Up to 10-30% of breast cancer patients will develop metastases to the brain or meninges. Radiotherapy remains one of the main treatments for intracranial metastases. Although radiotherapy prolongs the survival of breast cancer patients, it is associated with considerable toxicity, which is particularly manifested in cognitive function deterioration. Animal studies suggest that these sequelae result mainly from radiation damage to the hippocampus. Avoiding this structure during brain radiotherapy and its pharmacological protection have been the subjects of multiple trials. Another brain-sparing approach that has emerged in the standard management of countable brain metastases is stereotactic radiotherapy. We present current knowledge on the efficacy and safety of these strategies in breast cancer patients with brain metastases.

Breast cancer (BC) has surpassed lung cancer as the most commonly diagnosed malignancy among women (1). It is the second most common cause of malignant central nervous system (CNS) dissemination after lung cancer (2). According to the Surveillance, Epidemiology, and End Results Program, 10-30% of patients with BC develop brain or leptomeningeal metastases (BMs), making BMs the most common cause of BC-related deaths (3). New and more effective treatment methods, including anti-HER2 antibodies, CDK4/6 inhibitors, antibody−drug conjugates and immunotherapy, substantially prolong patients’ overall survival (OS), while the availability of precise CNS imaging increases the detection rate of asymptomatic BM (4). Currently, three options in BCBM treatment, i.e., systemic therapy, surgery and radiotherapy (RT), prolong OS by several months, mostly in patients with HER2-positive breast cancer (5). Owing to poor blood−brain barrier (BBB) penetration, chemotherapy has a limited role in the management of BM (6–8), but a better understanding of BM biology has facilitated the development of novel targeted therapies (9). In oligometastatic disease with fewer than five metastatic lesions, surgical excision and/or stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) are the treatments of choice (10–12). In patients with multiple or large BMs and uncontrolled extracranial disease, either whole-brain RT (WBRT) or partial-brain RT (PBRT) is used (13, 14). Although RT has significantly improved the survival of BCBM patients, a relatively large proportion of treated patients will develop radiation-related deterioration of cognitive functions (CFs), including deficits in memory, spatial information processing abilities, and learning difficulties that significantly affect their quality of life (15, 16). The incidence of radiation-induced brain damage is probably underestimated, but the use of novel magnetic resonance imaging (MRI) techniques, such as diffusion-weighted imaging, proton magnetic resonance spectroscopy, and perfusion MRI, has improved the ability to better characterize treatment-related changes. The frequency and severity of cognitive impairment following brain RT are affected by the patient’s age and education, tumor type, RT volume (WBRT, PBRT, SRS, and SRT), RT dose, time elapsed since treatment, definition of neurocognitive impairment, baseline neurocognitive function (NCF), and use of concurrent or previous chemotherapy, targeted agents or immunotherapy (17). We describe the current knowledge on the possibilities of neuroprotection in patients with BCBM receiving radiotherapy.

For a long time, WBRT has been the standard of care for patients with BM since it improves the median OS from 1 to 6 months compared with best supportive care (7, 18, 19). Clinical studies have shown no difference in OS among various fractionation regimens. Radiosensitizers were also found to fail to improve the prognosis of patients with BM treated with RT (20–22). Therefore, WBRT of 30 Gy in 10 fractions or 20 Gy in 5 fractions has remained the standard of treatment, regardless of BM histology (13, 14, 23–25).

In the case of a single BM from multiple primaries, surgical excision plus WBRT was compared with WBRT alone in randomized trials (26–28), and the results were inconclusive. Combined therapy was shown to be better than WBRT alone (median survival 9-10 months versus 3-6 months) in two studies (26, 27), especially in patients without active systemic disease. Patients with BCBM constituted only 7.5-12% of the studies population and the only histological stratification was the division into patients with NSCLC vs. other sites of cancer and no statistical difference was found. Wroński et. al (29) reported retrospective series of 70 BCBM patients (10% of patients operated due to brain metastases between 1974 and 1993 in their hospitals) treated with neurosurgery with mOS=16.2 months from the time of diagnosis of BM and mOS=14 months from the time of surgery. Among the favorable prognostic factors, the authors mentioned younger age of patients, smaller size of metastases (but not their number) and hormonal status with mOS=21.9 months for ER+ vs. 12.5 months for ER- BC. However, in multivariate analysis, only the use of WBRT after surgery and the absence of meningeal involvement had good prognostic significance. In another retrospective series of 198 patients with BCBM, mOS=14.9 months was also found, but only in the group of 28% of patients with single BM treated surgically or with the use of a gamma knife (SRS), while patients undergoing WBRT had mOS=5.4 months (30). In a more recent series of 53 patients with BCBM from 1994-2010 treated with resection and in 2/3 cases with radiotherapy (SRS-gamma knife, WBRT or both), mOS was 16 months, even though 30% were patients with TNBC and 45% patients with HER2+, probably due to the greater use of effective systemic therapies (31).

On the one hand, the better prognosis of patients with a limited number of BMs has led to interest in more aggressive local treatment. In the RTOG 9508 randomized trial, in patients with 1-3 BMs, a stereotactic boost added to WBRT improved not only the survival of those with a single unresectable brain metastasis (mOS: 6.5 vs. 4.9 months, p=0.0393) but also the functional autonomy of all patients (stable or improved Karnofsky Performance Status [KPS] score at 6 months in 43% vs. 27% in the WBRT group, p=0.03) (32). On the other hand, in the European Organisation for Research and Treatment of Cancer EORTC 22952-26001 study, OS and functionally independent survival were similar, regardless of the addition of WBRT to SRS in the treatment of 1-3 BM (33). These results have changed the paradigm of adding localized treatment of BM to WBRT by using SRS without WBRT, with a single dose of radiation precisely delivered to the BM, maximizing the chance for local control, and sparing the normal brain tissue by omitting WBRT. Although BCBM patients constituted only 12% in the EORTC study, retrospective data confirm very good results of SRS in this group of patients with mOS=15.7 months (34). In the analysis of 91 patients with BCBM who received SRS, a statistically significant prognostic factors were: receptor status, BCBM volume and stable extracranial disease. Patients with ER+/HER2- had mOS=13.8 months, the best results were obtained in patients ER+/HER2+ with mOS=21.4 months and ER-/HER2+ with mOS=20.4 months, and the worst prognosis was reported in patients with TNBC with mOS=8.5 months. These results were better than overall survival reported in other retrospective series of patients with BCBM (35, 36). BCBM volume > 10 cm3 was associated with a worse prognosis with mOS=9.2 months. The authors suggested the possibility of selecting this group of patients for combined treatment with SRS + WBRT, although in the light of the latest knowledge, these patients may also be candidates for FSRT, but the value of both approaches requires validation. Patients with stable extracranial disease undergoing SRS for BCBM had a better prognosis (mOS=20.1 months) compared to patients with progressive extracerebral lesions (mOS=11.4 months). Interestingly, patients without extracranial disease had an mOS of 13.4 months, but this is probably due to the significant proportion of TNBC patients in this group, in whom BMs are often the first manifestation of dissemination and the prognosis remains unfavorable.

In the lack of randomized trials comparing the outcomes of SRS with or without WBRT in BCBM patients, we summarized phase III randomized trials including patients with different numbers (single, up to three, and up to four), sizes and pathological types of BM, as well as resected single BM ( Table 1 ). Most of these studies have shown less cognitive impairment in patients with BM after SRS than after WBRT but at the cost of a higher risk of further intracranial progression. On the other hand, WBRT significantly decreased in-brain recurrences but increased the risk of death due to neurotoxicity in the setting of intact as well as resected BM (37, 38, 40, 41). Knowing that the mere presence of brain metastases causes cognitive disorders in patients with BM (42) and that the use of SRS/FSRT increases the risk of further brain metastases that aggravate these disorders and require further local treatment, the effects of which overlap with existing cognitive problems, it seems that the several months of observations in the cited studies (maximum 6 months) may be insufficient to assess long-term radiation-induced neurotoxicity.

However, CF was prospectively assessed in only a minority of those trials using various tools and methods, such as the Hopkins Verbal Learning Test-Revised [HVLT-R] Immediate Recall, Delayed Recall and Recognition; Grooved Pegboard Test; Controlled Oral Word Association Test [COWAT]; Trail Making Test Part A [TMT-A]; and/or Trail Making Test Part B [TMT-B]. Owing to the heterogeneity of the patient populations, it is very difficult to compare these results and draw conclusions. The Mini-Mental State Examination (MMSE) showed very low sensitivity to detect RT-induced cognitive impairment (37). Using the Hopkins Verbal Learning Test-Revised (HVLT-R), Chang et al. (38) proved that combined SRS+WBRT vs. SRS alone in patients with 1-3 BMs improved the treatment outcomes at the cost of significant deterioration of learning and memory function as early as at 4 months.

Despite the doubts about SRS/FSRT, the lack of long-term survival benefit of adding WBRT established the role of SRS/FSRT in the treatment of oligometastatic brain metastases, especially in cancers such as breast cancer where metastasectomy/stereotactic radiotherapy of a limited number of metastases to other organs was already standard.

Promising results of SRS in oligometastatic BMs were extrapolated to polymetastatic BM treatment. The noninferiority of stereotactic radiotherapy in 5-10 vs. 2-4 BMs has been demonstrated in a nonrandomized study (HR=0.97, 95% CI, 0.81-1.18; p=0.78) (43, 44).

The development of molecular diagnostics and further research on the prognosis of patients with BM depending on prognostic factors led to the creation of the graded prognostic assessment (GPA) for estimating the survival of patients with brain metastases, including a separate breast GPA, the use of which shows the longer survival of patients with BCBM in relation to other patients with BM.

The prolonged survival of patients with BC due to advances in systemic treatment has led to an increased risk of late complications following WBRT, especially in those with the HER2-positive subtype, in whom intracranial spreading is particularly frequent (45, 46). Because of the lack of a survival advantage of WBRT added to stereotactic radiotherapy, SRS/FSRT alone is recommended for most patients, even in patients with multiple metastases, especially if their total volume is ≤15 ml (11, 43, 44, 47–49). The SRS dose and BM volume did not correlate with posttherapy CF (44, 46–49). Thanks to new technical solutions, SRS/FSRT for BM therapy has become more accessible and less time-consuming. Modern arc RT planning systems enable the creation of a single plan for several focal lesions in the brain (mono-isocenter technique), which, compared with the conventional multi-isocenter technique, not only shortens the treatment planning time but also decreases neurotoxicity by reducing the dose to the healthy brain (50).

During standard radiation treatment (PBRT, WBRT, SRT, and SRS), healthy brain tissue is inevitably exposed to radiation. The exact mechanism underlying radiation-induced brain damage is not fully understood. For many years, the brain has been regarded as a highly radioresistant organ. Acute neurological symptoms were observed early after a single dose of 30 Gy, whereas white matter necrosis occurred after a conventionally fractionated dose of 60 Gy (51). With modern techniques, focal neurological deficits, epilepsy, and increased intracranial pressure have become less common (51, 52).

Early and early-delayed side effects, e.g., somnolence, headaches, drowsiness, attention deficits, and short-term memory loss, are caused by brain edema and transient demyelination, respectively. In contrast, late-delayed neurotoxicity is irreversible owing to white matter necrosis, vascular fibrosis, permanent demyelination, or gliosis (51). Biologically, these processes are associated with the proliferative capacity of glial and vascular endothelial cells. White matter necrosis is currently uncommon; however, the dynamic interplay among astrocytes, microglia, oligodendrocytes, endothelial cells, and neurons leads to radiation-induced neurocognitive dysfunction (16, 53). Most data on the mechanism of radiation-induced brain damage are obtained from studies on animal models, including rodents and nonhuman primates, and have suggested that the loss of hippocampal neurogenesis is a main problem (54, 55). Another hypothesis indicates that cognitive impairment after irradiation is caused by a neuroinflammatory cascade, including the disruption of the BBB, neural progenitor cell (NPC) death, hippocampal dysfunction, and direct activation of glia, causing the senescence-associated secretory phenotype (56).

The current understanding of BM biology and molecular underpinnings will facilitate the implementation of neuroprotective treatment protocols. The widespread use of brain RT has prompted the development of brain-sparing approaches. Available data were obtained from the studies performed in patients with various primary tumors. The most appealing treatment strategies include metastasis-directed RT (SRS/FSRT as previously described), hippocampus-avoiding (HA) radiation, and the use of memantine (12, 71–73). Effective systemic treatment of BCBM, which would allow clinicians to delay the use of intracranial radiotherapy, is still being researched, as well as completely novel approaches changing the paradigms of BCBM therapy.

The group of patients with BCBM is not homogeneous. The choice of BM treatment method is determined by the patient’s age, performance status, number, size and location of brain metastases and control of extracranial metastases.

Traditionally patients with a single brain metastasis, especially over 3 cm, with neurosurgical symptoms, severe edema and mass effect and/or located in the posterior cranial fossa with hydrocephalus, were eligible for neurosurgical treatment, if the extracranial metastases were stable and systemic treatment options were available.

In everyday practice, we increasingly qualify patients with BCBM for primary BM radiotherapy due to the increased risk of dissemination to the meninges after primary neurosurgical treatment, which in patients with TNBC may be as high as 24%. The qualification criteria for SRS/FSRT include the potential possibility of further systemic treatment, the slow dynamics of the disease, previous intracranial radiotherapy, and the patient’s general condition. If at least 2 out of 4 factors favor SRS/FSRT, we qualify patients for this method, even in the presence of >4 metastatic foci if they are countable. Traditionally, we qualified patients with a single BCBM <= 2 cm for SRS; currently, the final choice of irradiation technique is determined by the parameters of the radiotherapy plan. To diagnose intracranial spread, we use 3-Tesla magnetic resonance imaging using a SPACE sequence, thanks to which we detect more small lesions. If, when preparing the radiotherapy plan, the measured volume of metastases exceeds 25 cm3, it will not be possible to safely and effectively perform SRS and we qualify the patient for FSRT. In case of BCBM volume <25cm3, we prepare SRS. If the irradiation plan meets the radiosurgical criteria, i.e. with a dose of approximately 20Gy in 1 fraction for metastatic lesions, the volume of the healthy brain receiving a dose of 12Gy is less than 5 cm3 (V12<5 cm3) and the plan conformity index is <1.4 (CI<1, 4), we qualify the patient for SRS. If the radiotherapy plan does not meet the above parameters, we qualify the patient for FSRT, usually 27Gy in 3 fractions or 30/35Gy in 5 fractions, depending on meeting the remaining constraints for intracranial radiotherapy, including the average dose to the hippocampus below 7 Gy (Dmean<7Gy). Patients with poor general condition, short expected survival, lack of cooperation with medical staff and uncontrolled epilepsy are not eligible for SRS/FSRT.

For patients with BCBM who are not eligible for SRS/FSRT, e.g. due to uncountable brain metastases, or in the case of BCBM from TNBC undergoing neurosurgery, remaining in good general condition, cooperating with medical staff, in whom we expect > 3-month survival, we use WBRT. In each case in which we have available brain MRI, we use HA-WBRT, using 30Gy in 10 fractions (12 days of treatment), with the maximum dose (the highest dose in 0.03 cm3 of both hippocampi) limited to 16Gy [Dmax <=16Gy], and doses in the entire hippocampal volume up to 9 Gy [D100% <=9Gy]. Approximately 3 days before starting HA-WBRT, we start memantine. In the first week at a dose of 1 x 5mg orally in the morning, followed by the addition of a 5-mg dose in the evening during week 2. In week 3, we increase the morning dose to 10 mg. In the fourth week we reach a dose of 2 x 10 mg per day and continue this treatment for up to 24 weeks in total. In case of creatinine clearance below 30 mL/min the maximum dose is 5 mg orally twice daily and the treatment should not be administered if the creatinine clearance is less than 5 mL/min.

According to the previously cited clinical trial data, we know that both the metastatic changes themselves and oncological treatment, both with radiotherapy and systemic therapy, have a significant impact on the cognitive functions of a patient with BCBM. Basic screening tests such as MMSE have limited sensitivity in detecting these disorders, and oncologists and radiation oncologists in their daily practice do not have enough time or knowledge to perform more advanced tests. Due to the popularization of Breast Units, which comprehensively deal with the treatment of patients with breast cancer and bring together doctors of various specialties, senology nurses, dieticians and psychologists in one place, it seems reasonable that patients with BCBM should also be provided with care by neuropsychologists. This would allow us to obtain real-world data about the frequency, depth and persistence of cognitive disorders in BCBM patients and their dependence on oncological treatment.

HA-WBRT +/- memantine is not routine practice in radiotherapy facilities, despite phase III studies showing neurocognitive benefits and safety of such therapy. One of the reasons is the heterogeneity of the patient population included in these studies. Another criticism was short follow-up, but the recently published update of the NRG CC001 study demonstrated that the benefits persisted at one-year follow-up. Another reason is the mediocre benefit of the intervention - in the group of patients treated with HA-WBRT, 60% still have cognitive disorders after 6 months. There are also technical and economic aspects. WBRT can be planned and implemented easily in any radiotherapy facility, even within 5 days. HA-WBRT requires the use of MRI to contour the hippocampi and the use of intensity-modulated beam technique (IMRT) by physicists, and the usual regimen is 30 Gy in 10 fractions, which extends the procedure time to 2-3 weeks and significantly increases workload on par with SRS/FSRT planning. In some countries, despite the same amount of work, the HA-WBRT procedure may be less cost-effective than SRS/FSRT. For this reason, the results of a study comparing SRS with HA-WBRT + memantine in less than 5 BM may provide a solution for everyday practice (NCT03550391). We expect an increase in the use of stereotactic techniques in the treatment of BCBM, which will replace surgical treatment associated with a higher risk of meningeal metastases and allow for dose reduction not only in the hippocampus, but also in other parts of the healthy brain related to cognitive functions, such as the corpus callosum. Technological development now allows for safe and effective irradiation of patients with > 10 BM with FSRT.

Secondly, the radiotherapy community also expects the results of studies assessing the effectiveness of systemic treatment in BCBM, especially in HER2+ breast cancer, because small molecules with good penetration of the BBB may change the paradigm and replace intracranial radiotherapy or significantly delay its use. Old radiosensitizers have failed in the treatment of BM, but we expect that intracranial radiotherapy combined with modern hormone therapy, immunotherapy or PARP inhibitors will change the standards of management of BCBM.

Despite the significant incidence rate, patients with brain metastases from breast cancer (BCBMs) remain underrepresented in randomized clinical trials (RCTs) that investigate diverse strategies for minimizing cognitive deficits after intracranial radiotherapy. The bulk of available data originates from studies involving lung cancer patients, particularly those with non-small cell lung cancer (NSCLC). Given the disparities in clinical and molecular attributes along with variations in prognosis between NSCLC and distinct subtypes of breast cancer it becomes imperative to validate these findings within a cohort of BCBM (123, 124). This validation should consider the long-term repercussions of approaches aimed at mitigating radiation-induced neurotoxicity, in contrast to the prevailing trend of evaluating outcomes only at 6-month juncture, as observed in prior trials.

The augmented survival rate among breast cancer patients with well-regulated systemic control presents an opportunity to employ an efficacious and safe method for managing intracranial disease. Emerging systemic therapies, particularly those tailored for HER2-positive breast cancer, exhibit enhanced potency in managing brain metastases. This development may potentially defer the need for immediate radiotherapy in BCBMs (111, 125). However, for those with triple-negative breast cancer (TNBC) BCBMs, the optimal synergy between systemic treatment and intracranial radiotherapy - both in terms of efficacy and safety – remains uncertain. The anticipation of utilizing immunotherapies and PARP inhibitors for this indication is on the horizon.

In tandem with these advancements, novel treatment modalities like FLASH radiotherapy, nanoparticles facilitating drug delivery to the brain, and TMZ as the secondary prevention for HER2+ BCBM following stereotactic radiosurgery (SRS) and/or surgery, are subjects of intensive research.

These innovations have the potential to reshape the fundamental approaches to treat BCBMs. It is crucial to underscore that expecting comprehensive human data encompassing anatomopathological and molecular changes linked to radiotherapy is an impracticable endeavor. To synthesize drawing upon existing insights derived from animal studies concerning radiation-induced brain damage, along with strategies aimed at alleviating neurotoxicity in human cases, the suggestion is to prioritize stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) over whole-brain radiotherapy (WBRT) when addressing patients with oligometastatic brain metastases from breast cancer (BCBMs). Even in cases of polymetastatic BCBMs, that can be enumerated, FSRT stands as the preferred approach. In scenarios when WBRT is unavoidable, such as when facing uncountable number of BCBMs or in cases of surgically resected triple-negative BCBMs, hippocampal-avoidant WBRT (HA-WBRT) in conjunction with memantine administration may be considered.

All authors listed have made a substantial, direct, and intellectual contribution to the work, wrote the manuscript and approved it for publication.