- Email: [email protected]
Impact of Primary Tumor Surgery in Stage IV Male Breast Cancer
Original Study
Impact of Primary Tumor Surgery in Stage IV Male Breast Cancer Mahvish Muzaffar,1 Swapnil Kachare,2 Nasreen Vohra2 Abstract A Surveillance, Epidemiology, and End Results (SEER) database study demonstrated improvement in survival after primary tumor surgery in stage IV male breast cancer. Background: Primary tumor surgery (PTS) is not a standard treatment modality in stage IV breast cancer. Retrospective studies in female breast cancer show improved survival in women undergoing PTS; however, data regarding the impact of surgery in male breast cancer are lacking. The objective of this study was to analyze the impact of PTS on survival among men with metastatic breast cancer. Methods: A retrospective study was conducted of men diagnosed with metastatic breast cancer at diagnosis were identified from the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2011. Cox proportional hazards regression models were used to compare the differences in survival in men who did and did not undergo PTS. Results: A total of 439 men with stage IV breast cancer at diagnosis were identified, of which 222 (51%) underwent PTS, 171 (77%) mastectomy, and 51 (23%) partial mastectomy. The median age was 65 years; 74% of participants were white, 51% had tumors T2, 65% had estrogen receptor (ER)-positive tumor, and 24% had unknown ER status. Univariate analysis between the surgery and no-surgery arms showed that white race (P ¼ .04), lower T stage and grade (P ¼ .0003, P ¼ .004), ER positivity (P ¼ .0002), and later year of diagnosis (P < .0001) were associated with better survival. PTS was associated with improvement in median overall survival (29 vs. 11 months, P < .0001). On Cox regression analysis, ER negativity (hazard ratio ¼ 2.08; 95% confidence interval, 1.41-3.01; P < .0003) and not undergoing PTS were associated with diminished survival (hazard ratio ¼ 1.81; 95% confidence interval, 1.42-2.31; P < .0001). Conclusion: PTS among men with metastatic breast cancer was associated with improved survival in this retrospective analysis. Clinical Breast Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Metastatic breast cancer, Primary tumor surgery, Stage IV cancer, Survival
Introduction The incidence of male breast cancer has been increasing over the last few decades; however, it is still a rare disease, accounting for only 1% of breast cancer diagnoses in the United States.1-3 More than 40% of patients have advanced-stage disease at presentation, with larger primary tumors, more frequent lymph node involvement, and 8% to 10% stage IV disease.4,5 This is most likely due to a delay in recognition of this disease, absence of routine screening, and anatomic differences in the male breast that predispose this site to local invasion.4,6,7 Male breasts are smaller and have 1
Division of Hematology Oncology, Department of Internal Medicine Department of Surgery, Brody School of Medicine, East Carolina University, Greenville, NC 2
Submitted: Jul 31, 2016; Revised: Oct 27, 2016; Accepted: Nov 13, 2016 Address for correspondence: Mahvish Muzaffar, MD, Division of Hematology Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, Brody 3E127, 600 Moye Blvd, Greenville, NC 27834 Fax: (252) 744-3418; e-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2016.11.001
predominantly fatty tissue, with fewer ducts and stroma than the female breast. As a result, these patients often have skin and nipple involvement at presentation. Because of the rarity of this disease in men, the treatment recommendations are extrapolated from guidelines for management of female breast cancer.8 Metastatic breast cancer is still considered an incurable disease; systemic therapy is the main treatment modality. Metastatic breast cancer survival has improved over the last few decades.1,4,9-11 Recent advances in imaging modalities have resulted in the diagnosis of stage IV disease with lower tumor burdens than were seen in the past; this trend, along with an expanding armamentarium of systemic therapy, has resulted in an improvement in survival of stage IV breast cancer patients.9,10,12 The role of primary tumor surgery (PTS) in stage IV breast cancer is mostly limited to palliation for complications such as bleeding, ulceration, and infection at the primary tumor site, but mounting evidence from retrospective trials over the last few decades has demonstrated improved outcome with PTS in selected patients with stage IV disease.12-14 These data are in contrast to the findings from the limited randomized controlled
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Stage IV Male Breast Cancer trials conducted outside the United States, which confirmed better local disease control without survival advantage in women undergoing surgery.15,16 The data for the impact of PTS among men with stage IV disease are limited. Analysis of previously reported Surveillance, Epidemiology, and End Results (SEER) data showed that of all the women with stage IV breast cancer undergoing PTS, 52% had mastectomies.17 Male breast cancer patients tend to have more local symptoms and tend to present with locally advanced tumors, with an overwhelming majority of men with operable cancer undergoing mastectomy (87%), compared to less than half of all women (47%).4,18-21 It is likely that this trend also persists in men with stage IV disease to achieve palliation at the primary tumor site. We hypothesized that, similar to female breast cancer, PTS will improve survival in men with stage IV breast cancer. We report the results from our study, which was conducted to assess the role of PTS in the management of men with stage IV breast cancer, utilizing the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) registry from 1988 to 2011.22
Methods Data Source, Patient Selection, and Exclusion Criteria The SEER program, which is a National Cancer Instituteesupported database covering approximately 28% of the cancer cases in the US population, was utilized to identify the patient cohort for this study.22 A query of the SEER registry using SEER*Stat 8.1.2 was performed to identify all men with metastatic breast cancer at diagnosis between the years 1988 and 2011 (adjusted American Joint Committee on Cancer, 6th edition, criteria). We collected demographic data (age at diagnosis, race) and tumor characteristics (primary tumor size, nodal stage, tumor grade, histologic subtype, estrogen and progesterone receptor expression status, and human epidermal growth factor receptor 2 [HER-2] overexpression status). Treatment data collected included type of surgery and radiotherapy utilization.
Statistical Analysis A retrospective analysis was performed with median overall survival as the primary end point. Univariate descriptive analysis was performed by Student’s t test and the chi-square test where appropriate. Survival was analyzed using a combination of KaplanMeier curves and the log-rank test. Statistically significant variables on univariate analysis (P .2) were entered into a Cox regression analysis to determine independent associations with survival. Data analysis was performed by SAS 9.3 and JMP Pro 10.0.0 (2012) software (SAS Institute, Cary, NC, USA).
Results
2
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Four hundred thirty-nine men with stage IV breast cancer at diagnosis were identified in the SEER database for the years 1988 to 2011. Table 1 summarizes the characteristics of the study population. The mean age of the patient population was 65 years (range, 30-93 years) in the overall group. The majority of patients were white (73.6%). Invasive ductal carcinoma was the most predominant histologic subtype, with 68% of the patients having this subtype. Sixty-five percent of the patients had an estrogen receptor
Clinical Breast Cancer Month 2016
(ER)-positive tumor, and 11% had an ER-negative tumor. The number of ER-positive tumors was lower than expected but can be explained by the higher percentage of disease with unknown receptor status (24%). Primary tumor size was > 5 cm in 30% of patients, 61% of patients had nodal involvement, and 38% had grade 3 tumors (Table 1). A 3-fold increase in the number of male stage IV cases in the SEER database was noted in the time period 1999-2009 compared to 1988-1998. Of the 439 patients in the study, 222 patients (51%) underwent PTS and 217 (49%) did not undergo surgery. The mean age of patients who underwent PTS was 65.8 years (range, 33-90 years) compared to 65.2 years (range, 30-93 years) for patients who did not undergo surgery (P ¼ .64). In the surgery cohort, 78.4% of patients were white and 18% were black, compared to 68.7% white and 23.5% black in the no-surgery arm (P ¼ .04). Patients who underwent surgery were also more likely to have lower T stage (63.9% vs. 34.5%) compared to the no-surgery arm (P < .0001) (Table 1). Among patients undergoing surgery, 64% had tumor size of < 5 cm compared to 36% in the no-surgery cohort (P < .0001). As shown in Table 1, there were more ER-positive tumors in the surgery group than in the no-surgery group (72.5% vs. 57.6%, P ¼ .0002). Thirty-seven percent (n ¼ 84) of the patients in the surgery cohort versus 32.3% in the no-surgery cohort also received radiotherapy (SEER does not provide information on the site of radiation). As shown in Table 2, of the 222 patients undergoing surgery, 49% (n ¼ 109) underwent modified radical mastectomy, 26% (n ¼ 58) underwent mastectomy, 2% (n ¼ 4) underwent radical mastectomy, and 23% (n ¼ 51) had partial mastectomy. Of the patients who underwent PTS, 51% (n ¼ 117) patients underwent axillary node dissection, whereas 13% (n ¼ 28) patients did not undergo axillary surgery (Table 3). Information about the extent of axillary surgery was missing for 20% (n ¼ 81) patients who had PTS. As shown in Table 4, age > 50 years (P < .0001), white race (P < .0001), lower T stage (P ¼ .0003), ER-positive status (P ¼ .0013), lower tumor grade (P ¼ .004), and later years of diagnosis (1999-2010) (P < .0001) were associated with improved median survival with surgery. The study population had a median overall survival of 19 months. The median follow-up was 48 months. Patients who underwent PTS had a significantly greater median overall survival compared to patients who did not undergo PTS (29 vs. 11 months, P < .0001) (Figure 1). A Cox proportional hazards model demonstrated that ER-negative tumors (relative risk ¼ 2.08; 95% confidence interval [CI], 1.41-3.01; P ¼ .0003) had an increased risk of mortality (Table 5). PTS among men with stage IV breast cancer was associated with a significantly increased median overall survival; patients who did not undergo surgery were more likely to die during the study period compared to men who did undergo surgery (hazard ratio ¼ 1.81; 95% CI, 1.42-2.31; P < .0001) (Table 5).
Discussion To our knowledge, this is one of the first studies to address the impact of PTS in men with stage IV breast cancer. The study demonstrated a 3-fold increase in stage IV cancer cases among men in 1999-2009 compared to 1988-1998. Epidemiologic studies also report an increase in the incidence of male breast cancer.2
Mahvish Muzaffar et al The increase in male breast cancer noted in our study may partly be a result of improved capturing of cancer cases in the SEER registry over the 23-year time frame of our study. Our study demonstrates improved survival among men with metastatic breast cancer who underwent PTS compared to no surgery (29 vs. 11 months, P < .0001). The superior overall survival was demonstrated in both univariate and multivariate analyses.
The role of PTS in the metastatic setting is still controversial, with differing outcomes between limited randomized trials and retrospective studies.12,13,17,23-28 Recently published analyses using the SEER database of women with stage IV disease who underwent surgery reported similar results. Longer median survival was associated with having surgery (survival 28 vs. 19 months; 95% CI, 7.6-10.4). Women with stage IV breast cancer who received surgery
Table 1 Characteristics of Men With Stage IV Breast Cancer Who Did and Did Not Undergo Primary Tumor Surgery, Surveillance, Epidemiology, and End Results, 1988-2011 Characteristic
Total Population (n [ 439)
Surgery (n [ 222)
No Surgery (n [ 217)
Age (y) 65.6 12.5
65.8 12.95
Median
65
65.5
65
Range
30-93
33-90
30-93
Mean
P .64
65.2 12.06
Age (y)
.14
50
47 (10.7)
19 (8.6)
28 (12.9)
>50
392 (89.3)
203 (91.4)
189 (87.1)
White
323 (73.6)
174 (78.4)
149 (68.7)
Black
91 (20.7)
40 (18.0)
51 (23.5)
Other
25 (5.7)
8 (3.6)
17 (7.8)
6 (1.4)
2 (0.9)
4 (1.8)
T1-T2 (5 cm)
217 (49.4)
142 (63.9)
75 (34.5)
T3 (>5 cm)
130 (29.6)
59 (26.5)
71 (32.7)
86 (19.6)
19 (8.5)
67 (30.6.8)
Race
.04
<.0001
Tumor stage T0
TX Node stage
.0003
N0
79 (18.0)
43 (19.4)
36 (16.6)
N1
123 (28.0)
61 (27.5)
62 (38.6)
N2
145 (33.0)
87 (39.1)
58 (26.7)
92 (21.0)
31 (13.9)
61 (28.1)
NX Estrogen receptor
.0002
Positive
286 (65.1)
161 (72.5)
Negative
47 (10.7)
26 (11.7)
125 (57.6) 21 (9.7)
Unknown
106 (24.1)
35 (16.2)
71 (32.7)
Positive
225 (51.3)
127 (57.2)
98 (45.2)
Negative
103 (23.5)
59 (26.6)
44 (20.3)
Unknown
110 (25.2)
36 (16.2)
74 (34.5)
146 (32.3)
84 (37.8)
62 (28.5)
3
177 (40.3)
114 (51.4)
63 (29.0)
Unknown
116 (26.4)
24 (10.8)
92 (42.5)
Progesterone receptor
.0001
<.0001
Grade 1-2
Radiation
.38
Yes
154 (35.1)
84 (37.8)
70 (32.3)
No
277 (63.1)
135 (60.8)
142 (65.4)
8 (1.8)
3 (1.4)
5 (2.3)
1988-1998
86 (19.6)
48 (21.6)
38 (17.5)
1999-2011
353 (80.4)
174 (78.4)
179 (82.5)
Unknown Year of diagnosis
.28
Data are presented as n (%) unless otherwise indicated.
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Stage IV Male Breast Cancer Table 2 Type of Surgery Performed in Men With Metastatic Breast Cancer for Resection of Primary Tumor, Surveillance, Epidemiology, and End Results, 1988-2011 Type of Primary Tumor Surgery
Total Undergoing Surgery (n [ 222), N (%)
Modified radical mastectomy Radical mastectomy Mastectomy Mastectomy without ALND Partial mastectomy Partial mastectomy without ALND
109 4 45 13 36 15
(49.1) (1.9) (20.3) (5.8) (16.2) (6.7)
Abbreviation: ALND ¼ axillary lymph node dissection.
were 2.80 times more likely to survive at least 10 years compared to those who did not (95% CI, 2.08-3.77).12 Univariate survival analysis demonstrated a survival advantage of 18 months for patients undergoing PTS over no surgery. When controlling for known prognostic factors like tumor size, age at diagnosis, nodal status, ER status, and disease grade, this survival advantage persisted. Not undergoing PTS was associated with diminished survival (hazard ratio ¼ 1.81, 1.42-2.31, P < .0001). As expected, patients with lower T stage and with ER-positive disease had better outcomes with surgery on multivariate analysis. A decreasing trend toward surgery was noted, with 56% of patients with metastatic cancer undergoing surgery during 1988-1998 versus 52% during 1999-2009. This observation is similar to the recently reported trend among female stage IV breast cancer patients undergoing surgery.12 Surgical management of nonmetastatic male and female breast cancer patients has historically differed, with mastectomy performed more frequently among men versus women, who are equally likely to get a mastectomy or partial mastectomy based on the in-breast disease burden.29,30 In our study, 75% of the men who had PTS underwent mastectomy, and only 23% underwent partial mastectomy. Our analysis revealed that patients in the surgery group had more T1/T2 lesions compared to the no-surgery group. While PTS in metastatic breast cancer patients is performed for palliation of bleeding, ulceration, and symptomatic lesions, it also appears that patients with limited in-breast disease and manageable metastatic burden may be undergoing surgery to achieve better disease control and possibly prolong survival, as observed in retrospective studies.12,27 While we can surmise that disease control for ulceration and other local symptoms may also be a reason for patients with stage IV tumors undergo surgery, our analysis does not support this
Table 3 Extent of Axillary Surgery in Men With Metastatic Breast Cancer Undergoing Primary Tumor Surgery, Surveillance, Epidemiology, and End Results, 1988-2011 Axillary Surgery ALND No ALND Unknown
4
-
Abbreviation: ALND ¼ axillary lymph node dissection.
Clinical Breast Cancer Month 2016
Table 4 Univariate Analysis of Clinicopathologic Factors Affecting Overall Survival in Male Stage IV Breast Cancer Patients, Surveillance, Epidemiology, and End Results, 1988-2011
N (%) 113 (50.9) 28 (12.6) 81 (36.5)
OS (mo) Variable
Surgery
No Surgery
P
Age (y) 50
41
18.5
>50
28
10
<.0001
.16
Race White
29
10
<.0001
Black
21.5
18
.92
Other
48
10
.08
Tumor stage T0
—
—
T1-T2 (5 cm)
29
7
T3 (>5 cm)
33
17
.0003 .09
TX
11
6
.11
N0-N1
26
13
.019
N2
33
11
NX
11
5
33
21
Node stage .0012 .18
Estrogen receptor Positive Negative
5
.4
11
4
.04
Positive
35
23
Negative
15
7
.07
Unknown
13.5
4
.04 0.0038
Unknown
4.5
.0013
Progesterone receptor .0018
Grade 1-2
34
18
3
25
11
.014
Unknown
33
7
.017
Yes
30
12
.09
No
29
10
.0002
Radiation
Unknown
—
—
—
Year of diagnosis 1988-1998
27
11
.01
1999-2011
30
11
<.0001
29
11
<.0001
Median OS
as being the primary indication for surgery based on comparing the T stages in both groups. A possible explanation for this observation may be the impact of selection bias in this retrospective analysis. Stage IV breast cancer patients with favorable clinicopathologic features more often tend to undergo primary tumor resection. Our results are similar to other studies conducted in female breast cancer patients; patients in the surgery group had more T1 and T2 primary tumors compared to patients who did not undergo surgery.12,23,26 The justification for resection of the primary tumor is based on the biologic rationale of correlation between local tumor burden and
Mahvish Muzaffar et al Figure 1 Overall Survival for Primary Tumor Surgery Versus No-Surgery Groups in Male Stage IV Breast Cancer, Surveillance, Epidemiology, and End Results, 1988-2011
metastatic potential17,23,31—the cancer self-seeding hypothesis that proposes recirculation and seeding of the primary site,32 possible restoration of immunomodulation by removing potential source of immunosuppression from the primary tumor, and improved responsiveness to systemic therapy.33-36 The opponents of surgical resection cite the lack of randomized data demonstrating efficacy, morbidity associated with the surgical procedure, potential delay in systemic therapy administration, and the theory of increased angiogenesis and accelerated tumor growth associated with the surgical wound in metastatic cancer.34,37,38 We acknowledge the inherent limitations of this retrospective study, which include potential biases like unaccounted timing of surgery with systemic therapy and selection bias due to favorable patient characteristics like younger age, fewer comorbidities, and lower disease burden.26,28,39 The SEER database also has several limitations, which include unavailability of number and sites of metastases, timing and type of systemic therapy administered, margin status, completeness of resection, number of lymph nodes removed, and site of radiation.22 The small number of patients, along with the rarity of male breast cancer, also limits more meaningful statistical analysis. In this data set, only 65% of men had ER-positive tumors, while in over 24% of the patients, ER status was unknown or negative in 11%. This is in contrast with other male breast cancer studies, where over 85% of the tumors are reported to be ER positive.7,40,41 ER status was missing in a substantial number of patients, so the observation that ER negativity was associated with greater mortality should be interpreted with caution. Overall, our results are similar to other
SEER database studies conducted to study metastatic breast cancer in women.26,28,42 Multiple retrospective studies, mainly in female breast cancer, and the current study examining survival in male breast cancer provide evidence of a survival benefit of primary surgery in selected patients with stage IV breast cancer. Our male breast cancer study results are similar to female breast cancer studies.12,14,17,23,28,42,43 Two randomized trials from Turkey and India examining the impact of PTS did not find a survival advantage; however, these trials had many limitations. Nearly half of the patients included in the analysis were treated off protocol because they did not meet the eligibility criteria.15 The Turkish trial suggested that patients with solitary bone metastases had significantly improved survival after surgery, but this was a small subset of patients, and biopsy confirmation was lacking in some cases.16 In the United States and Canada, the recently closed Eastern Cooperative Oncology Group trial, EA2108, addressing this very question of the role of PTS on survival, recruited 383 patients with metastatic breast cancer. The trial was revised because of slow enrollment and ultimately reached accrual in July 30, 2015. The results are eagerly awaited. Despite its limitations, the SEER data set provides quality population-based data, especially for rare diseases like male breast cancer. Our study demonstrates that surgical removal of the primary tumor provides a survival advantage in men with metastatic breast cancer. Given the retrospective nature of the study and the inherent limitations of the data set, we cannot make any definitive conclusions regarding the role of surgery. However, these results do question the nihilistic approach that is often used in the management of patients
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Stage IV Male Breast Cancer Table 5 Multivariate Analysis of Clinicopathologic Factors Affecting Overall Survival in Stage IV Male Breast Cancer, Surveillance, Epidemiology, and End Results, 1988-2011 Variable
Hazard Ratio
95% Confidence Interval
P
0.86-1.83
.26
Age (y) 50
1
>50
1.24
Race White
1
Black
0.80
0.60-1.05
.10
Other
0.69
0.38-1.15
.16
T0
0.27
0.08-0.67
.003
T1-T2 (5 cm)
1
T3 (>5 cm)
0.80
0.61-1.06
.13
TX
0.86
0.62-1.18
.35
Conclusion PTS among men with stage IV breast cancer demonstrates a survival advantage, similar to their female counterparts. Given the inherent limitations of a retrospective analysis, the controversy surrounding local treatment in stage IV breast cancer will only be answered in well-designed randomized trials. Until we have wellestablished selection criteria for resecting primary tumors in patients with metastatic breast cancer, a careful individualized assessment of each patient will continue to be required to determine if they are appropriate candidates for PTS.
Clinical Practice Points Male breast cancer is a rare disease, and management strategies
Tumor size
Node stage N0-N1
1
N2
0.96
0.75-1.26
.83
NX
1.14
0.84-1.53
.39
Estrogen receptor Positive
1
Negative
2.08
1.41-3.01
.0003
Unknown
3.31
1.35-9.37
.007
Progesterone receptor
Positive
1
Negative
1.28
0.95-1.70
.10
Unknown
0.70
0.25-1.68
.45
Grade 1-2
1
3
1.21
0.92-1.59
.17
Unknown
0.82
0.59-1.15
.25
Radiation
Yes
1
No
1.03
0.82-1.30
.82
Unknown
0.84
0.31-1.89
.70
1988-1998
0.90
0.67-1.20
.49
1999-2011
1
1.42-2.31
<.0001
Year of diagnosis
Surgery Yes
1
No
1.81
are extrapolated from female breast cancer studies. Various studies have demonstrated that differences exist in the etiology, clinical presentation, and outcome of male and female breast cancers. PTS in metastatic breast cancer is currently limited to palliation alone because of a lack of clear survival benefit. Many retrospective large database studies and single-institution trials have suggested an improvement in survival after PTS in metastatic cancer, but these studies have inherent limitations resulting from their retrospective nature. Small randomized phase 3 trials conducted overseas did not demonstrate a survival benefit for primary tumor resection in stage IV breast cancer, although both these trials had multiple flaws.15,16 The majority of these retrospective and prospective studies did not include male breast cancer. To our knowledge, this is the first study to address the impact of PTS in stage IV male breast cancer utilizing the SEER database. We found that PTS among men with stage IV breast cancer demonstrated a survival advantage, similar to their female counterparts. In view of the rarity of this disease and the poor accrual of male breast cancer patients in randomized trials, this study provides an important insight into the outcome of stage IV male breast cancer after surgery. The controversy surrounding local treatment in stage IV breast cancer will only be answered by well-designed randomized trials. There is likely a subset of patients who will benefit the most from PTS, such as patients with oligometastatic disease and disease responsive to systemic therapy. Outside of a clinical trial, PTS should be limited for palliation in both male and female breast cancer, but it can be considered in selected patients with low tumor burden and at an appropriate time in a multidisciplinary setting. The results from ongoing studies and the ECOG 2108 study, conducted in North America, may help answer this question in a randomized setting.
Reference category denoted by hazard ratio ¼ 1.00.
with metastatic breast cancer. Despite the stage IV nature of the disease, we found that excellent and thoughtful surgical management plays an important role in the care of breast cancer patients at all stages of disease. PTS in stage IV breast cancer warrants further research in a prospective randomized setting. We hope that the ECOG 2108 study and other ongoing trials will provide more answers.
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Acknowledgment We thank Jason Brinkley, PhD has provided some statistical input to this work.
Disclosure The authors have stated that they have no conflict of interest.
Mahvish Muzaffar et al References 1. American Cancer Society. Cancer treatment and survivorship facts and figures, 2014-2015. Available at: http://www.cancer.org/acs/groups/content/@research/ documents/document/acspc-042801.pdf. 2. Giordano SH, Cohen DS, Buzdar AU, Perkins G, Hortobagyi GN. Breast carcinoma in men: a population-based study. Cancer 2004; 101:51-7. 3. Ferzoco RM, Ruddy KJ. The epidemiology of male breast cancer. Curr Oncol Rep 2016; 18:1. 4. Anderson WF, Althuis MD, Brinton LA, Devesa SS. Is male breast cancer similar or different than female breast cancer? Breast Cancer Res Treat 2004; 83: 77-86. 5. Agrawal A, Ayantunde AA, Rampaul R, Robertson JF. Male breast cancer: a review of clinical management. Breast Cancer Res Treat 2007; 103:11-21. 6. Ruddy KJ, Winer EP. Male breast cancer: risk factors, biology, diagnosis, treatment, and survivorship. Ann Oncol 2013; 24:1434-43. 7. Anderson WF, Jatoi I, Tse J, Rosenberg PS. Male breast cancer: a population-based comparison with female breast cancer. J Clin Oncol 2010; 28:232-9. 8. Giordano SH. Male breast cancer: it’s time for evidence instead of extrapolation. Onkologie 2008; 31:505-6. 9. Dawood S, Broglio K, Gonzalez-Angulo AM, Buzdar AU, Hortobagyi GN, Giordano SH. Trends in survival over the past two decades among white and black patients with newly diagnosed stage IV breast cancer. J Clin Oncol 2008; 26:4891-8. 10. DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA Cancer J Clin 2014; 64:52-62. 11. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014; 64:9-29. 12. 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. 13. Khan SA. De novo stage IV breast cancer: breast conserving resection of the primary tumor? J Surg Oncol 2014; 110:51-7. 14. Blanchard DK, Shetty PB, Hilsenbeck SG, Elledge RM. Association of surgery with improved survival in stage IV breast cancer patients. Ann Surg 2008; 247:732-8. 15. 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. 16. Soran A, Ozmen V, Ozbas S, et al. Early follow up of a randomized trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer; Turkish study (protocol MF07-01) [abstract S2-03]. Cancer Res 2013; 73(24 suppl):S2-03. 17. 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 1988-2003 SEER data. Ann Surg Oncol 2007; 14:2187-94. 18. Fields EC, DeWitt P, Fisher CM, Rabinovitch R. 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. 19. Bratman SV, Kapp DS, Horst KC. Evolving trends in the initial locoregional management of male breast cancer. Breast 2012; 21:296-302. 20. 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. 21. Giordano SH. Lumpectomy in male patients with breast cancer. Ann Surg Oncol 2013; 20:2460-1. 22. National Cancer Institute. Surveillance, Epidemiology, and End Results. Available at: http://seer.cancer.gov/. Accessed: May 31, 2014.
23. 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. 24. Khan SA, Stewart AK, Morrow M. Does aggressive local therapy improve survival in metastatic breast cancer? Surgery 2002; 132:620-6. 25. Criscitiello C, Giuliano M, Curigliano G, et al. Surgery of the primary tumor in de novo metastatic breast cancer: to do or not to do? Eur J Surg Oncol 2015; 41:1288-92. 26. Gnerlich J, Dueker JM, Jeffe DB, Deshpande AD, Thompson S, Margenthaler JA. Patient and tumor characteristics associated with primary tumor resection in women with stage IV breast cancer: analysis of 1988-2003 SEER data. Breast J 2008; 14:538-42. 27. 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. 28. Cady B, Nathan NR, Michaelson JS, Golshan M, Smith BL. Matched pair analyses of stage IV breast cancer with or without resection of primary breast site. Ann Surg Oncol 2008; 15:3384-95. 29. Foerster R, Foerster FG, Wulff V, et al. Matched-pair analysis of patients with female and male breast cancer: a comparative analysis. BMC Cancer 2011; 11:335. 30. Scott-Conner CE, Jochimsen PR, Menck HR, Winchester DJ. An analysis of male and female breast cancer treatment and survival among demographically identical pairs of patients. Surgery 1999; 126:775-80. 31. Di Libero L, Varricchio A, Iannace C, et al. Is primary surgery for locally advanced/ metastatic breast cancer a better choice than chemotherapic treatment? Ann Ital Chir 2014; 85:317-22. 32. Norton L. Cancer stem cells, self-seeding, and decremented exponential growth: theoretical and clinical implications. Breast Dis 2008; 29:27-36. 33. Danna EA, Sinha P, Gilbert M, Clements VK, Pulaski BA, Ostrand-Rosenberg S. Surgical removal of primary tumor reverses tumor-induced immunosuppression despite the presence of metastatic disease. Cancer Res 2004; 64:2205-11. 34. Gunduz N, Fisher B, Saffer EA. Effect of surgical removal on the growth and kinetics of residual tumor. Cancer Res 1979; 39:3861-5. 35. Hartmann S, Reimer T, Gerber B, Stachs A. Primary metastatic breast cancer: the impact of locoregional therapy. Breast Care (Basel) 2014; 9:23-8. 36. Hanrahan EO, Broglio KR, Buzdar AU, et al. Combined-modality treatment for isolated recurrences of breast carcinoma: update on 30 years of experience at the University of Texas MD Anderson Cancer Center and assessment of prognostic factors. Cancer 2005; 104:1158-71. 37. 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. 38. Fisher B, Gunduz N, Coyle J, Rudock C, Saffer E. Presence of a growthstimulating factor in serum following primary tumor removal in mice. Cancer Res 1989; 49:1996-2001. 39. Rashaan ZM, Bastiaannet E, Portielje JE, et al. Surgery in metastatic breast cancer: patients with a favorable profile seem to have the most benefit from surgery. Eur J Surg Oncol 2012; 38:52-6. 40. Chavez-Macgregor M, Clarke CA, Lichtensztajn D, Hortobagyi GN, Giordano SH. Male breast cancer according to tumor subtype and race: a population-based study. Cancer 2013; 119:1611-7. 41. D’Onofrio L, Tonini G, Santini D. Clinical features of male breast cancer and multimodal treatment: a comment to retrospective survey analysis at Italian centers. Tumori 2014; 100:169e-70e. 42. Warschkow R, Guller U, Tarantino I, et al. Improved survival after primary tumor surgery in metastatic breast cancer: a propensity-adjusted, population-based SEER trend analysis. Ann Surg 2016; 263:1188-98. 43. Khan SA. Surgery for the intact primary and stage IV breast cancer. lacking “robust evidence”. Ann Surg Oncol 2013; 20:2803-5.
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Impact of Primary Tumor Surgery in Stage IV Male Breast Cancer Mahvish Muzaffar,1 Swapnil Kachare,2 Nasreen Vohra2 Abstract A Surveillance, Epidemiology, and End Results (SEER) database study demonstrated improvement in survival after primary tumor surgery in stage IV male breast cancer. Background: Primary tumor surgery (PTS) is not a standard treatment modality in stage IV breast cancer. Retrospective studies in female breast cancer show improved survival in women undergoing PTS; however, data regarding the impact of surgery in male breast cancer are lacking. The objective of this study was to analyze the impact of PTS on survival among men with metastatic breast cancer. Methods: A retrospective study was conducted of men diagnosed with metastatic breast cancer at diagnosis were identified from the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2011. Cox proportional hazards regression models were used to compare the differences in survival in men who did and did not undergo PTS. Results: A total of 439 men with stage IV breast cancer at diagnosis were identified, of which 222 (51%) underwent PTS, 171 (77%) mastectomy, and 51 (23%) partial mastectomy. The median age was 65 years; 74% of participants were white, 51% had tumors T2, 65% had estrogen receptor (ER)-positive tumor, and 24% had unknown ER status. Univariate analysis between the surgery and no-surgery arms showed that white race (P ¼ .04), lower T stage and grade (P ¼ .0003, P ¼ .004), ER positivity (P ¼ .0002), and later year of diagnosis (P < .0001) were associated with better survival. PTS was associated with improvement in median overall survival (29 vs. 11 months, P < .0001). On Cox regression analysis, ER negativity (hazard ratio ¼ 2.08; 95% confidence interval, 1.41-3.01; P < .0003) and not undergoing PTS were associated with diminished survival (hazard ratio ¼ 1.81; 95% confidence interval, 1.42-2.31; P < .0001). Conclusion: PTS among men with metastatic breast cancer was associated with improved survival in this retrospective analysis. Clinical Breast Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Metastatic breast cancer, Primary tumor surgery, Stage IV cancer, Survival
Introduction The incidence of male breast cancer has been increasing over the last few decades; however, it is still a rare disease, accounting for only 1% of breast cancer diagnoses in the United States.1-3 More than 40% of patients have advanced-stage disease at presentation, with larger primary tumors, more frequent lymph node involvement, and 8% to 10% stage IV disease.4,5 This is most likely due to a delay in recognition of this disease, absence of routine screening, and anatomic differences in the male breast that predispose this site to local invasion.4,6,7 Male breasts are smaller and have 1
Division of Hematology Oncology, Department of Internal Medicine Department of Surgery, Brody School of Medicine, East Carolina University, Greenville, NC 2
Submitted: Jul 31, 2016; Revised: Oct 27, 2016; Accepted: Nov 13, 2016 Address for correspondence: Mahvish Muzaffar, MD, Division of Hematology Oncology, Department of Internal Medicine, Brody School of Medicine, East Carolina University, Brody 3E127, 600 Moye Blvd, Greenville, NC 27834 Fax: (252) 744-3418; e-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2016.11.001
predominantly fatty tissue, with fewer ducts and stroma than the female breast. As a result, these patients often have skin and nipple involvement at presentation. Because of the rarity of this disease in men, the treatment recommendations are extrapolated from guidelines for management of female breast cancer.8 Metastatic breast cancer is still considered an incurable disease; systemic therapy is the main treatment modality. Metastatic breast cancer survival has improved over the last few decades.1,4,9-11 Recent advances in imaging modalities have resulted in the diagnosis of stage IV disease with lower tumor burdens than were seen in the past; this trend, along with an expanding armamentarium of systemic therapy, has resulted in an improvement in survival of stage IV breast cancer patients.9,10,12 The role of primary tumor surgery (PTS) in stage IV breast cancer is mostly limited to palliation for complications such as bleeding, ulceration, and infection at the primary tumor site, but mounting evidence from retrospective trials over the last few decades has demonstrated improved outcome with PTS in selected patients with stage IV disease.12-14 These data are in contrast to the findings from the limited randomized controlled
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Stage IV Male Breast Cancer trials conducted outside the United States, which confirmed better local disease control without survival advantage in women undergoing surgery.15,16 The data for the impact of PTS among men with stage IV disease are limited. Analysis of previously reported Surveillance, Epidemiology, and End Results (SEER) data showed that of all the women with stage IV breast cancer undergoing PTS, 52% had mastectomies.17 Male breast cancer patients tend to have more local symptoms and tend to present with locally advanced tumors, with an overwhelming majority of men with operable cancer undergoing mastectomy (87%), compared to less than half of all women (47%).4,18-21 It is likely that this trend also persists in men with stage IV disease to achieve palliation at the primary tumor site. We hypothesized that, similar to female breast cancer, PTS will improve survival in men with stage IV breast cancer. We report the results from our study, which was conducted to assess the role of PTS in the management of men with stage IV breast cancer, utilizing the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) registry from 1988 to 2011.22
Methods Data Source, Patient Selection, and Exclusion Criteria The SEER program, which is a National Cancer Instituteesupported database covering approximately 28% of the cancer cases in the US population, was utilized to identify the patient cohort for this study.22 A query of the SEER registry using SEER*Stat 8.1.2 was performed to identify all men with metastatic breast cancer at diagnosis between the years 1988 and 2011 (adjusted American Joint Committee on Cancer, 6th edition, criteria). We collected demographic data (age at diagnosis, race) and tumor characteristics (primary tumor size, nodal stage, tumor grade, histologic subtype, estrogen and progesterone receptor expression status, and human epidermal growth factor receptor 2 [HER-2] overexpression status). Treatment data collected included type of surgery and radiotherapy utilization.
Statistical Analysis A retrospective analysis was performed with median overall survival as the primary end point. Univariate descriptive analysis was performed by Student’s t test and the chi-square test where appropriate. Survival was analyzed using a combination of KaplanMeier curves and the log-rank test. Statistically significant variables on univariate analysis (P .2) were entered into a Cox regression analysis to determine independent associations with survival. Data analysis was performed by SAS 9.3 and JMP Pro 10.0.0 (2012) software (SAS Institute, Cary, NC, USA).
Results
2
-
Four hundred thirty-nine men with stage IV breast cancer at diagnosis were identified in the SEER database for the years 1988 to 2011. Table 1 summarizes the characteristics of the study population. The mean age of the patient population was 65 years (range, 30-93 years) in the overall group. The majority of patients were white (73.6%). Invasive ductal carcinoma was the most predominant histologic subtype, with 68% of the patients having this subtype. Sixty-five percent of the patients had an estrogen receptor
Clinical Breast Cancer Month 2016
(ER)-positive tumor, and 11% had an ER-negative tumor. The number of ER-positive tumors was lower than expected but can be explained by the higher percentage of disease with unknown receptor status (24%). Primary tumor size was > 5 cm in 30% of patients, 61% of patients had nodal involvement, and 38% had grade 3 tumors (Table 1). A 3-fold increase in the number of male stage IV cases in the SEER database was noted in the time period 1999-2009 compared to 1988-1998. Of the 439 patients in the study, 222 patients (51%) underwent PTS and 217 (49%) did not undergo surgery. The mean age of patients who underwent PTS was 65.8 years (range, 33-90 years) compared to 65.2 years (range, 30-93 years) for patients who did not undergo surgery (P ¼ .64). In the surgery cohort, 78.4% of patients were white and 18% were black, compared to 68.7% white and 23.5% black in the no-surgery arm (P ¼ .04). Patients who underwent surgery were also more likely to have lower T stage (63.9% vs. 34.5%) compared to the no-surgery arm (P < .0001) (Table 1). Among patients undergoing surgery, 64% had tumor size of < 5 cm compared to 36% in the no-surgery cohort (P < .0001). As shown in Table 1, there were more ER-positive tumors in the surgery group than in the no-surgery group (72.5% vs. 57.6%, P ¼ .0002). Thirty-seven percent (n ¼ 84) of the patients in the surgery cohort versus 32.3% in the no-surgery cohort also received radiotherapy (SEER does not provide information on the site of radiation). As shown in Table 2, of the 222 patients undergoing surgery, 49% (n ¼ 109) underwent modified radical mastectomy, 26% (n ¼ 58) underwent mastectomy, 2% (n ¼ 4) underwent radical mastectomy, and 23% (n ¼ 51) had partial mastectomy. Of the patients who underwent PTS, 51% (n ¼ 117) patients underwent axillary node dissection, whereas 13% (n ¼ 28) patients did not undergo axillary surgery (Table 3). Information about the extent of axillary surgery was missing for 20% (n ¼ 81) patients who had PTS. As shown in Table 4, age > 50 years (P < .0001), white race (P < .0001), lower T stage (P ¼ .0003), ER-positive status (P ¼ .0013), lower tumor grade (P ¼ .004), and later years of diagnosis (1999-2010) (P < .0001) were associated with improved median survival with surgery. The study population had a median overall survival of 19 months. The median follow-up was 48 months. Patients who underwent PTS had a significantly greater median overall survival compared to patients who did not undergo PTS (29 vs. 11 months, P < .0001) (Figure 1). A Cox proportional hazards model demonstrated that ER-negative tumors (relative risk ¼ 2.08; 95% confidence interval [CI], 1.41-3.01; P ¼ .0003) had an increased risk of mortality (Table 5). PTS among men with stage IV breast cancer was associated with a significantly increased median overall survival; patients who did not undergo surgery were more likely to die during the study period compared to men who did undergo surgery (hazard ratio ¼ 1.81; 95% CI, 1.42-2.31; P < .0001) (Table 5).
Discussion To our knowledge, this is one of the first studies to address the impact of PTS in men with stage IV breast cancer. The study demonstrated a 3-fold increase in stage IV cancer cases among men in 1999-2009 compared to 1988-1998. Epidemiologic studies also report an increase in the incidence of male breast cancer.2
Mahvish Muzaffar et al The increase in male breast cancer noted in our study may partly be a result of improved capturing of cancer cases in the SEER registry over the 23-year time frame of our study. Our study demonstrates improved survival among men with metastatic breast cancer who underwent PTS compared to no surgery (29 vs. 11 months, P < .0001). The superior overall survival was demonstrated in both univariate and multivariate analyses.
The role of PTS in the metastatic setting is still controversial, with differing outcomes between limited randomized trials and retrospective studies.12,13,17,23-28 Recently published analyses using the SEER database of women with stage IV disease who underwent surgery reported similar results. Longer median survival was associated with having surgery (survival 28 vs. 19 months; 95% CI, 7.6-10.4). Women with stage IV breast cancer who received surgery
Table 1 Characteristics of Men With Stage IV Breast Cancer Who Did and Did Not Undergo Primary Tumor Surgery, Surveillance, Epidemiology, and End Results, 1988-2011 Characteristic
Total Population (n [ 439)
Surgery (n [ 222)
No Surgery (n [ 217)
Age (y) 65.6 12.5
65.8 12.95
Median
65
65.5
65
Range
30-93
33-90
30-93
Mean
P .64
65.2 12.06
Age (y)
.14
50
47 (10.7)
19 (8.6)
28 (12.9)
>50
392 (89.3)
203 (91.4)
189 (87.1)
White
323 (73.6)
174 (78.4)
149 (68.7)
Black
91 (20.7)
40 (18.0)
51 (23.5)
Other
25 (5.7)
8 (3.6)
17 (7.8)
6 (1.4)
2 (0.9)
4 (1.8)
T1-T2 (5 cm)
217 (49.4)
142 (63.9)
75 (34.5)
T3 (>5 cm)
130 (29.6)
59 (26.5)
71 (32.7)
86 (19.6)
19 (8.5)
67 (30.6.8)
Race
.04
<.0001
Tumor stage T0
TX Node stage
.0003
N0
79 (18.0)
43 (19.4)
36 (16.6)
N1
123 (28.0)
61 (27.5)
62 (38.6)
N2
145 (33.0)
87 (39.1)
58 (26.7)
92 (21.0)
31 (13.9)
61 (28.1)
NX Estrogen receptor
.0002
Positive
286 (65.1)
161 (72.5)
Negative
47 (10.7)
26 (11.7)
125 (57.6) 21 (9.7)
Unknown
106 (24.1)
35 (16.2)
71 (32.7)
Positive
225 (51.3)
127 (57.2)
98 (45.2)
Negative
103 (23.5)
59 (26.6)
44 (20.3)
Unknown
110 (25.2)
36 (16.2)
74 (34.5)
146 (32.3)
84 (37.8)
62 (28.5)
3
177 (40.3)
114 (51.4)
63 (29.0)
Unknown
116 (26.4)
24 (10.8)
92 (42.5)
Progesterone receptor
.0001
<.0001
Grade 1-2
Radiation
.38
Yes
154 (35.1)
84 (37.8)
70 (32.3)
No
277 (63.1)
135 (60.8)
142 (65.4)
8 (1.8)
3 (1.4)
5 (2.3)
1988-1998
86 (19.6)
48 (21.6)
38 (17.5)
1999-2011
353 (80.4)
174 (78.4)
179 (82.5)
Unknown Year of diagnosis
.28
Data are presented as n (%) unless otherwise indicated.
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Stage IV Male Breast Cancer Table 2 Type of Surgery Performed in Men With Metastatic Breast Cancer for Resection of Primary Tumor, Surveillance, Epidemiology, and End Results, 1988-2011 Type of Primary Tumor Surgery
Total Undergoing Surgery (n [ 222), N (%)
Modified radical mastectomy Radical mastectomy Mastectomy Mastectomy without ALND Partial mastectomy Partial mastectomy without ALND
109 4 45 13 36 15
(49.1) (1.9) (20.3) (5.8) (16.2) (6.7)
Abbreviation: ALND ¼ axillary lymph node dissection.
were 2.80 times more likely to survive at least 10 years compared to those who did not (95% CI, 2.08-3.77).12 Univariate survival analysis demonstrated a survival advantage of 18 months for patients undergoing PTS over no surgery. When controlling for known prognostic factors like tumor size, age at diagnosis, nodal status, ER status, and disease grade, this survival advantage persisted. Not undergoing PTS was associated with diminished survival (hazard ratio ¼ 1.81, 1.42-2.31, P < .0001). As expected, patients with lower T stage and with ER-positive disease had better outcomes with surgery on multivariate analysis. A decreasing trend toward surgery was noted, with 56% of patients with metastatic cancer undergoing surgery during 1988-1998 versus 52% during 1999-2009. This observation is similar to the recently reported trend among female stage IV breast cancer patients undergoing surgery.12 Surgical management of nonmetastatic male and female breast cancer patients has historically differed, with mastectomy performed more frequently among men versus women, who are equally likely to get a mastectomy or partial mastectomy based on the in-breast disease burden.29,30 In our study, 75% of the men who had PTS underwent mastectomy, and only 23% underwent partial mastectomy. Our analysis revealed that patients in the surgery group had more T1/T2 lesions compared to the no-surgery group. While PTS in metastatic breast cancer patients is performed for palliation of bleeding, ulceration, and symptomatic lesions, it also appears that patients with limited in-breast disease and manageable metastatic burden may be undergoing surgery to achieve better disease control and possibly prolong survival, as observed in retrospective studies.12,27 While we can surmise that disease control for ulceration and other local symptoms may also be a reason for patients with stage IV tumors undergo surgery, our analysis does not support this
Table 3 Extent of Axillary Surgery in Men With Metastatic Breast Cancer Undergoing Primary Tumor Surgery, Surveillance, Epidemiology, and End Results, 1988-2011 Axillary Surgery ALND No ALND Unknown
4
-
Abbreviation: ALND ¼ axillary lymph node dissection.
Clinical Breast Cancer Month 2016
Table 4 Univariate Analysis of Clinicopathologic Factors Affecting Overall Survival in Male Stage IV Breast Cancer Patients, Surveillance, Epidemiology, and End Results, 1988-2011
N (%) 113 (50.9) 28 (12.6) 81 (36.5)
OS (mo) Variable
Surgery
No Surgery
P
Age (y) 50
41
18.5
>50
28
10
<.0001
.16
Race White
29
10
<.0001
Black
21.5
18
.92
Other
48
10
.08
Tumor stage T0
—
—
T1-T2 (5 cm)
29
7
T3 (>5 cm)
33
17
.0003 .09
TX
11
6
.11
N0-N1
26
13
.019
N2
33
11
NX
11
5
33
21
Node stage .0012 .18
Estrogen receptor Positive Negative
5
.4
11
4
.04
Positive
35
23
Negative
15
7
.07
Unknown
13.5
4
.04 0.0038
Unknown
4.5
.0013
Progesterone receptor .0018
Grade 1-2
34
18
3
25
11
.014
Unknown
33
7
.017
Yes
30
12
.09
No
29
10
.0002
Radiation
Unknown
—
—
—
Year of diagnosis 1988-1998
27
11
.01
1999-2011
30
11
<.0001
29
11
<.0001
Median OS
as being the primary indication for surgery based on comparing the T stages in both groups. A possible explanation for this observation may be the impact of selection bias in this retrospective analysis. Stage IV breast cancer patients with favorable clinicopathologic features more often tend to undergo primary tumor resection. Our results are similar to other studies conducted in female breast cancer patients; patients in the surgery group had more T1 and T2 primary tumors compared to patients who did not undergo surgery.12,23,26 The justification for resection of the primary tumor is based on the biologic rationale of correlation between local tumor burden and
Mahvish Muzaffar et al Figure 1 Overall Survival for Primary Tumor Surgery Versus No-Surgery Groups in Male Stage IV Breast Cancer, Surveillance, Epidemiology, and End Results, 1988-2011
metastatic potential17,23,31—the cancer self-seeding hypothesis that proposes recirculation and seeding of the primary site,32 possible restoration of immunomodulation by removing potential source of immunosuppression from the primary tumor, and improved responsiveness to systemic therapy.33-36 The opponents of surgical resection cite the lack of randomized data demonstrating efficacy, morbidity associated with the surgical procedure, potential delay in systemic therapy administration, and the theory of increased angiogenesis and accelerated tumor growth associated with the surgical wound in metastatic cancer.34,37,38 We acknowledge the inherent limitations of this retrospective study, which include potential biases like unaccounted timing of surgery with systemic therapy and selection bias due to favorable patient characteristics like younger age, fewer comorbidities, and lower disease burden.26,28,39 The SEER database also has several limitations, which include unavailability of number and sites of metastases, timing and type of systemic therapy administered, margin status, completeness of resection, number of lymph nodes removed, and site of radiation.22 The small number of patients, along with the rarity of male breast cancer, also limits more meaningful statistical analysis. In this data set, only 65% of men had ER-positive tumors, while in over 24% of the patients, ER status was unknown or negative in 11%. This is in contrast with other male breast cancer studies, where over 85% of the tumors are reported to be ER positive.7,40,41 ER status was missing in a substantial number of patients, so the observation that ER negativity was associated with greater mortality should be interpreted with caution. Overall, our results are similar to other
SEER database studies conducted to study metastatic breast cancer in women.26,28,42 Multiple retrospective studies, mainly in female breast cancer, and the current study examining survival in male breast cancer provide evidence of a survival benefit of primary surgery in selected patients with stage IV breast cancer. Our male breast cancer study results are similar to female breast cancer studies.12,14,17,23,28,42,43 Two randomized trials from Turkey and India examining the impact of PTS did not find a survival advantage; however, these trials had many limitations. Nearly half of the patients included in the analysis were treated off protocol because they did not meet the eligibility criteria.15 The Turkish trial suggested that patients with solitary bone metastases had significantly improved survival after surgery, but this was a small subset of patients, and biopsy confirmation was lacking in some cases.16 In the United States and Canada, the recently closed Eastern Cooperative Oncology Group trial, EA2108, addressing this very question of the role of PTS on survival, recruited 383 patients with metastatic breast cancer. The trial was revised because of slow enrollment and ultimately reached accrual in July 30, 2015. The results are eagerly awaited. Despite its limitations, the SEER data set provides quality population-based data, especially for rare diseases like male breast cancer. Our study demonstrates that surgical removal of the primary tumor provides a survival advantage in men with metastatic breast cancer. Given the retrospective nature of the study and the inherent limitations of the data set, we cannot make any definitive conclusions regarding the role of surgery. However, these results do question the nihilistic approach that is often used in the management of patients
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Stage IV Male Breast Cancer Table 5 Multivariate Analysis of Clinicopathologic Factors Affecting Overall Survival in Stage IV Male Breast Cancer, Surveillance, Epidemiology, and End Results, 1988-2011 Variable
Hazard Ratio
95% Confidence Interval
P
0.86-1.83
.26
Age (y) 50
1
>50
1.24
Race White
1
Black
0.80
0.60-1.05
.10
Other
0.69
0.38-1.15
.16
T0
0.27
0.08-0.67
.003
T1-T2 (5 cm)
1
T3 (>5 cm)
0.80
0.61-1.06
.13
TX
0.86
0.62-1.18
.35
Conclusion PTS among men with stage IV breast cancer demonstrates a survival advantage, similar to their female counterparts. Given the inherent limitations of a retrospective analysis, the controversy surrounding local treatment in stage IV breast cancer will only be answered in well-designed randomized trials. Until we have wellestablished selection criteria for resecting primary tumors in patients with metastatic breast cancer, a careful individualized assessment of each patient will continue to be required to determine if they are appropriate candidates for PTS.
Clinical Practice Points Male breast cancer is a rare disease, and management strategies
Tumor size
Node stage N0-N1
1
N2
0.96
0.75-1.26
.83
NX
1.14
0.84-1.53
.39
Estrogen receptor Positive
1
Negative
2.08
1.41-3.01
.0003
Unknown
3.31
1.35-9.37
.007
Progesterone receptor
Positive
1
Negative
1.28
0.95-1.70
.10
Unknown
0.70
0.25-1.68
.45
Grade 1-2
1
3
1.21
0.92-1.59
.17
Unknown
0.82
0.59-1.15
.25
Radiation
Yes
1
No
1.03
0.82-1.30
.82
Unknown
0.84
0.31-1.89
.70
1988-1998
0.90
0.67-1.20
.49
1999-2011
1
1.42-2.31
<.0001
Year of diagnosis
Surgery Yes
1
No
1.81
are extrapolated from female breast cancer studies. Various studies have demonstrated that differences exist in the etiology, clinical presentation, and outcome of male and female breast cancers. PTS in metastatic breast cancer is currently limited to palliation alone because of a lack of clear survival benefit. Many retrospective large database studies and single-institution trials have suggested an improvement in survival after PTS in metastatic cancer, but these studies have inherent limitations resulting from their retrospective nature. Small randomized phase 3 trials conducted overseas did not demonstrate a survival benefit for primary tumor resection in stage IV breast cancer, although both these trials had multiple flaws.15,16 The majority of these retrospective and prospective studies did not include male breast cancer. To our knowledge, this is the first study to address the impact of PTS in stage IV male breast cancer utilizing the SEER database. We found that PTS among men with stage IV breast cancer demonstrated a survival advantage, similar to their female counterparts. In view of the rarity of this disease and the poor accrual of male breast cancer patients in randomized trials, this study provides an important insight into the outcome of stage IV male breast cancer after surgery. The controversy surrounding local treatment in stage IV breast cancer will only be answered by well-designed randomized trials. There is likely a subset of patients who will benefit the most from PTS, such as patients with oligometastatic disease and disease responsive to systemic therapy. Outside of a clinical trial, PTS should be limited for palliation in both male and female breast cancer, but it can be considered in selected patients with low tumor burden and at an appropriate time in a multidisciplinary setting. The results from ongoing studies and the ECOG 2108 study, conducted in North America, may help answer this question in a randomized setting.
Reference category denoted by hazard ratio ¼ 1.00.
with metastatic breast cancer. Despite the stage IV nature of the disease, we found that excellent and thoughtful surgical management plays an important role in the care of breast cancer patients at all stages of disease. PTS in stage IV breast cancer warrants further research in a prospective randomized setting. We hope that the ECOG 2108 study and other ongoing trials will provide more answers.
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Clinical Breast Cancer Month 2016
Acknowledgment We thank Jason Brinkley, PhD has provided some statistical input to this work.
Disclosure The authors have stated that they have no conflict of interest.
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