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Does Choice of Reconstruction Type Affect Survival in Patients With Metastatic Breast Cancer?
j o u r n a l o f s u r g i c a l r e s e a r c h - 2 0 1 9 ( - ) 1 e1 1
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Does Choice of Reconstruction Type Affect Survival in Patients With Metastatic Breast Cancer? Xin Qi, MD, Keren Wang, MD, PhD, Denghua Sun, MD, and Le Zhang, MD, PhD* Department of Breast Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
article info
abstract
Article history:
Background: To compare the breast cancerespecific survival (BCSS) and overall survival (OS)
Received 25 March 2019
between patients who underwent implant or tissue reconstruction after mastectomy with
Received in revised form
distant metastatic breast cancer (MBC).
2 August 2019
Materials and methods: Using the Surveillance, Epidemiology, and End Results database, we
Accepted 25 September 2019
enrolled 371 female MBC cases diagnosed during the years 2004-2014. Patients were subdivided
Available online xxx
into implant (176) and tissue groups (195) for survival comparison between the two groups. The end points were BCSS and OS. Comparisons of the distribution of clinicopathologic charac-
Keywords:
teristics were evaluated by chi-square test and Fisher exact test. Survival outcomes were
Metastatic breast cancer
compared by Kaplan-Meier model and multivariate Cox regression model for known clinico-
Breast reconstruction
pathologic variables in both the entire population and in the reconstruction cohorts.
Breast cancerespecific survival
Results: In the entire cohort, patients with implant exhibited distinctly better BCSS (log
Overall survival
rank, P ¼ 0.002) and OS (log rank, P ¼ 0.001) than patients with tissue reconstruction.
SEER
Multivariate Cox regression model revealed that patients, who received prosthetic implants, were married, and progesterone receptorepositive group showed better survival rates in BCSS and OS. In addition, after stratification of the implant group and tissue groups according to clinicopathologic variables, the survival rate of patients in the implant group was higher than that in the tissue reconstruction group under the influence of factors, such as married, estrogen receptorenegative, nonradiotherapy, and chemotherapy. Conclusions: Our study provides further survival evidence supporting the practice of mastectomy with prosthetic implant reconstruction in patients with MBC under certain conditions. ª 2019 Elsevier Inc. All rights reserved.
Introduction Breast cancer (BC) is the most common cancer among females in the United States, accounting for 30%, and the second leading cause of cancer death among women after lung cancer.1 With the rapid developments in the modern medical
imaging technology, the early diagnostic rate of BC has been improving, and subsequently, the prognosis has improved as well. Nevertheless, it has been reported that approximately 2.4%-6% of patients with BC develop metastases on initial diagnosis and 20%-30% during the course of treatment.2,3 Bone, lung, liver, and brain are the common sites that BC
* Corresponding author. Department of Breast Surgery, China-Japan Union Hospital, Jilin University, 126 Xiantai Street, Jingkai District, Changchun, Jilin 130033, China. Tel.: þ86 431 84995495; fax: þ86 431 84995495. E-mail address: [email protected] (L. Zhang). 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.09.057
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preferentially metastasizes, in decreasing order of frequency, and appear to have a close correlation with the patients’ survival outcome. The disease-free survival rates and overall survival (OS) for BC have significantly improved in recent years owing to combined therapy.4 Despite the advances in chemoradiotherapy fields, surgical intervention is still the cornerstone of the treatment of BC.4 Breast conservative surgery, sentinel lymph node dissection, oncoplastic technique, mastectomy, and breast reconstructive surgery are currently among the most common surgical procedures. As a vital part of comprehensive treatment of BC, mastectomy that is considered as a survival advantage in metastatic breast cancer (MBC) not only resects the primary tumor completely but also results in significant psychological distress for patients with BC.5,6 Breast reconstruction (BR) that aims to restore the shape of the breasts has been shown to improve the quality of life of patients without negatively influencing postoperative surveillance of tumor recurrence and adjuvant therapies.7,8 Most female patients agree that their sexuality, femininity, and intimate relationships are well maintained after BR.9 Medical development makes it possible for patients to prolong their lives and improve quality of life with prosthetic implants and autologous tissues. Thus, we sought it important to investigate prognostic factors of survival between prosthetic implants and autologous tissues in patients with MBC. Previous studies have not been able to definitively analyze the prognostic factors in some BC patient populations because of the limited number of cases. Surveillance, Epidemiology, and End Results (SEER) database is a population-based database launched in 1973, supported and managed by the National Cancer Institute in the United States, which covers 27.8% of the US population from 18 states. Data on patients with MBC who
underwent prosthetic implants and autologous tissue reconstruction were extracted from SEER database and used in the present study. The study aimed to investigate the prognostic factors of influencing survival between prosthetic implants and autologous tissue reconstruction in patients with MBC.
Materials and methods Cohort inclusion/exclusion criteria SEER*Stat version 8.3.5 (The Surveillance Research Program of the Division of Cancer Control and Population Sciences, National Cancer Institute) was used to filter and collect the information of patients who were diagnosed with BC from 2004 to 2014 and followed up before December 31, 2015. Patients who met the following criteria were included: (1) pathologicconfirmed diagnosis; (2) diagnosed with BC between 2004 and 2014; (3) first single primary cancer; (4) active follow-up; and (5) underwent simple/modified mastectomy and reconstructed with tissue or implant. The exclusion criteria were as follow: (1) diagnosed at autopsy or via death certificate; (2) male; (3) unknown status of estrogen receptor (ER) or progesterone receptor (PR); and (4) diagnosed without metastases. We chose patients who were diagnosed since 2004 to maintain the integrity and accuracy of patients’ information, and those diagnosed after 2014 were excluded to ensure enough time for follow-up. Finally, a total of 371 patients with MBC were eligible for analysis on the basis of our inclusion and exclusion criteria, and the flowchart of the subjects’ selection is shown in Figure 1. Our study had been approved by the ethics committee of China Japan Union Hospital of Jilin University.
Fig. 1 e Flowchart of patient selection for analyzing the risk factors for the morbidity and prognosis from implantation or tissue reconstruction in BC patients with metastases.
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qi et al outcomes between two breast reconstruction
Table 1 e Baseline of the demographic and related clinical features of two different BR surgeries for developing distant metastases in patients diagnosed with BC Characteristics
No. of patients with BC (2004-2014) Tissue
Implant
P
n ¼ 195 (%)
n ¼ 176 (%)
Chi-square 0.010
Age (Y) 40 and Younger
36 (18.46)
55 (31.25)
118 (60.51)
96 (54.55)
41 (21.03)
25 (14.20)
White
144 (73.85)
148 (84.09)
Black
34 (17.44)
18 (10.23)
Other
17 (8.72)
10 (5.69)
116 (59.49)
114 (64.77)
Unmarried
77 (39.49)
52 (29.55)
Unknown
2 (1.03)
10 (5.68)
Left
96 (49.23)
85 (48.30)
Right
99 (50.77)
91 (51.70)
Nipple/central portion
10 (5.13)
12 (6.82)
UIQ
16 (8.21)
12 (6.82)
LIQ
8 (4.10)
10 (5.69)
UOQ
50 (25.64)
48 (27.27)
LOQ
16 (8.21)
13 (7.39)
Other
95 (48.72)
81 (46.02)
15 (7.69)
7 (3.98)
Older than 40; 60 and younger Older than 60 Race
0.054
Marital status Married
0.010
Laterality 0.857
Primary site 0.919*
Histologic grade I II
58 (29.74)
55 (31.25)
III
110 (56.41)
101 (57.39)
IV
1 (0.51)
2 (1.14)
11 (5.64)
11 (6.25)
T1
20 (10.26)
20 (11.36)
T2
77 (39.49)
83 (47.16)
T3
32 (16.41)
46 (26.14)
T4
59 (30.26)
24 (13.64)
Tx
7 (3.59)
3 (1.71)
N0
23 (11.79)
23 (13.07)
N1
75 (38.46)
71 (40.34)
N2
45 (23.08)
36 (20.45)
N3
50 (25.64)
44 (25.00)
Nx
2 (1.03)
2 (1.14)
Positive
132 (67.69)
130 (73.86)
Negative
63 (32.31)
46 (26.14)
Positive
105 (53.850)
108 (61.36)
Negative
90 (46.15)
68 (38.64)
Unknown
0.624*
T stage 0.001*
N stage 0.969*
ER status 0.193
PR status 0.144
(continued)
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Table 1 e (continued ) Characteristics
No. of patients with BC (2004-2014) Tissue
Implant
P
n ¼ 195 (%)
n ¼ 176 (%)
Chi-square
159 (81.54)
149 (84.66)
0.669*
Lobular
14 (7.18)
13 (7.39)
IDC and lobular
10 (5.13)
8 (4.55)
Other
12 (6.15)
6 (3.41)
68 (34.87)
70 (39.77)
127 (65.13)
106 (60.23)
Histology IDC
Mastectomy type SM MRM
0.329
Radiotherapy Yes
83 (42.56)
81 (46.02)
No
112 (57.44)
95 (53.98)
Yes
160 (82.05)
150 (85.23)
No
35 (17.95)
26 (14.77)
0.503
Chemotherapy 0.410
Bold type of P value indicates significance. Histologic grade, I ¼ well differentiated; II ¼ moderately differentiated; III ¼ poorly differentiated; and IV ¼ undifferentiated. T1 ¼ 2 cm, T2 ¼ 5 cm, T3 ¼ >5 cm, T4 ¼ invasion of chest wall or skin, and Tx ¼ primary tumor cannot be assessed. N0 ¼ zero lymph nodes, N1 ¼ one to three lymph node metastasis, N2 ¼ four to nine lymph node metastasis, N3 ¼ 10 lymph node metastasis, and Nx ¼ regional lymph nodes cannot be assessed. UIQ ¼ upper inner quadrant; LIQ ¼ lower inner quadrant; UOQ ¼ upper outer quadrant; LOQ ¼ lower outer quadrant; T ¼ tumor size; N ¼ lymph node; IDC ¼ infiltrating duct carcinoma; SM ¼ simple mastectomy; MRM ¼ modified radical mastectomy. * Fisher exact test was used.
Statistical analysis The demographic and clinical features for developing distant metastases in patients diagnosed with BC were evaluated. The differences in clinical characteristics between the two groups (prosthetic implants and autologous tissue reconstruction) were examined using the chi-square test and Fisher exact test. Breast cancerespecific survival (BCSS) was defined from the date of diagnosis to the date of death, with BC death treated as an event. OS was defined from the date of diagnosis to the date of death, and death for any cause was considered as an event. For calculating BCSS and OS curves, the Kaplan-Meier method was used to estimate survival and risk curves, and survival differences were examined with log rank test for univariate analysis. Multivariate Cox regression models were built for analyzing BCSS and OS in the MBC population. After the identification of two groups (implant and tissue groups) of significant difference on survival, subgroup analysis was performed by univariate and multivariate Cox regression models. Univariate Cox regression analysis was performed for each prognostic variable, and those variables with statistical significance were included in the multivariate Cox model analysis. All analyses were performed using the SPSS for Windows, version 19.0, statistical software package (International Business Machines Corporation). P < 0.05 was defined as statistical significance.
Results Demographics and clinical characteristics of the study population A total of 371 patients in the United States were diagnosed with MBC between 2004 and 2014 and were included in the present analysis with a median follow-up of 61.0 mo. Of the 371 identified patients, 195 patients underwent autologous tissue reconstruction and 176 patients underwent prosthetic implant reconstruction. The patients’ demographic and related clinical features are presented in Table 1. We found no statistically significant differences in these factors between the two groups, except age, marital status, and T stage. Married patients tended to choose implant reconstruction. In terms of age distribution, 40-60-y-old patients accounted for 60.51% and 54.55% of the total number of patients in the tissue group and implant group, respectively. Compared with the implant group, patients older than 60 y were more likely to choose autologous tissue reconstruction methods.
Prognostic factors associated with BCSS and OS We analyzed BCSS and OS via Kaplan-Meier method. In univariate analysis (Table 2), we observed that race, marital status, histologic grade, T stage, ER status, PR status, and construction type had statistical significance in both BCSS and
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Table 2 e Univariate and multivariate Cox regression analyses of clinical features of BCSS and OS in patients with distant metastases diagnosed with primary BC Characteristics
BCSS Univariate analysis P
Age (Y)
OS Multivariate Cox regression
OR (95% CI)
P
0.116
Univariate analysis P
Multivariate Cox regression OR (95% CI)
P
0.149
40 and younger Older than 40; 60 and younger Older than 60 Race
0.005
0.021
White
Reference
Black
1.08 (0.70-1.68)
0.727
1.10 (0.71-1.71)
0.067
Other
0.39 (0.19-0.85)
0.017
0.53 (0.28-1.02)
0.058
Marital status
0.001
Married
0.002 Reference
Unmarried
1.51 (1.08-2.11)
Unknown
NA
Laterality
Reference
Reference 0.015
1.48 (1.07-2.05)
NA
NA
0.827
0.915
0.094
0.044
0.019 NA
Left Right Primary site Nipple/central portion
Reference
UIQ
1.72 (0.70-4.21)
0.235
LIQ
1.38 (0.51-3.77)
0.528
UOQ
1.95 (0.93-4.10)
0.08
LOQ
0.79 (0.27-2.29)
0.665
Other
2.01 (0.99-4.08)
0.054
Histologic grade
0.014
0.007
I
Reference
II
0.70 (0.32-1.54)
0.38
0.69 (0.33-1.47)
0.338
III
1.03 (0.48-2.18)
0.949
1.05 (0.51-2.16)
0.887
IV
0.00 (0.00-0.00)
0.96
0.00 (0.00-0.00)
0.945
NA
NA
Unknown T stage
Reference
<0.001
NA
NA
<0.001
T1
Reference
T2
0.64 (0.37-1.13)
0.126
0.74 (0.43-1.28)
0.277
T3
0.87 (0.47-1.60)
0.653
0.97 (0.54-1.77)
0.931
T4
1.54 (0.86-2.74)
0.145
1.63 (0.92-2.90)
0.096
Tx
0.21 (0.05-0.94)
0.041
0.39 (0.11-1.40)
0.149
N stage
Reference
0.503
0.152
<0.001
<0.001
N0 N1 N2 N3 Nx ER status Positive
Reference
Negative
0.93 (0.60-1.42)
PR status Positive
<0.001
Reference 0.723
1.00 (0.65-1.52)
0.982
<0.001 Reference
Reference (continued)
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Table 2 e (continued ) Characteristics
BCSS Univariate analysis P
Negative Histology
OS Multivariate Cox regression
OR (95% CI)
P
2.64 (1.73-4.03)
<0.001
0.391
Univariate analysis P
Multivariate Cox regression OR (95% CI)
P
2.45 (1.62-3.68)
<0.001
0.501
IDC Lobular IDC and lobular Other Mastectomy type
0.02
SM MRM Construction type
1.54 (1.08-2.19)
0.018
0.002
Tissue
0.001 Reference
Implant Radiotherapy
0.072 Reference
Reference
0.66 (0.47-0.91)
0.012
0.61 (0.44-0.85)
0.201
0.159
0.571
0.756
0.003
Yes No Chemotherapy Yes No Bold type of P value indicates significance. Histologic grade, I ¼ well differentiated; II ¼ moderately differentiated; III ¼ poorly differentiated; and IV ¼ undifferentiated. T1 ¼ 2 cm, T2 ¼ 5 cm, T3 ¼ >5 cm, T4 ¼ invasion of chest wall or skin, Tx ¼ primary tumor cannot be assessed. N0 ¼ zero lymph nodes, N1 ¼ one to three lymph node metastasis, N2 ¼ four to nine lymph node metastasis, N3 ¼ 10 lymph node metastasis, and Nx ¼ regional lymph nodes cannot be assessed. NA ¼ not available; UIQ ¼ upper inner quadrant; LIQ ¼ lower inner quadrant; UOQ ¼ upper outer quadrant; LOQ ¼ lower outer quadrant; T ¼ tumor size; N ¼ lymph node; IDC ¼ infiltrating duct carcinoma; SM ¼ simple mastectomy; MRM ¼ modified radical mastectomy.
OS. Mastectomy type had statistical significance in BCSS, whereas primary site had statistical significance only in OS. Compared with patients receiving autologous tissue reconstruction, patients receiving prosthetic implant reconstruction had better BCSS (log rank, P ¼ 0.002; Fig. 2A), which was more obvious in OS (log rank, P ¼ 0.001; Fig. 2B). These factors
with statistical significance were all included in the multivariate Cox analysis (Table 2). The multivariate Cox regression model showed that patients treated with prosthetic implant reconstruction had improved BCSS and OS (BCSS: hazard ratio [HR], 0.66; 95% confidence interval [95% CI], 0.47-0.91; P ¼ 0.012 and OS: HR, 0.61; 95% CI, 0.44-0.85; P ¼ 0.003) compared with
Fig. 2 e Kaplan-Meier curves of the (A) BCSS and (B) OS in BC patients with metastases undergoing implantation or tissue reconstruction. (Color version of figure is available online.)
qi et al outcomes between two breast reconstruction
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Fig. 3 e Kaplan-Meier curves of the BCSS and OS among BC patients with metastases, when stratified by (A and E) marital status, (B and F) ER, (C and G) radiotherapy, and (D and H) chemotherapy. (Color version of figure is available online.)
patients who underwent autologous tissue reconstruction. Other factors including married (versus unmarried) and positive PR were all associated with improved BCSS and OS. Compared with modified radical mastectomy, patients receiving simple mastectomy had better BCSS.
P ¼ 0.017 for BCSS and OS, respectively), the absence of radiotherapy (OR, 0.51; 95% CI, 0.32-0.81; P ¼ 0.004 and OR, 0.52; 95% CI, 0.33-0.80; P ¼ 0.003 for BCSS and OS, respectively), and the presence of chemotherapy (OR, 0.68; 95% CI, 0.47-0.98; P ¼ 0.039 and OR, 0.64; 95% CI, 0.45-0.91; P ¼ 0.014 for BCSS and OS, respectively).
Comparison of survival between implant and tissue reconstruction stratified according to clinical characteristics
Discussion To further investigate the probable factors influencing survival of the two reconstruction types, we stratified patients according to age (40 y and younger, older than 40 y, 60 y and younger, and older than 60 y), race (white, black, and others), marital status (married and unmarried), histologic grade (I, II, II, IV, and unknown), primary tumor (T) stage (T1, T2, T3, T4, and Tx), regional lymph node stage (N1, N2, N3, and Nx), ER status (positive and negative), PR status (positive and negative), histology (infiltrating duct carcinoma; lobular carcinoma; infiltrating duct carcinoma and lobular carcinoma; and other), mastectomy type (simple mastectomy and modified radical mastectomy), and the condition of radiotherapy and chemotherapy. Subgroup analysis was performed based on the aforementioned factors. As shown in Figure 3, survival and risk curves also confirmed that patients receiving prosthetic implant reconstruction had better BCSS and OS. As seen in Table 3, compared with tissue group, implant group had better survival in patients who were married (odds ratio [OR], 0.52; 95% CI, 0.32-0.84; P ¼ 0.007 and OR, 0.49; 95% CI, 0.31-0.78; P ¼ 0.002 for BCSS and OS, respectively), ER negative (OR, 0.40; 95% CI, 0.20-0.83; P ¼ 0.013 and OR, 0.43; 95% CI, 0.22-0.86;
The application of BR in the surgical management of BC has increased significantly in the past decade.10,11 The rate of BR after mastectomy in women with early stage BC in the United States increased from 15% in 2000 to 32% in 2011.10,12,13 Although the number of BR patients is increasing, the number of patients with MBC undergoing reconstruction remains small. Reconstruction reduces the psychological and physiological consequences of mastectomy and improves the quality of life of end-stage patients.13 Therefore, it is worth discussing which breast reconstructive method should be chosen for patients with MBC. The present study is a large populationbased study to investigate the prognostic factors of influencing survival between prosthetic implants and autologous tissue reconstruction in patients with MBC. Data were drawn from the SEER database, which made it a larger study and our findings more generalizable and less susceptible to individual variations. The approaches from prosthetic implants to autologous tissue reconstruction provide patients more choices to a large proportion of patients. Both these two approaches have their
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Table 3 e Univariate and multivariate Cox regression analyses of BCSS and OS comparing implant with tissue reconstruction stratified according to clinical characteristics Characteristics
Implant versus tissue (BCSS) Univariate analysis P
Implant versus tissue (OS)
Multivariate Cox regression OR (95% CI)
Univariate analysis P
P
Multivariate Cox regression OR (95% CI)
P
Age (Y) 40 and younger
0.139
0.74 (0.29-1.87)
0.524
0.062
0.68 (0.27-1.69)
0.401
Older than 40; 60 and younger
0.12
0.71 (0.45-1.11)
0.13
0.074
1.00 (0.66-1.51)
1.00
Older than 60
0.019
0.42 (0.12-1.41)
0.16
0.014
0.35 (0.11-1.19)
0.092
White
0.01
0.70 (0.48-1.03)
0.071
0.005
0.68 (0.47-0.99)
0.045
Black
0.178
0.34 (0.08-1.40)
0.136
0.161
0.36 (0.08-1.55)
0.171
Other
0.46
1.00 (0.00-1135.84)
1.00
0.161
1.00 (0.01-104.61)
1.00
Married
0.013
0.52 (0.32-0.84)
0.007
0.004
0.49 (0.31-0.78)
0.002
Unmarried
0.179
0.73 (0.41-1.31)
0.293
0.17
0.79 (0.44-1.41)
0.426
Unknown
NA
NA
NA
Race
Marital status
NA
NA
NA
Histologic grade I
0.545
0.00 (0.00-0.00)
0.382
0.444
0.00 (0.00-5.44)
0.103
II
0.289
0.84 (0.37-1.90)
0.669
0.186
0.66 (0.29-1.47)
0.306
III
0.003
0.73 (0.47-1.13)
0.156
0.001
0.70 (0.46-1.07)
0.101
IV
NA
NA
NA
NA
NA
NA
T stage T1
0.299
0.29 (0.05-1.85)
0.192
0.212
0.23 (0.37-1.39)
0.109
T2
0.137
0.58 (0.32-1.06)
0.076
0.087
0.55 (0.31-0.99)
0.046
T3
0.722
1.30 (0.50-3.38)
0.592
0.691
1.24 (0.51-3.03)
0.632
T4
0.046
0.43 (0.15-1.25)
0.122
0.025
0.32 (0.12-0.89)
0.03
N0
0.956
0.01 (0.00-0.30)
0.011
0.872
0.00 (0.00-0.07)
0.006
N1
0.027
0.74 (0.40-1.36)
0.332
0.019
0.70 (0.38-1.28)
0.251
N2
0.324
1.09 (0.47-2.55)
0.842
0.358
1.05 (0.47-2.35)
0.9
N3
0.025
0.42 (0.16-1.08)
0.071
0.014
0.40 (0.16-1.00)
0.049
Positive
0.225
0.72 (0.46-1.11)
0.139
0.107
0.64 (0.42-0.99)
0.043
Negative
0.001
0.40 (0.20-0.83)
0.013
0.001
0.43 (0.22-0.86)
0.017
Positive
0.383
0.80 (0.47-1.37)
0.42
0.223
0.70 (0.42-1.18)
0.178
Negative
0.001
0.67 (0.37-1.19)
0.166
0.001
0.66 (0.38-1.16)
0.146
0.80 (0.55-1.15)
0.75 (0.53-1.07)
0.11
N stage
ER status
PR status
Histology IDC
0.024
0.22
0.011
Lobular
0.344
90.89 (0.00-1.95E10)
0.65
0.344
90.89 (0.00-1.95E10)
0.645
IDC and lobular
0.311
1.00 (0.00-1975.82)
1.00
0.248
1.00 (0.00-1975.82)
1.00
Other Mastectomy type SM
0.212
0.75 (0.34-1.61)
0.456
0.055
0.56 (0.27-1.16)
0.119
MRM
0.007
0.66 (0.44-1.00)
0.05
0.006
0.67 (0.45-1.00)
0.049
Yes
0.4
0.86 (0.47-1.56)
0.611
0.21
0.79 (0.44-1.42)
0.435
No
0.001
0.51 (0.32-0.81)
0.004
<0.001
0.52 (0.33-0.80)
Radiotherapy 0.003 (continued)
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Table 3 e (continued ) Characteristics
Implant versus tissue (BCSS) Univariate analysis P
Implant versus tissue (OS)
Multivariate Cox regression OR (95% CI)
Univariate analysis P
P
Multivariate Cox regression OR (95% CI)
P
Chemotherapy Yes
0.012
0.68 (0.47-0.98)
0.039
0.004
0.64 (0.45-0.91)
0.014
No
0.048
0.23 (0.05-1.02)
0.052
0.052
0.31 (0.08-1.24)
0.097
Bold type of P value indicates significance. Histologic grade, I ¼ well differentiated; II ¼ moderately differentiated; III ¼ poorly differentiated; and IV ¼ undifferentiated. NA ¼ not available; T ¼ tumor size; N ¼ lymph node; IDC ¼ infiltrating duct carcinoma; SM ¼ simple mastectomy; MRM ¼ modified radical mastectomy.
advantages and can be applied to actual treatment according to different requirements. One of the advantages of the prosthetic implant reconstruction approach is taking shorter time to perform and for recovery.14 However, implants were associated with reduced cosmetic satisfaction and the incidence of anaplastic large cell lymphoma (ALCL), a rare peripheral T-cell lymphoma.15-17 And the cause of ALCL has not been confirmed. So far, there is a convincing explanation that ALCL is only associated with implants with textured surfaces because of the interaction between the rough implant surface and the inlayer of the capsule. To compare with implant, the autologous tissue has the advantages of creating a natural softer hand feel and more ptotic breast, but it is more likely to be associated with complications. Driven by growing concerns over cancer patients’ quality of life, it has become essential to evaluate the role of clinical factors and prognosis in selecting different breast reconstructive modalities. Metastasis of cancer cells is the main cause of treatment failure, and metastasis remains a clinical challenge and one of the leading causes of increased morbidity and eventual mortality in patients with BC.18-20 With the advent of more effective therapies, BR, previously considered unrelated to the prognosis of patients with MBC, should be reconsidered because of their pursuit of longer survival and improved quality of life. Previous studies showed that patients who underwent BR after mastectomy, even those with distant metastasis, have a significantly higher BC-specific survival than those who underwent mastectomy alone.21-23 The present study revealed that BCSS and OS of patients with MBC receiving prosthesis implant reconstruction were to some extent better than those receiving autologous tissue reconstructions. Chen et al.22 also reported that prosthetic implant reconstruction had better survival; however they attributed this difference to patients’ choice depending on different socioeconomic and clinical conditions. Whereas, we found no significant statistical differences in demographic and related clinical features between the two cohorts, suggesting that the choices of the reconstruction methods may not be associated with these factors. We tend to attribute better prognosis to differences between reconstruction methods themselves. Ouyang et al.8 speculated that the improvement of BCSS in N2-N3 BC patients with implant (versus tissue) reconstruction was based on several biological reasons, such as the effect of adipose tissue on the growth and
metastasis of BC.24 White adipose tissue (WAT) cells are widely used for BR because of their high regenerative potential and easy subcutaneous collection.24-27 Khandekar et al.28 demonstrated that WAT cells and progenitor cells had potential drivers of cancer cell proliferation and distant dissemination. Bertolini et al.29 believed that patients receiving WAT cell BR had a higher risk of local recurrence than those in the control group. Other possible reasons, including detection and monitoring of local recurrence, also had been reported in previous literatures.30,31 Simorre et al.32 pointed that some vitro studies were warning about the fact that lipofilling could promote tumor recurrence through increased neoangiogenesis or facilitate metastasis. Another study has shown that most vascular and fibrovascular stroma (pericytes, alpha-smooth muscle actin þ myofibroblasts, and endothelial cells) originates from neighboring adipose tissue in the processes of tumor growth.33 Compared with autologous tissue reconstruction, the tumor may be more directly and easily palpated in patients with implants placed in the submuscular plant, as the chest wall elevation and skin contact.31 By stimulating an immune response and separating the chest wall, breast implant may slow down the growth rate of BC cells.30 In addition, it is noteworthy that in our study population, especially in married, ER-negative, chemotherapy, or nonradiotherapy patients, BCSS and OS time of implant group was significantly longer than that of tissue group. Aurilio et al.27 revealed that immediate BR after mastectomy was associated with a better survival trend and a lower local recurrence rate in patients with early stage ER-negative BC. Capsular contracture is the most common complication of BR with prosthetic implants. Myofibroblast is an important component of the capsular tissue, which provides a sustained force to reduce the surface area of the capsule and stabilize the capsular contracture.34,35 Persichetti et al.36 demonstrated that myofibroblast of capsular tissue may promote ER expression. The effect of estrogen can increase the production of fibronectin and promote differentiation and contraction of myofibroblast, which in turn affects the subsequent systemic treatment and prognosis.36 However, it has been reported that BR after mastectomy may not delay any adjuvant therapies.37 Ricci et al.38 reported that the contradiction between better survival and more complications after radiotherapy (such as reconstruction failure and capsular contracture) became more complex.
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As indicated previously, the present study has compared BCSS and OS between prosthetic implants and autologous tissue reconstruction in patients with MBC. However, our study also has its limitations. It is well known that information on human epidermal growth factor receptor 2 status as well as the number and site of metastases were unavailable in the SEER database until 2010. To ensure that sufficient number of patients was included, we could not report details of human epidermal growth factor receptor 2 status and metastatic sites. Despite these limitations, the comparison of BCSS and OS between prosthetic implants and autologous tissue reconstruction in patients with MBC can be, to some extent, guide the clinical decision making.
Conclusion BR in patients with MBC is a challenging clinical question. Our study based on the SEER data indicates that prosthetic implant reconstruction is associated with improved BCSS and OS in patients with MBC compared with tissue reconstruction. Especially in married women, ER-negative, and MBC patients who cannot receive radiotherapy, or who can receive chemotherapy, prosthetic implant reconstruction may be a good choice. Of course, we need to include more patients in the future and extend the follow-up time to further confirm.
Acknowledgment Authors’ contributions: LZ developed the study design and conception. XQ and DS performed acquisition of the data. Data analysis and interpretation was performed by XQ, KW, and DS. Manuscript drafting was performed by XQ. LZ provided a critical revision of this manuscript. Funding: This study was supported by Wu Jieping Medical Foundation (320.6750.18120).
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
references
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6. Avis NE, Levine B, Naughton MJ, Case DL, Naftalis E, Van Zee KJ. Explaining age-related differences in depression following breast cancer diagnosis and treatment. Breast Cancer Res Treat. 2012;136:581e591. 7. Fanakidou I, Zyga S, Alikari V, Tsironi M, Stathoulis J, Theofilou P. Mental health, loneliness, and illness perception outcomes in quality of life among young breast cancer patients after mastectomy: the role of breast reconstruction. Qual Life Res. 2018;27:539e543. 8. Ouyang Q, Zhu L, Chen K, Su F. Effect of implant vs. tissue reconstruction on cancer specific survival varies by axillary lymph node status in breast cancer patients. PLoS One. 2015;10:e0118161. 9. Hart AM, Pinell-White X, Losken A. The psychosexual impact of postmastectomy breast reconstruction. Ann Plast Surg. 2016;77:517e522. 10. Frasier LL, Holden S, Holden T, et al. Temporal trends in postmastectomy radiation therapy and breast reconstruction associated with changes in national comprehensive cancer network guidelines. JAMA Oncol. 2016;2:95. 11. Lang JE, Summers DE, Cui H, et al. Trends in post-mastectomy reconstruction: a SEER database analysis. J Surg Oncol. 2013;108:163e168. 12. Agarwal S, Kidwell KM, Farberg A, Kozlow JH, Chung KC, Momoh AO. Immediate reconstruction of the radiated breast: recent trends contrary to traditional standards. Ann Surg Oncol. 2015;22:2551e2559. 13. Ho AY, Hu ZI, Mehrara BJ, Wilkins EG. Radiotherapy in the setting of breast reconstruction: types, techniques, and timing. Lancet Oncol. 2017;18:e742ee753. 14. Browne JP, Jeevan R, Gulliver-Clarke C, Pereira J, Caddy CM, van der Meulen JHP. The association between complications and quality of life after mastectomy and breast reconstruction for breast cancer. Cancer. 2017;123:3460e3467. 15. Kaartinen I, Sunela K, Alanko J, Hukkinen K, KarjalainenLindsberg ML, Svarvar C. Breast implant-associated anaplastic large cell lymphomaeefrom diagnosis to treatment. Eur J Surg Oncol. 2017;43:1385e1392. 16. Leberfinger AN, Behar BJ, Williams NC, et al. Breast implantassociated anaplastic large cell lymphoma: a systematic review. JAMA Surg. 2017;152:1161e1168. 17. Steffen LE, Johnson A, Levine BJ, Mayer DK, Avis NE. Met and unmet expectations for breast reconstruction in early posttreatment breast cancer survivors. Plast Surg Nurs. 2017;37:146e153. 18. Su M, Huang CX, Dai AP. Immune checkpoint inhibitors: therapeutic tools for breast cancer. Asian Pac J Cancer Prev. 2016;17:905e910. 19. Scully OJ, Bay BH, Yip G, Yu Y. Breast cancer metastasis. Cancer Genomics Proteomics. 2012;9:311e320. 20. Bado I, Gugala Z, Fuqua SA, Zhang XH. Estrogen receptors in breast and bone: from virtue of remodeling to vileness of metastasis. Oncogene. 2017;36:4527e4537. 21. Agarwal J, Agarwal S, Pappas L, Neumayer L. A populationbased study of breast cancer-specific survival following mastectomy and immediate or early-delayed breast reconstruction. Breast J. 2012;18:226e232. 22. Chen H, Zhang M, Wang M, Zhang P, Bai F, Wu K. Immediate breast reconstruction in de novo metastatic breast cancer: an analysis of 563 cases based on the SEER database. Clin Breast Cancer. 2019;19:e135ee141. 23. Baker JL, Mailey B, Tokin CA, Blair SL, Wallace AM. Postmastectomy reconstruction is associated with improved survival in patients with invasive breast cancer: a singleinstitution study. Am Surg. 2013;79:977e981. 24. Petit JY, Rietjens M, Botteri E, et al. Evaluation of fat grafting safety in patients with intra epithelial neoplasia: a matchedcohort study. Ann Oncol. 2013;24:1479e1484.
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25. Gutowski KA, ASPS Fat Graft Task Force. Current applications and safety of autologous fat grafts: a report of the ASPS Fat Graft Task Force. Plast Reconstr Surg. 2009;124:272e280. 26. Petit JY, Botteri E, Lohsiriwat V, et al. Locoregional recurrence risk after lipofilling in breast cancer patients. Ann Oncol. 2012;23:582e588. 27. Aurilio G, Bagnardi V, Nole F, et al. Outcome of immediate breast reconstruction in patients with nonendocrineresponsive breast cancer: a monoinstitutional case-control study. Clin Breast Cancer. 2015;15:e237ee241. 28. Khandekar MJ, Cohen P, Spiegelman BM. Molecular mechanisms of cancer development in obesity. Nat Rev Cancer. 2011;11:886e895. 29. Bertolini F, Lohsiriwat V, Petit JY, Kolonin MG. Adipose tissue cells, lipotransfer and cancer: a challenge for scientists, oncologists and surgeons. Biochim Biophys Acta. 2012;1826:209e214. 30. Zakhireh J, Fowble B, Esserman LJ. Application of screening principles to the reconstructed breast. J Clin Oncol. 2010;28:173e180. 31. Lavigne E, Holowaty EJ, Pan SY, et al. Breast cancer detection and survival among women with cosmetic breast implants: systematic review and meta-analysis of observational studies. BMJ. 2013;346:f2399. 32. Simorre M, Chaput B, Stephanopoli M, et al. Lipofilling in breast reconstruction: is there any population with higher
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risk of local recurrence? Literature systematic review. Gynecol Obstet Fertil. 2015;43:309e318. Kidd S, Spaeth E, Watson K, et al. Origins of the tumor microenvironment: quantitative assessment of adiposederived and bone marrow-derived stroma. PLoS One. 2012;7:e30563. Bachour Y, Verweij SP, Gibbs S, et al. The aetiopathogenesis of capsular contracture: a systematic review of the literature. J Plast Reconstr Aesthet Surg. 2018;71:307e317. Hwang K, Sim HB, Huan F, Kim DJ. Myofibroblasts and capsular tissue tension in breast capsular contracture. Aesthetic Plast Surg. 2010;34:716e721. Persichetti P, Segreto F, Carotti S, Marangi GF, Tosi D, Morini S. Oestrogen receptor-alpha and -beta expression in breast implant capsules: experimental findings and clinical correlates. J Plast Reconstr Aesthet Surg. 2014;67:308e315. Downes KJ, Glatt BS, Kanchwala SK, et al. Skin-sparing mastectomy and immediate reconstruction is an acceptable treatment option for patients with high-risk breast carcinoma. Cancer. 2005;103:906e913. Ricci JA, Epstein S, Momoh AO, Lin SJ, Singhal D, Lee BT. A meta-analysis of implant-based breast reconstruction and timing of adjuvant radiation therapy. J Surg Res. 2017;218:108e116.
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Does Choice of Reconstruction Type Affect Survival in Patients With Metastatic Breast Cancer? Xin Qi, MD, Keren Wang, MD, PhD, Denghua Sun, MD, and Le Zhang, MD, PhD* Department of Breast Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
article info
abstract
Article history:
Background: To compare the breast cancerespecific survival (BCSS) and overall survival (OS)
Received 25 March 2019
between patients who underwent implant or tissue reconstruction after mastectomy with
Received in revised form
distant metastatic breast cancer (MBC).
2 August 2019
Materials and methods: Using the Surveillance, Epidemiology, and End Results database, we
Accepted 25 September 2019
enrolled 371 female MBC cases diagnosed during the years 2004-2014. Patients were subdivided
Available online xxx
into implant (176) and tissue groups (195) for survival comparison between the two groups. The end points were BCSS and OS. Comparisons of the distribution of clinicopathologic charac-
Keywords:
teristics were evaluated by chi-square test and Fisher exact test. Survival outcomes were
Metastatic breast cancer
compared by Kaplan-Meier model and multivariate Cox regression model for known clinico-
Breast reconstruction
pathologic variables in both the entire population and in the reconstruction cohorts.
Breast cancerespecific survival
Results: In the entire cohort, patients with implant exhibited distinctly better BCSS (log
Overall survival
rank, P ¼ 0.002) and OS (log rank, P ¼ 0.001) than patients with tissue reconstruction.
SEER
Multivariate Cox regression model revealed that patients, who received prosthetic implants, were married, and progesterone receptorepositive group showed better survival rates in BCSS and OS. In addition, after stratification of the implant group and tissue groups according to clinicopathologic variables, the survival rate of patients in the implant group was higher than that in the tissue reconstruction group under the influence of factors, such as married, estrogen receptorenegative, nonradiotherapy, and chemotherapy. Conclusions: Our study provides further survival evidence supporting the practice of mastectomy with prosthetic implant reconstruction in patients with MBC under certain conditions. ª 2019 Elsevier Inc. All rights reserved.
Introduction Breast cancer (BC) is the most common cancer among females in the United States, accounting for 30%, and the second leading cause of cancer death among women after lung cancer.1 With the rapid developments in the modern medical
imaging technology, the early diagnostic rate of BC has been improving, and subsequently, the prognosis has improved as well. Nevertheless, it has been reported that approximately 2.4%-6% of patients with BC develop metastases on initial diagnosis and 20%-30% during the course of treatment.2,3 Bone, lung, liver, and brain are the common sites that BC
* Corresponding author. Department of Breast Surgery, China-Japan Union Hospital, Jilin University, 126 Xiantai Street, Jingkai District, Changchun, Jilin 130033, China. Tel.: þ86 431 84995495; fax: þ86 431 84995495. E-mail address: [email protected] (L. Zhang). 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.09.057
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preferentially metastasizes, in decreasing order of frequency, and appear to have a close correlation with the patients’ survival outcome. The disease-free survival rates and overall survival (OS) for BC have significantly improved in recent years owing to combined therapy.4 Despite the advances in chemoradiotherapy fields, surgical intervention is still the cornerstone of the treatment of BC.4 Breast conservative surgery, sentinel lymph node dissection, oncoplastic technique, mastectomy, and breast reconstructive surgery are currently among the most common surgical procedures. As a vital part of comprehensive treatment of BC, mastectomy that is considered as a survival advantage in metastatic breast cancer (MBC) not only resects the primary tumor completely but also results in significant psychological distress for patients with BC.5,6 Breast reconstruction (BR) that aims to restore the shape of the breasts has been shown to improve the quality of life of patients without negatively influencing postoperative surveillance of tumor recurrence and adjuvant therapies.7,8 Most female patients agree that their sexuality, femininity, and intimate relationships are well maintained after BR.9 Medical development makes it possible for patients to prolong their lives and improve quality of life with prosthetic implants and autologous tissues. Thus, we sought it important to investigate prognostic factors of survival between prosthetic implants and autologous tissues in patients with MBC. Previous studies have not been able to definitively analyze the prognostic factors in some BC patient populations because of the limited number of cases. Surveillance, Epidemiology, and End Results (SEER) database is a population-based database launched in 1973, supported and managed by the National Cancer Institute in the United States, which covers 27.8% of the US population from 18 states. Data on patients with MBC who
underwent prosthetic implants and autologous tissue reconstruction were extracted from SEER database and used in the present study. The study aimed to investigate the prognostic factors of influencing survival between prosthetic implants and autologous tissue reconstruction in patients with MBC.
Materials and methods Cohort inclusion/exclusion criteria SEER*Stat version 8.3.5 (The Surveillance Research Program of the Division of Cancer Control and Population Sciences, National Cancer Institute) was used to filter and collect the information of patients who were diagnosed with BC from 2004 to 2014 and followed up before December 31, 2015. Patients who met the following criteria were included: (1) pathologicconfirmed diagnosis; (2) diagnosed with BC between 2004 and 2014; (3) first single primary cancer; (4) active follow-up; and (5) underwent simple/modified mastectomy and reconstructed with tissue or implant. The exclusion criteria were as follow: (1) diagnosed at autopsy or via death certificate; (2) male; (3) unknown status of estrogen receptor (ER) or progesterone receptor (PR); and (4) diagnosed without metastases. We chose patients who were diagnosed since 2004 to maintain the integrity and accuracy of patients’ information, and those diagnosed after 2014 were excluded to ensure enough time for follow-up. Finally, a total of 371 patients with MBC were eligible for analysis on the basis of our inclusion and exclusion criteria, and the flowchart of the subjects’ selection is shown in Figure 1. Our study had been approved by the ethics committee of China Japan Union Hospital of Jilin University.
Fig. 1 e Flowchart of patient selection for analyzing the risk factors for the morbidity and prognosis from implantation or tissue reconstruction in BC patients with metastases.
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qi et al outcomes between two breast reconstruction
Table 1 e Baseline of the demographic and related clinical features of two different BR surgeries for developing distant metastases in patients diagnosed with BC Characteristics
No. of patients with BC (2004-2014) Tissue
Implant
P
n ¼ 195 (%)
n ¼ 176 (%)
Chi-square 0.010
Age (Y) 40 and Younger
36 (18.46)
55 (31.25)
118 (60.51)
96 (54.55)
41 (21.03)
25 (14.20)
White
144 (73.85)
148 (84.09)
Black
34 (17.44)
18 (10.23)
Other
17 (8.72)
10 (5.69)
116 (59.49)
114 (64.77)
Unmarried
77 (39.49)
52 (29.55)
Unknown
2 (1.03)
10 (5.68)
Left
96 (49.23)
85 (48.30)
Right
99 (50.77)
91 (51.70)
Nipple/central portion
10 (5.13)
12 (6.82)
UIQ
16 (8.21)
12 (6.82)
LIQ
8 (4.10)
10 (5.69)
UOQ
50 (25.64)
48 (27.27)
LOQ
16 (8.21)
13 (7.39)
Other
95 (48.72)
81 (46.02)
15 (7.69)
7 (3.98)
Older than 40; 60 and younger Older than 60 Race
0.054
Marital status Married
0.010
Laterality 0.857
Primary site 0.919*
Histologic grade I II
58 (29.74)
55 (31.25)
III
110 (56.41)
101 (57.39)
IV
1 (0.51)
2 (1.14)
11 (5.64)
11 (6.25)
T1
20 (10.26)
20 (11.36)
T2
77 (39.49)
83 (47.16)
T3
32 (16.41)
46 (26.14)
T4
59 (30.26)
24 (13.64)
Tx
7 (3.59)
3 (1.71)
N0
23 (11.79)
23 (13.07)
N1
75 (38.46)
71 (40.34)
N2
45 (23.08)
36 (20.45)
N3
50 (25.64)
44 (25.00)
Nx
2 (1.03)
2 (1.14)
Positive
132 (67.69)
130 (73.86)
Negative
63 (32.31)
46 (26.14)
Positive
105 (53.850)
108 (61.36)
Negative
90 (46.15)
68 (38.64)
Unknown
0.624*
T stage 0.001*
N stage 0.969*
ER status 0.193
PR status 0.144
(continued)
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Table 1 e (continued ) Characteristics
No. of patients with BC (2004-2014) Tissue
Implant
P
n ¼ 195 (%)
n ¼ 176 (%)
Chi-square
159 (81.54)
149 (84.66)
0.669*
Lobular
14 (7.18)
13 (7.39)
IDC and lobular
10 (5.13)
8 (4.55)
Other
12 (6.15)
6 (3.41)
68 (34.87)
70 (39.77)
127 (65.13)
106 (60.23)
Histology IDC
Mastectomy type SM MRM
0.329
Radiotherapy Yes
83 (42.56)
81 (46.02)
No
112 (57.44)
95 (53.98)
Yes
160 (82.05)
150 (85.23)
No
35 (17.95)
26 (14.77)
0.503
Chemotherapy 0.410
Bold type of P value indicates significance. Histologic grade, I ¼ well differentiated; II ¼ moderately differentiated; III ¼ poorly differentiated; and IV ¼ undifferentiated. T1 ¼ 2 cm, T2 ¼ 5 cm, T3 ¼ >5 cm, T4 ¼ invasion of chest wall or skin, and Tx ¼ primary tumor cannot be assessed. N0 ¼ zero lymph nodes, N1 ¼ one to three lymph node metastasis, N2 ¼ four to nine lymph node metastasis, N3 ¼ 10 lymph node metastasis, and Nx ¼ regional lymph nodes cannot be assessed. UIQ ¼ upper inner quadrant; LIQ ¼ lower inner quadrant; UOQ ¼ upper outer quadrant; LOQ ¼ lower outer quadrant; T ¼ tumor size; N ¼ lymph node; IDC ¼ infiltrating duct carcinoma; SM ¼ simple mastectomy; MRM ¼ modified radical mastectomy. * Fisher exact test was used.
Statistical analysis The demographic and clinical features for developing distant metastases in patients diagnosed with BC were evaluated. The differences in clinical characteristics between the two groups (prosthetic implants and autologous tissue reconstruction) were examined using the chi-square test and Fisher exact test. Breast cancerespecific survival (BCSS) was defined from the date of diagnosis to the date of death, with BC death treated as an event. OS was defined from the date of diagnosis to the date of death, and death for any cause was considered as an event. For calculating BCSS and OS curves, the Kaplan-Meier method was used to estimate survival and risk curves, and survival differences were examined with log rank test for univariate analysis. Multivariate Cox regression models were built for analyzing BCSS and OS in the MBC population. After the identification of two groups (implant and tissue groups) of significant difference on survival, subgroup analysis was performed by univariate and multivariate Cox regression models. Univariate Cox regression analysis was performed for each prognostic variable, and those variables with statistical significance were included in the multivariate Cox model analysis. All analyses were performed using the SPSS for Windows, version 19.0, statistical software package (International Business Machines Corporation). P < 0.05 was defined as statistical significance.
Results Demographics and clinical characteristics of the study population A total of 371 patients in the United States were diagnosed with MBC between 2004 and 2014 and were included in the present analysis with a median follow-up of 61.0 mo. Of the 371 identified patients, 195 patients underwent autologous tissue reconstruction and 176 patients underwent prosthetic implant reconstruction. The patients’ demographic and related clinical features are presented in Table 1. We found no statistically significant differences in these factors between the two groups, except age, marital status, and T stage. Married patients tended to choose implant reconstruction. In terms of age distribution, 40-60-y-old patients accounted for 60.51% and 54.55% of the total number of patients in the tissue group and implant group, respectively. Compared with the implant group, patients older than 60 y were more likely to choose autologous tissue reconstruction methods.
Prognostic factors associated with BCSS and OS We analyzed BCSS and OS via Kaplan-Meier method. In univariate analysis (Table 2), we observed that race, marital status, histologic grade, T stage, ER status, PR status, and construction type had statistical significance in both BCSS and
5
qi et al outcomes between two breast reconstruction
Table 2 e Univariate and multivariate Cox regression analyses of clinical features of BCSS and OS in patients with distant metastases diagnosed with primary BC Characteristics
BCSS Univariate analysis P
Age (Y)
OS Multivariate Cox regression
OR (95% CI)
P
0.116
Univariate analysis P
Multivariate Cox regression OR (95% CI)
P
0.149
40 and younger Older than 40; 60 and younger Older than 60 Race
0.005
0.021
White
Reference
Black
1.08 (0.70-1.68)
0.727
1.10 (0.71-1.71)
0.067
Other
0.39 (0.19-0.85)
0.017
0.53 (0.28-1.02)
0.058
Marital status
0.001
Married
0.002 Reference
Unmarried
1.51 (1.08-2.11)
Unknown
NA
Laterality
Reference
Reference 0.015
1.48 (1.07-2.05)
NA
NA
0.827
0.915
0.094
0.044
0.019 NA
Left Right Primary site Nipple/central portion
Reference
UIQ
1.72 (0.70-4.21)
0.235
LIQ
1.38 (0.51-3.77)
0.528
UOQ
1.95 (0.93-4.10)
0.08
LOQ
0.79 (0.27-2.29)
0.665
Other
2.01 (0.99-4.08)
0.054
Histologic grade
0.014
0.007
I
Reference
II
0.70 (0.32-1.54)
0.38
0.69 (0.33-1.47)
0.338
III
1.03 (0.48-2.18)
0.949
1.05 (0.51-2.16)
0.887
IV
0.00 (0.00-0.00)
0.96
0.00 (0.00-0.00)
0.945
NA
NA
Unknown T stage
Reference
<0.001
NA
NA
<0.001
T1
Reference
T2
0.64 (0.37-1.13)
0.126
0.74 (0.43-1.28)
0.277
T3
0.87 (0.47-1.60)
0.653
0.97 (0.54-1.77)
0.931
T4
1.54 (0.86-2.74)
0.145
1.63 (0.92-2.90)
0.096
Tx
0.21 (0.05-0.94)
0.041
0.39 (0.11-1.40)
0.149
N stage
Reference
0.503
0.152
<0.001
<0.001
N0 N1 N2 N3 Nx ER status Positive
Reference
Negative
0.93 (0.60-1.42)
PR status Positive
<0.001
Reference 0.723
1.00 (0.65-1.52)
0.982
<0.001 Reference
Reference (continued)
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Table 2 e (continued ) Characteristics
BCSS Univariate analysis P
Negative Histology
OS Multivariate Cox regression
OR (95% CI)
P
2.64 (1.73-4.03)
<0.001
0.391
Univariate analysis P
Multivariate Cox regression OR (95% CI)
P
2.45 (1.62-3.68)
<0.001
0.501
IDC Lobular IDC and lobular Other Mastectomy type
0.02
SM MRM Construction type
1.54 (1.08-2.19)
0.018
0.002
Tissue
0.001 Reference
Implant Radiotherapy
0.072 Reference
Reference
0.66 (0.47-0.91)
0.012
0.61 (0.44-0.85)
0.201
0.159
0.571
0.756
0.003
Yes No Chemotherapy Yes No Bold type of P value indicates significance. Histologic grade, I ¼ well differentiated; II ¼ moderately differentiated; III ¼ poorly differentiated; and IV ¼ undifferentiated. T1 ¼ 2 cm, T2 ¼ 5 cm, T3 ¼ >5 cm, T4 ¼ invasion of chest wall or skin, Tx ¼ primary tumor cannot be assessed. N0 ¼ zero lymph nodes, N1 ¼ one to three lymph node metastasis, N2 ¼ four to nine lymph node metastasis, N3 ¼ 10 lymph node metastasis, and Nx ¼ regional lymph nodes cannot be assessed. NA ¼ not available; UIQ ¼ upper inner quadrant; LIQ ¼ lower inner quadrant; UOQ ¼ upper outer quadrant; LOQ ¼ lower outer quadrant; T ¼ tumor size; N ¼ lymph node; IDC ¼ infiltrating duct carcinoma; SM ¼ simple mastectomy; MRM ¼ modified radical mastectomy.
OS. Mastectomy type had statistical significance in BCSS, whereas primary site had statistical significance only in OS. Compared with patients receiving autologous tissue reconstruction, patients receiving prosthetic implant reconstruction had better BCSS (log rank, P ¼ 0.002; Fig. 2A), which was more obvious in OS (log rank, P ¼ 0.001; Fig. 2B). These factors
with statistical significance were all included in the multivariate Cox analysis (Table 2). The multivariate Cox regression model showed that patients treated with prosthetic implant reconstruction had improved BCSS and OS (BCSS: hazard ratio [HR], 0.66; 95% confidence interval [95% CI], 0.47-0.91; P ¼ 0.012 and OS: HR, 0.61; 95% CI, 0.44-0.85; P ¼ 0.003) compared with
Fig. 2 e Kaplan-Meier curves of the (A) BCSS and (B) OS in BC patients with metastases undergoing implantation or tissue reconstruction. (Color version of figure is available online.)
qi et al outcomes between two breast reconstruction
7
Fig. 3 e Kaplan-Meier curves of the BCSS and OS among BC patients with metastases, when stratified by (A and E) marital status, (B and F) ER, (C and G) radiotherapy, and (D and H) chemotherapy. (Color version of figure is available online.)
patients who underwent autologous tissue reconstruction. Other factors including married (versus unmarried) and positive PR were all associated with improved BCSS and OS. Compared with modified radical mastectomy, patients receiving simple mastectomy had better BCSS.
P ¼ 0.017 for BCSS and OS, respectively), the absence of radiotherapy (OR, 0.51; 95% CI, 0.32-0.81; P ¼ 0.004 and OR, 0.52; 95% CI, 0.33-0.80; P ¼ 0.003 for BCSS and OS, respectively), and the presence of chemotherapy (OR, 0.68; 95% CI, 0.47-0.98; P ¼ 0.039 and OR, 0.64; 95% CI, 0.45-0.91; P ¼ 0.014 for BCSS and OS, respectively).
Comparison of survival between implant and tissue reconstruction stratified according to clinical characteristics
Discussion To further investigate the probable factors influencing survival of the two reconstruction types, we stratified patients according to age (40 y and younger, older than 40 y, 60 y and younger, and older than 60 y), race (white, black, and others), marital status (married and unmarried), histologic grade (I, II, II, IV, and unknown), primary tumor (T) stage (T1, T2, T3, T4, and Tx), regional lymph node stage (N1, N2, N3, and Nx), ER status (positive and negative), PR status (positive and negative), histology (infiltrating duct carcinoma; lobular carcinoma; infiltrating duct carcinoma and lobular carcinoma; and other), mastectomy type (simple mastectomy and modified radical mastectomy), and the condition of radiotherapy and chemotherapy. Subgroup analysis was performed based on the aforementioned factors. As shown in Figure 3, survival and risk curves also confirmed that patients receiving prosthetic implant reconstruction had better BCSS and OS. As seen in Table 3, compared with tissue group, implant group had better survival in patients who were married (odds ratio [OR], 0.52; 95% CI, 0.32-0.84; P ¼ 0.007 and OR, 0.49; 95% CI, 0.31-0.78; P ¼ 0.002 for BCSS and OS, respectively), ER negative (OR, 0.40; 95% CI, 0.20-0.83; P ¼ 0.013 and OR, 0.43; 95% CI, 0.22-0.86;
The application of BR in the surgical management of BC has increased significantly in the past decade.10,11 The rate of BR after mastectomy in women with early stage BC in the United States increased from 15% in 2000 to 32% in 2011.10,12,13 Although the number of BR patients is increasing, the number of patients with MBC undergoing reconstruction remains small. Reconstruction reduces the psychological and physiological consequences of mastectomy and improves the quality of life of end-stage patients.13 Therefore, it is worth discussing which breast reconstructive method should be chosen for patients with MBC. The present study is a large populationbased study to investigate the prognostic factors of influencing survival between prosthetic implants and autologous tissue reconstruction in patients with MBC. Data were drawn from the SEER database, which made it a larger study and our findings more generalizable and less susceptible to individual variations. The approaches from prosthetic implants to autologous tissue reconstruction provide patients more choices to a large proportion of patients. Both these two approaches have their
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Table 3 e Univariate and multivariate Cox regression analyses of BCSS and OS comparing implant with tissue reconstruction stratified according to clinical characteristics Characteristics
Implant versus tissue (BCSS) Univariate analysis P
Implant versus tissue (OS)
Multivariate Cox regression OR (95% CI)
Univariate analysis P
P
Multivariate Cox regression OR (95% CI)
P
Age (Y) 40 and younger
0.139
0.74 (0.29-1.87)
0.524
0.062
0.68 (0.27-1.69)
0.401
Older than 40; 60 and younger
0.12
0.71 (0.45-1.11)
0.13
0.074
1.00 (0.66-1.51)
1.00
Older than 60
0.019
0.42 (0.12-1.41)
0.16
0.014
0.35 (0.11-1.19)
0.092
White
0.01
0.70 (0.48-1.03)
0.071
0.005
0.68 (0.47-0.99)
0.045
Black
0.178
0.34 (0.08-1.40)
0.136
0.161
0.36 (0.08-1.55)
0.171
Other
0.46
1.00 (0.00-1135.84)
1.00
0.161
1.00 (0.01-104.61)
1.00
Married
0.013
0.52 (0.32-0.84)
0.007
0.004
0.49 (0.31-0.78)
0.002
Unmarried
0.179
0.73 (0.41-1.31)
0.293
0.17
0.79 (0.44-1.41)
0.426
Unknown
NA
NA
NA
Race
Marital status
NA
NA
NA
Histologic grade I
0.545
0.00 (0.00-0.00)
0.382
0.444
0.00 (0.00-5.44)
0.103
II
0.289
0.84 (0.37-1.90)
0.669
0.186
0.66 (0.29-1.47)
0.306
III
0.003
0.73 (0.47-1.13)
0.156
0.001
0.70 (0.46-1.07)
0.101
IV
NA
NA
NA
NA
NA
NA
T stage T1
0.299
0.29 (0.05-1.85)
0.192
0.212
0.23 (0.37-1.39)
0.109
T2
0.137
0.58 (0.32-1.06)
0.076
0.087
0.55 (0.31-0.99)
0.046
T3
0.722
1.30 (0.50-3.38)
0.592
0.691
1.24 (0.51-3.03)
0.632
T4
0.046
0.43 (0.15-1.25)
0.122
0.025
0.32 (0.12-0.89)
0.03
N0
0.956
0.01 (0.00-0.30)
0.011
0.872
0.00 (0.00-0.07)
0.006
N1
0.027
0.74 (0.40-1.36)
0.332
0.019
0.70 (0.38-1.28)
0.251
N2
0.324
1.09 (0.47-2.55)
0.842
0.358
1.05 (0.47-2.35)
0.9
N3
0.025
0.42 (0.16-1.08)
0.071
0.014
0.40 (0.16-1.00)
0.049
Positive
0.225
0.72 (0.46-1.11)
0.139
0.107
0.64 (0.42-0.99)
0.043
Negative
0.001
0.40 (0.20-0.83)
0.013
0.001
0.43 (0.22-0.86)
0.017
Positive
0.383
0.80 (0.47-1.37)
0.42
0.223
0.70 (0.42-1.18)
0.178
Negative
0.001
0.67 (0.37-1.19)
0.166
0.001
0.66 (0.38-1.16)
0.146
0.80 (0.55-1.15)
0.75 (0.53-1.07)
0.11
N stage
ER status
PR status
Histology IDC
0.024
0.22
0.011
Lobular
0.344
90.89 (0.00-1.95E10)
0.65
0.344
90.89 (0.00-1.95E10)
0.645
IDC and lobular
0.311
1.00 (0.00-1975.82)
1.00
0.248
1.00 (0.00-1975.82)
1.00
Other Mastectomy type SM
0.212
0.75 (0.34-1.61)
0.456
0.055
0.56 (0.27-1.16)
0.119
MRM
0.007
0.66 (0.44-1.00)
0.05
0.006
0.67 (0.45-1.00)
0.049
Yes
0.4
0.86 (0.47-1.56)
0.611
0.21
0.79 (0.44-1.42)
0.435
No
0.001
0.51 (0.32-0.81)
0.004
<0.001
0.52 (0.33-0.80)
Radiotherapy 0.003 (continued)
9
qi et al outcomes between two breast reconstruction
Table 3 e (continued ) Characteristics
Implant versus tissue (BCSS) Univariate analysis P
Implant versus tissue (OS)
Multivariate Cox regression OR (95% CI)
Univariate analysis P
P
Multivariate Cox regression OR (95% CI)
P
Chemotherapy Yes
0.012
0.68 (0.47-0.98)
0.039
0.004
0.64 (0.45-0.91)
0.014
No
0.048
0.23 (0.05-1.02)
0.052
0.052
0.31 (0.08-1.24)
0.097
Bold type of P value indicates significance. Histologic grade, I ¼ well differentiated; II ¼ moderately differentiated; III ¼ poorly differentiated; and IV ¼ undifferentiated. NA ¼ not available; T ¼ tumor size; N ¼ lymph node; IDC ¼ infiltrating duct carcinoma; SM ¼ simple mastectomy; MRM ¼ modified radical mastectomy.
advantages and can be applied to actual treatment according to different requirements. One of the advantages of the prosthetic implant reconstruction approach is taking shorter time to perform and for recovery.14 However, implants were associated with reduced cosmetic satisfaction and the incidence of anaplastic large cell lymphoma (ALCL), a rare peripheral T-cell lymphoma.15-17 And the cause of ALCL has not been confirmed. So far, there is a convincing explanation that ALCL is only associated with implants with textured surfaces because of the interaction between the rough implant surface and the inlayer of the capsule. To compare with implant, the autologous tissue has the advantages of creating a natural softer hand feel and more ptotic breast, but it is more likely to be associated with complications. Driven by growing concerns over cancer patients’ quality of life, it has become essential to evaluate the role of clinical factors and prognosis in selecting different breast reconstructive modalities. Metastasis of cancer cells is the main cause of treatment failure, and metastasis remains a clinical challenge and one of the leading causes of increased morbidity and eventual mortality in patients with BC.18-20 With the advent of more effective therapies, BR, previously considered unrelated to the prognosis of patients with MBC, should be reconsidered because of their pursuit of longer survival and improved quality of life. Previous studies showed that patients who underwent BR after mastectomy, even those with distant metastasis, have a significantly higher BC-specific survival than those who underwent mastectomy alone.21-23 The present study revealed that BCSS and OS of patients with MBC receiving prosthesis implant reconstruction were to some extent better than those receiving autologous tissue reconstructions. Chen et al.22 also reported that prosthetic implant reconstruction had better survival; however they attributed this difference to patients’ choice depending on different socioeconomic and clinical conditions. Whereas, we found no significant statistical differences in demographic and related clinical features between the two cohorts, suggesting that the choices of the reconstruction methods may not be associated with these factors. We tend to attribute better prognosis to differences between reconstruction methods themselves. Ouyang et al.8 speculated that the improvement of BCSS in N2-N3 BC patients with implant (versus tissue) reconstruction was based on several biological reasons, such as the effect of adipose tissue on the growth and
metastasis of BC.24 White adipose tissue (WAT) cells are widely used for BR because of their high regenerative potential and easy subcutaneous collection.24-27 Khandekar et al.28 demonstrated that WAT cells and progenitor cells had potential drivers of cancer cell proliferation and distant dissemination. Bertolini et al.29 believed that patients receiving WAT cell BR had a higher risk of local recurrence than those in the control group. Other possible reasons, including detection and monitoring of local recurrence, also had been reported in previous literatures.30,31 Simorre et al.32 pointed that some vitro studies were warning about the fact that lipofilling could promote tumor recurrence through increased neoangiogenesis or facilitate metastasis. Another study has shown that most vascular and fibrovascular stroma (pericytes, alpha-smooth muscle actin þ myofibroblasts, and endothelial cells) originates from neighboring adipose tissue in the processes of tumor growth.33 Compared with autologous tissue reconstruction, the tumor may be more directly and easily palpated in patients with implants placed in the submuscular plant, as the chest wall elevation and skin contact.31 By stimulating an immune response and separating the chest wall, breast implant may slow down the growth rate of BC cells.30 In addition, it is noteworthy that in our study population, especially in married, ER-negative, chemotherapy, or nonradiotherapy patients, BCSS and OS time of implant group was significantly longer than that of tissue group. Aurilio et al.27 revealed that immediate BR after mastectomy was associated with a better survival trend and a lower local recurrence rate in patients with early stage ER-negative BC. Capsular contracture is the most common complication of BR with prosthetic implants. Myofibroblast is an important component of the capsular tissue, which provides a sustained force to reduce the surface area of the capsule and stabilize the capsular contracture.34,35 Persichetti et al.36 demonstrated that myofibroblast of capsular tissue may promote ER expression. The effect of estrogen can increase the production of fibronectin and promote differentiation and contraction of myofibroblast, which in turn affects the subsequent systemic treatment and prognosis.36 However, it has been reported that BR after mastectomy may not delay any adjuvant therapies.37 Ricci et al.38 reported that the contradiction between better survival and more complications after radiotherapy (such as reconstruction failure and capsular contracture) became more complex.
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As indicated previously, the present study has compared BCSS and OS between prosthetic implants and autologous tissue reconstruction in patients with MBC. However, our study also has its limitations. It is well known that information on human epidermal growth factor receptor 2 status as well as the number and site of metastases were unavailable in the SEER database until 2010. To ensure that sufficient number of patients was included, we could not report details of human epidermal growth factor receptor 2 status and metastatic sites. Despite these limitations, the comparison of BCSS and OS between prosthetic implants and autologous tissue reconstruction in patients with MBC can be, to some extent, guide the clinical decision making.
Conclusion BR in patients with MBC is a challenging clinical question. Our study based on the SEER data indicates that prosthetic implant reconstruction is associated with improved BCSS and OS in patients with MBC compared with tissue reconstruction. Especially in married women, ER-negative, and MBC patients who cannot receive radiotherapy, or who can receive chemotherapy, prosthetic implant reconstruction may be a good choice. Of course, we need to include more patients in the future and extend the follow-up time to further confirm.
Acknowledgment Authors’ contributions: LZ developed the study design and conception. XQ and DS performed acquisition of the data. Data analysis and interpretation was performed by XQ, KW, and DS. Manuscript drafting was performed by XQ. LZ provided a critical revision of this manuscript. Funding: This study was supported by Wu Jieping Medical Foundation (320.6750.18120).
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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