Analysis of the metastatic mechanism and progress in the treatment of breast cancer liver metastasis: a narrative review

Introduction

The 5-year survival rate for women with metastatic breast cancer (MBC) is only approximately 25%, although it is treatable (1). There are four main target organs of metastasis: bone, lung, liver, and brain. Liver metastasis is usually secondary to lung metastasis in approximately 50% of MBC patients (2). Breast cancer liver metastasis (BCLM), however, has a poor survival rate compared to some other target organs, such as bone and lung metastasis, with an estimated 5-year overall survival (OS) rate of 8.5% (3). The molecular types of tumors reflect different tumor biology, which results in differences in the targets and patterns of the metastasis process. In patients with metastasis, different molecular types can also predict different prognoses (4). One study observed the longest median OS in patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-positive breast cancer compared to other molecular subtypes, while the shortest OS was observed with the triple-negative breast cancer subtype in patients with BCLM (5).

BCLM can manifest symptoms such as nausea, loss of appetite, and abdominal discomfort. When metastasis damages or destroys the liver structure, pain in the liver area, hepatomegaly, ascites, and jaundice can also appear. There has been relatively more research devoted to the mechanism and treatment of bone and lung metastasis from breast cancer, but less attention has been focused on liver metastasis. Possibly due to differences in metastatic pathways and biological features, BCLM is still considered a systemic disease and is primarily treated with systemic therapy, such as chemotherapy, hormonal therapy, and supportive therapy (6). There are also some specific treatment methods, such as anti-HER2 therapy, bone modifying agents, anti-VEGF therapy, and immune checkpoint inhibitor therapy. Some research has also reported improvements in survival with local treatments, although further studies are required to determine more specific selection criteria for these treatments for BCLM. It is difficult to define the roles of surgery or less-invasive local procedures in the treatment of BCLM. Current treatment programs still confer restricted benefits because of the absence of research on the mechanism of BCLM. Research on its molecular mechanism is important for developing new therapeutics for BCLM. Therefore, understanding the process of breast cancer cell metastasis to the liver and the latest treatment options is crucial. We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2463/rc).

Methods

We searched the MEDLINE/PubMed database for relevant literature written in English from 1987 to 2022 using the following search terms: (“breast neoplasms” OR “breast cancer” OR “breast carcinoma”) AND (“liver”) AND (“neoplasm metastasis” OR “metastasis” OR “metastatic”) AND (“mechanism”) AND (“therapeutics” OR “treatment” OR “therapy”). Articles appropriate to the topic of this review were fully reviewed. In this article, we summarized the research on the metastatic process of BCLM and current therapeutic methods, which contributed to advancing the clinical study of this disease (Table 1).

Discussion

The mechanism of BCLM in vivo

The liver, a blood-rich organ, has diverse molecular targets and a specific tumor microenvironment. Compared with lung and bone, the liver exhibits its own characteristic tumor microenvironment and unique structure, such as a specific hepatic sinusoidal structure, which may be an important factor in the development of BCLM. Although the exact mechanism remains unclear, this is a frontier that is currently being explored (7). The process of BCLM involves multiple steps, and a variety of factors are able to influence it. These include the environmental characteristics of breast cancer itself, the induction of multiple chemokines during metastasis, and the environmental characteristics of the liver itself. The process includes local infiltration of breast cancer cells, infiltration into the circulatory system, migration to the target organ through the circulatory system, exfiltration from the circulatory system, adhesion and colonization of the target organ, and formation of metastatic foci (Figure 1). Understanding the concrete steps of the metastasis mechanism provides a strong theoretical foundation for therapeutic methods.

Figure 1 Major process of breast cancer liver metastasis in the microenvironment. a: Cancer cells infiltrate locally in the breast. b: Breast cancer cells and stem cells expressing CD44, which improves metastasis, permeate the circulatory system. c: Breast cancer cells infiltrate the liver tissue from the circulatory system by the key hepatic sinusoidal endothelium structure and transmembrane proteins such as claudin, promoting this process. Various factors, such as VEGFR and exosomes expressing integrin αvβ5, create a microenvironment associated with inflammation and metastasis in the liver. VEGFR, vascular endothelial growth factor receptor.

The most widely accepted metastasis model of the mechanism by which tumors migrate to the liver and continue to proliferate was the ‘seed and soil’ hypothesis proposed by Paget (8). It initially revealed that the formation of metastasis to a secondary organ required the intrinsic properties of tumor cells and a compatible and supportive microenvironment (9). Two other classical models of tumor metastasis, the parallel progression model and the linear progression model, were also widely accepted; these two models suggested a similar but not identical view that genetic and nongenetic alterations and selective pressures from the microenvironment led to heterogeneous cell populations and metastatic potential (10).

Generation of the microenvironment

Several factors and cells are involved in tumor progression, including vascular endothelial growth factor receptor (VEGFR), bone marrow-derived haematopoietic progenitor cells (HPCs), and tumor-derived exosomes. Vascular endothelial growth factor (VEGF) is a key player in tumor neoplasia (11), and breast cancer cells cause haematopoietic stem cells expressing VEGFR to migrate into liver tissue prior to colonization, thus creating a fibronectin-rich microenvironment, which helps circulating breast cancer cells to remain in liver tissue. Kaplan et al. (12) showed that removing cells expressing VEGFR from the bone marrow of mice could significantly inhibit the formation of a premetastatic microenvironment, which in turn inhibited metastasis. However, resupplying these cells promoted metastasis. Chien et al. (13) found that the inhibition of VEGFR kinase remarkably minimized the formation of liver metastasis and decreased the growth of primary breast cancer. Furthermore, exosomes are related to the metastatic microenvironment as well. Sun et al. (14) suggested that exosomes secreted by breast cancer cells first accumulated in liver tissue before liver metastasis occurred and fused with hepatocyte membranes by causing a convergent change in the microenvironment, ultimately producing an environment suitable for the colonization of breast cancer cells. Exosome proteomics shows unique integrin expression profiles, such as integrin αvβ5, which is associated with liver metastasis. During metastatic progression, integrin αvβ5 binds to liver Kupffer cells and contributes to the creation of the premetastatic microenvironment to promote cancer progression. Thus, targeting αvβ5 may reduce the development of BCLM (15).

In this metastatic process, diverse chemokine receptors and their ligands also participate in the formation of the microenvironment. For example, the important chemokine receptor C-X-C chemokine receptor type 4 (CXCR4) promotes metastasis through interaction with its ligand C-X-C chemokine ligand 12 (CXCL12)/stromal cell-derived factor 1α (SDF-1α) (16). In addition, C-C chemokine motif ligand 5 (CCL5) released by tumor cells plays a role in tumor growth (17). Regarding the inflammatory response, tumor necrosis factor-α (TNF-α) induces E-selectin expression in hepatic sinusoidal cells, which is an essential step in generating a proinflammatory microenvironment (10). Goodla et al. found that a notably elevated level of the inflammatory factor interleukin 6 (IL-6) was associated with cancer development and progression in patients with liver metastasis (18). Moreover, the inflammatory response itself enhances metastasis (19). For instance, the formation of neutrophil extracellular traps is an important function of neutrophils that can promote breast cancer cells to migrate to the liver.

The formation of metastasis

The sinusoidal endothelium lacking a subendothelial basement membrane can implicate the capability of cancer cells to transmigrate into the liver via blood vessels by controlling liver-specific microvascular exchange and interaction with the microenvironment (20). Tumor cells adhere to the perforated hepatic sinusoidal endothelium from the circulatory system and pass through it into the Disse space to infiltrate the liver tissue, which is the direct route between breast cancer cells and hepatocytes (10). Thus, metastasis occurs.

There are many factors involved in adhesion and colonization as well. Claudin is a crucial transmembrane protein in the tight junction complex, participating in homotypic and heterotypic interactions between adjacent cells (21). Claudin-2, claudin-4, and claudin-7 are essential for the colonization and growth of breast cancer cells in the liver. Among these, claudin-2 facilitates the capability of tumor cells to adhere to other proteins and functional integrin complexes (fibronectin and collagen IV receptors) (22). Currently, it has been shown that in Balb-c mice, the deletion of claudin-4 and claudin-7 improves liver metastasis of breast cancer cells (23). In addition, the high expression of E-cadherin due to loss of methylation increases the adhesion and colonization of breast cancer cells to hepatocytes and boosts the formation of subsequent metastasis, which may be associated with mesenchymal-epithelial transition (MET), considered a marker of increased invasiveness (24). Breast cancer cells with cluster of differentiation-44 (CD44) or cluster of differentiation-24 (CD24) exhibit strong stem cell properties. Cells with high CD44 expression display the characteristics of powerful adhesion, invasiveness, inhibition of apoptosis and promotion of metastasis (25). The stem cell marker CD44, mainly CD44 v5 and v6, can be detected in the serum of breast cancer patients, especially those with liver metastasis, and patients with breast cancer expressing CD44 v6 are more likely to develop liver metastasis (26). This suggests that advanced detection of CD44 expression on breast cancer cells might effectively predict the likelihood of metastasis, which might contribute to the development of targeted therapies.

The vascular system is also likely vital in metastasis. Liang et al. (10) demonstrated that metastasis resulted in a nonangiogenic growth pattern in the initial phase, a phase that was not harmful to the organism; in the late phase, the development of the vascular system at the site of liver metastasis supported breast cancer cells to thrive. During the transition from a nonangiogenic dormant phenotype to an angiogenic phenotype, the expansion of tumor size was connected with the recruitment of endothelial cells from the tumor tissue (27).

Treatment for BCLM

Drug therapy

Chemotherapy

BCLM is currently treated by chemotherapy drugs such as taxanes, anthracyclines, gemcitabine, cisplatin, vinblastine, fluorouracil, etc. In clinical practice, adjuvant and perioperative chemotherapy aim to eradicate early micrometastatic disease, decrease recurrence rates, and improve survival outcomes. Patients with MBC who have not received adjuvant anthracyclines or taxanes in the past should consider them as first-line treatment options (1). However, with their increasing application in the adjuvant treatment of breast cancer, the choices of anthracyclines and taxanes may decrease accordingly after recurrence and metastasis (28). It was recommended to use capecitabine, vinorelbine, or eribulin for breast cancer patients with distant metastases following prior treatment with anthracycline and taxane (29). The CBCSG006 trial demonstrated the status of cisplatin-containing combination regimens in the first-line treatment of MBC (30). The study showed a statistically significant difference of 7.73 [95% CI: 6.46–9.00] months of progression-free survival (PFS) in the cisplatin combined with gemcitabine (GP) group compared with 6.07 [95% CI: 5.32–6.83] months in the paclitaxel combined with gemcitabine (GT) group (P=0.005). In this trial, the status of homologous recombination (HR) deficiency was significantly related to a higher objective response rate (ORR) and longer PFS in the GP group than in the GT group (71.9% vs. 38.7%, P=0.008; 10.37 vs. 4.30 months, P=0.011). Patients with germ-line BRCA1/2 (gBRCA1/2) mutations had numerically higher ORR and longer PFS in the GP group than in the GT group (83.3% vs. 37.5%, P=0.086; 8.90 vs. 3.20 months, P=0.459). Germline mutations of BRCA1/2 and the HR panel are potential biomarkers for better performance of cisplatin-based regimens. In addition, a recent study by Park et al. (31) showed that for patients with MBC, when combined with gemcitabine, the 6-month PFS rates were 72% (eribulin group) and 73% (paclitaxel group) (P=0.457), and there was no significant difference in OS and PFS between the two groups. The authors suggested that the eribulin group had less neurotoxicity than the paclitaxel group. A recent phase IV study also demonstrated that eribulin was a well-tolerated treatment option in MBC, and its toxicity rarely resulted in treatment discontinuation (32). However, the overall population contained patients with heterogeneous subtypes in the study, and this limited the probability of specific toxicity analysis in biological subtypes, which necessitates further exploration in the future. Hepatic arterial treatment (HAT) combined with chemotherapy has also gradually attracted increasing attention. A study suggested that HAT oxaliplatin in combination with capecitabine for liver metastases in patients with MBC had high response rates of 42.3% (95% CI: 28.7–56.8%) and a long median PFS of 10.8 months (95% CI: 6.9–14.7 months) and OS of 27.6 months (95% CI: 20.4–34.8 months) (33). Furthermore, when combined with atezolizumab, chemotherapy treatment yielded a clinically meaningful OS benefit in patients with related immune biomarker cell-positive metastatic triple-negative breast cancer and might be a significant therapeutic choice (34).

In terms of the duration of systemic chemotherapy, most expert recommendations indicated continuation of effective treatment until disease progression or unacceptable toxicity. In actual clinical work, special attention should be given to the impact of treatment on the patient’s general condition and quality of life, and a balance between efficacy and quality of life should be pursued.

Endocrine therapy

Commonly used first-line endocrine therapy includes selective estrogen receptor modulators (tamoxifen), selective estrogen receptor downregulators (fulvestrant), or third-generation aromatization enzyme inhibitors for postmenopausal patients (anastrozole, letrozole, exemestane).

The Society of Medical Oncology recommended that endocrine therapy should be the preferred treatment for patients with hormone receptor-positive advanced breast cancer (ABC) with or without visceral metastasis unless there was evidence of visceral crisis or clear endocrine resistance (1). Endocrine drug resistance is a major barrier to current endocrine therapy. The mechanism of endocrine drug resistance in breast cancer is not yet clear, but some studies have found that changes in the phosphatidylinositol-3-kinase (PI3K) signaling pathway are related to resistance (35-38). In the phase III SOLAR-1 randomized study, the PI3K inhibitor alpelisib combined with fulvestrant increased median PFS by approximately 5 months in postmenopausal women with hormone receptor-positive, HER2-negative, PIK3CA-mutated MBC, which is a crucial breakthrough in the history of endocrine therapy (39). This trial also indicated that the median OS (95% CI) in patients with BCLM was 37.2 months (28.7–43.6 months) and 22.8 months (19.0–26.8 months) in the alpelisib-fulvestrant and placebo-fulvestrant arms, respectively [HR =0.68 (0.46–1.00)] (40). The combination of endocrine therapy with other treatments was also reported by Schettini et al. (41). They suggested that endocrine therapy with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, as first- or second-line treatments, might prolong PFS for patients with hormone receptor-positive/HER2-negative MBC. The combination may also improve OS compared to endocrine therapy alone (41). In addition, although CDK4/6 inhibitors have shown clinical efficacy in patients with estrogen receptor-positive MBC, estrogen receptor-positive breast cancer cells can rapidly adapt to CDK4/6 inhibition and escape cytostatic inhibition, resulting in primary and acquired drug resistance: combination therapy can also successfully prevent this (42).

Targeted therapy

Breast cancer cells in the liver thrive in a microenvironment characterized by the absence of a subendothelial basement membrane and fenestrated endothelium in sinusoidal capillaries (43). The binding of VEGFs to the VEGFR1-3 receptors activates the VEGF signaling pathway in endothelial cells (44). Therefore, the inhibition of VEGFR kinases decreased metastasis to the liver. Bevacizumab, a humanized monoclonal antibody that binds to all circulating VEGF-A isoforms, was the first antiangiogenic therapy available. There was a report of a woman with a BRCA2 germline mutation who was successfully treated with a combination of bevacizumab/paclitaxel/carboplatin (BPC). Despite liver metastases and pregnancy, the patient maintained a complete clinical response for approximately five years (45). This finding suggested that blocking VEGF pathways with drugs such as bevacizumab could be considered a good treatment option for MBC.

HER2 is a transmembrane tyrosine kinase protein belonging to the human epidermal growth factor receptor (EGFR) family of proteins. HER2 amplification and overexpression are associated with aggressive tumor biology and poorer prognosis (46). Several anti-HER2 agents have been developed for clinical use, including monoclonal antibodies (trastuzumab, pertuzumab), small molecule tyrosine kinase inhibitors (lapatinib, neratinib), and antibody-drug conjugates (T-DM1). Ji et al. (5) found that compared to the hormone receptor-positive/HER2-negative subgroup, the hormone receptor-positive/HER2-positive subgroup had a significantly lower risk of death (HR =0.74; 95% CI: 0.58–0.95; P<0.001) for patients receiving HER2-targeted therapy. A phase III randomized clinical study indicated that for patients with hormone receptor-positive and HER2-positive MBC subgroups, in contrast to the single targeted drug (lapatinib/trastuzumab) combined with aromatase inhibitor therapy, the PFS was significantly prolonged when these two targeted drugs were combined with aromatase inhibitor therapy (47). This combination provides an effective and safe alternative treatment option to chemotherapy for this patient population subgroup. Moreover, studies on single-agent vs. double-agent chemotherapy combined with trastuzumab for the treatment of HER2-positive MBC had mixed results (48). To resolve this contradiction, a meta-analysis by Yu et al. (49) showed that the PFS and OS of patients with HER2-positive MBC treated with dual-drug chemotherapy combined with trastuzumab were better, but the treatment-related toxicity was more severe. BCLM can cause liver function damage, so the scope of application of dual-drug chemotherapy combined with trastuzumab needs to be explored in relevant clinical trials. A recent study by Xie et al. (50) indicated that pyrotinib plus trastuzumab and a single chemotherapeutic agent offered a promising choice with a manageable safety profile for patients with heavily pretreated HER2-positive MBC with a median PFS of 7.5 months (95% CI: 4.7 to 9.9 months) and ORR of 50.5% (20/40). However, to further confirm the efficacy and safety of this combination regimen, multicenter randomized controlled trials in larger populations are needed.

Surgery

Although BCLM can be treated with systemic therapies such as chemotherapy, antiangiogenic therapy, and targeted therapy, the prognosis remains poor (51). Therefore, other types of effective treatments, including local treatments such as surgery, are urgently needed. However, contrary to the substantial evidence for treating colorectal liver metastases locally, there are limited data on the resection of BCLM.

Growing evidence suggests that liver resection improves 5- or 10-year survival after BCLM surgery (52). He et al. (53) showed that the 5-year OS of the BCLM patient cohort was as high as 32.2%, and the median survival time was 57.59 months, which both indicated that surgery was an important management strategy in improving the prognosis of selected patients. A limited number of BCLM patients are eligible for surgery because of the extent and location of the disease and physical condition. For patients who have undergone liver surgery, primary tumor characteristics, such as small tumor size, low-grade tumor, node negativity, and early stage, might indicate a better prognosis, as demonstrated by a recent review (54). However, it is controversial whether radical or nonradical resection results in a better outcome. Elias et al. (55) showed that the median survival after R0 or R1/R2 resection was 40 and 31 months, respectively, without a significant difference. Nevertheless, Orlandi et al. (56) found that in a retrospective analysis, negative resection margin (R0) was the only factor that significantly enhanced OS compared to positive resection margin [78 vs. 16 months; HR 0.083, 95% CI (not mentioned), P<0.0001] and disease-free interval (DFI) [16 vs. 5 months; HR 0.17, 95% CI (not mentioned), P=0.0058]. Presently, there is no consensus on the specific method for liver resection. A retrospective study focused on performing anatomical resection (standard liver lobectomy, liver segment resection) or nonanatomical resection (wedge resection, excavation, etc.), but there was no evidence to support the difference in survival between the two groups (57).

Moreover, regarding the prognostic factor related to hormone receptors, there is a study pointing out that their status was not associated with postoperative outcome (52). Abbott et al. (58) and Elias et al. (55) reported a negative impact of hormone receptor deficiency on disease-free survival (DFS), but only in a univariate analysis. Complications were seldom described (including type and grade) in the literature. Only Abbott et al. (58) and Adam et al. (59) detailed the ratio between minor events (15–19%) and major events (5%). Furthermore, in the retrospective analysis by Orlandi et al. (56), surgical complications occurred in only two patients, and their data suggested that liver metastasis resection might be a safe procedure. In summary, based on most studies, almost no life-threatening complications were noted in patients with BCLM who had undergone surgery (60-62). Due to its invasiveness, surgical resection of BCLM is still controversial despite some promising reports. Liver recurrences and extrahepatic recurrences were diagnosed at a mean interval of 15 months and 22 months after hepatectomy (63).

Intervention therapy

Intervention therapy, a local treatment including ablation and transcatheter arterial chemoembolization (TACE), is attempted for patients at high surgical risk and shows positive results. Radiofrequency ablation (RFA) includes three main approaches: ultrasound-guided percutaneous RFA, laparoscopic RFA and intraoperative RFA. The standard RFA technique can elevate the temperature of local tissue beyond 100 ℃, causing coagulative necrosis of the tumor tissue and surrounding liver parenchyma. Meanwhile, the vascular tissue around the tumor forms a reaction zone, which prevents continued blood supply. The necrosis rate after RFA for BCLM exceeds 90% (64), comparable to the necrosis rate observed in the literature for colorectal liver metastasis (CRLM) or hepatocellular carcinoma, and this technique has a low incidence of postoperative complications. Even so, it is still contested whether the technique offers good efficacy for surgically unresectable primary or metastatic hepatic tumors. Some small-scale prospective studies of breast cancer patients with 1 to 3 liver metastases proposed that RFA was effective in 75% to 92% of patients, and the 1-year survival rate was 64% to 95% (54,65,66). However, according to another study, patients with BCLM >2.5 cm have significantly reduced survival after RFA (67). Meloni et al. (68) reported their experience with RFA (n=52), describing a 5-year survival rate of 27% and finding worse OS in patients with lesions >2.5 cm. More generally, the literature reviews presented by Taşçi et al. and Vogl et al. (69,70) concluded that post-RFA OS for BCLM was between 10 and 60 months, with recurrence rates between 13% and 58%, especially for patients with larger lesions. Microwave ablation (MWA) is another important ablation strategy with greater and more rapid thermal energy transfer (71). It has a more effective local control ability than RFA (100% coverage of metastatic lesions vs. 85–97%), with a median survival time of 32 months and a local progression rate of 9.6% (72-74). In addition, the recurrence rate of MWA is also relatively low, at approximately 10% (70). With regard to TACE, a recent development was that Chang et al. (6) discovered drug-eluting beads for transarterial chemoembolization (DEB-TACE), a novel drug delivery system using microspheres as embolic agents to load chemotherapeutic drugs for the treatment of BCLM. DEB-TACE is characterized by minimal trauma, a low rate of complications, and is safe and effective. This approach has been applied in clinical practice, with higher intratumoral concentrations and lower systemic drug concentrations than conventional TACE.

Radiotherapy

Bale et al. (54) suggested that there were three main types of treatment for BCLM: selective internal radiation therapy (SIRT) mainly for palliative care, stereotactic body radiation therapy (SBRT), and interstitial brachytherapy (BT). SIRT is still being evaluated in many pathologies, and its status remains to be determined. The indication of SIRT for BCLM patients based on studies is unresectable or progressive disease with systemic chemotherapy (52). Unlike conventional radiation therapy, SIRT delivers high-dose radiation selectively to targeted lesions and minimizes collateral damage to normal liver tissue (75). It is based on the administration of yttrium-90 (90 Y) microspheres with a diameter of approximately 30 µm via the arterial blood supply of liver tumors (54). A study showed that 58 patients with BCLM treated with SIRT had a median OS of 47 weeks (76). However, exact figures are still not identical due to a lack of extensive research. A report showed that adverse events of SIRT included radioembolization-induced liver disease (REILD), postradioembolization syndrome (PRS), biliary complications, radiation pneumonitis, gastroduodenal ulceration, lymphopenia, vascular injury, and portal hypertension (77). Onal et al. (78) retrospectively analyzed patients with BCLM receiving SBRT. The 1- and 2-year OS rates were 85% and 57%, respectively, and the 1- and 2-year local control rates were 100% and 88%, respectively. None of the treated patients developed grade 4 or 5 treatment-related toxicity. Another study from 25 centers considered that patients with BCLM treated with SBRT had an OS of 21 months, and they found that BED10 (with dose fractionations normalized to BED10) ≥100 Gy improved OS (79). Based on the reports, we supposed that SBRT was an effective option for patients with BCLM with good local control and promising survival rates, which was also consistent with the study by Oymak et al. (80). The selection criteria for patients with SBRT and the optimal dose for the liver are being studied. CT-guided BT is a safe and effective treatment, but further research is still needed because of the absence of data.

Conclusions

This article demonstrated the major mechanisms related to metastasis and the currently available treatment options in the management of BCLM. The process of BCLM is multistep, and there may be other factors affecting the metastasis process and potential mechanisms waiting to be explored further. At present, the survival of patients with BCLM is not promising. Due to the unique characteristics (especially tumor phenotype) of every BCLM patient, each treatment plan should take into account age, patient general status, hormonal status, HER2 overexpression, number and location of metastases, absence of disease interval and other personalized parameters. However, because of the lack of clinical data, there are still no specific standard-of-care therapeutic strategies indicated for patients with BCLM. Research on the mechanism of BCLM has promoted the development of treatments for this disease and provided an inspiring theoretical basis. The choice of a more efficacious management strategy to improve the prognosis of patients needs to be probed in the future.

Acknowledgments

The authors would like to thank Figdraw for helping to generate the figure.

Funding: This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2020-I2M-C&T-B-026); the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2020-I2M-C&T-B-019); Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province (No. CXPJJH1200008-10); Beijing Municipal Natural Science Foundation Project (No. 7222130); and the Teaching Reform Program of Peking Union Medical College (No. 2020zlgc0123).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2463/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2463/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2463/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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