of estrogen/progesterone receptor positivity, and BRCA mutation are adverse prognostic factors in men, just as they are in women.7,10,11,19 Modeling MBC after female breast cancer may just be the necessary consequence of the rarity of cases. Another point to consider is that, if there is a role for the local therapy of surgery in the setting of metastatic disease, there may be a role for other local therapies, such as radiotherapy. Radiotherapy can also be used to palliate local symptoms including pain and ulceration. In addition, radiotherapy can induce cell death, which may result in decreased circulating tumor cells and cancer cell seeding, just like with surgery. Radiotherapy may be combined with surgery as consolidation, just like with localized breast cancer. However, radiotherapy does have issues similar to systemic therapy, as relatively avascular/hypoxic areas are less susceptible to treatment; a problem that is circumvented with surgical removal. One study found radiotherapy alone was comparable with the combination of surgery and radiation to the primary in stage IV disease.32 Clearly, further study and randomized trials must be performed before any recommendations can be made. Our study has several limitations. First, we must acknowledge the retrospective design of this study and all the inherent biases associated. In addition, there are also limitations related to the weaknesses of the SEER database. Chemotherapy or systemic therapy use is not recorded in SEER, so it is unknown if this may contribute to some of the differences in survival based on observed prognostic factors. This is particularly important given the prominent role of systemic therapy in the treatment of stage IV disease. In addition, molecular and genetic factors of interest, including BRCA1/2 status and androgen receptor positivity, are not recorded. Furthermore, because Her2 status was only reported from 2010 onwards, the majority of patients did not have this information available. Finally, we must recognize the possibility of miscoded information in the SEER database, which has been previously discussed in regards to breast cancer.33
Conclusion
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To date, this is the largest analysis of stage IV MBC. OS and CSS at 5 years remains low. Consistent with previous analyses, hormone receptor-negative disease is a poor prognostic factor for this population. On the other hand, younger age, smaller tumor size, and
Clinical Breast Cancer Month 2017
surgical resection of the primary tumor were associated with improved OS and CSS, adding to the growing debate about the role of local therapy and surgery in the setting of metastatic disease. More definitive answers will likely be obtained after results from randomized trials and prospective studies in women are published.
Clinical Practice Points MBC represents < 1% of all patients with breast cancer.
Although MBC shares some features with female breast cancer, there are significant differences in the presentation, epidemiology, and prognosis between the 2 disease entities. National database and institutional-based data suggest that MBC patients with older age, higher grade disease, advanced stage, lack of estrogen/progesterone receptor positivity, and BRCA mutation have a worse prognosis. In addition, men with breast cancer who do receive therapies standard in women (ie, mastectomy, radiotherapy, endocrine therapy, or anti-Her2-neu therapy) have better outcomes. However, there is limited data on patients with stage IV MBC. This is a small subset of a rare disease, and only single-institution studies with low patient numbers describe this population. Our study is the largest analysis of stage IV MBC to date. Consistent with previous analyses, hormone receptor-negative disease is a poor prognostic factor for this population. On the other hand, younger age, smaller tumor size, and surgical resection of the primary tumor were associated with improved OS and CSS. Although there is some preliminary evidence supporting the use of primary surgical resection in stage IV disease, our findings only add to the growing debate about the role of local therapy in the setting of metastatic disease. More definitive answers will likely be obtained after results from randomized trials and prospective studies are published.
Acknowledgment This work was supported by Grants from the Natural Science Foundation of China (81402244).
Disclosure The authors have stated that they have no conflicts of interest.
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