Patients characteristics
A total of 3927 MBC patients were obtained from the SEER database, and 1129 of these patients with available information required for analysis were screened out and used to perform subsequent analysis. The detailed clinicopathologic characteristics of included patients were presented in Table 1. All included patients were allocated randomly into two datasets, including 753 patients randomly assigned to the training set and 376 patients to the validation set. Of these patients, 620 (54.92% patients were diagnosed at the age more than 60 years, most patients (76.62%) were white. The cut-off value was set as 58 mm by X-tile software, and 14.26% patients had a tumor more then 58 mm diameter. For the degree of cancer differentiation, poorly differentiated (Grade III) was the most type 877 (77.68%). 883 (78.21%) 977 (86.54%), and 1065 (94.33%) patients were observed to negatively express ER, PR and HER2, respectively. According to the AJCC7 system, stage II was the most type (61.65%), follow by stage I (23.91%) and stage III (14.44%). Most patients (51.64%) were categorized as T2 stage. Meanwhile, most patients (78.12%) were categorized as N0 stage. More than half of patients (66.43%) had undergone chemotherapy, while 47.03% patients had undergone radiotherapy.
Table 1
Characteristics of the training and validation cohorts.
Variables
|
All patients
(N = 1129)
|
Training set
(n = 753)
|
Validation set
(n = 376)
|
N
|
%
|
N
|
%
|
N
|
%
|
Age
|
|
< 60
|
509
|
45.08
|
344
|
0.46
|
165
|
0.44
|
≥ 60
|
620
|
54.92
|
409
|
0.54
|
211
|
0.56
|
Race
|
|
White
|
865
|
76.62
|
580
|
0.77
|
284
|
0.76
|
Black
|
180
|
15.94
|
120
|
0.16
|
60
|
0.16
|
Others
|
84
|
7.44
|
53
|
0.07
|
31
|
0.08
|
Tumor size (mm)
|
|
≤ 58
|
968
|
85.74
|
647
|
0.86
|
321
|
0.85
|
> 58
|
161
|
14.26
|
106
|
0.14
|
55
|
0.15
|
Grade
|
|
G1
|
61
|
5.40
|
41
|
0.05
|
20
|
0.05
|
G2
|
160
|
14.17
|
109
|
0.14
|
50
|
0.13
|
G3
|
877
|
77.68
|
584
|
0.78
|
291
|
0.77
|
G4
|
31
|
2.75
|
18
|
0.02
|
13
|
0.03
|
ER
|
|
negative
|
883
|
78.21
|
601
|
0.80
|
282
|
0.75
|
positive
|
246
|
21.79
|
152
|
0.20
|
94
|
0.25
|
PR
|
|
negative
|
977
|
86.54
|
650
|
0.86
|
327
|
0.87
|
positive
|
152
|
13.46
|
103
|
0.14
|
49
|
0.13
|
HER2
|
|
0.00
|
|
0.00
|
|
0.00
|
negative
|
1065
|
94.33
|
714
|
0.95
|
351
|
0.93
|
positive
|
64
|
5.67
|
39
|
0.05
|
25
|
0.07
|
Stage ajcc7
|
|
I
|
270
|
23.91
|
183
|
0.24
|
87
|
0.23
|
II
|
696
|
61.65
|
461
|
0.61
|
234
|
0.62
|
III
|
163
|
14.44
|
109
|
0.14
|
54
|
0.14
|
Stage_T
|
|
T1
|
299
|
26.48
|
198
|
0.26
|
101
|
0.27
|
T2
|
583
|
51.64
|
385
|
0.51
|
197
|
0.52
|
T3
|
179
|
15.85
|
121
|
0.16
|
58
|
0.15
|
T4
|
68
|
6.02
|
49
|
0.07
|
19
|
0.05
|
Stage_N
|
|
N0
|
882
|
78.12
|
597
|
0.79
|
285
|
0.76
|
N1
|
178
|
15.77
|
114
|
0.15
|
64
|
0.17
|
N2
|
50
|
4.43
|
32
|
0.04
|
18
|
0.05
|
N3
|
19
|
1.68
|
10
|
0.01
|
9
|
0.02
|
Chemotherapy
|
|
No/unknown
|
379
|
33.57
|
253
|
0.34
|
126
|
0.34
|
Yes
|
750
|
66.43
|
500
|
0.66
|
250
|
0.66
|
Radiation
|
|
No/unknown
|
598
|
52.97
|
395
|
0.52
|
203
|
0.54
|
Yes
|
531
|
47.03
|
358
|
0.48
|
173
|
0.46
|
Prognostic Factors Of Os And Css
According to univariate analysis performed among the training cohort, nine variables including age, race, tumor size, grade, TNM stage, T stage, N stage, chemotherapy and radiotherapy were significantly associated with OS in patients with MBC. Meanwhile, those variables, except for chemotherapy, were also found to be significantly associated with CSS of MBC patients. Further multivariate analysis indicated that age, TNM stage, T stage, chemotherapy and radiotherapy were identified as independent prognostic factors of OS of patients with MBC. Moreover, age, race, TNM stage, T stage, and radiotherapy were also identified as independent prognostic factors of CSS of MBC patients, as shown in Table 2 and Table 3.
Table 2
Univariate and multivariate analyses of variables associated with OS
Variables
|
Univariate analysis
|
Multivariate analysis
|
HR (95%CI)
|
P value
|
HR (95%CI)
|
P value
|
Age
|
|
< 60
|
Reference
|
|
|
|
≥ 60
|
1.871(1.396–2.507)
|
< 0.001
|
1.663(1.197–2.310)
|
0.002
|
Race
|
|
0.031
|
|
|
White
|
Reference
|
|
|
|
Black
|
0.869(0.595–1.268)
|
0.466
|
|
|
Others
|
1.564(0.918–2.664)
|
0.100
|
|
|
Tumor size (mm)
|
|
|
|
|
≤ 58
|
Reference
|
|
|
|
> 58
|
4.069(3.047–5.432)
|
< 0.001
|
|
|
Grade
|
|
0.002
|
|
|
G1
|
Reference
|
|
|
|
G2
|
1.913(0.730–5.013)
|
0.187
|
|
|
G3
|
2.526(1.037–6.151)
|
0.041
|
|
|
G4
|
5.935(2.091–16.850)
|
0.001
|
|
|
ER
|
|
|
|
|
negative
|
Reference
|
|
|
|
positive
|
0.886(0.629–1.248)
|
0.488
|
|
|
PR
|
|
|
|
|
negative
|
Reference
|
|
|
|
positive
|
0.782(0.510–1.197)
|
0.257
|
|
|
HER2
|
|
|
|
|
negative
|
Reference
|
|
|
|
positive
|
0.886(0.482–1.627)
|
0.696
|
|
|
Stage ajcc7
|
|
< 0.001
|
|
0.001
|
I
|
Reference
|
|
|
|
II
|
2.726(1.657–4.482)
|
< 0.001
|
2.577(0.858–7.619)
|
0.092
|
III
|
8.312(4.950−13.955)
|
< 0.01
|
5.194(1.683–16.032)
|
0.004
|
Stage_T
|
|
< 0.001
|
|
< 0.001
|
T1
|
Reference
|
|
|
|
T2
|
1.999(1.249–3.199)
|
0.004
|
0.890(0.325–2.440)
|
0.820
|
T3
|
6.480(3.990−10.525)
|
< 0.001
|
2.627(0.954–7.235)
|
0.062
|
T4
|
9.776(5.711–16.736)
|
< 0.001
|
2.469(0.838–7.273)
|
0.101
|
Stage_N
|
|
< 0.001
|
|
|
N0
|
Reference
|
|
|
|
N1
|
1.648(1.164–2.334)
|
0.005
|
|
|
N2
|
2.811(1.737–4.551)
|
< 0.001
|
|
|
N3
|
3.546(1.864–6.746)
|
< 0.001
|
|
|
Chemotherapy
|
|
|
|
|
No/unknown
|
Reference
|
|
|
|
Yes
|
0.578(0.445–0.774)
|
< 0.001
|
0.665(0.486–0.911)
|
0.011
|
Radiation
|
|
|
|
|
No/unknown
|
Reference
|
|
|
|
Yes
|
0.534(0.401–0.710)
|
< 0.001
|
0.511(0.377–0.693)
|
< 0.001
|
Table 3
Univariate and multivariate analyses of variables associated with CSS
Variables
|
Univariate analysis
|
Multivariate analysis
|
HR (95%CI)
|
P value
|
HR (95%CI)
|
P value
|
Age
|
|
< 60
|
Reference
|
|
|
|
≥ 60
|
1.477(1.073–2.034)
|
0.017
|
1.560(1.111–2.190)
|
0.010
|
Race
|
|
0.002
|
|
0.027
|
White
|
Reference
|
|
|
|
Black
|
0.881(0.571–1.359)
|
0.566
|
0.891(0.572–1.388)
|
0.609
|
Others
|
1.977(1.115–3.506)
|
0.020
|
1.673(0.934–2.995)
|
0.084
|
Tumor size (mm)
|
|
|
|
|
≤ 58
|
Reference
|
|
|
|
> 58
|
4.571(3.315–6.303)
|
< 0.001
|
|
|
Grade
|
|
0.003
|
|
|
G1
|
Reference
|
|
|
|
G2
|
1.990(0.576–6.873)
|
0.277
|
|
|
G3
|
3.423(1.090−10.751)
|
0.035
|
|
|
G4
|
7.381(1.998–27.269)
|
0.003
|
|
|
ER
|
|
|
|
|
negative
|
Reference
|
|
|
|
positive
|
0.920(0.627–1.350)
|
0.670
|
|
|
PR
|
|
|
|
|
negative
|
Reference
|
|
|
|
positive
|
0.935(0.596–1.467)
|
0.771
|
|
|
HER2
|
|
|
|
|
negative
|
Reference
|
|
|
|
positive
|
1.036(0.546–1.965)
|
0.914
|
|
|
Stage ajcc7
|
|
< 0.001
|
|
0.001
|
I
|
Reference
|
|
|
|
II
|
2.989(1.632–5.475)
|
< 0.001
|
2.436(0.681–8.715)
|
0.171
|
III
|
10.936(5.893–20.293)
|
< 0.01
|
5.443(1.462–20.267)
|
0.012
|
Stage_T
|
|
< 0.001
|
|
< 0.001
|
T1
|
Reference
|
|
|
|
T2
|
2.177(1.238–3.827)
|
0.007
|
0.939(0.293–3.009)
|
0.915
|
T3
|
7.814(4.402–13.870)
|
< 0.001
|
2.863(0.889–9.222)
|
0.078
|
T4
|
12.081(6.469–22.562)
|
< 0.001
|
2.692(0.778–9.319)
|
0.118
|
Stage_N
|
|
< 0.001
|
|
|
N0
|
Reference
|
|
|
|
N1
|
2.037(1.398–2.967)
|
< 0.001
|
|
|
N2
|
3.439(2.052–5.764)
|
< 0.001
|
|
|
N3
|
3.869(1.880–7.962)
|
< 0.001
|
|
|
Chemotherapy
|
|
|
|
|
No/unknown
|
Reference
|
|
|
|
Yes
|
0.962(0.691–1.340)
|
0.819
|
|
|
Radiation
|
|
|
|
|
No/unknown
|
Reference
|
|
|
|
Yes
|
0.633(0.461–0.869)
|
0.005
|
0.518(0.373–0.720)༉
|
< 0.001
|
Construction And Validation Of Os And Css
According to the results of multivariate analysis, all independent prognostic factors in the training set were incorporated to create the nomograms for estimating 3- and 5- year OS and CSS of patients with MBC. Figure 2(A) and Fig. 2(B) showed the prediction of the 3- and 5-year OS and CSS in the nomogram, respectively. Each factor was allocated a score on the points scale in the nomogram, and we can estimate the 3- and 5-year survival probability of patients with MBC by calculating the total score via adding up all points on the basis of personal patients features.
Nomograms were validated using C-index in the training set and validation set, respectively. The results showed sufficient accuracy in forecasting the prognosis of MBC in training set and validation set. The C-index of the nomogram for OS and CSS is 0.744 (95% CI, 0.701–0.787) and 0.746 (95% CI, 0.695–0.797) in the training set, respectively (Table 4). The C-index calculated from the validation set is 0.818 (95% CI, 0.775–0.861) in OS and 0.800 (95% CI, 0.747–0.853) in CSS, respectively. The calibration plots showed good coordination between prediction by nomogram models and observed outcomes in the probability of 3- and 5-year OS and CSS of patients with MBC in both training cohort and validation set (Fig. 3).