The incidence of BCLM in patients and the subsequent survival of such patients was described in this study. It was reported that the incidence of liver as the first metastatic site varied from 17.8%-35% [11, 15, 16]. We found that the incidence of first LM was 25.6% in the SEER database and 35.59% in the FUSCC database, similar to a previous study. Purushotham et al suggested that patients with young age and high-grade and invasive ductal carcinoma had an increased risk of visceral metastases [17].Zengel et al compared the clinicopathological features of patients with invasive ductal, invasive lobular, and invasive ductal and lobular carcinoma (mixed-type) of the breast. They found that the ratio of bone metastases was higher in invasive lobular carcinoma and mixed-type tumors than in invasive ductal carcinoma [18].In this study, we also found that young age, invasive ductal carcinoma, and high pathological grade were significantly associated with the presence of de novo LM, consistent with the previously published literature. In addition, our current results demonstrated that patients with the HER2-positive and triple-negative subtypes had significantly greater odds of having liver metastases at diagnosis than patients with the HR+/HER2- subtype, and these findings are in accordance with previously published data focused primarily on the metastatic pattern of breast cancer subtypes[8, 15-17].In one study, no evidence of metastases was detected by liver ultrasonography or chest radiography in patients with stage I or II disease, while the prevalence of a positive liver ultrasound and positive chest X-ray was 6% and 7%, respectively, among patients with stage III breast cancer[19]. Because studies have shown no additional value of routine systemic imaging in patients with early-stage disease, guidelines have reiterated that these studies are not indicated for patients with early breast cancer in the absence of signs or symptoms of metastatic disease[19-21].When liver metastases are identified early, they are usually amenable to diverse and potentially effective treatments, such as stereotactic body radiation therapy(SBRT), interventional therapy or hepatic resection[13, 22-26], which may eventually lead to long-term survival in selected patients. Our results support the need for further investigation of the high-risk populations of patients with liver metastases.
The median survival after LM diagnosis was 20.00 months in the SEER database (vs 27.30 months in the FUSCC dataset) and varied significantly by tumor subtype. In both approximately 30% of the population from the SEER dataset (from the United States) and patients treated at the Academic Cancer Center from the FUSCC data, HR+/HER2+ patients had the longest survival (median survival, 38.00 vs 34.00 months), whereas triple-negative breast cancer was associated with the poorest survival (median survival, 9.00 vs 15.63 months). Both HR+/HER2+ and HR-/HER2+BCLM patients had a more favorable outcome than HR+/HER2-BCLM patients in the SEER database, but there was no significant difference in the FUSCC dataset. According to the data from FUSCC, HER2-positive BCLM patients who did not receive HER2-targeted therapy after liver metastases had worse outcomes, similar to those of the triple-negative subgroup, whereas significantly improved clinical outcomes were observed among the population receiving HER2-targeted therapy after LM, and HR+/HER2+ patients had a 26% reduction in the hazard ratio for overall mortality, findings that were identical to the SEER data. Although the results from HER2-positive BCLM patients receiving HER2-targeted therapy in the FUSCC database were still slightly different from those found with the SEER database, they indicated that HR+/HER2+ or even HR-/HER2+BCLM patients had a better prognosis than HR+/HER2- BCLM patients owing to the introduction of HER2-targeted therapy. The gene that encodes HER2 is amplified and overexpressed in 15-20% of newly diagnosed breast cancers[27], which is associated with a worse survival for women with breast cancer[28]. Nevertheless, diverse HER2-directed drugs have significantly improved survival in patients with HER2-positive metastatic breast cancer, including monoclonal antibodies (trastuzumab and pertuzumab), several HER2 tyrosine kinase inhibitors (lapatinib, neratinib, and pyrotinib), and an antibody–drug conjugate, trastuzumab emtansine[29-34]. Even for the many patients with HER2positive metastatic breast cancer, which is a virtually incurable disease, antiHER2 therapy results in considerable and long-lasting improvement in quality of life and overall survival[35]. Furthermore, continuous anti-HER2 therapy is of utmost significance for the improvement of survival outcomes in metastatic breast cancer[31, 36, 37].However, these treatments are expensive and require expertise in delivery, factors that limit their availability in and continuous use for patients without adequate health insurance and those in lowerincome countries[35],which may result in differences between the SEER and the FUSCC data.
Historically, the HR+/HER2- subtype was associated with the best prognosis in early breast cancer [38], whereas the HR+/HER2+ subtype had the most favorable outcome, and there were no statistical differences in the HR+/HER2- and HR-/HER2+ subgroups among de novo metastatic breast cancer patients in the HER2-targeted therapy era[39]. Among breast cancer patients with de novo brain or bone metastases, results that were consistent with those of de novo metastatic breast cancer patients were seen[40, 41]. Interestingly, the HR-/HER2+ subgroup had a worse prognosis than the HR+/HER2- subgroup among breast cancer patients with de novo lung metastases[42]. In contrast, we found that even HR-/HER2+ BCLM patients had a better prognosis than the HR+/HER2- subgroup in this study, which was different from the findings in breast cancer with other metastatic sites. There are several potential reasons.HR+/HER2- patients with visceral metastases are often considered less likely to respond to hormonal therapy than those without visceral metastases[43]. In the FALCON study, the median progression-free survival(PFS) in patients receiving fulvestrant 500mg as first-line treatment with and without visceral disease was 13.8 months and 22.3 months, respectively[44].M. He et al found that heterogeneity existed among different visceral metastatic sites, and the median PFS was longer in patients with lung metastases than in those with liver metastases after fulvestrant therapy (9.6 and 3.7 months, respectively, P < 0.001)[43]. Kimbung et al also identified a 17-gene liver metastasis-specific signature (including CDH11, COL11A1, FBN1, MFAP5, SFRP4, and SPON1), which was significantly and independently prognostic for poor relapse-free and overall survival in ER-positive tumors[45]. Fortunately, substantial progress has been made after major advances in our understanding of the biology of ER+/HER2– breast cancer in the past 20 years, such as the development of CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib),mTOR inhibitors(everolimus and temsirolimus), PI3K inhibitors(alpelisib and taselisib), histone deacetylase inhibitors (tucidinostat and entinostat)[46].Subgroup analyses suggested that patients with visceral metastases also benefited from the addition of these targeted therapies to endocrine therapy[47-50]. On the basis of the above findings, endocrine therapy combined with these novel targeted therapies may be a more appropriate choice for HR+/HER2- BCLM patients than endocrine therapy alone, but further research is required.
In addition, we also found that survival was poorer among elderly BCLM patients and patients with more extrahepatic metastatic sites in both cohorts, in agreement with previous studies[10, 11, 17, 45].Interestingly, unmarried and uninsured status were associated with decreased overall median survival in the first cohort. These results indicated that lower socioeconomic status (SES), whether measured at the individual or area level, is associated with numerous health disadvantages and increased mortality across races and ethnicities[1]. Several retrospective studies showed that locoregional treatment correlated with significantly improved survival in patients with de novo metastatic breast cancer[51], and a similar result was observed in this study. However, there is no evidence to suggest that locoregional treatment of the primary tumor affects overall survival in patients with metastatic breast cancer at initial presentation according to a randomized controlled trial[51]. Therefore, the survival benefits associated with surgery may be attributed to selection bias.
Limitations
We acknowledge that there are some limitations in our study. First, this retrospective study inevitably resulted in selection biases, and we had a limited ability to control potential confounding factors, thus affect the final result. Second, some detailed information that may have effects on survival was not available in the SEER and FUSCC databases, including other metastatic sites (such as the pleura and contralateral breast), number and maximum diameter of liver metastases and performance status. Third, it was not possible to further evaluate the effect of different HER2-targeted therapies, endocrine therapies and surgery on the prognosis of liver metastases to provide more individualized treatment for these specific populations because there was a lack of more detailed treatment information.