Baseline characteristics and the incidence of liver metastases
A total of 311573 patients from SEER database diagnosed between 2010 and 2016 were included in the present study. Of these patients, there were 15884 MBC patients and 4067 BCLM patients at initial diagnosis (Table 1). In the FUSCC dataset, there were 1728 of 3048 metastatic breast cancer patients had liver metastases during the follow-up (Table 2). The consistent and inconsistent characteristics of two datasets were shown in Table 1 and 2. The baseline characteristics showed a higher proportion of patients with infiltrating duct carcinoma (73.1% vs 80.8%), extrahepatic metastases (73.9% vs 67.5%) and HR+/HER2− subtype (39.6% 44.3%) in the both SEER and FUSCC dataset. However, the differences between SEER and FUSCC were significant as well, such age, race, stage at initial diagnosis. The patients in the FUSCC dataset were younger and almost all of them were Asian patients, different from those in the SERR database. Most notably, the majority of FUSCC patients (88.3%) were recurrent breast cancer who underwent curative resection for primary tumors while all patients from the SEER database were diagnosed with de novo metastatic breast cancer.
As presented in Table S1, the 4067 BCLM patients accounted for 1.31% of the entire cohort and 25.6% of the MBC patients, including 1612 patients with HR+/HER2- subtype tumors (39.64%), 884 with HR+/HER2+ tumors (21.74%), 601 with HR-/HER2+ tumors (14.78%), 544 with triple-negative tumors (13.38%), and 426 with unknown tumors (10.47%). The proportion of patients with HR-/HER2+ tumors ranked highest (4.27% of the entire cohort and 44.13% of the metastatic subclass), while those with HR+/HER2- tumors ranked lowest proportion in both entire and metastatic patients (0.76% of the entire cohort and 19.34% of the metastatic subclass, Table S1). For patients from FUSCC, patients with first liver metastases attributed to 35.59% proportion of all MBC patients (Table S2).
Risk factors for liver metastasis
Using breast cancer patients aged between 18-40 as reference, the increase of age was associated with significant trend towards decreased risk of liver metastasis, with OR of 0.59, 0.46, and 0.46 for those aged between 41-60, 61-80 and those older than 80-years age, respectively (P<0.001 for all, Table 3). The risk of liver metastasis was decreased in Hispanic (OR=0.82, 95% CI=0.74-0.91; P<0.001) and Asian or Pacific Islander patients (OR=0.81; 95% CI=0.72-0.92; P=0.001), but was increased for black patients (OR=1.54; 95% CI=1.41-1.67; P<0.001) in comparison with white patients. Married (OR=0.64; 95% CI=0.60-0.68; P<0.001) and insured status (OR=0.53; 95% CI=0.45-0.63; P<0.001) was associated with significantly decreased risk of liver metastasis when compared with the status of unmarried and uninsured, respectively. Compared with infiltrating duct carcinoma, lobular carcinoma (OR=0.68; 95% CI=0.59-0.77; P<0.001) and the mix of infiltrating duct and lobular carcinoma (OR=0.66; 95% CI=0.55-0.79; P<0.001) were both associated with decreased risk of liver metastasis. Tumors with higher pathological grade more inclined to metastasize to liver, in the comparison of grade II versus I (OR= 3.89; 95% CI=3.28-4.65; P<0.001) and grade III/IV versus I (OR=8.59; 95% CI=7.26-10.23; P<0.001). The analysis on molecular subtype indicated that HR+/HER2+ (OR=3.13; 95% CI=2.87-3.41; P<0.001), HR-/HER2+ (OR=4.75; 95% CI= 4.30-5.25; P<0.001), and triple-negative subtypes (OR=1.92; 95% CI=1.73-2.12; P<0.001) were all predictors for increased risk of liver metastasis in comparison with HR+/HER2- subtype, indicating the important role in disease progression played by HER2 status.
Survival and prognostic factors
Median survival among BCLM patients, as stratified by subtype, is displayed in Table S1 and S2. The median survival among the entire cohort was 20.00 months in the SEER database (vs 27.30 months in the FUSCC dataset), with patients with the HR+/HER2+ subtype experiencing the longest median survival (38.00 vs 34.00 months) and patients with the triple-negative subtype experiencing the shortest median survival (9.00 vs 15.63 months) in the two cohorts. Additionally, breast cancer patients with first liver metastases showed distinctly longer survival times than those patients with subsequent liver metastases when the time was calculated from the diagnosis of liver metastasis (33.80 vs 17.47 months, Figure 2A). However, patients with liver metastases had a shorter survival time than breast cancer patients developing liver metastases during the subsequent disease course when the time was calculated from the diagnosis of MBC (42.57 vs 33.80 months, Figure 2B). The overall survival of all BCLM patients and the overall survival stratified by subtype or extent of extrahepatic metastatic disease are graphically displayed in Figure 1.
Multivariate Cox proportional hazards models were used to assess the prognostic factors of patients with BCLM in the SEER database (Table 4) and the FUSSCC dataset was used for further exploration (Table 5). In the SEER database, older patients had worse survival, with a HR of 1.39, 1.84 and 3.62 for patients aged 41-60, 61-80, and >80 years in comparison with those aged 18-40 years (P<0.001 for all). Moreover, black and Hispanic race were associated with increased death risk compared with white race, with a HR of 1.35 (P<0.001) and 1.16 (P=0.028), respectively). Results also showed a prolonged survival in presence of the status of married and insurance (HR=0.84 for married vs. unmarred, and 0.71 for insured vs. uninsured, with P<0.001 for all). For the survival comparisons among clinical factors, we found that increased pathological grade, treatment without chemotherapy and surgery of primary site, increased number of extrahepatic metastatic sites and triple-negative pathological type were all associated with poor prognosis. Specifically, compared with grade I disease, the HR was 1.35 (P=0.013) for grade II and 1.69 for grade III-IV (P<0.001), respectively. Treatment without surgery of primary site and chemotherapy generated a HR of 1.52 and 1.63, respectively compared with those received the treatments (P<0.001 for all). As expected, the HR increased from 1.42 to 3.43 as number of extrahepatic sites increased from 1 to 3, compared with no extrahepatic metastasis (P<0.001 for all). In line of most previous studies, triple-negative subtype remained the deadliest type of cancer, with HR of 2.46 in comparison with HR+/HER2- cancers (P<0.001). Interestingly, compared with HR+/HER2- subtype, we observed that HER2+ might decrease the death risk in the SEER database, with HR of 0.69 for HR+/HER2+ (P<0.001) and 0.85 (P=0.014) for HR-/HER2+ subtype, probably due to the introduction of HER2-targeted therapy.
Despite the substantial differences in baseline characteristics, the significant association of older age and greater number of extrahepatic metastasis sites with worse prognosis of the BCLM patients was also successfully observed in FUSCC datasets, similar to the former observation in the SEER database (Table 5). Additionally, histological type exerted no effect on the prognosis and patients with triple negative BCLM had the worst survival in both SEER and FUSCC dataset. Notably, specific results were obtained due to data availability in two different populations, such as race, marital and insurance status, pathological grade and recurrent sequence. However, no significant difference was observed between survival of HER2+ patients with HR+/HER2- patients (P>0.05) in FUSCC dataset different from the result of SEER database, probably owing to difference in clinical application of HE2-targeted therapies.
HER2-targeted therapy
Owing to inconsistent results in the terms of the prognostic influence of molecular subtype in BCLM patients, we next explored whether HER2-targeted therapy leaded to these results. According to the results from the FUSCC, we found that in patients who did not receive HER-2 targeted therapy after liver metastases, HER2+ patients had an unfavorable prognosis compared with HR+/HER2- patients, with HR of 2.62 for HR+/HER2+ and 3.43 for HR-/HER2+ patients (P<0.001 for all, Table 6). However, HR+/HER2+ patients had a better prognosis than HR+/HER2- patients in patients who underwent HER2-targeted therapy after liver metastasis, with HR of 0.74 (P<0.001). Unfortunately, we only observed an insignificant trend towards decreased death risk induced by HER2-targeted therapy for HR-/HER2+ patients compared with HR+/HER2- patients, with a HR of 0.81 (P=0.110). Overall survival among BCLM patients with or without HER2-targeted therapy stratified by subtype were visualized in Figure 2.