According to the above inclusion and exclusion criteria, 18322 patients were enrolled in this study. Table 1 showed the demographic and clinicopathological characteristics of stage IV patients according to metastatic sites. Bone metastasis accounted for about 39.8% of patients (7292), followed by multiple metastasis (33.07%, 6059), lung metastasis (10.94%, 2005), liver metastasis (7.34%, 1346), other metastasis (7.34%, 1344), and brain metastasis (1.51%, 276). The median follow-up was 14 months. The mean age of liver metastasis (59.0 years) was the lowest and lung metastasis(66.2 years) was the highest among all the groups (range, 61.2-64.3 years). Liver metastasis was more frequent of poorly/undifferentiated tumor (48.66%), followed by lung metastasis (47.16%) and brain metastasis (42.39%). Bone was the predominant site of metastasis for the HR+/HER2- (64.4%) and HR+/HER2+ (11.76%) groups and the least common site in the HR-/HER2+ group (3.24%). Of patients in the brain, lung, and liver metastasis subgroups, 26.9%, 21.22%, and 14.42%, respectively, are the triple negative subtype. Patients with lung metastasis (50.69%) and multiple metastases (48.07%) tend to have larger tumors of T3-T4 at initial diagnosis. Furthermore, these two groups of patients also have a higher proportion of later N stage(N3), making up 29.48% and 33.94% respectively. The detailed patient characteristics are presented in Table 1.
Kaplan-Meier Survival analysis
Of all the 18322 patients finally recruited, 9880 patients were dead at the end of the last follow‐up, and 7239 of them were dead of breast cancer specifically. The Kaplan‐Meier plots were displayed in Figure 2 to show the survival of all population. Figure 2A shows the breast cancer-specific survival(BCSS) according to metastatic sites of stage IV patients. Brain metastasis had the worst survival: the 3-year BCSS rate was 2.1%. The 3-year BCSS rate of lung, liver, and multiple metastases were, 7.86%, 8.10%, and 6.95% respectively. Bone and other metastasis had better BCSS, for which the 3-year BCSS rate was 13.48% and 10.95%, respectively (p < 0.001). Figure 2B shows the overall survival (OS) according to metastatic sites of stage IV patients who were enrolled into the study. Similar to BCSS, patients with bone metastasis had the best survival, with 3-year OS rate of 4.7%, followed by patients with other metastasis, multiple metastases, and liver metastasis, and the OS rate was 4.33%, 3.70%, and 3.34% respectively. Patients with brain metastasis and liver metastasis had worse OS than other subgroups: the 3-year OS rate was 1.81%, and 2.89%, respectively (p < 0.001).
Cox regression analysis of survival
In order to further figure out the effect of multiple factors on BCSS and OS, the Cox proportional hazard model was applied in the analysis. In univariate analysis of BCSS and OS, unmarried status, race of black, higher grade, larger tumor size, later N stage, Her2 positive and triple negative subtypes, were proved to be risk factors for poor survival (hazard ratio [HR] > 1, p < 0.001). By contrast, married status, other race, chemotherapy, radiotherapy, and surgery were found to be protective factors for better survival (hazard ratio [HR] < 1, p < 0.001) (Table 2). As for metastatic sites, the results were consistent with those of Kaplan-Meier analysis. Patients with bone metastasis had the best BCSS and OS, followed by patients with other, liver, lung, and multiple metastases. Specifically, patients with brain metastasis exhibited the worst BCSS (hazard ratio [HR] =1.708, 95% confidence interval [CI] = 1.442-2.023, p < 0.001) and OS (hazard ratio [HR] = 2.492, 95% confidence interval [CI] =2.161-2.874, p < 0.001).
The variables mentioned above were enrolled in the multivariate Cox analysis subsequently. After adjusting for age, race/ethnicity, marital status, tumor grade, breast cancer subtype, tumor size, nodal status, surgery, radiotherapy, and chemotherapy in the analysis, metastatic sites remained an independent prognostic factor of BCSS and OS. The detailed results of Cox regression analysis of BCSS and OS are available in Table 3. Compared to patients with bone metastasis, the BCSS (HR 0.994, 95% CI 0.881–1.122, p = 0.921) and OS (HR 0.994, 95% CI 0.897–1.100, p = 0.902) of patients with lung metastasis were not significantly different. Patients with other metastasis had similar BCSS (HR 0.955, 95% CI 0.827-1.103, p = 0.532) as patients with bone metastasis, but worse OS (HR 1.127, 95% CI 1.001-1.269, p = 0.048). Patients with liver (HR 1.384, 95% CI 1.208–1.586, p < 0.001; OS, HR 1.428, 95% CI 1.272–1.602, p < 0.001) and multiple metastases (BCSS, HR 1.475, 95% CI 1.361–1.599, p< 0.001; OS, HR 1.806, 95% CI 1.684–1.937, p< 0.001) had worse BCSS and OS than bone metastasis. Similarly, the multivariate analysis also indicated that those patients with brain metastasis had significant inferior BCSS (HR 1.975, 95% CI 1.551-2.514, p < 0.001) and OS (HR 2.307, 95% CI 1.862-2.859, p < 0.001) over other metastatic sites. Age, marital status, tumor grade, triple negative subtype, tumor size, surgery, chemotherapy were also the independent prognostic factors of survival outcomes.