Radiotherapeutic management of brain metastases in patients with breast cancer: a narrative review

Introduction

The occurrence of brain metastases in breast cancer (BCBM) patients is on the rise, primarily due to the increasing incidence of breast cancer and advancements in systemic therapies that bring better systemic control and extend survival (1). BM are estimated to occur in approximately 50% of patients with metastatic human epidermal receptor 2 (HER2)-positive breast cancer and in 25–45% of those with metastatic triple-negative breast cancer (1-3).

In the era of modern advanced radiotherapy techniques and novel treatment approaches, clinical management of brain involvement continues to pose a significant challenge in oncology. The role of metastases-directed local therapy involving radiation and surgery is important and irreplaceable in most clinical scenarios (4). Although evidence-based or expert consensus-based recommendations for the management of BM are available (5,6), given the emergence of new clinical trials, evolving treatment modalities, and persistent challenges in managing BCBM, it is necessary to synthesize the updated evidences reported in the past 5 years.

In this review, we will address advances and applications of radiation therapy for BM based on the latest researches and clinical trials, showcasing the evolving landscape of novel treatment strategies. Furthermore, we provide an algorithm to guide the management of these challenging clinical scenarios, underscoring the need for comprehensive and personalized treatment plans for each patient while balancing potential benefits and risks. We present this article in accordance with the Narrative Review reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-39/rc).

Methods

A systematic search was conducted across five databases: PubMed/MEDLINE, Web of Science, ClinicalTrials.gov, Scopus, and Google Scholar, covering publications from January 1, 2009 to November 1, 2025. The search strategy was tailored for each database and incorporated Medical Subject Headings (MeSH) terms for research articles investigating the role of local treatment (primarily surgery and radiotherapy) for breast cancer and brain metastases. Nonrandomized clinical trials, case series, and cohort studies were included. Information used to write this paper was collected from the sources presented in Table 1. To ensure that all relevant studies were identified, we manually checked references of similar systematic reviews and found the advances in drug therapy for the management of BCBM and included accordingly. Only publications in English were considered.

Discussion

Prognostic model for BM from breast cancer

As one of the most heterogeneous tumors, breast cancer has a number of prognostic factors, including age, subtype, performance status, extracranial metastases, and number of BM. Several studies have focused on developing prognostic models for BCBM. In 2012, breast cancer-specific graded prognostic assessment (breast-GPA) (including the first 4 factors) was first proposed and validated in a large patient population (7). Then, a modified breast-GPA integrating the number of BM was developed in 2015 and presented excellent predictive performance, with the median overall survival (OS) of 2.6–28.8 months in patients with different modified breast-GPA scores (8). Recently, new prognostic factors are identified and incorporated into an updated breast GPA (free online at brainmetgpa.com) from a large contemporary cohort (9). These studies collectively contribute to the understanding and prediction of outcomes for patients with BCBM, however, their applicability in the current era of effective HER2-targeted therapies and novel antibody-drug conjugates (ADC) remains uncertain.

Over the past decade, several HER2-targeted regimens, especially tyrosine kinase inhibitors (TKIs; e.g., lapatinib, pyrotinib, and tucatinib)—containing treatment and ADC drugs, have been documented to achieve significant response in central nervous system (CNS) (10-12). Thus, anti-HER2 therapies improve clinical outcomes in HER2-positive patients with reported survival of more than 3 years after the diagnosis of BM (9,11). Furthermore, HER2-low expression [immunohistochemistry (IHC) 1+ or 2+/fluorescence in situ hybridization (FISH) negative] has gained clinical significance and is introduced to the conventional binary HER2 classification system (13), owing to the effective HER2-targeted therapy brought by novel ADCs for this substantial patient population. The DESTINY-Breast04 (DB-04) trial presents a considerable overall response rate (ORR) and progression-free survival (PFS) in both intracranial and extracranial tumors treated with trastuzumab deruxtecan (T-DXd) that is superior to physician’s choice of chemotherapy (14). Hence, with the refinement of three-tiered HER2 classification (i.e., HER2-negative, HER2-positive, and HER2-low expression), it is now imperative to establish a more suitable and precise prognostic scoring system for each molecular subtype of breast cancer, combining specific variables and treatment modalities (including systemic therapy and local treatment).

The role of surgical resection in the treatment of BM

As a rapid and effective diagnostic and treatment modality, surgical resection is considered the preferred approach for most patients with: (I) solitary BM without extracranial metastasis, where surgery offers considerable diagnostic value; (II) large BM lesion with neurological symptoms, where surgical resection can promptly relieve the mass effect and provide histopathological feature and molecular subtype; (III) recurrent lesion after previous local treatment (radiotherapy or surgical procedure) or symptomatic radiation necrosis (RN), salvage surgical resection can be considered a preferred local treatment option.

Current guidelines recommend confirming the molecular subtype in the metastatic setting owing to its clinical significance and potential prognostic value in patients with breast cancer. Receptor discordance often occurred and the main conversion pattern observed was the loss for hormone receptor (HR) expression, which occurred in 24–35% of patients with HR-positive primary tumors, when comparing primary tumors to BM (15,16). Likewise, the receptor status in extracranial lesions does not always correspond to the receptor status in brain lesions, with reported discordance rates of 18% for HR and 3% for HER2. Significantly, with the introduction of a three-tiered categorization of HER2, gain of HER2-low expression occurred in more than 40% of patients with HER2-negative primary tumor, suggesting the potential chance for novel anti-HER2 therapies (15).

Gross total resection of BM is preferred when feasible, as some studies have shown improved survival compared to subtotal resection (17). However, other research has indicated that the extent of BM resection neither influenced the local recurrence (LR) nor the OS in patients receiving interdisciplinary adjuvant treatment (18). For patients with multiple BM along with large lesion, surgery may postpone radiotherapy and the role of surgery remains unclear. Therefore, whether surgery can be successfully performed and then prolong intracranial control needs to be thoroughly evaluated for multiple BM disease, considering the symptoms, receptor phenotype, Karnofsky Performance Status (KPS) score, disease burden, and life expectancy.

The role of salvage surgery was discussed recently. A retrospective study of 37 patients with recurrent BM showed significant improvement in postoperative KPS status following salvage surgery with a low incidence of surgery-related morbidity and mortality (19). Meanwhile, the authors emphasized the complexities and potential complications of second surgical interventions in patients with previous radiotherapy.

Postoperative radiotherapy

As a gross tumor resection (R1/R2) rather than a R0 resection, surgical interventions for BM are supposed to have a high recurrence rate. A pivotal randomized trial (EORTC 22952-26001) demonstrated that adjuvant whole brain radiotherapy (WBRT) following local therapy [surgery or stereotactic radiosurgery (SRS)] for patients with 1–3 BMs significantly improved intracranial control, reducing the 2-year relapse rate both at initial sites (surgery: 59% to 27%; radiosurgery: 31% to 19%) and at new sites (surgery: 42% to 23%; radiosurgery: 48% to 33%) (P<0.05) (20). The second pivotal study reported by Brown et al. in 2017, explored the optimal post-operative radiotherapy modality for patients with one resected BM. Single fraction SRS targeting the resection cavity (measuring <5 cm) was shown to significantly improve cognitive-deterioration-free survival compared to WBRT, with no difference in OS between the two groups (21). As a result, postoperative SRS is regarded as level I evidence and is commonly utilized in contemporary clinical practice.

There are some details and issues that should be noted and require further investigation when administering postoperative radiation therapy. Firstly, delaying treatment following surgery for more than 3 weeks was reported as a risk factor of LR. The volume of the surgical cavity changes dynamically over time, with an average volume reduction of 15–43% at 4 weeks post-operation. And most of the volume reduction occurs within the first 3 weeks, correspondingly, experts recommend administering SRS/fractionated stereotactic radiotherapy (FSRT) to the surgical cavity within a maximum of 4 weeks after surgery (22).

Secondly, low-dose radiation therapy was another risk factor for LR. Single fraction SRS has shown an excellent local control for small surgical bed. However, large tumor is associated with poor local control in preoperative setting, FSRT may be a more appropriate radiotherapy regimen for tumor greater than 2.5 cm in diameter by allowing delivery of higher biological effective dose. Several studies investigated FSRT (up to 5 fractions) to the tumor bed resection cavity and the local control ranged from 84% to 91% with a median prescription dose of 30 Gy in 5 fractions (23-25). Currently, the widely used FSRT regimens include 24–27 Gy in 3 fractions and 25–35 Gy in 5 fractions (24,26,27).

Thirdly, the pattern of failure following postoperative SRS/FSRT needs to be defined for precise delineation of target volume. A recent analysis of failure patterns involving 85 patients who underwent postoperative SRS indicates that 100% of cavities where the tumor was in contact with the dura mater/meninges ultimately experienced LR (28). Therefore, for tumor contacting the dura pre-operatively, consensus contouring guidelines suggest treating the surgical cavity and entire surgical corridor, plus an additional expansion of 5–10 mm along the bone flap while respecting anatomic barriers. Tumor that contacts the sinuses anteriorly is suggested an expansion of 1–5 mm along the sinuses. Three-dimensional expansion of 2–3 mm to the planning target volume (PTV) should also be considered (22,29). It should be noted that whether the entire surgical tract should be included in the target volume remains controversial.

Lastly, the incidence of RN was reported to be 3–25% at 1-year after postoperative SRS, and a fatal risk is the development of leptomeningeal disease (LMD) owing to intraoperative tumor contamination and disruption of meningeal anatomy. The incidence of LMD was reported from 7.2% to 24% and breast cancer histology is a risk factor for the occurrence of LMD (21,30,31). Thus, further prospective research is warranted to investigate the optimal target delineation to achieve ideal local control while minimum toxicity and the development of LMD.

Preoperative radiotherapy

The proposal for preoperative radiotherapy is likely based on the theory of neoadjuvant therapy, which aims to reduce the dissemination of tumor cells during surgery and thus lower the risk of LMD and local failure. Meanwhile, the prescribed dose of preoperative radiotherapy is reduced by about 20% compared to definitive dose in postoperative setting, which also decreases the incidence of RN.

A retrospective study on preoperative FSRT in patients with one large or symptomatic lesion and limited intracranial metastases burden aimed to minimize rates of local failure, RN, and LMD (32). And the results showed an improved composite endpoint of 8% for preoperative FSRT compared to previously reported rates with postoperative SRS. Another multi-institutional study involving 279 patients who underwent surgical resection showed that the composite incidences for preoperative and postoperative FSRT were 7.5% and 17%, respectively (33). The median time from last radiation fraction to surgery was 2 [interquartile range (IQR), 1–4.5] days. These findings underscore the importance of timing and fractionation in stereotactic radiotherapy in the context of surgical interventions for BM. And preoperative FSRT may be a beneficial approach for patients with limited BM who are candidate for surgery. A randomized clinical trial is ongoing to compare preoperative and postoperative SRS with primary endpoint of 1-year LMD-free rate (NCT03741673). Overall, while the literature review does not directly address preoperative radiotherapy for breast cancer histology, the evolving treatment strategies underscore the multidisciplinary approach required for preferable management of BM.

Radiotherapy for large BM lesions

The definition of ‘large lesion’ varies among studies and is typically characterized as tumors exceeding 2–3 cm in maximum diameter or 6 cm³ in volume. Large BM present a distinct clinical challenge for radiotherapy when surgical resection cannot be performed due to complex morphology, eloquent location, or patient comorbidities. Patients frequently present with neurological symptoms that necessitate prompt intervention, however, it takes time for tumor shrinkage following SRS, and there is a risk of temporary exacerbation of symptoms caused by swelling (owing to increased vascular permeability) in the initial stage of radiotherapy. Mannitol and corticosteroids have been reported to offer partial symptomatic relief; however, the effectiveness is limited in severe/refractory edema and related symptoms. Anti-angiogenic agents (e.g., bevacizumab) have demonstrated superior efficacy in the improvement of edema. However, bevacizumab is not recommended prior to radiotherapy mainly owing to the continuous remission of peritumoral edema and the diminishment of the Gd-enhanced area on T1 imaging compared with pretreatment. This may lead to tumor displacement and a reduction in target volume, potentially compromising the accuracy and efficacy of radiotherapy. Therefore, in the context of large lesions, in addition to the salient symptom management, there are other potential concerns that necessitate consideration following SRS, such as RN, LR, and LMD.

The size of tumor is negatively correlated with local control of radiotherapy. Furthermore, an increase in the volume of BM is associated with an increase in the volume of normal brain tissue surrounding the lesions that is exposed to radiation, which leads to a high risk of RN. The results of RTOG 90-05 trial indicated the incidences of acute and chronic toxicities were significantly higher in patients with large lesions than in those with small lesions following the same dose of SRS (34). Milano et al. analyzed data from 51 studies to identify dosimetric predictors of radiation-induced brain toxicity after SRS or FSRT (35). The results showed that the risk of symptomatic RN following SRS was approximately 10%, 15%, and 20% when the 12 Gy irradiation volume (V12) encompassing the target area was 5, 10, and >15 cc, respectively. In the context of 3-fraction FSRT, normal brain tissue V18 <30 cc and V23 <7 cc was associated with <10% risk of RN. A meta-analysis including 24 trials showed that FSRT for large lesion constitutes an optimal treatment regimen with satisfactory local control while reduced RN compared with SRS (36).

In addition to FSRT and surgery, staged stereotactic radiosurgery (SSRS) has emerged as a promising alternative strategy to address challenges of large BM, which was initially described by Higuchi et al. in 2009 (37). This approach involves delivering radiation in two or three sessions with a multi-week interval between fractions, allowing for tumor shrinkage and adaptation of treatment plans based on the response of tumor. SSRS is particularly beneficial for large lesions, which may be too extensive for single-session SRS due to the risk of RN and other complications. A meta-analysis encompassing 14 studies and 958 patients was conducted to evaluate the efficacy and safety of 2-stage SRS for large BM with a diameter >2 cm or a volume ≥4 cm³ (38). The findings indicated that 2-stage SRS exhibited efficacy and safety outcomes, evidenced by a high complete remission rate of 44.63% and a low neurological mortality rate of 16.28%, which included cases of RN, neoplasm expansion, and edematous intracranial hypertension. A recent large retrospective study including 295 cases of large BM with a volume of ≥8 cm³ has indicated the 12-month local control rate of 83% and the 12-month symptomatic RN rate of 26% following SSRS. The therapeutic effect can be further improved when combining with systemic therapy (39). SSRS is becoming an effective treatment option for large-volume BM, as the field continues to evolve, ongoing research will be crucial in refining treatment protocols and patient selections.

Recently, radiomics and machine learning analyses have been explored for their potential application in radiotherapy for BM, including the accurate segmentation of multiple larger metastases and prediction of local response after radiosurgery (40). Therefore, the management of large BM with radiotherapy requires consideration of factors such as tumor size, radiation fraction, dose optimization, and potential acute side effects to optimize patient outcomes and quality of life.

Radiotherapy for multiple BM

For patients with multiple BM, WBRT has been a standard treatment option for inoperable cases for several decades. WBRT with a simultaneous integrated boost to multiple lesions using volumetric modulated arc therapy has been explored as a treatment approach (41), and SRS is commonly applied as a salvage modality. Early in 2012, research conducted by Grandhi found that SRS can safely and effectively treat intracranial disease in patients with 10 or more BM, achieving a high rate of local control (42). Furthermore, the JLGK0901 study demonstrated that SRS alone as the initial treatment is not inferior for 5–10 lesions when compared to 2–4 lesions (43). Increasingly powerful studies have shown the improved outcomes and reduced toxicities using advanced SRS techniques for multiple BM. Hence, SRS as a valuable treatment option has replaced the reflex use of WBRT in selected patients with favorable prognosis, particularly when dealing with up to 10 lesions and conditionally more than 10 lesions.

For patients with unfavorable prognosis and miliary/disseminated BM or LMD, WBRT remains the mainstay of management. WBRT is recommended with hippocampal avoidance where possible and uptake of memantine to relieve the deterioration of neurocognitive function induced by WBRT (44). Additionally, In the context of HER2-positive patients with active/untreated multiple BM, several trials evaluating TKIs or ADC drugs have demonstrated excellent efficacy with reported intracranial ORR of 45.5–74.6% and median PFS of 11.3–18.5 months (11,12,45). Notably, T-DXd exhibited considerate efficacy in HER2-low expression BM with ORR of 25% and PFS time of 9.7 months (14). These highlights the complexity of treatment decisions for this patient population, considering factors such as tumor subtype, HER2 status, intracranial tumor burden, and treatment response. Innovative approaches such as the use of gadolinium nanoparticles in combination with WBRT are being investigated in clinical trials, such as the NANO-RAD study, to assess safety and tolerability in patients with multiple BM (46). Further researches are needed to explore novel treatment strategies that may offer improved outcomes for patients with multiple BM.

Timing of radiotherapy

The timing of radiotherapy for BM can be roughly classified into three categories: initial radiotherapy, delayed radiotherapy, and salvage radiotherapy. Delayed radiotherapy specifically refers to radiation treatment for controlled BM following initial systemic treatment, and should be considered as combination treatment strategy as well as initial radiotherapy. In the realm of HER2-negative disease, there is no guideline recommending systemic therapy for these patients with BM, making it clear that initial local therapies remain the mainstay of management for most patients, although increasing data from systemic regimens reporting clinically modest response rates in the CNS. U-BOMB trial investigated utidelone plus bevacizumab for HER2-negative BCBM and showed promising responses with CNS-ORR rate of 40.4% and CNS-PFS time of 10.6 months (47). In EMBRCA trial, talazoparib, a poly (ADP-ribose) polymerase inhibitor (PARPi), showed advantages for patients with BRCA-associated BM subgroup compared to chemotherapy (48).

The timing of radiation treatment for HER2-positive BM is a critical aspect of patient care. Recent clinical trials on TKIs and novel ADC drugs for BCBM highlights the evolving landscape of systemic therapy for HER2-positive and HER2-low expression disease. Combining radiotherapy with targeted therapy has shown improved prognosis in the treatment of HER2-positive BCBM in real-world analysis and a single arm trial (49-51), although high-level evidence is insufficient. It is noted that the type and timing of systemic therapy can also impact outcomes. Studies have shown that the combination of ADC drugs with stereotactic radiotherapy (SRT, including SRS and FSRT) may increase the risk of RN. Trastuzumab emtansine (T-DM1), an ADC drug, was associated with a 13.5-fold increased risk of RN when combined with SRT (52). Another retrospective study showed that the cumulative RN rate was 7.1% in patients who received concurrent ADC, compared to 0.7% in patients who did not receive ADC. For lesions that had previously received radiotherapy, the 24-month risk of RN was significantly increased to 42.0% for combined ADC therapy compared to 9.4% for not receiving ADC therapy (53). Collectively, these findings suggest that careful consideration of radiotherapy timing relative to ADC administration is crucial for minimizing toxicity.

The pros and cons of the decision of radiotherapy for HER2-positive BCBM are listed in Table 2. Furthermore, we outline the general management for BCBM, focusing on the timing and type of treatment modalities (Figure 1). Briefly, whether active BM is symptomatic and requires immediate local treatment is the foremost factor when deciding on the timing of metastases-directed local approach. Meanwhile, targeted therapy is recommended regardless of existing extracranial disease or not, and the optimal regimen depends on evaluating prior response of treatment and systemic therapy options. If patient has asymptomatic or modest symptomatic presentation and can be alleviated by mannitol and steroids, the management of BM should involve a multidisciplinary approach to tailor treatment strategies for optimal outcomes and minimal toxicities.

Figure 1 Management algorithm for patients with HER2-positive breast cancer and newly diagnosed brain metastases. The algorithm is applicable for HER2-positive patients with newly diagnosed brain metastases who have not received prior local treatment. Green boxes indicate key decision points to be evaluated. Decisions regarding treatment should be made following discussion within a multidisciplinary team. The WBRT protocol is inclusive of WBRT with hippocampal sparing when applicable. BM, brain metastasis; HER2, human epidermal receptor 2; SRT, stereotactic radiotherapy; WBRT, whole brain radiotherapy.

This review has several limitations. First, the proposed management algorithm (Figure 1) is specific to HER2-positive BCBM. Due to the insufficient evidence for the efficacy of ADC for patients with HER2-low expression tumor, Figure 1 is not applicable to this tumor subtype. While we have reviewed radiotherapeutic strategies for all subtypes, the development of equally detailed, evidence-based algorithms for triple-negative and HR-positive HER2-negative BCBM remains a future challenge. The management of these subtypes currently relies more on local treatment, as outlined in the preceding sections. Future efforts should focus on generating high-quality evidence to enable the creation of subtype-specific algorithms for all major breast cancer biological subgroups.

Conclusions

Overall, radiation therapy for BCBM still faces several challenges, especially for patients with HER2-positive disease, whose unique biology and effective systemic agents make the decision regarding radiotherapy more complex and personalized. Optimizing the timing of radiotherapy, employing more advanced radiotherapy techniques, and developing effective treatment strategies are expected to improve therapeutic effect and reduce long-term side effects, pending validation in future well-designed studies. However, current treatment decision should involve discussions among a multidisciplinary team and patients, weighing the risks and benefits of each treatment modality to aim for prolonging survival while preserving quality of life.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-39/rc

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-39/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-39/coif). The authors have no conflicts of interest to declare.

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

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