Patient characteristics
A total of 2263 MBC patients were enrolled in final cohort, of which 35.7% (809) synchronously presented with lung metastases upon initial MBC diagnosis and Table 1 listed their clinicathological characteristics stratified by breast cancer subtype. It showed that 15.1% (122) of BCLM patients were diagnosed with de novo metastatic disease. BCLM patients with HR+/HER2-, HR-/HER2+, HR+/HER2 + and triple-negative subtypes accounted for 47.7%, 14.3%, 16.1% and 21.9%, respectively. Compare with other subsets, triple-negative patients with lung metastases were younger (P = 0.015), had a earlier N-stage of primary breast cancer (P = 0.005), presented with more recurrent diseases (P = 0.002) and less liver metastases (P = 0.001). HER2+ (HR-/HER2 + and HR+/HER2+) patients with BCLM were more frequently diagnosed with de novo stage IV breast cancer than HER2- (HR+/HER2- and triple-negative) patients (P = 0.002). BCLM patients with HR+/HER2- subtype had the highest rate of bone metastases (P = 0.000).
Table 1
Clinicopathological characteristics of patients with lung metastases upon initial metastatic breast cancer diagnosis according to breast cancer subtype.
Characteristic | HR+/HER2-, N (%) | HR-/HER2+, N (%) | HR+/HER2+, N (%) | Triple-negative, N (%) | P value |
All patients | 386 (47.7) | 116 (14.3) | 130 (16.1) | 177 (21.9) | |
Age | | | | | 0.015 |
< 50 | 172 (44.6) | 44 (37.9) | 62 (47.7) | 99 (55.9) | |
≥ 50 | 214 (55.4) | 72 (62.1) | 68 (52.3) | 78 (44.1) | |
ECOG | | | | | 0.194 |
0 | 91 (23.6) | 24 (20.7) | 23 (17.7) | 46 (26.0) | |
1 | 278 (72.0) | 88 (75.9) | 102 (78.5) | 117 (66.1) | |
2 | 17 (4.4) | 4 (3.4) | 5 (3.8) | 14 (7.9) | |
T-stage | | | | | 0.065 |
T1 | 104 (26.9) | 24 (20.7) | 32 (24.6) | 47 (26.6) | |
T2 | 169 (43.8) | 50 (43.1) | 52 (40.0) | 83 (46.9) | |
T3 | 20 (5.2) | 6 (5.2) | 5 (3.8) | 17 (9.6) | |
T4 | 18 (4.7) | 12 (10.3) | 9 (6.9) | 6 (3.4) | |
Unknown | 75 (19.4) | 24 (20.7) | 32 (24.6) | 24 (13.6) | |
N-stage | | | | | 0.005 |
N0 | 113 (29.3) | 25 (21.6) | 30 (23.1) | 65 (36.7) | |
N1 | 96 (24.9) | 23 (19.8) | 43 (33.1) | 45 (25.4) | |
N2 | 66 (17.1) | 22 (19.0) | 23 (17.7) | 31 (17.5) | |
N3 | 67 (17.4) | 35 (30.2) | 20 (15.4) | 19 (10.7) | |
Unknown | 44 (11.4) | 11 (9.5) | 14 (10.8) | 17 (9.6) | |
M-stage | | | | | 0.002 |
M0 | 339 (87.8) | 88 (75.9) | 103 (79.2) | 157 (88.7) | |
M1 | 47 (12.2) | 28 (24.1) | 27 (20.8) | 20 (11.3) | |
Liver metastases | | | | | 0.001 |
No | 308 (79.8) | 85 (73.3) | 88 (67.7) | 152 (85.9) | |
Yes | 78 (20.2) | 31 (26.7) | 42 (32.3) | 25 (14.1) | |
Brain metastases | | | | | 0.625 |
No | 370 (95.9) | 108 (93.1) | 124 (95.4) | 170 (96.0) | |
Yes | 16 (4.1) | 8 (6.9) | 6 (4.6) | 7 (4.0) | |
Bone metastases | | | | | 0.000 |
No | 226 (58.5) | 91 (78.4) | 89 (68.5) | 134 (75.7) | |
Yes | 160 (41.5) | 25 (21.6) | 41 (31.5) | 43 (24.3) | |
HR hormone receptor, HER2 human epidermal growth factor receptor 2, ECOG Eastern Cooperative Oncology Group. |
Incidence
Table 2 displayed the incidence of patients with lung metastases stratified by breast cancer subtype. HR+/HER2-, HR-/HER2+, HR+/HER2 + and triple-negative subtypes accounted for 52.1%, 13.3%, 16.1% and 18.5% of the entire MBC population, respectively. Patients with triple-negative subtype (42.3%) harbored the highest incidence proportions of lung metastases.
Table 2
Incidence of patients with lung metastases at first metastatic breast cancer diagnosis stratified by breast cancer subtype.
| All metastatic patients, N (%) | With lung metastases | Incidence of lung metastases, % |
HR+/HER2- | 1180 (52.1) | 386 | 32.7 |
HR-/HER2+ | 300 (13.3) | 116 | 38.6 |
HR+/HER2+ | 365 (16.1) | 130 | 35.6 |
Triple-negative | 418 (18.5) | 177 | 42.3 |
All subtypes | 2263 (100.0) | 809 | 35.7 |
HR hormone receptor, HER2 human epidermal growth factor receptor 2. |
Association between the presence of lung metastases at initial MBC diagnosis and variables assessed by multivariate logistic regression was showed in Table 3. Age ≥ 50 years (vs. < 50 years, OR = 1.32, 95% CI = 1.11–1.57, P = 0.002), ECOG 2 (vs. ECOG 0, OR = 1.66, 95% CI = 1.04–2.63, P = 0.034), and triple-negative subtype (vs. HR+/HER2-, OR = 1.43, 95% CI = 1.13–1.81, P = 0.003) were remarkably associated with higher incidence of lung metastases at diagnosis. N3 (vs. N0, OR = 0.75, 95% CI = 0.57–0.99, P = 0.045), liver metastases (vs. without liver metastases, OR = 0.78, 95% CI = 0.63–0.96, P = 0.021) and bone metastases (vs. without bone metastases, OR = 0.75, 95% CI = 0.62–0.91, P = 0.003) were significantly correlated with lower odds of lung metastases at diagnosis.
Table 3
Multivariate logistic regression for the presence of lung metastases at initial diagnosis of metastatic breast cancer.
Characteristic | OR (95% CI) | P value |
Age | | |
< 50 | Reference | |
≥ 50 | 1.32 (1.11, 1.57) | 0.002 |
ECOG | | |
0 | Reference | |
1 | 1.17 (0.95, 1.44) | 0.143 |
2 | 1.66 (1.04, 2.63) | 0.034 |
T-stage | | |
T1 | Reference | |
T2 | 1.03 (0.83, 1.29) | 0.771 |
T3 | 0.74 (0.50, 1.10) | 0.136 |
T4 | 1.28 (0.81, 2.02) | 0.290 |
Unknown | 0.83 (0.62, 1.11) | 0.202 |
N-stage | | |
N0 | Reference | |
N1 | 1.02 (0.80, 1.29) | 0.906 |
N2 | 0.91 (0.69, 1.19) | 0.476 |
N3 | 0.75 (0.57, 0.99) | 0.045 |
Unknown | 1.07 (0.74, 1.54) | 0.718 |
M-stage | | |
M0 | Reference | |
M1 | 1.08 (0.82, 1.42) | 0.597 |
Subtype | | |
HR+/HER2- | Reference | |
HR-/HER2+ | 1.26 (0.96, 1.66) | 0.096 |
HR+/HER2+ | 1.16 (0.90, 1.49) | 0.262 |
Triple-negative | 1.43 (1.13, 1.81) | 0.003 |
Liver metastases | | |
No | Reference | |
Yes | 0.78 (0.63, 0.96) | 0.021 |
Brain metastases | | |
No | Reference | |
Yes | 1.12 (0.72, 1.73) | 0.613 |
Bone metastases | | |
No | Reference | |
Yes | 0.75 (0.62, 0.91) | 0.003 |
OR odds ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, HR hormone receptor, HER2 human epidermal growth factor receptor 2. |
Survival
The median survival among the whole MBC cohort was 45.4 months, with a median follow-up of 61.6 months. Figure 1 showed that the prognosis of patients with lung metastases upon MBC diagnosis (median OS, 41.7 months) was significantly worse than those without lung metastases (median OS, 47.9 months, P = 0.001). Figure 2 provided the survival of BCLM patients according to breast cancer subtype. The survival of BCLM patients with HR+/HER2- subtype (49.0 months) was the longest, while triple-negative (26.8 months, P = 0.000) the shortest. BCLM patients with HR-/HER2+ (vs. HR+/HER2-, P = 0.009) and HR+/HER2+ (vs. HR+/HER2-, P = 0.746) subtypes experienced the median OS of 31.6 and 44.1 months, respectively.
The prognostic factors of BCLM patients assessed by univariate and multivariate Cox regression analyses were presented in Table 4. The significant variables with P value < 0.05 in univariate analysis were further included in multivariate Cox regression model. ECOG 2 (vs. ECOG 0, HR = 1.71, 95% CI = 1.10–2.68, P = 0.018), N3 (vs. N0, HR = 1.43, 95% CI = 1.05–1.95, P = 0.023), HR-/HER2 + subtype (vs. HR+/HER2-, HR = 1.44, 95% CI = 1.07–1.94, P = 0.016), triple-negative subtype (vs. HR+/HER2-, HR = 1.96, 95% CI = 1.52–2.52, P = 0.000), liver metastases (vs. without liver metastases, HR = 2.57, 95% CI = 2.05–3.21, P = 0.000) and bone metastases (vs. without bone metastases, HR = 1.33, 95% CI = 1.08–1.64, P = 0.007) were significantly correlated with poor survival of BCLM patients.
Table 4
Univariate and multivariate cox regression analyses of OS in BCLM patients.
Univariable analysis | Multivariable analysis |
Characteristic | Hazard ratio (95% CI) | P value | Characteristic | Hazard ratio (95% CI) | P value |
Age | | | Age | | |
< 50 | Reference | | < 50 | | |
≥ 50 | 1.04 (0.86, 1.25) | 0.715 | ≥ 50 | | |
ECOG | | | ECOG | | |
0 | Reference | | 0 | Reference | |
1 | 1.23 (0.96, 1.59) | 0.099 | 1 | 1.12 (0.87, 1.44) | 0.397 |
2 | 2.62 (1.71, 4.01) | 0.000 | 2 | 1.71 (1.10, 2.68) | 0.018 |
T-stage | | | T-stage | | |
T1 | Reference | | T1 | Reference | |
T2 | 1.17 (0.92, 1.47) | 0.197 | T2 | 1.06 (0.83, 1.35) | 0.650 |
T3 | 1.51 (1.01, 2.26) | 0.044 | T3 | 1.15 (0.75, 1.75) | 0.522 |
T4 | 1.41 (0.94, 2.11) | 0.095 | T4 | 1.09 (0.70, 1.70) | 0.690 |
Unknown | 0.93 (0.70, 1.24) | 0.625 | Unknown | 0.94 (0.67, 1.31) | 0.708 |
N-stage | | | N-stage | | |
N0 | Reference | | N0 | Reference | |
N1 | 1.17 (0.90, 1.52) | 0.241 | N1 | 1.10 (0.84, 1.43) | 0.510 |
N2 | 1.34 (1.01, 1.77) | 0.045 | N2 | 1.14 (0.84, 1.54) | 0.393 |
N3 | 1.79 (1.36, 2.36) | 0.000 | N3 | 1.43 (1.05, 1.95) | 0.023 |
Unknown | 1.19 (0.84, 1.69) | 0.330 | Unknown | 1.10 (0.73, 1.66) | 0.645 |
M-stage | | | | | |
M0 | Reference | | | | |
M1 | 1.15 (0.89, 1.49) | 0.296 | | | |
Subtype | | | Subtype | | |
HR+/HER2- | Reference | | HR+/HER2- | Reference | |
HR-/HER2+ | 1.43 (1.08, 1.90) | 0.013 | HR-/HER2+ | 1.44 (1.07, 1.94) | 0.016 |
HR+/HER2+ | 1.04 (0.79, 1.37) | 0.769 | HR+/HER2+ | 1.06 (0.80, 1.40) | 0.688 |
Triple-negative | 1.73 (1.36, 2.19) | 0.000 | Triple-negative | 1.96 (1.52, 2.52) | 0.000 |
Liver metastases | | | Liver metastases | | |
No | Reference | | No | Reference | |
Yes | 2.71 (2.20, 3.35) | 0.000 | Yes | 2.57 (2.05, 3.21) | 0.000 |
Brain metastases | | | | | |
No | Reference | | | | |
Yes | 1.40 (0.94, 2.10) | 0.100 | | | |
Bone metastases | | | Bone metastases | | |
No | Reference | | No | Reference | |
Yes | 1.43 (1.18, 1.74) | 0.000 | Yes | 1.33 (1.08, 1.64) | 0.007 |
OS overall survival, BCLM breast cancer lung metastases, CI confidence interval, ECOG Eastern Cooperative Oncology Group, HR hormone receptor, HER2 human epidermal growth factor receptor 2. |