Central Nervous System Metastases in Breast Cancer

Abstract

Opinion Statement

Breast cancer metastasizing to the central nervous system (CNS) encompasses two distinct entities: brain metastases involving the cerebral parenchyma and infiltration of the leptomeningeal space, i.e., leptomeningeal disease. CNS metastases affect 10–15% of patients with hormone receptor-positive-status and nearly one-half of those with HER2-positive and triple-negative breast cancer with distant metastatic disease. Significant clinical morbidity and heterogeneous penetration of the blood–brain barrier by systemic therapies contribute to the poor prognosis associated with brain metastases. Recent advances in radiotherapy, including stereotactic approaches and morbidity-reducing strategies such as the use of memantine and hippocampal avoidance in whole brain radiation, coupled with the development of more effective CNS-penetrant systemic therapies, including small molecules and antibody–drug conjugates, have significantly improved patient outcomes. Consequently, patients with breast cancer CNS metastases have improved survival compared to prior decades, and longitudinal care has become increasingly complex, necessitating a multidisciplinary approach to achieve optimal outcomes for patients.

Introduction

Although often underestimated, 5–10% of breast cancer patients and 40% of patients with metastatic disease develop central nervous system (CNS) metastases, which include two distinct entities: cerebral parenchymal involvement (brain metastases, BM) and infiltration of the cerebrospinal fluid-filled leptomeningeal space (leptomeningeal disease, LMD) [1, 2, 3–4]. CNS involvement remains a major clinical challenge, in part because of the protective roles of the blood–brain and blood-CSF barriers, and because CNS disease frequently occurs in the setting of heavily pretreated, treatment-refractory cancer. Additionally, a unique microenvironment consisting of neurons, astrocytes, microglia, and oligodendrocytes, coupled with metabolic constraints that are exclusive to this area, imposes selective pressure on tumor cells [3, 4]. Consequently, metastases to the CNS represent a distinct entity with a unique evolutionary trajectory compared to extracranial metastases [5]. The combination of a distinct phenotype and heterogeneous penetration of the blood–brain barrier by systemic therapies could explain the frequent observation of progressive BM, even in patients with controlled extracranial disease. Consequently, cerebral involvement leads to a poor prognosis, resulting in neurological death in 20–50% of patients [6, 7]. Given that the risk of developing CNS metastases increases with the duration of metastatic disease and by line of therapy [8, 9] and that patients live longer with better control of extracranial disease through new systemic therapies, the incidence of CNS metastases is expected to rise. Furthermore, novel therapies that have improved survival and reduced extracranial relapse in early-stage breast cancer, such as pembrolizumab in early-stage triple-negative breast cancer (TNBC) and trastuzumab-emtansine in early-stage HER2-positive breast cancer with residual disease, have not reduced rates of CNS relapse [10, 11]. This trend highlights an urgent unmet need for patients with CNS metastases.

Metastatic breast cancer (MBC) is the second most common cause of BM and LMD, indicating a pronounced tropism for these sanctuary spaces, more pronounced for HER2-positive and triple-negative breast cancers (TNBC) than luminal subtypes [3]. Overall survival has improved for some BM subtypes, particularly those with HER2-positive BM [12]. This improvement is mainly attributed to the development of systemic therapies that are effective in the CNS and extracranially. The movement in the last decade to include patients with BM in registrational clinical trials has accelerated progress. Local therapy advances such as stereotactic radiosurgery have improved morbidity but not overall survival in most populations. The management of patients with CNS metastases has thus become complex, requiring a multidisciplinary approach to achieve optimal outcomes.

Epidemiology

Unfortunately, the exact incidence of BM in breast cancer remains unknown, as current registries do not reliably capture brain metastases after initial diagnosis of malignancy and because mandated central reporting of brain metastases is not currently standard in the United States, along with the fact that screening for BM is not routinely performed for many primary cancers, underreporting of new metastatic sites post-diagnosis, and potential underdiagnosis in patients with minimal symptoms. Ongoing screening programs are expected to provide more precise data on the incidence of BM soon (NCT04030507).

The main factors associated with the risk of CNS metastases are initial stage, metastatic disease-free interval, overall burden of metastatic disease, HER2-positive subtype, triple-negative subtype, young age, and BRCA2 germinal status [9, 13, 14–15]. A lobular histological type is a specific risk factor of LMD [16].

Population-based data from the SEER (Surveillance, Epidemiology, and End Results) registry in the United States indicates that 0.4% of patients, including early-stage patients, had BM at the initial breast cancer diagnosis. However, 7.6% of patients with de novo MBC had BM at diagnosis, including 11.5% of patients with Hormone Receptor-negative and HER2-positive (HR-/HER2 +) de novo MBC, 11.4% with de novo TNBC, and 5.56% with HR-positive/HER2-negative (HR + /HER2-) MBC [13]. In the metastatic setting within a large French national cohort (ESME), the cumulative incidence rates of CNS metastases at 24 months were 14.4%, 29.2%, 49.0%, and 44.8% for patients with HER2-/HR + , HER2 + /HR + , HER2 + /HR-, and TNBC, respectively. The incidence continued rising across all tumor subtypes with no evidence of plateauing. In this cohort, among patients with CNS metastases at MBC diagnosis (de novo), 43.1% had only CNS involvement (isolated CNS) [9]. An analysis based on the metastatic treatment line from the Flatiron cohort revealed that at metastatic diagnosis, the prevalence of BM was 6.3%, 11.2%; 2.7% and 11.1% HER2-/HR + , HER2 + /HR + , HER2 + /HR-, and TNBC, respectively. Then in the second/fourth line, the prevalence of BM was 4.4%/7.2%, 17.6%/26.1%, 31.2%/37.1%, and 17.6%/24.7% among patients with HER2-/HR + , HER2 + /HR + , HER2 + /HR-, and TNBC, respectively [8]. To note, the HER2-low expression did not impact BM prevalence within historical subtypes.

It is important to highlight the biomarker (i.e. Her2 and estrogen expression) discordance is often observed between primary tumors and their corresponding brain metastases. This discordance is characterized by a loss of HR alongside a gain of HER2 expression, resulting in nearly three-quarters of all CNS metastases expressing HER2 (positive or low) [17, 18–19].

LMD is less common and may affect 5–20% of MBC patients [20, 21–22]. LMD typically emerges as a late complication in MBC, often coinciding with systemic disease progression. The subtype distribution mirrors that of BM, with an overrepresentation of HER2-positive and TNBC subtypes: 18–27% for HER2-positive, 44–51% for HR-positive/HER2-negative, and 15–37% for TNBC, respectively. Risk factors for developing LMD in breast cancer patients include lobular histology, HER2-positive, TNBC subtype, existing BM (particularly those near the meningeal space or infratentorial), and BM resection [23, 24, 25, 26–27].

Prognostic factors among MBC Patients with CNS Metastases

CNS involvement is associated with inferior prognosis across all subtypes of MBC compared to those without CNS dissemination. Among patients with CNS metastases, the key factors independently associated with survival include performance status and tumor subtype, with HR + /HER2 + having a better prognosis than HR-/HER2 + , followed by HR + /HER2- and then TNBC [9, 28, 29]. Other significant prognostic factors include the patient's age, the number of BM, and the presence of extracranial metastases. These prognostic factors have been integrated into a Graded Prognostic Assessment (GPA) score [29, 30]. The median overall survival (OS) from the diagnosis of BM ranged from 6 months for those in the GPA 0 group to 36 months for patients in the GPA 3.5–4.0 group. The status of extracranial disease (stable or progressive) was also a major prognostic factor, with a doubling of OS observed in patients with stable extracranial disease (17.9 versus 8.0 months), as demonstrated in a meta-analysis encompassing all cancer types [31]. Finally, the Brain Metastasis Velocity (BMV) is a prognostic measure recently defined for patients experiencing cerebral recurrence after initial stereotactic radiosurgery (SRS) for BM, calculated by dividing the number of new BM that develop post-SRS by the time interval (in years) since the initial SRS. BMV has been identified as an independent prognostic factor in a large, multi-institutional, pan-tumor cohort. Median OS from the initial SRS for BMV categories as low-risk (< 4 brain metastases), intermediate-risk (4–13 metastases), and high-risk (> 13 new metastases per year) were 12.5 months, 7.0 months, and 4.6 months, respectively [32]. This finding was also corroborated in a separate cohort of patients with MBC, with a hazard ratio (HR) of 1.03 for each increment in BMV, regardless of the subtype [33].

Brain metastases prognosis can vary widely, and there is often a challenge with the competing risk of extracranial visceral metastases. With many systemic therapy options across breast cancer subtypes, understanding which patients are at highest risk of death from their brain metastases is of interest. One would prioritize treatment regimens with the highest intracranial penetration and CNS progression-free survival (CNS-PFS) in those with a presumed high risk of dying from their BM. Patients with HER2 + BM have a higher risk of neurological death compared to TNBC or HR + subtypes. Number of brain metastases, upfront whole brain radiotherapy, and progressive extracranial disease were also multivariate risk factors of neurologic death [7].

Patients with LMD have the direst prognosis, with OS ranging from 3 to 10.5 months. A similar trend to that seen in patients with brain metastases is observed according to subtype, with patients with HER2-positive disease having longer survival (4.4–20.0 months) compared to those with HR-positive (3.7–6.0 months) and TNBC (2.0–3.0 months) [16].

Treatment of Brain Metastases among MBC Patients

Clinical Categories of Brain Metastases

BM treatment aims to prevent or delay neurological deterioration and prolong survival with an acceptable quality of life [2, 34, 35]. However, BM presentations are heterogeneous and have distinct clinical scenarios with specific therapeutic implications. BM are usually described by their clinical stability and treatment history as either 1) treated/stable or 2) active. This has risen in relevancy due to the inclusion of stable BM patients in most trials but the exclusion of active BM patients. Treated/stable BM describes lesions that have previously received CNS-specific local treatment with subsequent validation of stable or non-progressive disease on imaging. Active BM describes either new BM that have not been treated with CNS-directed therapy or progressive BM despite local CNS-directed therapy [36].

The tumor burden, defined by the number and size of lesions, varies widely. Concurrent extracranial disease status, with isolated cerebral progression or multisite progressions, also adds to the complexity of treating BM patients. Finally, treatment may differ depending on the presence or absence of neurological symptoms [2, 34, 35]. Local CNS-directed therapies should be prioritized urgently in patients with symptoms. Patients with symptomatic BM historically have inferior OS compared to those with asymptomatic disease [37]. Treatment objectives and systemic therapy choice will differ based on stable/active status, symptomatic versus asymptomatic status, extracranial disease status, and number of brain metastases. For patients with stable BM without high-risk features of neurologic death, standard systemic therapy algorithms for extracranial disease apply after local therapy. For patients with active BM with progressive disease despite prior radiation, prioritizing regimens with the highest intracranial response rates is necessary. Algorithm treatment for BM breast cancer is shown in Fig. 1.

[See PDF for image]

Fig. 1

Algorithm treatment brain metastases breast cancer. BM, Brain metastases, CNS Central Nervous System.

Local Treatments

Limited Number of Brain Metastases

Surgery followed by cavity radiation is generally considered for a single metastasis and an option for patients with a limited number of BM, particularly in those with bulky, symptomatic lesions or diagnostic uncertainty when observation is less viable. Two prospective trials demonstrated a survival benefit of surgery followed by whole brain radiotherapy (WBRT) compared with WBRT alone in patients with CNS metastases from solid tumors, with a median OS of 10–9 months versus 3.5–6 months. Notably, no OS benefit was observed in the subgroup with active extracranial disease, and one prospective study showed no significant difference in patients with impaired performance status [38, 39–40]. In the randomized NCCTG-N107C trial, stereotactic radiosurgery (SRS) was compared with WBRT for treatment of the surgical cavity following resection of a single brain metastasis. Although no significant difference in overall survival was observed (with a median of approximately 12 months), there was a reduction in the recurrence rate of the cavity at one year in the WBRT group (40% vs. 20%) and a reduction in the rate of cognitive function decline at six months (52% vs. 85%) with SRS [41]. To date, no prospective data exist on surgical treatment of more than one brain metastasis. Therefore, combining surgery and radiotherapy is recommended to treat patients with a limited number of bulky lesions in the context of modest extracranial disease. This approach is also beneficial for patients without a primary cancer diagnosis, for evaluating pathologic diagnosis or re-evaluating biomarkers (like HER2 status), and for large metastases with mass effect. Stereotactic radiation administered to the postoperative cavity is often preferred to WBRT because of the better preservation of cognitive function. Note that SRS is associated with an increased risk of pachymeningeal seeding beyond the radiation field (approximately 8% although higher in some series) [42].

Extensive Brain Metastases

Radiation therapy, particularly SRS, is fundamental in treating patients with a limited number of metastases. The choice of cut-off between stereotactic radiosurgery (SRS) versus WBRT is still debated, but it likely involves both the number and volume of brain metastases [34, 43] among other factors such as patient age, performance status, brain metastasis velocity, primary tumor type, extracranial disease status, and available systemic options. SRS improves disease control and potentially enhances survival in patients who have not undergone resection compared to those who receive no radiation. Importantly, SRS was less associated with cognitive deterioration compared to WBRT. In contrast, WBRT provides greater intracranial control but is also associated with more cognitive decline. Combining SRS and WBRT leads to further cognitive deterioration without improving survival outcomes and has little role in the contemporary management of patients [44, 45]. Nonetheless, WBRT remains a crucial treatment for multiple BM, especially in cases of a large intracranial disease burden. In such cases, memantine and hippocampal avoidance, when viable, should be used to reduce neurocognitive toxicity [46, 47]. SRS can lead to adverse radiation effects, most commonly radiation necrosis, which is defined as an inflammatory and necrotic process occurring in the brain. The incidence is about 8%, although the incidence varies widely, and can appear months or even years after exposure (median ∼7–8 months post-radiation). Diagnosing this condition and differentiating it from a recurrent tumor is a significant diagnostic challenge, and it causes neurological symptoms in half of the cases [48]. Its incidence appears to be increased when co-administered with an antibody–drug conjugate (ADC) [49]. Treatment options for radiation necrosis include corticosteroids, and for refractory cases, options extend to bevacizumab, laser interstitial thermal therapy, surgical resection, or hyperbaric oxygen therapy [48].

Systemic Treatment Options per Subtype for Brain Metastases

It has long been believed that systemic therapies' ineffectiveness on BM was due to their inability to penetrate the BBB. However, the BBB is often significantly disrupted by CNS metastases, making it permeable to agents that typically do not cross it, such as monoclonal antibodies [50]. In retrospective studies, systemic therapy following local, regional therapy to BM improves overall survival in luminal and HER2 + breast cancer, even in the setting of isolated brain progression [51]. The choice of the optimal systemic treatment after BM is highly variable and patient-specific, dependent upon performance status, breast cancer subtype, extracranial disease status, stable or active BM, and prior treatments. Data from prospective trials assessing the intracerebral activity of systemic treatments based on subtype are summarized in Table 1.

Table 1. Prospective clinical trial with outcomes on MBC patients with Brain metastasis

Trial name and References	Treatment regimen	Type of BM	Number of BM patients	Rate of Prior BM local therapy	CNS-ORR, % (95% CI)	ORR % (95% CI)	CNS-PFS Median month (mo), (95% CI)	PFS, Median mo, (95% CI)	OS Median mo, (95% CI)
HER2 positive
Antibody Drug Conjugates and monoclonal antibodies anti HER2
DEBBRAH [52]	T-Dxd	Cohort 1: non-progressing BM after local therapy	8	87.5%	-	80.0% (28.4–99.5)	-	16-week PFS rate 87.5% (47.3–99.7)	-
		Cohort 2: asymptomatic untreated BM	4	2:0%	50.0% (6.7–93.2)	50.0% (6.7–93.2)	-	-	-
		Cohort 3: progressing BM after local therapy	9	100%	44.4% (13.7–78.8)	66.7% (29.9–92.5)	-	-	-
		Cohort 5: HER2 + or HER2-Low with LMD	7	0%	20%	0%	-	8.9 mo (2.1 – NR)	13.3 mo (2.5 – NR)
TUXEDO [53]	T-Dxd	Active	15	-	73.3% (48.1–89.1%)	-	-	21 (13.3-NR)	NR (22.2-NR)
DESTINY-Breast01 [54]	T-Dxd	Stable	24	75%	47.1%	-	-	18.1 mo (6.7–18.1)	-
DESTINY-Breast03 [55]	T-Dxd	Stable	43	53.5%	65.7%	-	-	15.0 mo (12.5–22.2)	-
	TDM1		39	51.3%	34.3%	-	-	3.0 mo (0.8–5.8)	-
Pooled-Analysis DESTINY 01 02 03 [56]	T-Dxd	Stable and Active BM	148	70.3%	Stable = 45.2% Active = 45.5%	-	Stable = 12.3 mo (11.1–13.8) Active = 18.5 mo (13.6–23.3)	-	-
	Trastuzumab/Lapatinib + Capecitabine or TDM1		83	69.9%	Stable = 27.6% Active = 12.0%	-	Stable = 8.7 mo (6.3–11.8) Active = 4.0 mo(2.7–5.7)	-	-
DESTINY-Breast12 [57]	T-Dxd	Stable and Active BM	263	60.1%	Overall 71.7% (64.2–79.3) Stable 79.2% (70.2–88.3) Active 62.3% (50.1–74.5)	Overall 51.7% (45.7–57.8) Stable 49.7 (41.9–57.5) Active 54.7 (45.2–64.2)		Overall 17.3 (13.7–22.1)
KAMILIA [58]	TDM1	Stable and Active BM	398	47%	42.9% (34.1–52.0)	21.4% (14.6–29.6)	-	5.5 mo (5.3–5.6)	18.9 mo (0.1–21.3)
PATRICIA [59]	Pertuzumab + high dose trastuzumab (6 mg/Kg weekly)	Active pretreated BM with stable extracranial disease	40	100%	11% (3.0–25.4)	-	4.6 mo (4.0–8.9)	4.6 mo (4.0–8.9)	27.2 mo (16.1–NR)
Tyrosine kinase inhibitors anti HER2
EGF105084 [60]	Lapatinib	Active	242	100%	6%	15%	-	2.73 mo (1.87–3.45)	9.56 (6.18-n/e)
LANDSCAPE [61]	Lapatinib + Capecitabine	Active not previously treated with WBRT, capecitabine, or lapatinib	45	0%	65.9% (50.1–79.5)	44·1% (27.2–62.0)	5·5 mo (4.5–6.1)	5·5 mo (4·3–6·0)	17·0 mo (13·7–24·9)
LAPTEM [62]	lapatinib–temozolomide	Recurrent or progressive BM	18	83%	0%	-	-	2.60 mo (1.82–3.37)	10.94 mo (1.09–20.79)
Lin et al. 2013 [63]	Lapatinib + WBRT	Active BM	35	0%	79% (59–92)	-	-	4.8 mo (range 0–58.3)	19 mo (range 1–62)
NRG Oncology − KROG/ RTOG1119 [64]	WBRT or SRS + Lapatinib	unirradiated BM	71	0%	53% (39–67)	51% (37,65)	-	-	-
	WBRT or SRS Alone		65		66% (51–81)	58% (42–74)	-	-	-
TBCRC 022 [65]	Neratinib	Active BM	40	100%	8% (2 −22)	-	-	1.9 months	8.7 months
TBCRC 022 [66]	Neratinib + Capecitabine	Active BM	37 lapatinib naïve	92%	49% (32—66)	-	-	5.5 mo (range, 0.8 to 18.8)	13.3 mo (range, 2.2 to 27.6
TBCRC 022 [67]	Neratinib + TDM1	Active BM	6 previously untreated BM	0%	50.0% (18.8- 81.2)	-	-	-	-
			17 progressing after prior local therapy without prior exposure to T-DM1	100%	25.0% (8.3–52.6)	-	-	-	-
			21 progressing after prior local therapy with prior exposure to T-DM1	100%	38.1% (19.0–61.3%)	-	-	-	-
NALA [68]	Capecitabine + Neratinib	Stable BMs	51	86.3%	26.3%	-	12.4 mo (5.6–17.9)	5.6 mo (3.7–7.1)	13.9 (8.9–17.5)
	Capecitabine + Lapatinib		50	74%	15.4%	-	8.3 mo (4.3–NE)	4.3 mo (2.8–5.6)	12.4 (9.7–16.9)
HER2CLIMB [12, 69]	Capecitabine + Trastuzumab + Tucatinib	Active or Stable BM	198 Active = 118 Stable = 80	70%	All: 47.3% (33.7% – 61.2%) Active: 47.3% (33.7–61.2)	-	9.9 (8.4–11.7) Active 9.6 mo Stabl: 13.9mo	-	21.6 mo (18.1–28.5) Active 21.4 Stable 21.6
	Capecitabine + Trastuzumab + Placebo		93 Active = 56 Stable = 37	70%	All 20,0% (5,7%- 43,7%) Active: 20.0% (5.7%−43.7%)	-	4.2 mo (3.6–5.7) Active 4.0 mo Stable 5.6 mo	-	12.5 mo (11.2–16.9) Active 11.8 mo Stable 16.4 mo
HER2CLIM2	Tucatinib + TDM1	Active or Stable BM	70	-	-	-	-	7.8 mo (6.7 – 10)	-
	TDM1		85	-	-	-	-	5.7 mo (4.6 – 7.5)	-
BROPTIMA [70]	Radiotherapy with pyrotinib and capecitabine	New Active BM	40	12.5%	85%	-	18.0 mo (15.5 – NR)	17.6 mo (12.8–34.)	-
CDK4/6 inhibitors
I3Y-MC-JPBO [71]	Abemaciclib + Trastuzumab + endocrine therapy	Active	27	96%	0%	0%	2.7 mo (1.4–4.0)	7.3 mo (3.3–13.3)	10.1 mo (4.2–14.3)
HER2 negative
Targeted Therapy
I3Y-MC-JPBO [71]	Abemaciclib + endocrine therapy	HR + Active BM	58	81%	5.2% (0.0%–10.9%)	3.4% (0.0–8.1)	4.9 mo (2.9–5.6)	6.6 mo (4.3–12.4)	12.5 mo (9.3–16.4)
Leone et al [72]	Bevacizumab + Carboplatin (+ Trastuzumab if HER2 +)	Active BM	38 29 HER2 +  9 HER2-	87%	63% (46–78)	-	-	5.62 mo (.03–6.51)	14.1 mo (11.7- 20.7)
Lu et al [73]	Bevacizumab followed by BEEP	Refractory to WBRT	35 23 HER2 +  12 HER2-	100%	77.1% (59.9–89.6)		7.3 mo (6.5–8.1)	6.1 mo (5.0–7.2)	10.5 mo (7.8–13.2)
Antibody Drug Conjugates
DESTINY-Breast04 [74]	T-Dxd	HER2- low Stable BM	24 (11 HR +)	100%	25%		9.7 mo (4.4–15.1)		16.7 mon (6.7–24.5)
	capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel		11 (8 HR +)	100%	0%
ASCENT [75]	Sacituzumab Govitecan	TNBC Stable BM	32	100%	-	3%	-	2.8 mo (1.5–3.9)	7 mo (4.7–14.7)
	capecitabine, eribulin, vinorelbine, or gemcitabine		29		-	0%	-	1.6 mo (1.3–2.9)	7.5 mo (4.7–11.1)
TROPION-Breast01	Datopotamab Deruxtecan	HR + Stable BM	35	100%	-	-	-	5.6 mo (3.0–8.1)	-
	capecitabine, eribulin, vinorelbine, or gemcitabine		23		-	-	-	4.4 (1.4–5.7)	-
Chemotherapy
A-PLUS [76]	3 cycles of BEEP followed by WBRT	All subtype Active BM	77	0%	59.5%	-	8.1 mo (range, 0.3–29.5)	7.9 mo	15.9 mo (range, 0.8–58.1)
	WRBT alone		41	0%	65.8%	-	6.5 mo (range, 0.9–25.5)	5.0 months	16.4 (range, 1.1–58.2)
Rviviera et al [77]	Capecitabine + Temozolomide	All subtype Active BM	24		16%	–	12 weeks (range, 3–70)	8 weeks (range, 6–64)	-
Franciosi et al [78]	Cisplatin + Etoposide	All subtype Newly diagnosed BM	56	0%	38%		-	4 mo	-
Christodoulou et al [79]	Cisplatin + Temozolomide	Progressive brain metastases,	32 (15 breast)	53%	31%	-	-	2.9 mo (2.2–3.7;	5.5mo (3.4–7.7)

MBC Metastatatic Breast Cacner, BM Brain Metastases, CNS Central Nervous System, 95% CI 95% Confidence interval, ORR objective Response Rate, PFS Progression Free Survival, OS Overall Survival, Mo: Months, LMD Leptomeningeal Disease, T-Dxd Tratuzumab-Deruxtecan, Dato-Dxd Daptopotamab-Deruxtecan, TDM1 Trastuzumab Emtansine, WBRT Whole Brain Radiation Therapy, SRS Stereotactic Radiation Surgery, BEEP bevacizumab, etoposide, and cisplatin, TNBC triple negative breast cancer

HER2-Positive

The combination of pertuzumab, trastuzumab (HP), and taxanes is the first-line treatment for HER2-positive MBC following the results of the CLEOPATRA trial, which demonstrated a survival benefit with this regimen compared to taxanes plus trastuzumab. However, patients with CNS metastases were excluded from this trial [80]. Evidence supports the benefit of dual HER2 blockade with HP with respect to CNS outcomes. First, in the CLEOPATRA trial, the median time to the appearance of CNS metastases as the first site of disease progression was significantly longer in the pertuzumab group compared to the placebo group (15.0 months vs. 11.9 months; HR = 0.58, p = 0.0049). However, the incidence of CNS metastases as the first site of disease progression was similar between the arms (around 13%) [81]. Second, real-world data from a cohort of 252 patients with de novo BM showed significantly longer OS with first-line HP compared to treatments with other or without HER2-targeting therapies (44 vs 17 vs 3 months, p < 0.001) [82].

For second-line treatment, two regimens are highly active for patients with HER2-positive BM: trastuzumab-deruxtecan (T-DXd) and the combination of tucatinib, trastuzumab and capecitabine (HER2CLIMB regimen). In the sub-analysis of the DESTINY-Breast 03 trial among patients with BM, the median progression-free survival (PFS) was 15 months [95% confidence interval (CI) 12.5–22.2 months] for T-DXd compared to 3 months (95%CI 2.8–5.8 months) for Trastuzumab-emtansine (TDM1) (HR = 0.25, 95%CI 0.31–0.45). The CNS objective response rate (CNS-ORR) observed in DESTINY-Breast03 was 65.7% with T-DXd versus 34.3% with T-DM1 [55]. These data are consistent with the results from the non-comparative trials TUXEDO-1 and DEBBRAH, which reported CNS-ORRs between 44.4% and 73.3% in small numbers of patients with active BM [52, 83]. Moreover, in a pooled analysis of the DESTINY-Breast 01, 02, and 03 trials, patients with active and stable BM were treated with T-DXd compared to the reference treatment (Trastuzumab/Lapatinib + Capecitabine or TDM1). The CNS-ORR was 45% for active and stable BM with T-DXd compared to 12.0% and 27.6% with the reference treatment. The median CNS-PFS in the T-DXd group vs. standard treatment was 18.5 months (95%CI 13.6–23.3) vs. 4.0 months (95%CI 2.7–5.7) and 12.3 months (95%CI 11.1–13.8) vs. 8.7 months (95% CI 6.3–11.8) (HR = 0.19 and 0.59), respectively [56]. However, in these studies, an active BM refers only to asymptomatic cerebral lesions that have not been locally treated, as per the inclusion criteria. Patients with brain metastases that had progressed after local therapy were excluded, and therefore the patient population was not representative of all patients with active BM [84]. The DESTINY-Breast study12 is a real-world phase 3b/4 trial with the largest enrollment of BM patients (n = 263), including stable (n = 157) and active (n = 106) patients, with a distinction between untreated active patients (n = 39) and BM patients in progression (treated/progressed; n = 67) [57]. In contrast to previous studies, patients had received a median of 1(0–4). prior therapy. The median PFS for all BM patients was 17.3 months (CI95% 13.7–22.1). The 12-month PFS-CNS rates were 57.8% (95% CI: 48.2–66.1) and 60.1% (95% CI: 49.2–69.4) in patients with stable and active BM, respectively. The ORR-CNS rates were 79.2% (95% CI: 70.2–88.3), 82.6% (95% CI: 67.1–98.1) and 50.0% (95% CI: 34.1–65.9) in patients with stable, untreated and previously treatment/progressing BM, respectively. Toxicity was characterized by interstitial lung disease and pneumonitis observed in 16% of cases (grade 5: 2%), reminding us of the importance of considering Pneumocystis jirovecii pneumonia prophylaxis in patients taking chronic corticosteroids for symptoms of BM [57].

In the HER2CLIMB clinical trial, which compared tucatinib, trastuzumab, and capecitabine versus trastuzumab plus capecitabine in patients previously treated with taxanes, HP, and T-DM1 who had stable or active/progressive HER2-positive BM, the tucatinib group demonstrated significant benefits. These included improved CNS-PFS and CNS-ORR compared to the control arm of 9.9 vs. 4.2 months (HR = 0.39; p < 0.001) and 47.3% vs. 20.0% and, respectively. In addition, there was a reduction in the risk of developing new BM as the first site of progression or death (HR = 0.55, 95%CI 0.36–0.85). Finally, there was a significant increase in OS of 21.6 vs. 12.5 months (95%CI, 18.1–28.5 vs. 11.2–16.9, HR = 0.60; p < 0.001). The results were consistent in patients with both active and stable BM [12]. Preliminary data from the HER2CLIMB-02 trial, which compared TDM1 plus tucatinib to placebo in patients with HER2-positive MBC, have been reported. Forty percent of the participants had BM, half of which were active. The median PFS for patients with BM was 7.8 months compared to 5.7 months for the placebo group (95%CI, 6.7–10.0; 4.6–7.5; HR = 0.64). We await data on intracranial endpoints from this clinical trial.

No direct comparison has been made between these two treatments in patients with HER2-positive BM. Given the differences in the populations selected in these two trials, particularly in the lines and types of prior therapies and the inclusion criteria around active BM. In addition, patients enrolled in DESTINY12 could not have received prior tucatinib treatment, making it impossible to assess cross-resistance. The DESTINY12 results confirm the intracranial activity of T-DXd, which should be used as second-line treatment in patients with and without central nervous system (CNS) metastases after progression on trastuzumab and doublet pertuzumab. The HER2CLIMB-04 trial (NCT04539938) will evaluate whether the combination of tucatinib and TDXd is beneficial in patients with HER2 + MBC with or without BM.

For subsequent lines of treatment, neratinib and lapatinib in combination with capecitabine have shown intracranial response rates in patients with active brain metastases in the TBCRC 022 and LANDSCAPE trials (non-irradiated). The CNS-ORRs were 49% (95%CI 32–66) and 65.9% (95%CI 50.1–79.5), respectively, with a median PFS of around 5 months [61, 66]. The activity of either regimen after prior tucatinib are unknown, although the TBCRC 022 study did demonstrate activity of neratinib after prior lapatinib exposure. The combination of neratinib with T-DM1 has also demonstrated intracerebral activity in patients with untreated brain metastases (n = 6), those progressing after prior CNS-directed local therapy without prior exposure to T-DM1 (n = 16), and those with prior exposure to T-DM1 (n = 21), with CNS-ORR of 50.0% (95% CI 18.8–81.2%), 25.0% (95% CI 8.3–52.6%), and 38.1% (95% CI 19.0–61.3%), respectively [67].

For patients with isolated CNS progression despite previous radiotherapy, high-dose intravenous trastuzumab (6 mg/kg per week) in combination with pertuzumab and the continuation of systemic therapy is an option. In the PATRICIA trial, among 40 heavily pretreated HER2-positive MBC patients with brain metastases (70% had received WBRT at the initial diagnosis of CNS metastases, and 70% had undergone SRS at the time of CNS progression), the CNS-ORR was 11% (95% CI: 3.0–25.4). The median CNS-PFS was 4.6 months (95%CI: 4.0–8.9), and the clinical benefit rate (CBR) in the CNS at six months was 51% (95%CI: 34.4–68.1) [59, 85].

HR-Positive

BM tend to occur after a longer interval of metastatic disease in patients with HR + /HER2- MBC. Pivotal trials for cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) generally excluded patients with BM. The phase II JPBO trial assessed abemaciclib plus endocrine therapy in patients with active BM who had not previously received CDK4/6i. These patients had received a median of three prior treatments. The CNS-ORR was 5.2% (95% CI, 0.0–10.9). The median PFS and OS were 4.4 months (95% CI, 2.6–5.5) and 12.5 months (95% CI, 9.3–16.4) [71]. The post-marketing phase IIIb CompLEEment-1 study evaluated ribociclib plus letrozole in patients with HR + /HER2- MBC and demonstrated a safety profile, time to progression, and extracranial response rates similar between patients with CNS metastases (n = 51) and the overall population (n = 3,246). These results suggest a comparable benefit of Ribociclib in patients with CNS metastases from HR + /HER2- MBC as observed in the overall study population, but without providing information on intracranial responses [86].

Antibody–drug conjugates (ADC) are promising in treating BM across MBC subtypes. T-DXd was evaluated in a cohort of patients with HER2-low BM in the DESTINY-04 clinical trial. Among the 35 patients with BM, most of whom had HR-positive disease (approximately 75%), 24 received T-DXd, and 11 received chemotherapy. The median PFS for T-DXd was 9.7 months (95% CI, 4.4–15.1 months) compared to not evaluable for chemotherapy due to the small number of patients. The CNS objective response rate (ORR-CNS) was 6/24 (25%) (95% CI, 9.8%−46.7%) for T-DXd and 0/11 (95% CI, 0%−28.5%) for chemotherapy. In subsequent lines, preliminary data from the TROPION-Breast01 trial, which compared datopotamab-deruxtecan (Dato-DXd) with standard chemotherapy in patients with HR-positive MBC previously treated with chemotherapy, showed a significant improvement in PFS (HR 0.63; p < 0,0001). Among patients with stable and asymptomatic BM (35 in the Dato-DXd group and 23 in the chemotherapy group), there was no significant difference in median PFS, which was 5.6 months for the Dato-DXd group versus 4.4 months for the chemotherapy group (HR = 0.73, 95%CI 0.39–1.42) [87]. Data from the TROPICS trial of Sacituzumab-Govitecan (SG) in HR + patients with BM have not been released. However, preliminary data from a window-of-opportunity study planned one dose of SG to be administered prior to BM resection and continued until progression in 13 patients with MBC (all subtype). In this highly selected population, median PFS was 8 months (range 2–26.5 months) with a CNS ORS of 50%. Morover, SN-38 levels in bone marrow tissue reached therapeutic levels after a single injection [88]. These data suggest intracranial activity of SG, which will be validated in SWOG S2007 (NCT04647916), a phase 2 trial of SG in patients with HER2-negative MBC and BM. Finally, several cases have been reported in which endocrine therapies and a PI3K inhibitor, alpelisib, have led to durable responses in BM in patients with HR-positive tumors [89].

TNBC

In the ASCENT trial, 61 out of 529 (12%) enrolled patients had stable BM at the time of selection and received either SG (n = 32) or standard chemotherapy (n = 29). In this subgroup, the median PFS was 2.8 months (95%CI, 1.5–3.9) for SG compared to 1.6 months (95%CI, 1.3–2.9) for chemotherapy. The median OS was 6.8 months (95%CI, 4.7–14.1) for SG versus 7.5 months (95%CI, 4.7–11.1) for the chemotherapy group. The ORR for SG vs chemotherapy was 3% (1/32) versus 0%, respectively [75]. The efficacy of Sacituzumab-Govitecan in patients with active brain metastases is unknown and is currently under investigation (NCT04647916). We lack data on the combination of pembrolizumab with chemotherapy as a first-line treatment in TNBC due to the exclusion of patients with active BM and the small number of patients included with stable BM (3%). However, the presence of BM should not preclude the addition of pembrolizumab, considering the clinical benefit rate of 36.4% (4/7) observed in monotherapy among pretreated TNBC patients in a multi-histology BM phase II basket trial with pembrolizumab [90].

HER2-Low

In patients with HER2-low cancer, T-DXd demonstrated a significant median PFS gain of 4.8 months compared to standard treatment. In an exploratory study, among patients with stable asymptomatic BM (35 patients [24 T-DXd; 11 controls]), the CNS-ORR was 25% vs 0%. In the T-DXd group, the PFS and OS were 9.7 months (95%CI, 4.4–15.1) and 16.7 months (95%CI, 6.7–24.5), respectively [74]. These data align with findings from the DAISY trial, which evaluated T-DXd in patient cohorts with HER2-low and HER2-negative. Among patients with stable BM, the best objective responses (BOR) were observed at 30% (3/10; (95%CI 6.7–65.2) for the HER2-low group and 50% (1/2; (95% CI 1.3–98.7) for the HER2-negative group, respectively [91].

All Subtypes

Bevacizumab has shown benefits in PFS but not in OS in MBC; however, all phase 3 trials of bevacizumab in MBC strictly excluded patients with any history of brain metastases due to concern for intracranial hemorrhage. Since then, two phase 2 studies have demonstrated significant response rates of 63–77% in patients with BM when combined with chemotherapy (and trastuzumab if HER2-positive). No clinically significant intracranial hemorrhages were reported in either study [72, 73]. Chemotherapies have demonstrated activity in the CNS, largely based on case series capecitabine, anthracyclines, and platinum agents, with response rates ranging from 18–54%, 17–41%, and 28–38%, respectively [77, 78–79, 92, 93]. Retrospective data are also available for eribulin and irinotecan [94, 95]. Despite its known ability to cross the BBB, temozolomide has not shown efficacy in BM in randomized trials [96]. Finally, PARP inhibitors have also been the subject of case reports in patients with BRCA germline alteration [97].

Treatment of LMD among MBC Patients

Treatments for LMD are based on studies with low levels of evidence, including small prospective studies and retrospective cohorts. Treatment decisions should be made through a multidisciplinary approach tailored to each case.

Radiation Therapy

Radiation therapy (RT) remains an effective treatment for improving neurological symptoms in LMD. WBRT should be reserved for patients with extensive LMD and coexisting BM [98]. In contrast, local involvement could receive involved-field RT (IFRT) or hypo-fractionated stereotactic RT [99]. Craniospinal irradiation (CSI) with photons has been described but was rarely used due to its significant systemic side effects. However, proton craniospinal irradiation (pCSI) limits the radiation beyond the neurological axis, thereby reducing systemic side effects. A phase II study with solid tumors, including breast cancer, showed a significant advantage in terms of CNS-PFS and OS over pCSI compared to photon-based IFRT, median 7.5 months (CI95%, 6.6 months to not reached (NR)) vs. 2.3 months; (CI95%, 1.2- 5.8; p < 0.001) and 9.9 months (CI95%, 7.5-NR) vs. 6.0 months (CI95% 3.9-NR; p = 0.029) without new or additive toxicity [100]. Unfortunately, the utility of pCSI for the treatment of LMD is limited by cost and the relative scarcity of centers capable of delivering proton therapy. Further studies evaluating pCSI in the management of LMD are being developed.

Intrathecal Therapy

The rationale for choosing intrathecal administration is to achieve higher cerebrospinal drug concentrations while minimizing systemic toxicity. Initially developed with chemotherapy, several trials and cohorts have evaluated methotrexate (MTX), liposomal cytarabine, and irinotecan [16]. However, no trials have demonstrated an improvement in OS. The DEPOSEIN clinical trial, which compared liposomal-cytarabine combined with systemic treatment against systemic treatment alone, reported a median LM-PFS (leptomeningeal progression-free survival) of 2.2 months (95%CI 1.3–3.1) in the control group versus 3.8 months (95%CI 2.3–6.8) in the experimental group (HR = 0.61, p = 0.04). Despite these findings, the quality of life up to progression did not differ between groups [101]. Retrospective data have shown that intrathecal topotecan resulted in clearing of CSF malignancy in 10/21 (48%) patients with a median duration of 15.9 months (range, 1.4–34.5) [102]. A second intrathecal treatment option involves the administration of trastuzumab, which has demonstrated a tolerable safety profile and extended survival in two phase 2 trials, with OS ranging from 8 to 10 months [103, 104].

Systemic Therapy

Systemic therapy data for LMD come from retrospective cohorts or subgroups within prospective trials. However, promising efficacy data from new anti-HER2 therapies, notably T-Dxd, have been reported. Two cohorts from the United States and Japan involving heavily pretreated HER2-positive MBC patients with progressive LMD showed response rates of 50–78% and median OS exceeding 12 months [105, 106]. Additionally, the tucatinib regimen has demonstrated intracranial response, improved symptoms, improved quality of life, and extended survival in patients with LMD in the TBCRC049 study. Median OS was 10 months (95% CI: 4.1, not reached), and most patients with target deficits at baseline experienced improvement with the tucatinib regimen [107, 108]. Standard chemotherapies have not demonstrated long-term benefits for LMD patients. However, some agents like capecitabine, high-dose IV methotrexate and platinum-based therapies have shown some activity and may be considered [16]. Endocrine therapies have also shown some activity based on case. Abemaciclib was evaluated in the prospective JPBO clinical trial, which included an LMD cohort and observed one response in seven patients with a median PFS of 5.9 months (95% CI 0.7–8.6) and median OS of 8.4 months (95% CI 3.3–23.5) [71].

Surveillance and Follow-up of CNS Metastases among MBC Patients

Patients with CNS metastases should undergo regular clinical and radiologic follow-up to detect any treatment complications or intracranial progression [34, 109]. Clinical evaluation should include periodic neurologic and cognitive assessments, possibly using the Neurologic Assessment in Neuro-Oncology (NANO) scale [110]. Imaging should include MRI with intravenous gadolinium-based contrast every 2–3 months or earlier based on symptoms. Perfusion and spectroscopic MRI and amino acid PET scans can help distinguish between radionecrosis and progression of brain metastases in cases of doubt [111, 112–113]. Although the RANO-BM criteria were developed for clinical trials, they are also useful in routine practice. Unlike the RECIST criteria, RANO-BM considers changes in both target and non-target lesions on conventional contrast-enhanced MRI, neurological status, and steroid use [114]. The RANO-LM criteria provide support for the follow-up of patients with LMD. In addition to clinical examination and neuroaxis MRI, they also include CSF analysis [115].

Prevention of CNS Recurrence: Limited Success to Date

Unfortunately, few adjuvant therapies have been shown to reduce the risk of CNS recurrence. A meta-analysis of trials evaluating adjuvant trastuzumab showed that it was associated with a significant increase in the risk of CNS metastases as the site of first recurrence 2.56% versus 1.94% (RR = 1.35, p = 0.038), suggesting a greater reduction in extracranial than intracranial relapse risk with trastuzumab [116]. In the APHINITY trial, no difference was observed in the incidence of CNS metastases (2.0% in both groups) with the addition of pertuzumab to adjuvant trastuzumab [117]. Similarly, patients with residual disease after neoadjuvant treatment who received T-DM1 versus adjuvant trastuzumab in the KATHERINE trial had a higher risk of first CNS relapse (7.0% vs. 5.1%) [10]. However, in a post-hoc analysis, HR-positive/HER2-positive patients treated with adjuvant neratinib in the ExteNET trial had a lower cumulative incidence of CNS relapse at 5 years compared to placebo (0.7% vs. 2.1%), suggesting a potential signal in favor of the HER2 TKI [118]. The ongoing phase 3 clinical trial COMPASS-HER2 RD is comparing the combination of TDM1 with or without tucatinib for HER2 + patients with residual disease after neoadjuvant treatment. Brain metastases-free survival (BMFS) is a secondary objective to evaluate whether tucatinib prevents CNS metastases for these at-risk patients (NCT04457596).

In patients with TNBC, adding pembrolizumab to neoadjuvant and adjuvant chemotherapy in the KEYNOTE 522 trial reduced the overall risk of CNS relapse (3.6% vs. 2.1%). However, in the RCB-0 and RCB-1 categories, more than half of the recurrences occurred in the CNS, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group [11]. These results are consistent with retrospective data from patients with HER2 + MBC [6]. Brain micrometastases are "protected" within the CNS and require additional strategies for patients with complete pathologic responses.

Promising Novel Therapeutics

Numerous new treatments and combinations capable of crossing the BBB or blood-tumor barrier are under development and showing promising results in patients with CNS metastases. All active trials are summarized in Table 2. The results from T-Dxd have spurred significant development of new ADCs for patients with CNS metastases, including HER2-targeting ADCs like ARX788 and SHR-A1811, TROP2-targeting ADC SHR-A1921, and HER3-targeting ADC patritumab-deruxtecan. Innovative treatments such as CAR-T cell therapy targeting HER2 are currently being studied in a phase 1 trial (NCT03696030) in patients with BM and LMD.

Table 2. Recruiting or Not Yet recruiting clinical trials on systemic treatment in Breast Cancer Patients with CNS Metastases

NCT Number ACRONYM	Trial Name	Interventions	Primary Outcome Measures	Phases	Completion Date
MBC patients with Brain Metastases
HER2-POSITIVE
NCT04334330	Palbociclib, Trastuzumab, Pyrotinib and Fulvestrant Treatment in Patients with BM From ER/PR Positive, HER-2 Positive BC: A Multi-center, Prospective Study in China	Palbociclib, Trastuzumab, Pyrotinib and Fulvestrant	CNS-ORR (RECIST 1.1)	2	2024–12
NCT06152822	Pyrotinib Combined with Capecitabine and Bevacizumab for Patients with HER2 Positive BC and BM	Pyrotinib Combined with Capecitabine and Bevacizumab	CNS-ORR (RECIST 1.1)	2	2025–11
NCT05553522	Tucatinib, Trastuzumab, and Capecitabine with SRS for BM From HER-2 Positive BC	Combined use of SRS with Tucatinib, Trastuzumab, and Capecitabine	dose-limiting toxicities	1	2025–11
NCT04582968	Pyrotinib Combined with Brain Radiotherapy in BC Patients With BM	Pyrotinib Plus Capecitabine combined with brain radiotherapy	Assess safety and tolerability	1/2	2023–08
NCT03417544	Atezolizumab + Pertuzumab + Trastuzumab in CNS Mets In BC	Atezolizumab + Pertuzumab + Trastuzuma	CNS ORR (RANO-BM)	2	2025–12
NCT04760431 HER2BRAI	TKIs vs. Pertuzumab in HER2 + BC Patients with Active BM (HER2BRAIN)	Anti-HER2 TKI versus Pertuzumab in Combination with Dose-dense Trastuzumab and Taxane	ORR	2	2025–09
NCT05042791	A Study of Pyrotinib Plus Capecitabine Combined with SRT in HER2 + MBC With BM	Pyrotinib Plus Capecitabine Combined With SRT	CNS-ORR,	2	2025–09
NCT05018702	ARX788 in HER2-positive BC Patients With BM	ARX788 ((HER2-targeting ADC)	CNS-CBR (RANO-BM)	2	2023–06
NCT06361979	SHR-A1811 Combined with Bevacizumab in HER2-positive BC With BM	SHR-A1811 (HER2-targeting ADC) Combined with Bevacizumab	CNS-ORR (RANO-BM)	2	2026–05
NCT05769010	Study of SHR-A1811 in HER2-expression MBC er with BM	SHR-A1811 (HER2-targeting ADC) plus Pyrotinib and Bevacizumab	CNS-ORR (RANO-BM)	2	2026–04
NCT05323955 BRIDGET	Secondary BM Prevention After Isolated Intracranial Progression on Trastuzumab/Pertuzumab or T-DM1 in Patients With aDvanced Human Epidermal Growth Factor Receptor 2 + BC With the Addition of Tucatinib	Tucatinib plus Trastuzumab/Pertuzumab or T-DM1	Bicompartmental PFS (RANO-BM)	2	2025–04
NCT06015113	Efficacy and Safety of Disitamab Vedotin Plus Pyrotinib or Naratinib in HER2-positive BC Patients With BM	Disitamab Vedotin Plus Pyrotinib or Naratinib	PFS (RECIST1.1)	2	2027–04
NCT05041842 InTTercePT	Treatment With Tucatinib in Patients with an Isolated Brain Progression of a MBC	Tucatinib with Pertuzumab/Trastuzumab (and endocrine therpy)	PFS (RECIST1.1)	2	2026–03
NCT03765983	GDC-0084 in Combination with Trastuzumab for Patients with HER2-Positive BC BM	GDC-0084 (inhibitor of PI3K and mTOR) in Combination with Trastuzumab	ORR (RANO-BM)	2	2025–11
NCT06088056	A Phase II Study of T-DXd Plus SRT in HER2-positive BC BM	T-DXd Plus stereotactic radiotherapy	CNS-ORR (RANO-BM)	2	2026–07
NCT03691051	A Study of Pyrotinib Plus Capecitabine in Patients with BM From HER2-positive MBC	Pyrotinib Plus Capecitabine	CNS-ORR (RECIST1.1)	2	2024–12
TNBCpé
NCT03483012	Atezolizumab + Stereotactic Radiation in Triple-negative BC and BM	Atezolizumatrob + Stereotactic Radiation	bi-compartmental-PFS (RANO-BM)	2	2025–09
NCT06210438	SHR-A1921 Combined with Bevacizumab in Triple-negative BC With BM	SHR-A1921 (TROP2-targeting ADC)) Combined with Bevacizumab	CNS ORR (RANO-BM)	2	2026–06
NCT06238921	Sacituzumab Govitecan and Zimberelimab w/SRS in the Management of Metastatic TNBC With BM	Sacituzumab Govitecan and Zimberelimab (anti-PD1) w/ SRS	Phase I: Neurologic Toxicity, Phase II: PFS	1/2	2027–02
NCT05866432 TUXEDO-2	Phase II Study of Dato-DXd in Triple-negative BC Patients with Newly Diagnosed or Progressing BM	Dato-DXd	CNS-ORR (RANO-BM)	2	2026–05
HR-positive / HER2-negative
NCT04791384	Phase Ib/II Trial of Abemaciclib and Elacestrant in Patients with BM Due to HR + /Her2- BC	Abemaciclib and Elacestrant	Phase I: Safety Phase II: CNS-ORR (RANO-BM)	1/2	2025–01
NCT05386108 ELECTRA	Study of Abemaciclib and Elacestrant in Patients with BM Due to HR + /HER2- BC	Abemaciclib and Elacestrant	Safety	1/2	2025–12
NCT04923542	Stereotactic Radiation & Abemaciclib in the Management of HR + /HER2- BC BM	Stereotactic Radiation & Abemaciclib	CNS-PFS (RANO-BM)	1/2	2024–12
NCT05872347	Efficacy and Safety of SPH4336 in Combination with Endocrine Therapy in BC Patients With BM	SPH4336 (CDK 4/6 inhibitor) in Combination with Endocrine Therapy	CNS-ORR (RANO-BM)	2	2025–12
All Subtype
NCT05305365	Study Assessing QBS72S For Treating BM	QBS72S	ORR (RANO-BM)	2	2026–08
NCT03807765	Stereotactic Radiation and Nivolumab in the Management of MBC BM	Nivolumab Stereotactic Radiosurgery	Safety and Neurologic dose limiting toxicities	1	2024–04
NCT05357417	Utidelone Plus Bevacizumab for MBC With BM	Utidelone Plus Bevacizumab	CNS-ORR (RECIST1.1)	2	2024–05
NCT03328884 Phenomenal	Evaluation of the Efficacy and Safety of Nal-IRI for Progressing BM in BC Patients	Irinotecan Hydrochloride	CNS-ORR (RANO-BM)	2	2025–06
NCT03449238	Pembrolizumab And Stereotactic Radiosurgery (Srs) Of Selected BM In BC Patients	Pembrolizumab And Stereotactic Radiosurgery	Tumor response for non-irradiated brain (RECIST1.1)	1/2	2027–12
NCT05535413	UTD1 Combined with Capecitabine in Metastatic HER2-negative BC Patients With BM	UTD1 Combined with Capecitabine	CNS-ORR (RANO-BM)	1/2	2025–07
NCT06048718 TUXEDO-4	T-DXd Therapy for HER2-low Breast Cancer Patients With BM	T-DXd	CNS-ORR (RANO-BM)	2	2026–07
NCT04711824 SOLARA	Study of Stereotactic Radiosurgery with Olaparib Followed by Durvalumab and Physician's Choice Systemic Therapy in Subjects with BC BM	Stereotactic Radiosurgery with Olaparib Followed by Durvalumab	Phase I: Safety Phase II: CNS-ORR (RANO-BM)	1/2	2026–09
NCT05781633	The Efficacy and Safety of Eutideron, Etoposide, and Bevacizumab in Patients with BM From BC	Eutideron, Etoposide, and Bevacizuma	CNS-ORR (RANO-BM)	2	2025–07
NCT04348747	Dendritic Cell Vaccines Against Her2/Her3 and Pembrolizumab for the Treatment of BM From TNBC or HER2 + BC	Dendritic Cell Vaccines Against Her2/Her3 and Pembrolizumab	CNS-ORR (RANO-BM)	2	2026–12
NCT04647916	Testing Sacituzumab Govitecan Therapy in Patients with HER2-Negative BC and BM	Sacituzumab Govitecan	ORR	2	2026–12
NCT02595905	Cisplatin With or Without Veliparib in Treating Patients with Recurrent or Metastatic TNBC and/or BRCA Mutation-Associated BC With or Without BM	Cisplatin With or Without Veliparib	PFS	2	2024–10
MBC patients with Brain Metastases and or LMD
NCT06176261 DATO-BASE	DATO-BASE: DATOpotamab-deruxtecan for BC BM	Datopotamab Deruxtecan	ORR (RANO-BM)	2	2029–01
NCT03696030	HER2-CAR T Cells in Treating Patients with Recurrent Brain or LMD	HER2-CAR T Cells	Safety	1	2025–02
MBC patients with LMD
NCT05746325	Tumor Treating Fields for the Treatment of LMD of the Spine in Patients With BC	tumor treating fields (TTF)	Safety	NA	2027–03
NCT03501979	Tucatinib, Trastuzumab, and Capecitabine for the Treatment of HER2 + LMD	Tucatinib, Trastuzumab, and Capecitabine	OS	2	2024–07
NCT03613181 ANGLeD	ANG1005 in Leptomeningeal Disease From BC	ANG1005 (taxane linked to Angiopep-2)	OS	3	2024–12
NCT05800275 ETIC-LM	Capecitabine, Tucatinib, and Intrathecal Trastuzumab for Breast Cancer Patients With LMD	Capecitabine, Tucatinib, and Intrathecal Trastuzumab	OS	2	2027–06
NCT04588545	Radiation Therapy Followed by Intrathecal Trastuzumab/Pertuzumab in HER2 + Breast LMD	Radiation Therapy Followed by Intrathecal Trastuzumab/Pertuzumab	Phase 1: Maximum Tolerated Dose Phase 2: OS	1/2	2024–11
NCT06016387	Tucatinib With Brain and/or Spinal XRT in Patients with HER2 + MBC and LMD	Tucatinib With Brain and/or Spinal XRT	OS	2	2028–10

BC Breast Cancer, MBC Metastatatic Breast Cacner, BM Brain Metastases, CNS Central Nervous System, TNBC triple negative breast Cancer

Utidelone, an epothilone analog engineered through genetic engineering, has recently shown promise in a phase 2 trial in combination with etoposide and bevacizumab in heavily pretreated breast cancer patients with CNS metastases, achieving a CNS-ORR of 73% (8/11 patients) [119]. The primary adverse event (AE) was peripheral neuropathies in 9% (1/11, grade 3) of patients. ANG1005, a novel taxane derivative consisting of paclitaxel covalently linked to Angiopep-2, designed to penetrate the CNS via the LRP1 transport system, demonstrated a CNS-ORR of 15% in a phase II study among adult patients with MBC CNS metastases (BM n = 72 and LDM n = 28). In the LMD subgroup, 79% of patients achieved intracranial disease control with an estimated median OS of 8.0 months (95%CI, 5.4–9.4) [120].

Innovative trials, such as the phase 2 Alliance A071701 trial (NCT03994796), are ongoing and evaluate genomic-guided treatment choices for BM. This trial assesses abemaciclib, GDC-0084 (a PI3K and mTOR inhibitor), and entrectinib in patients with alterations in NTRK, ROS1, CDK, or PI3K genes in brain metastasis. Also, trials like BRIDGET (NCT05323955) and InTTercePT (NCT05041842) are evaluating the addition of tucatinib and the continuation of ongoing treatment (HP or TDM1) in cases of isolated brain progression, thus potentially delaying radiotherapy.

Summary

CNS metastases are a common occurrence and an unmet need associated with significant morbidity and poor prognosis in MBC patients. However, advances in local and systemic treatments have significantly improved the OS of these patients. Multimodal treatment strategies require a multidisciplinary approach. Local treatment remains the cornerstone of active, especially newly diagnosed, BM. However, the emergence of highly effective systemic therapies may soon lead to a paradigm shift in the multidisciplinary therapeutic approach to BM.

Key References

• Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-Weiner A, Jones RT, et al. Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discovery. 2015;5:1164–77.

  • ○ Genetic profiling of 86 matched brain metastases, primary tumors, and normal tissue demonstrated that in 53% of cases, we found potentially clinically informative alterations in the brain metastases that were not detected in the matched primary tumor sample.

• Reese RA, Lamba N, Catalano PJ, Cagney DN, Wen PY, Aizer AA. Incidence and Predictors of Neurologic Death in Patients with Brain Metastases. World Neurosurgery. 2022;162:e401–15.

  • ○ Study of incidence in CNS metastases patients across type of cancer

• Lin NU, Murthy RK, Abramson V, Anders C, Bachelot T, Bedard PL, et al. Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial. JAMA Oncology. 2023;9:197–205.

  • ○ The first phase 3 trial with significant improvement in CNS-PFS and OS that included patients with active brain metastases.

• Sperduto PW, Mesko S, Li J, Cagney D, Aizer A, Lin NU, et al. Beyond an Updated Graded Prognostic Assessment (Breast GPA): A Prognostic Index and Trends in Treatment and Survival in Breast Cancer Brain Metastases From 1985 to Today. International Journal of Radiation Oncology*Biology*Physics. 2020;107:334–43.

  • ○ Study demonstrating the association with overall survival of the Graded Prognostic Assessment (Breast GPA).

• McTyre ER, Soike MH, Farris M, Ayala-Peacock DN, Hepel JT, Page BR, et al. Multi-institutional validation of brain metastasis velocity, a recently defined predictor of outcomes following stereotactic radiosurgery. Radiotherapy and Oncology. 2020;142:168–74.

  • ○ Study demonstrating the association with overall survival of brain metastasis velocity

• Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JHC, Hoekstra FH, et al. Treatment of single brain metastasis: Radiotherapy alone or combined with neurosurgery. Annals of Neurology. 1993;33:583–90.

  • ○ Phase 3 study demonstrated a significant OS gain for surgery followed by radiation therapy for a brain metastasis.

• Patchell Roy A., Tibbs Phillip A., Walsh John W., Dempsey Robert J., Maruyama Yosh, Kryscio Richard J., et al. A Randomized Trial of Surgery in the Treatment of Single Metastases to the Brain. New England Journal of Medicine. 1990;322:494–500.

  • ○ Phase 3 study demonstrated a significant OS gain for surgery followed by radiation therapy for a brain metastasis.

• Brown PD, Pugh S, Laack NN, Wefel JS, Khuntia D, Meyers C, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro-Oncology. 2013;15:1429–37.

  • ○ Study of memantine for prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy

• Brown PD, Gondi V, Pugh S, Tome WA, Wefel JS, Armstrong TS, et al. Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001. JCO. 2020;38:1019–29.

  • ○ Study of hippocampal avoidance for prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy

• Hurvitz SA, Modi S, Li W, Park YH, Chung W, Kim S-B, et al. 377O A pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2 +) metastatic breast cancer (mBC) with brain metastases (BMs) from DESTINY-Breast (DB) −01, −02, and −03. Annals of Oncology. 2023;34:S335–6.

  • ○ Pooled analysis of DESTINY-Breast (DB) −01, −02, and −03 on patients with brain metastases (BMs)

• Harbeck N, Ciruelos E, Jerusalem G, Müller V, Niikura N, Viale G, et al. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nat Med. 2024;1–10.

  • ○ Largest trial evaluating T-DXd in HER2-positive patients with stable, active BM

• Yang JT, Wijetunga NA, Pentsova E, Wolden S, Young RJ, Correa D, et al. Randomized Phase II Trial of Proton Craniospinal Irradiation Versus Photon Involved-Field Radiotherapy for Patients With Solid Tumor Leptomeningeal Metastasis. Journal of Clinical Oncology [Internet]. 2022

  • ○ Phase II study of Proton Craniospinal Irradiation for LMD patients

Acknowledgements

The authors used generative artificial intelligence tools such as ChatGPT and DeepL to improve the syntax and language. The first author would like to thank Lucile Cabanel for her unfailing help.

Author Contribution

All authors contributed to the reveiw conception . T.G wrote the first draft of the manuscript. S.S supervised the course of the article. All authors critically reviewed the manuscript and approved the final manuscript.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of Interests

TG discloses Travel fees from AstraZeneca, Gilead, and Pfizer. Consulting/Advisor role for AstraZeneca and a personal Grant from the Philippe Foundation.

AA notes research funding from Varian and NH TherAguix as well as consulting for Novartis and Seagen.

NUL declares consulting honorarium from Seagen, Daichii-Sankyo, AstraZeneca, Olema Pharmaceuticals, Janssen, Blueprint Medicines, Stemline/Menarini, Artera Inc., Eisai; travel support from Olema Pharmaceuticals; research support (to institution) from Genentech, Zion Pharmaceuticals (as part of GNE), Pfizer, Seagen, Merck, Olema Pharmaceuticals, AstraZeneca; royalties from Up To Date.

SS declares research funding to their institution from Astra Zeneca, Eli Lilly, Relay, SEAGEN and Sermonix; and consulting fees from Foundation Medicine, Astra Zeneca, Daichii Sankyo, Eli Lilly, Pfizer, Incyclix, Relay, Gilead, Sermonix and Novartis.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any authors.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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