Chinese Society of Clinical Oncology breast cancer expert consensus on the diagnosis and treatment of breast cancer brain metastasis (2025)

Introduction

Brain metastases (BMs) occur in 10–20% of breast cancer (BC) patients, encompassing both parenchymal BMs from BC and leptomeningeal metastasis (LM). Approximately 80% of BMs localize to the cerebral hemispheres, 15% to the cerebellum and 5% to the brainstem. Cacho-Díaz et al. reported that 47.6% of cases presented with multifocal lesions, while 26.4% exhibited solitary lesions, predominantly at the cortical-medullary junction, where vascular lumens narrow. LM occurred less frequently (6.9%), and concurrent BM/LM (3.6%) correlated with worse prognoses (1,2).

The prevalence of breast cancer brain metastases (BCBM) exhibits significant molecular subtype heterogeneity. Population-based studies demonstrate that BM develops in approximately 15% of advanced hormone receptor (HR)-positive cases, 50% of advanced human epidermal growth factor receptor 2 (HER2)-positive metastatic cases, and 33% of patients with triple-negative breast cancer (TNBC) (3,4). Notably, germline BReast CAncer gene 1/2 (BRCA1/2) mutations confer elevated BM risk, with mutation carriers showing substantially increased central nervous system (CNS) metastatic propensity relative to individuals harboring the wild-type genotype (5).

In recent years, BCBM has become a research hotspot, with significant advances achieved in understanding metastatic mechanisms, therapeutic strategies, and prospective research directions. Local treatment remains one of the main modalities for BM, including surgery and radiation therapy. In terms of drug therapy, antibody-conjugated drugs (ADCs) such as trastuzumab deruxtecan (T-DXd) have demonstrated significant intracranial control in patients with HER2-positive BM. There are also emerging findings for HER2-low BC as well as HER2-negative BM drugs.

The Specialized Committee of Breast Cancer, Chinese Society of Clinical Oncology (CSCO) and Specialized Committee of Nervous System Oncology, CSCO jointly organized relevant experts to develop the Expert Consensus on the Diagnosis and Treatment of Brain Metastases from Breast Cancer in 2022. To further promote standardized management of BCBM, the expert group updated the consensus and summarized the new evidence-based medical evidence and latest advances related to the treatment of BCBM in recent years.

Methods

Professor Zefei Jiang, President-elect of the CSCO, took the lead in formulating an expert consensus on BCBM. On 20 February 2025, the consensus expert group convened to define the diagnosis and treatment of BCBM, including imaging examinations, pathological diagnosis, medical treatment, combination of pharmacotherapy and local therapy, timing of radiotherapy and systemic therapy, and so on. After discussion and summary of multiple meetings, the panel finalized the CSCO Expert Consensus on BCBM.

Results

Clinical presentation

The most prevalent clinical feature of BMs is fatigue, which can affect up to 90% of patients (6). In BCBM, the most common presenting symptoms are headache (61.5%), followed by weakness and lethargy (26.9%), dizziness, blurred vision/blindness, and convulsions (each 15.4%) (7). LM frequently exhibits non-specific clinical features, presenting with a broad spectrum of neurological signs and symptoms, predominantly involving cerebral parenchymal dysfunction and meningeal irritation (such as headache, vomiting, nuchal rigidity, cognitive impairment, altered mental status, and the development of seizures attributable to structural brain lesions), cranial nerve deficits, elevated intracranial pressure and progressive neurological decline. Distinguishing LM from parenchymal BMs or therapy-related neurotoxicity can be challenging. In certain instances, LM may present solely as gradually worsening cervical and shoulder pain. When tumor dissemination extends along the irritation of the spinal cord or spinal nerve roots may occur, characterized by radicular pain, segmental sensory deficits, paresthesia, sensory ataxia, and diminished or absent deep tendon reflexes (8-11).

Imaging evaluation

Magnetic resonance imaging (MRI)

Cranial MRI is a cornerstone in the diagnostic workup, therapeutic response assessment, and longitudinal surveillance of individuals with CNS metastases (12). As the imaging modality of choice for both brain and leptomeningeal metastases, it offers radiation-free high-resolution soft-tissue contrast, multiparametric capabilities, and superior sensitivity. Nevertheless, it should not be performed in patients with ferromagnetic metallic implants or marked claustrophobia due to safety and tolerability concerns. Meningeal involvement in BC is categorized into leptomeningeal, dural, and combined subtypes. MRI typically reveals dural metastases as uninterrupted, heterogeneous linear thickening of the meninges along the cerebral convexities or tentorium cerebelli, typically confined to the outer meningeal surface without extension into the sulci or cerebral fissures. The extent of involvement may be widespread, and in advanced stages, local nodules or irregular mass-like lesions can develop, which shows pronounced contrast enhancement. MRI findings in leptomeningeal metastases typically demonstrate curvilinear enhancement patterns along cortical gyri, sulcal spaces, fissures, cisternal surfaces, and ventricular ependymal lining. They exhibit irregular morphologies, and nodular formation may additionally occur. Infiltration of adjacent brain tissues may result in localized parenchymal edema. In certain cases, BC meningeal metastases may present exclusively as hydrocephalus in the absence of meningeal enhancement, making diagnosis challenging with MRI alone; cerebrospinal fluid (CSF) evaluation may therefore be of diagnostic assistance.

Computed tomography (CT)

CT imaging typically demonstrates BCBM as isodense or hypodense lesions, with attenuation potentially increased in the setting of hemorrhagic components. On contrast-enhanced CT, BCBM typically presents as small intracranial masses accompanied by extensive perilesional edema and marked intense contrast uptake in the solid portions, exhibiting nodular, ring-like, or irregular enhancement configurations. For patients with contraindications to MRI, CT continues to serve as a clinically useful supplementary modality. Small isodense metastatic lesions are often challenging to identify, particularly in the posterior fossa, where surrounding osseous structures may obscure detection. Calcification within BCBM is exceedingly uncommon.

Positron emission tomography/computed tomography (PET-CT)

PET-CT enables the simultaneous acquisition of anatomical and metabolic data, making it a useful tool for evaluating systemic tumor burden. However, the high physiological glucose uptake in cerebral gray matter results in elevated background tracer activity in normal brain tissue, limiting the ability to distinguish intracranial lesions from adjacent parenchyma. Consequently, localized imaging is frequently necessary. presenting with clinical signs of BMs, urgent neuroimaging with cranial MRI or CT is warranted to evaluate total tumor burden.

Recommended candidates and frequency for imaging surveillance

The occurrence rate of BCBM varies according to molecular subtype, with TNBC and HER2⁺ BC patients exhibiting a higher risk of BM. Additionally, high histological grade, elevated tumor proliferative activity, greater tumor burden, younger age, and BRCA1/2 gene mutations are recognized as significant predisposing factors for the development of BMs. The neurological impact of BMs depends on their specific anatomical location but is commonly associated with elevated intracranial pressure, functional impairments, and irritative symptoms, which may contribute to impaired quality of life (13). With increasing number of prior systemic therapies, so does the likelihood of BM occurrence. Moreover, once BMs develop, patient survival is typically shortened.

Among individuals with advanced BC who exhibit CNS symptoms (e.g., headache, projectile vomiting, seizures, altered mental status, etc.), immediate brain imaging is warranted. For those with progressive extracranial disease (such as newly developed pulmonary or hepatic metastases), additional brain imaging should also be considered. Asymptomatic BM patients generally present with less severe disease and demonstrate relatively better prognosis compared to symptomatic patients (14). Advanced neuroimaging techniques such as cranial MRI facilitate the detection of more asymptomatic cases. Even in instances of multiple small intracranial metastases, stereotactic radiosurgery (SRS) often achieves effective local control, which may be further supplemented by systemic therapies with CNS activity. It should be noted during efficacy evaluation that radiation necrosis (RN), a delayed post-radiotherapy complication, arises from disruption of the blood-brain barrier (BBB) and necrosis of brain tissue (15). Its imaging features, namely, contrast enhancement and edema, are non-specific and closely mimic tumor recurrence, making the two entities notoriously difficult to distinguish on conventional follow-up scans (15). Therefore, reliance on conventional MRI alone is insufficient. A multimodal approach is recommended (16), including perfusion MRI (for cerebral blood volume), magnetic resonance spectroscopy (for metabolic profiling), amide proton transfer (APT) imaging, and amino acid PET (e.g., ¹⁸F-FACBC) to assess tumor metabolic activity (17). When imaging remains inconclusive, diagnosis should be guided by multidisciplinary review, serial imaging, or biopsy if necessary (18). For BC patients with newly diagnosed or recurrent systemic metastases who are at high risk of developing BMs, baseline brain imaging should be recommended even if they are asymptomatic (19). In contrast, symptomatic BMs may necessitate additional interventions such as craniotomy for mass effect reduction and are associated with poorer clinical outcomes (20).

Currently, there is no universal consensus on imaging strategies for patients with advanced BC. After extensive deliberation, the CSCO Breast Cancer Expert Committee recommends brain imaging surveillance for BC patients exhibiting symptoms suggestive of BMs or those with high-risk features for CNS involvement. Early detection through such imaging modalities, followed by prompt targeted interventions, enables more effective disease control. This approach contributes to improved clinical outcomes, enhanced quality of life, and prolonged overall survival (OS) in this patient population. In individuals with advanced TNBC or HER2⁺ BC who are asymptomatic for BMs and show no disease progression post-treatment, semi-annual brain imaging surveillance is recommended. For those with baseline symptoms of BMs, despite the absence of disease progression after treatment, brain imaging should be performed at approximately three-month intervals. In cases of disease progression with extracranial lesions, immediate brain MRI is warranted. For patients with advanced Luminal-subtype BC who demonstrate absence of disease progression post-treatment, annual brain imaging is advised. However, if disease progression occurs, prompt brain imaging should be conducted (21,22).

Pathological diagnosis

In patients with a high index of clinical suspicion for BCBM, tissue confirmation through biopsy of the metastatic site is advised when feasible from a clinical standpoint. Histopathological evaluation and immunohistochemical profiling of both the primary breast carcinoma and histopathological evaluation of metastatic lesions is recommended for definitive diagnosis of BCBM. Immunohistochemical profiling using a validated marker panel is advised, which encompass cytokeratin 7 (CK7), GATA binding protein 3 (GATA3), mammaglobin, trichorhinophalangeal syndrome 1 (TRPS1), gross cystic disease fluid protein 15 (GCDFP-15), and SRY-related HMG-box (SOX10). In patients in whom biopsy material is unavailable, CSF analysis including cytological examination and immunohistochemical staining, may serve as a tool to aid in the diagnosis of BCBM. Significant temporal and spatial heterogeneity in advanced BC can lead to discrepancies in molecular profiles between primary tumors and metastatic sites. Re-evaluation of the molecular subtype of metastatic lesions, based on progesterone receptor (PR), estrogen receptor (ER), HER2, and Ki-67 status is recommended. The HER2 status of metastatic lesions should be assessed whenever feasible. Combined immunohistochemistry (IHC) and in situ hybridization (ISH) are recommended for HER2 evaluation (23): (I) HER2 positivity: IHC 3+ or IHC 2+ with ISH positive; (II) low HER2 expression: IHC 1+ or 2+ with ISH negative; (III) HER2 ultra-low expression: defined as ≤10% of invasive tumor cells demonstrating incomplete and faint membrane staining in HER2 IHC 0; and (IV) HER2 negativity: IHC 0 (24).

Treatment

The management of BCBM should integrate both systemic and local therapies, with an emphasis on multidisciplinary approaches to develop personalized optimal treatment strategies. The overarching goal remains consistent with that of advanced BC therapy to prolong patient survival while maintaining quality of life. Currently, local therapies constitute the mainstay of BCBM treatment, including neurosurgical resection, whole-brain radiotherapy (WBRT), and SRS. Pharmacological interventions demonstrate efficacy in specific patient subgroups. In recent years, novel anti-HER2 targeted therapies have shown promising results in HER2-positive and even HER2-low expressing BCBM. For HER2-negative BCBM, drug therapies remain limited in efficacy, though certain agents such as poly (ADP-ribose) polymerase inhibitors (PARPi), ADCs, and immune checkpoint inhibitors (ICIs) have demonstrated modest therapeutic activity.

Surgical intervention

Surgical excision of BMs can effectively lower intracranial pressure, relieve neurological symptoms, mitigate the progression of focal deficits and seizure occurrence, and reduce dependence on corticosteroid therapy. Resected specimens provide critical tissue for definitive histopathological diagnosis and are valuable for molecular profiling and guiding targeted therapeutic strategies. Surgical intervention represents an effective treatment modality in individuals with solitary BMs, particularly those harboring large lesions with mass effect, offering greater clinical benefit compared to individuals with multiple metastases or significant systemic disease burden. Patchell et al. carried out a randomized trial involving 48 patients with BM, including 3 with BC origin, who were assigned to surgical resection or WBRT alone. The study demonstrated a significantly lower recurrence rate with a rate of 20% in the surgical group compared to 52% in the WBRT-alone group, along with a substantially extended median survival (40 vs. 15 weeks) (25). Surgical resection may also be beneficial for patients with two to three BMs and stable general condition, yielding outcomes comparable to those seen in individuals with a single metastatic lesion (level IIIb) (26).

Margin status represents a key prognostic determinant, as postoperative residual disease is significantly associated with increased risks of tumor recurrence and disease progression (level IIIb) (27); a meta-analysis reported that gross total resection in patients with posterior fossa metastases is linked to a lower recurrence risk, with leptomeningeal spread observed in only 5–6% of cases—substantially less than rates following partial resection (level IIIb) (28). A further investigation reported that early postoperative MRI detected residual tumor in approximately 20% of patients following metastasis resection, which showed a significant association with the occurrence of local recurrence (level IIIb). Multimodal imaging and navigation methods, including preoperative functional MRI and intraoperative neuro-navigational guidance, and corticospinal tract reconstruction (level IV), may preserve brain function and lower complication rates during complete resection of BMs. Magnetic resonance-guided laser interstitial thermal therapy (LITT) is a minimally invasive modality under ongoing development. It offers a therapeutic alternative for individuals with deep-seated intracranial lesions, elderly or medically fragile patients unsuitable for prolonged surgery, and those affected by RN. A case-control study showed that laser interstitial thermal therapy provides comparable local control efficacy to surgical resection in the management of BMs. Local control rates at 6 months ranged from 54% to 81.9% for recurrent BM and from 56.5% to 100% for radiation-induced necrosis (29,30). Pooled data from a meta-analysis and findings from a retrospective cohort study demonstrated that laser-induced thermotherapy achieves comparable, and in some aspects superior, efficacy to bevacizumab in managing radiation-induced necrosis among patients with BMs (31,32). Furthermore, laser-induced thermotherapy treatment was not associated with deterioration in Karnofsky Performance Status (KPS) scores or patient-reported outcomes and overall well-being (29), and modestly reduced corticosteroid utilization (29,33). A further multicenter prospective study demonstrated that it achieves effective control of BMs located in surgically inaccessible regions (34). It also effectively manages brain edema resulting from RN. Domestically developed LITT systems in China have shown efficacy for both treatment-naïve and recurrent BMs, including those with RN. The 2021 European Association for Neuro-Oncology (EANO)-European Society for Medical Oncology (ESMO) joint guidelines recognize LITT as an emerging therapy for recurrent BMs and RN, though its clinical utility awaits full establishment.

Radiotherapy

Goals

Current radiotherapeutic approaches for BCBM encompass stereotactic radiotherapy (SRT) and WBRT, the latter in the presence or absence of hippocampal-avoidance strategies. In clinical practice, treatment approaches tailored to distinct therapeutic objectives are commonly guided by individual patients’ estimated life expectancy. Non-prospective evidence suggests that the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) score may aid clinical management planning for patients with BMs via enhanced risk categorization (35,36). A survey of management strategies for patients with multiple BMs showed that 33% of physicians incorporate the Recursive Partitioning Analysis (RPA) or Graded Prognostic Assessment (GPA) score when determining eligibility for SRS (37). Accordingly, the updated GPA (Breast GPA) is recommended to inform treatment objectives and support stratified, rational, and individualized management of BMs. This scoring system is expected to undergo continuous refinement as systemic therapies and local treatment modalities evolve.

SRT

SRT offers superior target precision, higher biological effective doses, abbreviated treatment duration, and reduced neurotoxicity, enabling effective preservation of cognitive function while achieving intracranial disease control and alleviation of neurological deficits. As a result, SRT has increasingly become the cornerstone of local therapy for BM, supplanting WBRT. Based on dose fractionation, SRT is classified as either SRS or fractionated stereotactic radiotherapy (FSRT).

(I) Postoperative SRT
In individuals affected by BMs undergoing surgical excision as the sole intervention, approximately 50% develop intracranial local recurrence within 6 months of surgery (38). Postoperative WBRT has been shown to reduce the risk of local recurrence and distant intracranial recurrence by 50%, while also contributing to survival prolongation (39-41). A number of observational investigations have evaluated the effectiveness of SRT following surgery (42-45). Following single- or hypofractionated postoperative SRT, local control at 1 year at the intracranial resection cavity range from 73% to 90%, similar to rates observed following postoperative WBRT. Mahajan et al. (46) assessed 132 patients with 1 to 3 BMs randomized to postoperative SRS or observation, and demonstrated that postoperative SRS markedly enhances local control at the resection site. The NCCTG N107C/CEC3 trial (47) included 194 individuals following surgical resection of BMs, with at least one lesion resected and up to three unresected metastases permitted. Although OS did not differ between groups, the SRS group exhibited superior median cognitive deterioration–free survival and a lower rate of cognitive decline at 6 months. Local control rates at the surgical site were inferior in the SRT group relative to the WBRT group, with 6-month rates of 80% vs. 87% and 12-month rates of 61% vs. 81%, likely attributable to the fact that 40% of patients had a resection cavity exceeding 3 cm.

Therefore, postoperative radiotherapy is recommended for patients with limited BCBM to enhance intracranial local control. Compared with postoperative WBRT, postoperative tumor bed SRT can achieve comparable local control of the resection cavity and is associated with a lower incidence of cognitive decline, without adversely affecting OS. Thus, when technically feasible, postoperative SRT should be prioritized over WBRT as the preferred radiotherapy modality. Nevertheless, the risk of intracranial recurrence remains significant, particularly in individuals with a large surgical cavity (>3 cm), necessitating intensified follow-up through serial clinical evaluation and imaging surveillance.

(II) SRT alone
The RTOG 9508 trial (48) demonstrated that the combination of WBRT and SRS is both effective and well-tolerated in patients harboring up to three BMs. Later trials evaluated the comparative benefits and adverse effects of WBRT-SRS integration vs. SRS alone within this cohort (38,49-51). Relative to SRS monotherapy, the incorporation of WBRT was associated with approximately a 50% decrease in the likelihood of intracranial disease progression; nonetheless, it failed to prolong OS and was associated with increased rates of adverse events, including cognitive decline. Several randomized trials have endorsed SRS as a primary management strategy for appropriately selected patients with limited BMs (Table 1). Given the potential toxicity associated with WBRT, it is typically withheld in the majority of individuals meeting criteria for upfront SRS and exhibiting low-volume intracranial disease. The majority of prior randomized clinical trials included patients with up to four BMs, each ≤3 cm in maximum diameter (Table 1).

The strongest available data on SRS for patients with multiple BMs originate from the Japanese prospective, single-arm, multicenter JLGK0901 trial (55), which enrolled 1,194 individuals with 1 to 10 intracranial lesions. Patients with 5 to 10 BMs exhibited comparable OS, toxicity profiles, and rates of subsequent CNS progression following SRS, relative to those with 2 to 4 lesions. A further randomized controlled trial [NCT02353000 (53)] evaluated the efficacy and toxicity of WBRT vs. SRS in patients with 4 to 10 BMs. Despite premature termination owing to limited accrual, evaluation of the 29 participants in the SRS arm revealed a 1-year actuarial brain relapse-free survival rate of 50%, a 1-year OS rate of 57%, and sustained patient-reported functional well-being.

(III) Fractionation
To date, no prospective randomized trial has evaluated the clinical advantages of varying dose and fractionation schedules in SRT. Dosing for postoperative single-fraction SRS may be guided by the NCCTG N107C/CEC3 trial (47) (Table 1). To date, the use of postoperative multifraction SRT has been primarily investigated in non-randomized studies (45,56-58), and a prospective trial evaluating postoperative SRT fractionation regimens (NCT04114981) is currently underway. The RTOG 9005 dose-escalation trial of standalone SRT defined the maximum tolerated single-fraction doses as 24 Gy for BMs ≤20 mm in diameter, 18 Gy for those 21–30 mm, and 15 Gy for lesions measuring 31–40 mm (59). In addition, across the aforementioned prospective studies, a single-fraction dose of 20–24 Gy has been commonly administered for BMs with a maximum diameter ≤2 cm or a volume <4 cm³ (38,49,50,55). A large retrospective analysis demonstrated satisfactory local control for BMs ≤2 cm in diameter treated with a single fraction of 24 Gy; in contrast, lesions >2 cm showed inferior local control when treated with single-fraction regimens of 15 to 18 Gy (60). Fractionated SRT is associated with improved local control and a reduced risk of radiation-induced brain necrosis in this patient population, particularly for solitary BMs exceeding 3 cm in maximal diameter (61). Commonly accepted SRT fractionation regimens include 27 Gy/3 fractions (Fx) or 30 Gy/5 Fx and 35 Gy/5 Fx (62). Beyond maximum tumor diameter, the intracranial substructure of the lesion and the dose tolerance also affect the recommended SRS/SRT dosing. Across various SRT schedules, a biologically effective dose (BED10) of ≥50 Gy has been associated with improved local tumor control (63).

For BMs with maximal diameter ≤2 cm, single-fraction SRS at 20–24 Gy is recommended. For lesions 2.1–2.9 cm in size, single-fraction SRS at 18 Gy or fractionated SRT may be considered. For tumors measuring 3.1 to 4.0 cm, fractionated SRT is advised. Given that prior prospective trials of single-fraction SRS for the treatment of BMs have excluded lesions exceeding 4 cm in diameter, SRT is recommended for such tumors when technically feasible. However, the use of SRT for tumors exceeding 6 cm in diameter remains unsupported owing to limited clinical data (64).

WBRT with or without hippocampal avoidance

WBRT administered with or without hippocampal-sparing techniques remains a treatment option. Despite growing challenges to the use of WBRT due to advancements in SRT (65), it continues to be a viable treatment strategy for individuals with widespread BMs, regardless of leptomeningeal disease status. Clinical data suggest that patients with extensive intracranial disease (typically characterized by 20 or more lesions) may achieve meaningful survival following WBRT (66). Cognitive decline associated with WBRT is widely acknowledged, with less than 10% of BMs located within 5 mm of the hippocampal region. As demonstrated in the RTOG 0933 trial (67), a lower dose of hippocampal irradiation was associated with less pronounced cognitive function deterioration. The NRG ONCOLOGY CC001 trial (54) demonstrated that hippocampal-sparing WBRT (HA-WBRT), when combined with memantine, helps maintain cognitive performance while preserving intracranial disease control and OS. In individuals with widespread BMs, favorable prognosis, and a minimum lesion-to-hippocampus distance of at least 1 cm, HA-WBRT combined with memantine is recommended, given its high therapeutic efficacy and low toxicity. Also, combining HA-WBRT with SRT to specific metastatic lesions may be considered to improve local control. The WBRT dose should follow that of the NCCTG N107C/CEC3 trial (47), with a recommended regimen of 30 Gy delivered in 10 Fx (Table 1).

The QUARTZ trial (68) demonstrated that WBRT provides no survival benefit compared to best supportive care in patients with poor prognostic profiles. For this population, appropriate management strategies include palliative or end-of-life care; alternatively, those with symptomatic BMs may receive abbreviated-course WBRT (e.g., 20 Gy in 5 Fx). Radiotherapeutic management for BMs may be especially critical in patients with a limited burden of disease, defined as 1 to 4 anatomically distinct metastatic lesions. These patients have access to a broader range of therapeutic options. Treatment stratification and categorization can be performed according to their performance status, prognosis of BMs, and patient preferences. Figure 1 summarizes evidence-based strategies for local treatment in patients with limited BMs. Regardless of modality—SRS, fractionated SRT, or WBRT with or without hippocampal-sparing techniques—the total biologically effective dose administered to metastatic lesions remains a consistent determinant of local tumor control.

Figure 1 Recommendations on local therapy for patients with a limited number of brain metastases. D_max, maximum diameter; HA-WBRT, hippocampal-avoidance whole-brain radiotherapy; PS, performance status; SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy; WBRT, whole-brain radiotherapy.

Beyond treating established BMs, the prophylactic use of WBRT, known as prophylactic cranial irradiation (PCI), has been evaluated in historical and small-scale studies for preventing BMs in high-risk BC patients (69). While these studies suggested a potential reduction in BM incidence, PCI is not recommended in current clinical practice guidelines. This is due to the lack of evidence for an OS benefit from large phase III trials, coupled with concerns about potential neurocognitive toxicity. The focus for preventing BM in high-risk patients has shifted towards the use of modern systemic therapies with high intracranial efficacy (e.g., certain HER2-targeted agents) (70,71).

Medical treatment

Chemotherapy

Chemotherapeutic agents exhibit limited BBB penetration due to high molecular weight, charged structure, and high plasma protein binding, particularly to albumin. As a result, systemic chemotherapy alone generally yields limited efficacy against BMs. To date, there is no conclusive evidence demonstrating BBB penetration of anthracyclines or taxanes (72). Moreover, due to the widespread use of anthracyclines and taxanes in adjuvant or salvage therapy, their specific role in the management of BMs has been infrequently evaluated in clinical studies. Other chemotherapeutic agents, including capecitabine, topotecan, platinum, have demonstrated objective response rates (ORRs) varying between 4% and 55% among individuals with BCBM, with reported median progression-free survival (PFS) typically under 4 months (73-79).

Utidelone Injection is a novel, China-developed epothilone-class microtubule inhibitor. Preclinical studies demonstrated that following intravenous administration in Sprague-Dawley (SD) rats, utidelone achieved substantial drug concentrations in brain tissue, indicating its ability to cross the BBB. This pharmacokinetic property suggests potential antitumor activity against intracranial lesions.

The U-Brain study is a single-arm, multicenter phase II clinical trial in which patients received bevacizumab (15 mg/kg IV, day 1) combined with utidelone (30 mg/m² IV, days 1–5) until intolerable toxicity or disease progression occurred. Between May 5, 2022 and October 25, 2023, a total of 47 patients were enrolled, including 35 with untreated CNS lesions and 12 with progressive BMs following local radiotherapy. With a median follow-up of 14.6 months, the CNS ORR was 42.6% (20/47) in the overall population: 33.3% (9/27) in the HR-positive subgroup and 55% (11/20) in the HR-negative subgroup. The median PFS was 7.7 months [95% confidence interval (CI): 5.6–9.7] for the entire cohort. Subgroup analyses revealed a median PFS of 5.9 months (95% CI: 5.51–10.8) in HR-positive patients and 8.4 months [95% CI: 4.95–not reached (NR)] in HR-negative patients (80).

However, this evidence stems largely from small-sample, exploratory clinical studies, the majority of which were single-arm studies integrating chemotherapy and radiotherapy. Thus, adequate evidence is lacking to justify the use of monotherapy with conventional cytotoxic agents as the primary treatment approach for BMs.

HER2-targeted therapy

Currently, the primary HER2-targeted agents can be classified into three major categories: antibody-drug conjugates (ADCs), tyrosine kinase inhibitors (TKIs), and monoclonal antibodies (mAbs). For patients with HER2-positive BMs, anti-HER2 ADCs and TKIs have demonstrated definitive intracranial efficacy, whereas mAbs exhibit limited therapeutic effectiveness against intracranial lesions.

(I) ADCs
ADCs that integrate trastuzumab as the targeting moiety and a cytotoxic agent as the payload have demonstrated encouraging antitumor activity in patients with stable BMs. Trastuzumab emtansine (T-DM1) is an ADC that links the mAb trastuzumab to the microtubule inhibitor DM1, a maytansinoid derivative. In two phase III trials, 443 patients with asymptomatic BMs received T-DM1, with a median PFS was 5.5 to 5.9 months. Among 126 patients with measurable BMs, the best overall response (BOR) rate was 21.4% (81,82).

T-DXd is an ADC consisting of trastuzumab linked to deruxtecan, a topoisomerase I inhibitor. It has demonstrated substantial antitumor activity in patients with stable BMs following treatment. Compared to T-DM1, T-DXd demonstrates a higher drug-to-antibody ratio and exhibits a pronounced bystander effect while maintaining favorable pharmacokinetic properties. This agent has demonstrated remarkable efficacy in patients with stable BMs following treatment. Clinical studies have established T-DXd’s substantial activity against HER2-positive BMs. A pooled analysis of DESTINY-Breast01, 02, and 03 trials revealed ORR of 45.2% and 45.5% in HER2⁺ patients with stable and active BMs, respectively. Notably, complete responses (CRs) were achieved in a considerable proportion of cases, with CR rates of 16.3% in stable BMs and 15.9% in active lesions. Patients with stable BMs had a median PFS of 12.3 months, compared to 18.5 months in those with active disease (83). Further supporting these findings, results from DESTINY-Breast12 demonstrated durable clinical efficacy in both stable and active BMs. The 12-month PFS rates were 62.9% and 59.6%, while CNS-specific ORRs were 79.2% and 62.3% for stable and active BMs, respectively (84).

T-DXd has shown notable efficacy in HER2-low BCBM. A subgroup analysis from the DESTINY-Breast04 trial provided compelling evidence: in patients with baseline BMs, T-DXd achieved an intracranial ORR of 25.0%, compared to 0% in the control arm (85). The DAISY study further corroborated T-DXd’s antitumor activity in HER2-low expressing BMs, reporting a confirmed BOR rate of 30% and clinical benefit rate (CBR) of 50% (86). Preliminary results from the phase II DEBBRAH study were particularly encouraging, demonstrating a 50% intracranial ORR among HER2-low advanced BC patients with active CNS metastases treated with T-DXd (87).

(II) Epidermal growth factor receptor (EGFR)-TKIs
Among patients with BCBM, the four approved EGFR-targeted TKIs have shown promising therapeutic activity. Pyrotinib, an irreversible and highly potent agent, exerts inhibitory effects on HER1, HER2, and HER4.The prospective, randomized, controlled, phase III PHOEBE trial (88) demonstrated that pyrotinib exhibits significantly greater efficacy compared to lapatinib. The phase III PHENIX trial confirmed that pyrotinib significantly delays intracranial disease progression in patients with asymptomatic BMs (89). The multicenter, single-arm, two-cohort phase II PERMEATE trial demonstrated that the combination of pyrotinib and capecitabine demonstrated a CNS ORR of 42.1% and a median PFS of 5.6 months in patients whose BMs had progressed following radiotherapy; among those with previously untreated HER2-positive BMs, the CNS-ORR was 74.6% and PFS reached 11.3 months, with outcomes similar to those seen in patients with systemic disease (90). Therefore, the combination of pyrotinib and capecitabine may be considered the optimal systemic regimen for patients with EGFR-TKI-naïve active BMs and manageable local symptoms. Neratinib, an irreversible TKI with activity against HER1, HER2, and HER4, has been associated with a lower incidence of CNS-related interventions in the phase III NALA trial (91). A single-arm trial evaluating neratinib in patients with BMs progressing after radiotherapy demonstrated a CNS-ORR of 33% to 49% and a median PFS ranging from 3.1 to 5.5 months (92).

Lapatinib is a reversible inhibitor with dual tyrosine kinase activity against epidermal growth factor receptor (EGFR/HER1) and HER2. A meta-analysis of aggregated patient data from clinical trials involving 799 individuals demonstrated that exhibits clinical activity in individuals with BMs who have been exposed to various treatment regimens (93). In the prospective, single-arm, phase II LANDSCAPE trial (94), lapatinib combined with capecitabine achieved a CNS-ORR of 57.1% in patients with HER2-positive metastatic BC and untreated BMs without prior WBRT, delaying the initiation of radiotherapy by 8.3 months. The LANDSCAPE trial was the first to demonstrate the therapeutic efficacy of a small-molecule TKI on BMs.

Tucatinib, a potent and selective TKI targeting HER2, demonstrates robust intracranial efficacy in controlling BMs in individuals with advanced disease receiving second-line or subsequent systemic therapy (95). In the phase III HER2CLIMB trial, which included 291 (47%) participants with BMs, the incorporation of tucatinib to trastuzumab and capecitabine substantially extended the time to CNS progression, with median CNS PFS improving from 4.2 to 9.9 months and OS increasing from 12.0 to 18.1 months (96). As a result, the US Food and Drug Administration has granted approval of tucatinib for the management of BCMC.

(III) mAbs
Large-molecule mAbs do not exhibit superior BBB permeability compared with small-molecule TKI. To date, there is no clinical evidence that large-molecule mAbs exert a meaningful therapeutic effect on intracranial lesions. Trastuzumab and pertuzumab are mAbs that specifically bind to extracellular domains (ECDs) IV and ECD II of HER2. In the phase III CLEOPATRA trial, the addition of pertuzumab prolonged the median time to CNS metastases as the initial site of disease progression (97); in the PHEREXA trial, pertuzumab combined with trastuzumab and capecitabine demonstrated limited efficacy in patients with BCBM, with a reported PFS of less than 4 months (98); in a prospective, single-arm phase II study, individuals with HER2⁺ metastatic BC and BMs who experienced CNS progression despite prior radiotherapy were administered pertuzumab in combination with high-dose trastuzumab administered at 6 mg/kg per week, resulting in a CNS-ORR of11%, which did not reach statistical significance (99).

(IV) ADC-TKI combination
Both ADC monotherapy and TKI monotherapy have demonstrated breakthrough efficacy in the treatment of BCBM, while their combination has shown superior therapeutic outcomes. In the BM subgroup analysis of the HER2CLIMB-02 trial, the combination of tucatinib with T-DM1 demonstrated significantly improved outcomes compared to placebo plus T-DM1 in BCBM patients. The tucatinib-containing regimen prolonged median PFS (7.8 vs. 5.7 months; hazard ratio =0.64), corresponding to a 36% reduction in disease progression risk (100). These results provide compelling evidence that ADC-TKI combinations can enhance treatment efficacy for BM patients. The exploration of ADC-based combination therapies with other antitumor agents represents an emerging research direction in BM treatment, with several ongoing investigations. Furthermore, the single-arm, open-label phase II HER2CLIMB-04 study is currently evaluating the potential synergistic effects of T-DXd combined with tucatinib. This trial is anticipated to provide additional evidence supporting ADC-TKI combination strategies while potentially advancing treatment outcomes for HER2-positive BM patients.

Other targeted therapies

For patients with HER2-negative BMs, targeted therapies have limited value and there is a paucity of evidence. Local treatment of intracranial lesions is preferred, and medical treatment options may be comprehensively considered based on the systemic conditions. Given that TNBC is characterized by the absence of ER, PR, and HER2 expression, it lacks actionable targets for endocrine therapy and anti-HER2 treatments. However, the emergence of novel targeted agents, including PARPi, ADCs, and ICIs, has provided new therapeutic opportunities for TNBC patients with BCBM. Further research is ongoing to evaluate the intracranial efficacy of these agents in HER2-negative BCBM.

(I) PARPi
Multiple clinical studies have demonstrated the therapeutic benefit of PARPi in TNBC patients with BMs. Two phase III studies of PARPi enrolled patients with HER2-negative metastatic BC and a germline BRCA mutation (101,102). Compared with standard therapy, olaparib and talazoparib prolonged PFS in patients with BMs (103). Furthermore, in a phase I trial, the combination of veliparib with WBRT demonstrated promising efficacy in BCBM, achieving a 6-month OS rate of 61% and an intracranial ORR of 41% (104). Similarly, iniparib, which also exhibits BBB penetration, was evaluated in a phase II trial in combination with irinotecan for TNBC with BMs. The study reported an intracranial lesion response rate of 12%, with a CBR of 27%. In contrast, extracranial lesions showed a lower response rate of 5% and a CBR of 11% (105).

(II) TROP2 ADC
Sacituzumab govitecan (SG) in BCBM: the phase III ASCENT trial evaluating SG in metastatic TNBC enrolled 61 patients with stable BMs. Subgroup analysis demonstrated superior efficacy of SG compared to conventional chemotherapy, with improved median PFS (2.8 vs. 1.6 months) and PFS rates at 3 and 9 months (41% vs. 28% and 9% vs. 0%, respectively). Multiple real-world studies have further substantiated SG’s therapeutic potential in TNBC-BMs, consistently showing survival benefit in this patient population (106,107).

Datopotamab deruxtecan (Dato-DXd) in BCBM: Dato-DXd shares the same cytotoxic payload as T-DXd but targets TROP-2 instead. The phase III TROPION-Breast01 trial compared this TROP-2-directed ADC with chemotherapy selected by the treating physician in individuals with inoperable or metastatic HR-positive/HER2-negative BC. Prespecified subgroup analysis of patients with baseline BMs revealed a median PFS of 5.6 months with Dato-DXd vs. 4.4 months with chemotherapy (hazard ratio =0.73, 95% CI: 0.39–1.42) (108). Preliminary results from the phase II TUXEDO-2 study suggest potential efficacy in TNBC-BM, demonstrating an ORR of 37.5% and median PFS of 4.2 months (109).

ICIs

Recent investigations have identified PD-L1 expression in 53% of BCBM cases, independent of molecular subtypes, suggesting potential therapeutic utility of ICIs in this setting (110). This biological rationale has prompted several clinical trials (e.g., NCT03483012, NCT03449238) currently evaluating the combined efficacy of radiotherapy and immunotherapy regimens for BCBM management.

Other therapies

The incidence of BMs is relatively low in patients with HR-positive BC, and BMs usually appear late in the process of tumor recurrence and metastasis. CDK4/6 inhibitors have become a standard of care for patients with advanced HR-positive BC. The CDK4/6 inhibitor abemaciclib was found to be able to penetrate the BBB, resulting in a CNS-ORR of 5.2% in patients with ER⁺/HER2-BC (111). However, its efficiency is not satisfactory and needs further investigation.

Also, the anti-angiogenic drug bevacizumab can relieve brain edema caused by radiotherapy (112). When used in combination with chemotherapy, it yielded a CNS-ORR of 47% to 77% and a PFS of 5.6 to 6.1 months in patients with BCBM who progressed after WBRT (113,114).

Combination of pharmacotherapy and local therapy

Given that the BBB impedes the delivery of therapeutic agents to the CNS, pharmacologic treatment was previously regarded as having minimal impact on intracranial lesions originating from BC. Nonetheless, preclinical evidence indicates that radiation exposure may disrupt the BBB and increase the permeability of therapeutic agents (115,116) which establishes a mechanistic rationale for the integration of pharmacotherapy with cranial radiotherapy in the management of BMs (117,118). The combination of intracranial radiotherapy with systemic therapy enhances BBB permeability and drug delivery, though it may also increase the risk of adverse effects.

A single-arm, single-center, non-randomized phase II study involving 40 HER2-positive BM patients demonstrated promising outcomes with radiotherapy combined with TKI therapy. The regimen of CNS radiotherapy plus pyrotinib and capecitabine achieved a 1-year CNS PFS rate of 74.9%, with a median CNS PFS of 18.0 months and an impressive CNS ORR of 85%. The incidence of RN remained within acceptable limits (119). Additional retrospective, small-scale, non-controlled studies have reported improved local tumor control with acceptable toxicity when combining radiotherapy with targeted or immunotherapies. Two studies evaluating T-DXd plus radiotherapy in HER2⁺ and HER2-low expressing BCBM demonstrated manageable safety profiles, with T-DXd and SRS and combination therapy showing strong local tumor control with no concomitant increase in RN risk (120,121). Notably, Ippolito et al. reported outstanding outcomes with synchronous SRT and dual HER2 blockade (trastuzumab + pertuzumab) in HER2-positive BMs, demonstrating a median OS of 33.9 months, 100% intracranial CBR, and 68.7% ORR with no intracranial progression (122). However, conflicting evidence exists regarding toxicity profiles. Stumpf et al.’s retrospective analysis of 45 patients identified a strong association between T-DM1 plus SRS and clinically significant RN in HER2-positive BCBM (123), while Mills et al.’s case series found no such correlation (124). To validate the toxicities of combined therapies, optimize treatment dosing, and establish risk stratification, further clinical studies are needed.

Timing of radiotherapy and systemic therapy

The integration of radiotherapy and pharmacotherapy requires a synergistic approach, as these modalities are not mutually exclusive but rather complementary. Current consensus on treatment sequencing advocates for a personalized approach based on molecular subtypes. For asymptomatic HER2-positive BCBM patients with controlled local symptoms, clinical practice supports prioritizing systemic therapy with high CNS-penetrant targeted agents (e.g., TKIs and ADCs), followed by radiotherapy for progression or consolidation; in contrast, the triple-negative subtype, due to a lack of effective systemic options, typically is established local radiotherapy (e.g., SRS) as the cornerstone of initial management; for HR-positive patients with stable extracranial disease and asymptomatic BMs, priority may be given to systemic control and active surveillance.

LM treatment

There is currently no standardized treatment protocol for LM, with management options including radiotherapy, intrathecal therapy, systemic treatment, and supportive care. Therapeutic decisions should be based on comprehensive prognostic evaluation through multidisciplinary team (MDT) discussion.

WBRT may be considered for patients with extensive nodular lesions or symptomatic LM, while focal radiotherapy is appropriate for localized, symptomatic cases. For patients with confirmed malignant cells in CSF analysis, intrathecal chemotherapy represents a potential option, though careful monitoring for treatment-related toxicity is essential.

Intrathecal delivery refers to the direct administration of therapeutic agents into the CSF within the subarachnoid space, with the goal of increasing intrathecal drug concentrations to achieve effective tumor cell eradication. Intrathecal drug delivery is commonly employed in the management of LM. For patients with leptomeningeal involvement secondary to HER2-positive BC, intrathecal trastuzumab represents a potential therapeutic option. A meta-analysis involving 58 recipients of intrathecal trastuzumab demonstrated resolution of clinical symptoms in 55%, supporting its favorable safety profile and therapeutic efficacy (125). Intrathecal delivery of cytotoxic agents, such as methotrexate and cytarabine, may be an option for the management of leptomeningeal disease among individuals with HER2-negative BC (126,127). Nonetheless, intrathecal therapy is associated with a broad range of adverse effects, including neurotoxicity; consequently, the use of glucocorticoids alongside chemotherapy may help mitigate these complications.

T-DXd has demonstrated superior clinical outcomes compared to previous treatment regimens for both HER2-positive and HER2-low expressing LM. The ROSET-BM study, evaluating T-DXd in real-world clinical settings for HER2-positive patients with parenchymal BMs or LM, reported an ORR of 55.7% and a 12-month OS rate of 74.9%, with a median PFS of 16.1 months (128). Subgroup analysis revealed even more promising results in LM patients, demonstrating a median PFS of 17.5 months (83). A retrospective analysis of heavily pretreated HER2-positive LM patients (n=8) showed clinical benefit from T-DXd, with 4 patients achieving partial response (129). The international, multicenter, open-label, phase II DEBBRAH study further evaluated T-DXd across five cohorts, including HER2-positive/HER2-low advanced BC with LM. Among 7 evaluable LM patients: 5 maintained stable disease for ≥24 weeks (CBR =71.4%), 1 achieved complete intracranial response, none of the 5 patients with disease progression experienced intracranial progression or worsening leptomeningeal symptoms at treatment failure (130). These findings collectively position T-DXd as a promising therapeutic option for LM across the HER2 expression spectrum, though larger prospective studies are warranted to confirm these observations.

Symptomatic and supportive treatment

Throughout the diagnostic and treatment process, individuals with BCBM frequently experience diverse symptoms that impair quality of life and may lead to life-threatening Thus, symptomatic and supportive care constitutes a critical element in the whole-course management of BCBM.

Cerebral edema secondary to BMs increases intracranial pressure, potentially resulting in headache, nausea, and vomiting, and increasing seizure susceptibility. Initial management should include intensive osmotic and diuretic therapies, such as mannitol, furosemide and glycerol fructose, aimed at reducing elevated intracranial pressure. For example, a 125 to 250 mL dose of 20% mannitol solution can be administered intravenously every six to eight hours based on clinical presentation, with close monitoring of plasma electrolyte levels and urinary output. Glucocorticoids, particularly dexamethasone, are effective in reducing cerebral edema, relieving meningeal irritation, and enhancing quality of life, yet have not been shown to confer survival benefit (131,132). Dexamethasone is commonly administered, frequently in conjunction with mannitol. Glucocorticoid therapy should be reserved for patients with clear clinical indications and delivered at the lowest effective dose and shortest duration necessary. There is currently inadequate evidence to support definitive treatment recommendations for asymptomatic patients with BMs in the absence of mass effect. Administration of glucocorticoids in the perioperative period may reduce cerebral edema surrounding BMs, whereas use during radiotherapy may mitigate acute radiation-induced toxicities. Intrathecal chemotherapy represents a key therapeutic approach for meningeal metastases. Concomitant glucocorticoid administration during intrathecal chemotherapy may mitigate chemotherapy-associated neurotoxicity and alleviate neurological symptoms. Nonetheless, clinicians should remain vigilant for potential glucocorticoid-related adverse effects, such as peptic ulceration and hyperglycemia. Moreover, glucocorticoids therapy requires careful administration among individuals with diabetes. Furosemide is typically given administered as an intravenous bolus injection of 20 to 40 mg over a short duration, with dose titration based on intracranial pressure, clinical symptoms, close monitoring of electrolyte imbalances, particularly hyponatremia and hypokalemia, is essential. Bevacizumab has demonstrated efficacy in reducing cerebral edema and ameliorating radiation-induced brain necrosis (133). Ventriculoperitoneal shunting offers sustained symptomatic control in patients with symptomatic hydrocephalus. In cases of persistent headache, nausea, or vomiting refractory to prior interventions, adjunctive pharmacologic management with antiemetics and analgesics may be indicated. Seizure management is a critical aspect of the diagnosis and treatment of BMs. As antiepileptic drugs have not been shown to reduce seizure risk in patients without prior epileptic manifestations, they are typically reserved for individuals with active seizure symptoms and are not recommended for routine prophylaxis (131-134). Antiepileptic drugs with minimal potential for interaction with systemic anticancer agents, such as levetiracetam, lamotrigine, and lacosamide, should be used for seizure management, as they offer a more favorable pharmacokinetic profile compared phenytoin, carbamazepine, and valproic acid. The use of secondary prophylactic anticonvulsants may be warranted in individuals with a history of seizure episodes. Medical staff must be alert to the potential side effects of antiepileptic therapy, such as abnormal liver function, cognitive impairment, and ataxia.

Antitumor treatments may induce a range of symptoms. For instance, radiotherapy is associated with dizziness, headache, nausea, anorexia, and fatigue, while bedridden patients are at increased risk of infection. Supportive interventions such as nutritional supplementation, moderate exercise, electrolyte monitoring, and infection prophylaxis should be considered. Patients receiving glucocorticoid therapy for several weeks may have an elevated risk of developing Pneumocystis jirovecii pneumonia (PJP). Prophylaxis with trimethoprim-sulfamethoxazole (TMPSMX) prophylaxis may be warranted in patients receiving concomitant systemic immunosuppressive therapy. Venous thromboembolism prophylaxis should be considered in confined to hospital care or exhibiting prolonged bed rest patients with acute illness who are immobilized. The use of low-molecular-weight heparin or unfractionated heparin is indicated for the initial prophylaxis and treatment of venous thromboembolism. Predisposing factors associated with venous thromboembolism among individuals with BMs encompass certain primary tumor types, glucocorticoid administration, chemotherapy, elevated body mass index, and extended periods of immobilization or bed rest (131-134).

Prognosis

The clinical outcome in patients with BC is strongly influenced by molecular classification of the primary tumor. Among 1,147 individuals with invasive BC, OS was significantly shorter in those with TNBC compared to patients with HER2-enriched tumors (P<0.001). Median survival after BM was 386 days for luminal tumors, 310 days for HER2-enriched subtypes, and 147 days for TNBC (P=0.03). Individuals with luminal BC exhibit a lower incidence of BMs and the most prolonged BM-free survival, while individuals with HER2-positive or TNBC are at significantly greater risk. The duration of solitary first BM in the HER2-enriched group was twice that observed in the TNBC group (52). With the abundance of systemic therapies, the median PFS of HER2-positive BCBM patients has been significantly prolonged to 17.3 months, and the 12-month OS rate reached 90.3% (84). A retrospective analysis of 206,913 individuals with BC in the Surveillance, Epidemiology, and End Results database demonstrated that the median OS among patients with BMs was 12 months for luminal A, 23 months for luminal B, 10 months for HER2-positive, and 6 months for TNBC, with a statistically significant difference (P<0.001); among patients with BMs but no visceral involvement, the corresponding survival durations were 14, 34, 17, and 8 months (P<0.001). In multivariable modeling, across the entire cohort of patients with BMs, the ranking of molecular subtypes according to favorable prognosis was luminal B, luminal A, HER2, and TNBC, in patients with BMs and no visceral involvement, the order was luminal B, HER2, luminal A, and TNBC (135).

Emerging evidence has consistently shown that outcomes in individuals with BC, derived parenchymal BMs, are influenced by baseline performance and neurologic function (KPS), patient age, features of the primary malignancy (including anatomic site, tumor burden, histopathologic subtype, and local control), volume and distribution of intracranial disease, surgical intervention, presence of systemic dissemination, disease recurrence, and the duration between initial diagnosis and CNS involvement (136). Multiple prognostic scoring systems have been established in response to these findings. The Breast GPA, developed by Sperduto and colleagues as an adaptation of the original GPA, is supported by robust clinical evidence (137). The original Breast GPA classified BCBM into three prognostic tiers based on the KPS score, molecular subtype of the tumor, and patient age, with age considered only in individuals with a KPS of 60 to 80. In 2015, investigators at The University of Texas MD Anderson Cancer Center refined the Breast GPA to establish the The University of Texas MD Anderson Cancer Center (MDACC)-GPA, a four-stratum prognostic scoring system that enhanced risk stratification for BMs in BC by incorporating a grade 4 category. Upon inclusion of the number of BMs as a prognostic variable, the concordance index rose from 0.78 (95% CI: 0.77–0.80) to 0.84 (95% CI: 0.83–0.85), as presented in Table 2 (138). In 2020, Sperduto et al. updated the Breast GPA by incorporating the presence of extracranial disease and the duration between initial cancer diagnosis and the development of BMs onset as prognostic factors, while retaining the original four-tier grading system (Table 3) (137). Sperduto et al. have made their scoring tools publicly available at https://brainmetgpa.com/.

LM is a rare complication of BC; yet associated with high mortality. This signifies that the disease has reached an advanced stage with a dismal prognosis. In the absence of effective intervention, median survival ranges from 6 weeks to 2 months. With the clinical treatment strategies, the median survival ranges from 3 to 6 months, and approximately 15% of individuals achieve survival beyond one year. Death is frequently attributable to progressive neurological deterioration. Prognosis is associated with histological grade, CSF protein concentration, primary tumor molecular subtype, patient age, tumor size, presence of extracranial metastases, and KPS score at the time of diagnosis (139).

Surveillance and disease monitoring

Although the annual incidence of BMs is increasing, existing clinical practice guidelines for BC do not endorse universal imaging surveillance in patients at risk for BMs owing to insufficient evidence of survival benefit. Consequently, the majority of BMs are diagnosed in response to neurological symptoms, necessitating prompt and proactive clinical interventions. HER2 positivity is a well-established risk factor for BM. Approximately half of patients with HER2⁺ BC will develop BMs during the disease course. BMs in this subtype represent a continuous risk and can occur even years after diagnosis. Moreover, approximately 50% of patients with HER2⁺ BCBM succumb to CNS disease progression despite therapeutic intervention. Thus, owing to the elevated prevalence of BMs in HER2-positive BC and the intricate nature of therapeutic decision-making, brain MRI is indicated in a timely manner among individuals harboring this molecular subtype who present with neurologic manifestations to facilitate timely diagnosis and prompt therapeutic intervention. However, current guidelines do not recommend routine brain MRI screening for these individuals. BCBM patients are generally recommended to undergo regular follow-up after diagnosis and treatment, including a comprehensive assessment comprising medical history review, physical examination, serum tumor marker evaluation, and imaging studies. Post-treatment monitoring should occur every 1 to 2 months, with prompt medical evaluation warranted upon detection of clinical changes. In cases of stable intracranial disease, follow-up intervals may be extended to a duration of 3 to 6 months (Table 4).

Conclusions

This updated consensus establishes a practical and standardized framework for managing BCBM, marking a shift towards evidence-based and individualized care. It incorporates key advances in diagnosis, systemic therapy, and the integration/sequencing of local and systemic treatments. By synthesizing the latest evidence and authoritative guidelines, this document is designed to guide clinicians in making rational decisions, ultimately aiming to improve patient outcomes.

Acknowledgments

We acknowledge all the members who participated in the discussions. Members of the expert panel: Jiayi Chen (Ruijin Affiliated Hospital of Shanghai Jiao Tong University School of Medicine); Qianjun Chen (Guangdong Provincial Hospital of Traditional Chinese Medicine); Rui Ge (Huadong Hospital of Fudan University); Chunfang Hao (Tumor Hospital of Tianjin); Zefei Jiang (The Fifth Medical Center of PLA General Hospital); Tao Jiang (Tiantan Hospital); Man Li (The Second Affiliated Hospital of Dalian Medical University); Hongyuan Li (The First Affiliated Hospital of Chongqing Medical University); Jianbin Li (The Fifth Medical Center of PLA General Hospital); Jia Liu (Fujian Province Cancer Hospital); Jian Liu (Fujian Provincial Cancer Hospital); Qiang Liu (Sun Yat-sen Memorial Hospital, Sun Yat-sen University); Shu Liu (Affiliated Hospital of Guizhou Medical University); Xinlan Liu (Cancer Hospital of Ningxia Medical University); Yueping Liu (Fourth Hospital Affiliated of Hebei Medical University); Yunjiang Liu (Fourth Hospital Affiliated of Hebei Medical University); Xueli Mo (Peking University Shougang Hospital); Dan Ou (Ruijin Affiliated Hospital of Shanghai Jiao Tong University School of Medicine); Quchang Ouyang (Hunan Province Cancer Hospital); Yueyin Pan (The First Affiliated Hospital of University of Science and Technology of China); Biyun Wang (Cancer Hospital Affiliated to Fudan University); Haibo Wan (Affiliated Hospital of Qingdao University); Kun Wang (Guangdong Provincial People’s Hospital); Shusen Wang (Sun Yat-sen Memorial Hospital, Sun Yat-sen University); Tao Wang (The Fifth Medical Center of PLA General Hospital); Xiaojia Wang (Zhejiang Province Cancer Hospital); Juyi Wen (The Sixth Medical Center of PLA General Hospital); Bing Sun (The Fifth Medical Center of PLA General Hospital); Gang Sun (Cancer Hospital Affiliated to Xinjiang Medical University); Yuee Teng (The First Affiliated Hospital of China Medical University); Min Yan (The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital); Jin Yang (The First Affiliated Hospital of Xi’an Jiaotong University); Yongmei Yin (Jiangsu Provincial People’s Hospital); Zhigang Yu (Second Hospital of Shandong University); Yan Xue (Cancer Hospital of Xi’an International Medical Center); Qingyuan Zhang (Heilongjiang Province Cancer Hospital); Jun Zhang (Fourth Hospital Affiliated of Hebei Medical University); Jian Zhang (Cancer Hospital Affiliated to Fudan University); Shaohua Zhang (The Fifth Medical Center of PLA General Hospital); Juan Zhou (The Fifth Medical Center of PLA General Hospital).

Footnote

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-51/prf

Funding: This study was funded by the Beijing Natural Science Foundation (No. 7232161), the Capital’s Funds for Health Improvement and Research (No. 2024-2-5064), and the Beijing Science and Technology Innovation Medical Development Foundation (No. KC2022-ZZ-0091-7).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-51/coif). C.H. and Y.L. serve as unpaid editorial board members of Translational Breast Cancer Research from May 2025 to December 2027. E.S. and Jiayi Chen serve as unpaid editorial board members of Translational Breast Cancer Research from March 2026 to February 2028. Z.J. serves as the Editor-in-Chief of Translational Breast Cancer Research from November 2019 to December 2027. The other 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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