Outcomes of CyberKnife Stereotactic Radiosurgery for the Brain Metastases in Patients with Li Fraumeni Syndrome

Outcomes of CyberKnife Stereotactic Radiosurgery for the Brain Metastases in Patients with Li Fraumeni Syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Outcomes of CyberKnife Stereotactic Radiosurgery for the Brain Metastases in Patients with Li Fraumeni Syndrome Muhammad Izhar, Yusuke S. Hori, Ahed H. Kattaa, Paul M. Harary, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9295398/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 mutations and an increased risk of radiation-induced malignancies, posing significant challenges in the management of brain metastases (BM). Data regarding the safety and efficacy of stereotactic radiosurgery (SRS) for BM in this population remain limited. Methods We performed a retrospective analysis of patients with LFS who underwent SRS for BM at our institution. Patient-level, lesion-level, and treatment-related data were collected. Outcomes assessed included local tumor control (LTC), overall survival (OS), distant progression-free survival (DPFS), radiographic response, and treatment-related adverse events. Results A total of 5 patients with 16 BM lesions were treated with SRS. The median age at treatment was 49 years (range, 37–65). Lesions were typically small (median diameter 6.1 mm) and predominantly supratentorial (87.5%). Most lesions (93.7%) were treated with single-fraction SRS with a median prescribed dose of 24 Gy. LTC was 100% at 3 months, 6 months, and at last follow-up. Median OS and DPFS were 11.03 months (95% CI, 9.53–12.54) and 7.5 months (95% CI, 7.3–7.7), with all deaths attributable to systemic disease rather than neurological progression. Importantly, no cases of radiation necrosis or radiation-induced secondary malignancies were observed during a median follow-up of 45 weeks. Conclusions SRS demonstrated excellent local control and a favorable safety profile for the treatment of BM in patients with LFS. Given the tendency for lesions to be small and multifocal, along with the need to minimize radiation exposure, SRS represents a rational, focal treatment approach in this high-risk population. However, longer follow-up and prospective studies are needed to better define long-term safety, particularly regarding the risk of radiation-induced malignancies. Li Fraumeni Syndrome CyberKnife Brain Metastases Radiosurgery Gamma Knife Figures Figure 1 Figure 2 Figure 3 1. INTRODUCTION Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer predisposition syndrome characterized by a high risk of developing a wide range of malignancies, often at an early age. Most tumors in LFS are represented by five core cancer types: adrenocortical carcinoma, breast cancer (BC), central nervous system (CNS) tumors, osteosarcoma, and soft-tissue sarcomas. In addition, individuals with LFS are susceptible to several other malignancies, including leukemia, colorectal, gastric, and lung cancers, melanoma, pediatric head and neck tumors, as well as pancreatic and prostate cancers. Cancer survivors within this population remain at substantial risk for developing multiple primary malignancies and therapy-related secondary cancers. The estimated lifetime cancer risk approaches approximately 90% in women and 70% in men, with nearly half of all cancers occurring before the age of 40 years ( 1 ). Approximately 60–80% of LFS cases are caused by germline mutations in the tumor suppressor gene TP53 , which regulates the cell cycle, DNA repair, and apoptosis ( 2 – 4 ). In contrast, LFS-like syndrome lacks detectable mutations within the coding regions of the gene ( 3 , 5 ). This discordance between TP53 mutation status and the classic LFS phenotype suggests underlying biological complexity, potentially due to post-translational alterations of p53, complete gene deletions, the influence of modifier genes, or compensatory alterations in related molecular pathways that modulate phenotypic expression ( 2 ). Given the high lifetime burden of malignancy in LFS patients, many individuals develop aggressive extracranial cancers with metastatic potential. Consequently, the occurrence of brain metastases (BM) represents a clinically significant challenge in this population, particularly as improvements in systemic therapies continue to prolong survival. Despite this, there are currently no established treatment guidelines for the management of BM in LFS patients, and this clinical scenario remains largely unaddressed in the existing literature. To our knowledge, this study represents the first investigation specifically evaluating the safety and efficacy of stereotactic radiosurgery (SRS) for the treatment of BM in LFS patients. SRS for BM from primary cancers is associated with high rates of local tumor control (LTC) ( 6 – 16 ). 2. METHODS Participants This retrospective study, approved by the Institutional Review Board of Stanford University Medical Center (protocol no. 3910), reviews all LFS patients with BM who underwent SRS at our institution. Electronic medical records were retrospectively screened to identify patients and collect their demographic, clinical, and radiological data. The inclusion criteria consisted of patients diagnosed with LFS who later developed BM and received SRS at Stanford Medical Center between 1998 and 2025. Patients were excluded if they lacked follow-up brain imaging or had incomplete clinical data. Target Delineation and Planning SRS was delivered using the CyberKnife robotic radiosurgery system (Accuray Inc., Sunnyvale, California, USA). Treatment planning involved high-resolution, contrast-enhanced magnetic resonance imaging (MRI) or computed tomography (CT) scans with thin slices through the region of interest. Following informed consent, patients underwent Aquaplast mask fabrication and acquisition of thin-section CT and contrast-enhanced T1-weighted MRI. These stereotactic scans were reviewed for completeness and adequacy for image fusion using the Precision system (Accuray Inc., Sunnyvale, CA, USA). They were then fused using the CK multi-plan treatment planning workstation for further analysis and planning. Target delineation was performed with gross tumor volumes defined based on contrast-enhancing lesions. Treatment plans were iteratively developed for each lesion, with dose prescription and delivery guided by previously established protocols ( 17 , 18 ). Follow-Up and Assessment Patients were closely monitored following treatment, with scheduled follow-up visits every three months or sooner if new symptoms emerged. Radiographic assessments, including contrast-enhanced MRI, were performed every 3 months for the first 2 years and then every 6 months to evaluate treatment response and detect disease progression. Tumor response to CK SRS was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines ( 19 ). According to RECIST guidelines, LTC was defined as complete response (CR), partial response (PR), or stable disease (SD), while progressive disease (PD) indicated local failure. Overall survival (OS) was defined as the time from the start of treatment to death from any cause or the last follow-up clinic date. Distant progression-free survival (DPFS) was defined as the time from the treatment to the development of a new lesion outside the previously irradiated field or the last follow-up. Statistical Analysis Statistical analysis was performed using SPSS version 29 (IBM SPSS version 29.0, Chicago, IL). Descriptive statistics were used to summarize the demographic characteristics of the study population and treatment outcomes. Continuous variables were summarized as medians and ranges. Categorical variables were reported as frequencies and associated percentages. Survival outcomes were assessed using Kaplan-Meier analysis. OS and DPFS durations were reported with a 95% confidence interval (CI). 3. RESULTS Among 800 patients screened, 152 were identified as having LFS. During their lifetime, 104 of these 152 LFS patients (68%) developed non-CNS primary cancers. 13 LFS patients with non-CNS primary cancers developed BM (12.5%). A total of five patients with 16 BM lesions were treated with CK SRS (Fig. 1 ). The cohort was predominantly female (80%), with a median age of 49 years (range, 37–65) at the time of BM treatment. Most patients had a pre-treatment ECOG performance status of 1 (60%), while the remainder had ECOG scores of 2 or 3. All patients harbored germline TP53 mutations and had no history of primary CNS malignancy. One patient (20%) had a benign CNS tumor (pituitary adenoma). The median number of primary non-CNS malignancies was 3 (range, 2–5). At the time of BM diagnosis, the primary disease was uncontrolled in most patients (80%), and extracranial metastases were present in 80% of cases (Table 1 ). Table 1 Patient-level baseline characteristics and prior treatment history Factor Number (%) or Median (range) Total number of patients 5 No. of lesions per patient 2 ( 1 – 7 ) Sex Female 4 (80%) Male 1 (20%) Age at BM treatment (years) 49 (37–65) Pre-treatment ECOG score 1 3 (60%) 2 1 (20%) 3 1 (20%) No. of primary non-CNS cancer 3 ( 2 – 5 ) Primary CNS Cancer No 5 (100%) Yes 0 (0%) Other benign CNS tumors No 4 (80%) Yes a 1 (20%) Primary disease controlled No 4 (80%) Yes 1 (20%) Extracranial metastasis No 1 (20%) Yes 4 (80%) Prior surgery for non-index lesion No 5 (100%) Yes 0 (0%) Prior systemic therapy No 0 (0%) Yes 5 (100%) Prior WBRT No 5 (100%) Yes 0 (0%) BM: Brain metastases, WBRT: Whole-brain radiotherapy, CNS = Central Nervous System, a = one patient had Pituitary adenoma, LFS = Li Fraumeni Syndrome, NSCL = Non-Small Cell Lung Cancer, The median number of lesions per patient was 2 (range, 1–7), with a median cumulative tumor volume per lesion of 26.9 cm³ (range, 4.66–43.9). At the time of treatment, lesions were generally small, with a median maximum diameter of 6.1 mm (range, 3.2–29.5). Most lesions were located in the supratentorial compartment (87.5%), with fewer infratentorial lesions (12.5%) and no involvement of the brainstem. Lesions were more frequently located in the right hemisphere (62.5%) compared to the left (37.5%). With respect to treatment parameters, the median individual lesion volume was 0.12 cm³ (range, 0.02–18.9). The median prescribed dose was 24 Gy (range, 20–27 Gy), with a median maximum dose of 33.6 Gy (range, 29.3–35.3), delivered at a median isodose line of 72% (range, 68–82%). Most lesions (93.7%) were treated with single-fraction SRS, while a small proportion (6.3%) received two fractions, and no lesions were treated with three fractions (Table 2 ). Table 2 Lesion-Level Characteristics and Radiosurgical Treatment Parameters Characteristic Number (%) or Median (range) Total number of lesions 16 Total volume of lesions (cm 3 ) 26.9 (4.66–43.9) Maximum diameter (mm) 6.1 (3.2–29.5) Laterality Left 6 (37.5%) Right 10 (62.5%) Location Supratentorial 14 (87.5%) Infratentorial 2 (12.5%) Brainstem 0 (0%) SRS treatment parameters Lesion volume (cm 3 ) 0.12 (0.02–18.9) Prescribed dose (Gy) 24 ( 20 – 27 ) Maximum dose (Gy) 33.6 (29.3–35.3) Isodose line (%) 72 (68–82) Number of fractions Single 15 (93.7%) Three 1 (6.3%) SRS = stereotactic radiosurgery, wks = weeks The cohort demonstrated marked heterogeneity in histology and molecular profiles of primary tumors metastatic to the brain, reflecting the diverse oncologic spectrum associated with LFS. Histologies of primary tumors include non–small cell lung cancer (NSCLC) (20%), pleomorphic sarcoma (20%), gastric adenocarcinoma (20%), leiomyosarcoma (20%), and one unknown primary (20%). Tumors were predominantly of moderate to poor differentiation, consistent with aggressive biological behavior. All evaluable cases harbored pathogenic TP53 alterations, including missense mutations (p.Arg174Trp, p.G245S, p.Arg282Trp) and a frameshift variant (p.R306fs). In addition to TP53 alterations, multiple co-occurring genomic aberrations of clinical significance were identified, suggesting complex oncogenic signaling networks (Table 3 ) . The NSCLC case demonstrated actionable EGFR alterations, including an exon 19 deletion and a p.T790M mutation, which are potential targets for tyrosine kinase inhibitors. The gastric adenocarcinoma case exhibited extensive genomic amplification, including ERBB2 (HER2), CCNE1 , and EGFR , along with PIK3CA mutation and biallelic loss of CDKN2A and MTAP , reflecting a highly proliferative and genomically unstable phenotype. Similarly, the pleomorphic sarcoma case demonstrated amplification of cell-cycle and growth-regulatory genes ( CCND3, YAP1, TFEB ) alongside biallelic deletion of CDKN2A/B , further underscoring dysregulation of cell-cycle control. The leiomyosarcoma case also exhibited CCNE1 amplification. Table 3 Histologies and Molecular Alterations of Primary Cancer Metastatic to the Brain Primary Tumor Histology Grading TP53 variants Genomic alterations of Clinical Significance Method of BM diagnosis Unknown NR NR NR NA NSCLC Moderately differentiated c.520A > T (p.Arg174Trp) EGFR E746_A750del, EGFR T790M (also positive on FISH for CSF) Biopsy after surgical resection Pleomorphic sarcoma Undifferentiated c.909_ 916dupCACTAAGC (p.R306fs) CCND3 amplification, TFEB amplification, biallelic deletion in CDKN2A and CDKN2B, amplification of YAP 1 Biopsy after surgical resection Gastric adenocarcinoma Poorly differentiated c.733G.A (p.G245S) ERBB2 (HER2) Amplification, CCNE1 Amplification, CDKN2A Biallelic Loss (Homozygous Deletion), EGFR Amplification, ESR1 Amplification, MTAP Biallelic Loss (Homozygous Deletion), PIK3CA (H1047R) Biopsy after surgical resection Leiomyosarcoma Grade II c.844C > T (p.Arg282Trp) CCNE1 amplifications Biopsy after surgical resection BM = Brain Metastases, CSF = Cerebrospinal fluid The median maximum lesion diameter decreased over time, measuring 4.31 mm (range, 0–25.7) at 3 months, and reaching 0 mm at both 6-month follow-up (range, 0–27) and last follow-up (range, 0–29), reflecting substantial radiographic response. At 3 months, most lesions demonstrated either PR (43.7%) or SD (37.5%), with a CR observed in 18.7% of lesions and no cases of progressive disease. By 6 months, CR rates increased to 43.75%, with PR and SD each observed in 18.75% of lesions. At the last follow-up, CR was achieved in 56.3% of lesions, with the remainder demonstrating PR (18.6%) or SD (25.1%). Notably, no lesions exhibited radiographic progression at any time point (Table 4 ). Table 4 Post-treatment Response Summary Factor Number (%) or Median (Range) Lesion maximum diameter (mm) 3-month follow-up 4.31 (0–25.7) 6-month follow-up 0 (0–27) Last follow-up 0 (0–29) Radiological response at 3 months Complete response 3 (18.7%) Partial response 7 (43.7%) Stable disease 6 (37.5%) Progressive disease 0 (0%) Radiological response at 6 months Complete response 7 (53.84%) Partial response 3 (23.08%) Stable disease 3 (23.08%) Progressive disease 0 (0%) Radiological response at last follow-up Complete response 9 (56.3%) Partial response 3 (18.6%) Stable disease 4 (25.1%) Progressive disease 0 (0%) No local progression was observed among the 16 treated lesions, corresponding to a 100% LTC rate at 3 months, 6 months, and the last follow-up. All individuals were deceased at the time of analysis, with deaths attributed exclusively to systemic disease rather than neurological causes. The median follow-up duration was 45 weeks (range, 33.4–503), and the median OS was 11.03 months (95% CI, 9.53–12.54). The OS rates were 100% at 3 and 6 months, decreasing to 40% at 12 months (Fig. 2 ). The median DPFS was 7.5 months (95% CI = 7.3–7.7), with DPFS rates of 80% at 3 and 6 months and 20% at 12 months (Fig. 3 ). Importantly, no adverse radiation-related outcomes were observed, including radiation necrosis or radiation-induced secondary malignancies (Table 5 ). Table 5 Summary of Patient- and Lesion-Level Outcomes Factor Number (%) or Median (Range) Local progression No 16 (100%) Yes 0 (0%) Final survival status Alive 0 (0%) Deceased 5 (100%) Cause of death Neurological 0 (0%) Systemic 5 (100%) Follow up duration (wks) 45 (33.4–503) Median overall survival (months) (95% CI) 11.03 (9.53–12.54) Overall survival rate # 3 months 100% 6 months 100% 12 months 40% Median DPFS (months) (95% CI) 7.5 (7.3–7.7) DPFS rate # 3 months 80% 6 months 80% 12 months 20% Local tumor control rate* 3 months 100% 6 months 100% Last follow up 100% Adverse outcomes Radiation necrosis* 0 (0%) Radiation-Induced Cancer# 0 (0%) * = Lesion-based, # = Patient-based, CI = confidence Interval, 4. DISCUSSION 4.1 Incidence of BM in LFS The prevalence of BM in LFS patients is not well-reported. However, TP53 perturbation and p53 pathway downregulation are strongly associated with BM across multiple carcinomas ( 20 ). For instance, Grote et al. ( 21 ) investigated the prevalence of AKT1, ERBB2, ESR1, PIK3CA, and TP53 mutations in 521 BC metastases of the four major metastatic sites, including bone, brain, liver, and lung, via next-generation sequencing and pyrosequencing. They found TP53 in 51% of BCBM. Across molecular subtypes of NSCLC, Laue et al. ( 20 ) reported that TP53 alterations were significantly more frequent in BM than in extracranial metastatic sites. Bubb et al. ( 22 ) reported that 66% of BM samples had highly expressed TP53. Similarly, Lasota et al. ( 23 ) reported that TP53 mutations were identified in 69% of colorectal cancer BM. Moreover, in an in vivo study, Laue et al. ( 20 ) also demonstrated that TP53 knockdown in TP53-wild-type (WT) EMT6 murine BC cell lines, generating TP53-null EMT6 cells, selectively enhanced the development of BM compared to their TP53-WT counterparts. Furthermore, TP53-null cells produced larger tumors with many metastatic lesions in the brain relative to other organs ( 20 ). Despite the established role of TP53 alterations in metastatic progression, it remains poorly defined whether germline TP53 mutations in LFS predispose to an increased incidence of BM or confer a distinct organotrophic bias toward the brain. However, in our study, we reported that 12.5% of the LFS patients with primary cancers develop BM in the disease course. Future investigations with larger, multicenter cohorts and integrated molecular profiling are warranted to determine whether germline TP53 status independently influences the frequency, timing, and organ-specific dissemination of metastatic disease. 4.2 TP53 role in Radioresistance Preclinical evidence suggests that expression of mutant TP53 may be associated with increased resistance to chemotherapy and radiation across multiple tumor types ( 24 ); however, robust clinical evidence supporting this association remains limited and inconsistent. In contrast, our findings demonstrated excellent response to SRS, with a 100% LTC rate at last follow-up, suggesting that high-dose, focal radiation may overcome potential mechanisms of radioresistance in this setting. 4.3 Diagnosis of BM in LFS The clinical diagnosis of BM differs significantly between patients without LFS and those with LFS. In non-LFS patients, BM are typically suspected in the context of a known primary malignancy, most commonly lung, breast, or melanoma, and are often diagnosed following the onset of neurological symptoms such as headaches, seizures, or focal deficits, prompting neuroimaging. In contrast, patients with LFS frequently develop multiple primary malignancies over their lifetime and are commonly followed up in structured surveillance programs, including periodic whole-body and brain MRI. As a result, BM in LFS patients are more likely to be detected incidentally at an earlier, often asymptomatic stage, and may arise in the setting of multiple synchronous or metachronous primary cancers. This distinction has important clinical implications, as early detection in LFS may contribute to smaller lesion size at diagnosis and broaden the feasibility of focal treatment strategies such as SRS. However, in patients with multiple primary malignancies, the exact histological origin of BM cannot always be definitively determined. In our cohort, one patient with BM in the setting of multiple primary cancers underwent SRS without histopathological confirmation of the lesion origin, whereas the remaining four patients had surgical resection with biopsy-based determination of histology (Table 3 ). In such scenarios, minimally invasive approaches, such as cerebrospinal fluid (CSF)-based liquid biopsy, may serve as valuable diagnostic tools ( 25 – 27 ). Notably, in our cohort, CSF analysis in one patient identified EGFR mutations concordant with tissue biopsy findings, supporting the potential utility of liquid biopsy in guiding diagnosis and management. 4.4 Current Literature on BM in LFS patients Despite the well-established cancer predisposition associated with LFS, the literature on the management of BM in this population remains strikingly deficient. To our knowledge, existing evidence is limited to a single case report, Sumou et al. ( 28 ), reporting a 23-year-old female with LFS who was diagnosed with bilateral triple-positive BC. She underwent multimodal treatment consisting of systemic chemotherapy, HER2-targeted therapy, total mastectomy, and locoregional radiotherapy. Four years later, she developed a BM in the left parieto-occipital region, which was treated with surgical resection and RT (40 Gy in 10 fractions). Despite subsequent treatment with capecitabine, lapatinib, a gonadotropin-releasing hormone (GnRH) agonist, and tamoxifen, disease progression occurred with the development of multiple new intracranial lesions after 14 months. A second-line regimen comprising capecitabine, neratinib, a GnRH agonist, and letrozole was initiated; however, further progression of brain metastases was observed after 7 months. Six years later, therapy with Fam-trastuzumab deruxtecan (T-DXd) was initiated, resulting in a favorable response at 4 months, characterized by a sustained decline in cancer antigen 15 − 3 levels, reduction in the size of the dominant brain lesion, and no evidence of new intracranial metastases. At the age of 30, the patient remains on T-DXd therapy with continued disease control. Similarly, Leng et al. ( 29 ) evaluated 225 non-LFS patients with NSCLC BM treated with SRS. On subgroup analysis, LTC rates were numerically higher in patients harboring pathogenic TP53 variants compared to those with TP53 wild-type tumors; however, this difference did not reach statistical significance. In contrast, our cohort demonstrated a 100% LTC rate following SRS for BM in LFS patients, suggesting a potentially enhanced radiosensitivity in this population. The high LTC rates observed in our LFS cohort may be attributable to several factors. First, BM in this population is often detected at a small size, as a result of intensive surveillance protocols following an LFS diagnosis, which facilitate early identification of intracranial disease. Second, the concurrent or sequential use of active systemic therapies may have contributed to improved intracranial disease control, potentially augmenting the therapeutic effect of SRS. 4.5 Safety of SRS in BM Radiation therapy (RT) in patients with LFS is generally approached with caution due to the potential risk of treatment-related secondary malignancies ( 30 ). Prior studies have reported the development of radiation-induced tumors and hematologic malignancies in this population ( 31 ). However, some evidence suggests that not all post-radiation malignancies represent de novo secondary cancers; for instance, a small series demonstrated that, among individuals with LFS who developed malignancies within prior radiation fields, a proportion were attributable to local tumor recurrence rather than new primary tumors ( 32 ). At our institution, one patient with LFS (unpublished data) was treated with surgical resection (SR) and adjuvant RT for an IDH-mutant anaplastic astrocytoma and later developed a recurrence within the irradiated field at the resection cavity. Interestingly, histopathological and molecular evaluation of the recurrent lesion demonstrated a glioma with an NTRK fusion and IDH wild-type status, indicating a potential shift in tumor biology and raising concern for either clonal evolution or a radiation-associated secondary neoplasm. In another patient with LFS (unpublished data), treatment with SR and adjuvant RT for an IDH-mutant anaplastic astrocytoma was followed by the development of a skull-based osteosarcoma, consistent with a likely radiation-associated secondary malignancy in this genetically susceptible population. Consequently, while radiation exposure should be minimized when feasible, it should not be categorically withheld when clinically indicated. Instead, treatment decisions should be guided by a careful risk-benefit assessment, with priority given to oncologic control. In such cases, close longitudinal surveillance is recommended to monitor for the development of secondary malignancies within irradiated fields ( 1 ). Given the heightened susceptibility to radiation-induced malignancies in patients with LFS, a highly conformal, focal radiation to intracranial lesions with a steep dose fall-off delivered by SRS could potentially minimize radiation exposure to surrounding normal brain tissue compared to conventional RT ( 33 – 35 ). In addition, SRS is typically administered in a single or a limited number of fractions, resulting in limited radiation exposure. However, further studies are needed to establish whether SRS provides a clinically significant reduction in the risk of radiation-induced CNS malignancies ( 36 ). Moreover, it is important to acknowledge that SRS planning typically involves CT-based imaging, which introduces additional radiation exposure. Nevertheless, the dose associated with diagnostic or planning CT is substantially lower than that delivered during therapeutic radiation. Future efforts should focus on optimizing and standardizing imaging protocols, particularly in patients with multiple lesions who may require repeated imaging, in order to minimize cumulative radiation exposure while maintaining accurate treatment planning. In our cohort of 16 lesions treated with CyberKnife SRS, predominantly delivered in a single fraction, no secondary intracranial malignancies were observed. However, the median follow-up duration was limited, and longer-term surveillance is necessary to adequately assess the risk of radiation-induced tumors in LFS patients with BM. 4.6 Safety of Systemic Therapy Similarly, the use of conventional cytotoxic chemotherapy may confer an increased risk of secondary cancers in LFS ( 30 ); however, most experts advocate prioritizing treatment efficacy over potential long-term adverse effects, particularly in the setting of aggressive or life-threatening disease ( 1 ). However, the role of cytotoxic chemotherapy in BM is very limited. Therefore, targeted therapies and immunotherapies may represent attractive alternatives. For example, the presence of a BRAF V600E mutation could render a patient eligible for BRAF inhibitor therapy, tumors exhibiting hypermutation may be responsive to immune checkpoint blockade, and NF1 mutations could identify candidates for MEK inhibitor treatment ( 37 ). Similarly, EGFR alterations identified in our cohort represent clinically actionable targets, supporting the potential role of tyrosine kinase inhibitors (TKIs) in the management of these patients. Also as given above, Sumou et al. ( 28 ) reported a 23-year-old female with LFS, treated for bilateral triple-positive BC BM with T-DXd therapy, and the lesions responded well. These precision-based approaches offer the potential for effective tumor control while minimizing exposure to DNA-damaging agents, which is particularly relevant in this genetically susceptible population. 4.7 Role of Surgical Resection Surgical resection remains a standard treatment modality for BM, particularly for patients with large or symptomatic lesions causing significant mass effect, as it provides rapid decompression and histopathological diagnosis ( 38 , 39 ). However, its role becomes increasingly limited in the setting of multiple and small BM, where surgical intervention is often impractical or infeasible due to the need for multiple craniotomies and associated morbidity ( 38 , 39 ). In patients with LFS, BM are typically multiple and small due to early detection through surveillance. Therefore, surgical resection may be appropriate for larger or symptomatic lesions. 4.8 Limitations and Future Directions This study has several limitations that warrant consideration. First, its retrospective design, relatively small sample size, and limited follow-up duration restrict the generalizability of our findings and preclude definitive conclusions regarding long-term outcomes. In particular, the short follow-up limits the ability to assess late adverse effects, including the risk of radiation-induced secondary malignancies in this genetically susceptible population. Future studies should focus on prospective, multicenter collaborations to better define the prevalence of BM in patients with LFS and to establish standardized neuro-oncological management guidelines. Additionally, subgroup analyses based on primary tumor histology and underlying molecular profiles, including specific TP53 alterations and co-mutations, are needed to understand differential treatment responses better and optimize patient selection for SRS. Finally, extended longitudinal follow-up will be essential to evaluate the long-term safety of SRS, particularly with respect to the incidence of radiation-induced secondary neoplasms, and to further clarify its role as a potentially safer, focal therapeutic approach in this high-risk population. 5. Conclusion In this study, SRS demonstrated excellent LTC and a favorable safety profile for the management of BM in patients with LFS. In our cohort, all treated lesions achieved durable local control without evidence of radiation necrosis or secondary malignancies during the follow-up period. Given the tendency for BM in LFS to be multiple and small, often detected early through intensive surveillance, SRS represents a particularly suitable and minimally invasive therapeutic option. However, the risk of radiation exposure should not be underestimated. Nevertheless, given the limited sample size and follow-up, further prospective, multicenter studies with longer surveillance are warranted to validate these findings, better define long-term risks, and establish evidence-based guidelines for the optimal management of brain metastases in patients with Li-Fraumeni syndrome Declarations Ethical approval and consent to participate: This study was conducted with prior approval from the Stanford University Institutional Review Board (no. 3910) panel on Medical Human Subjects. AI tools: During the preparation of this manuscript, the author(s) used Grammarly AI to improve the grammar and readability of the manuscript. No AI-generated idea has been used in this manuscript. The authors have reviewed and edited the output and take full responsibility for the content of this publication. Competing Interests: The authors have no relevant financial or non-financial interests to disclose. Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Availability of supporting data: The data supporting the findings of this study are available from the corresponding author upon reasonable request. Author Contribution M.I. contributed to conceptualization, study design, and Methodology, performed data collection and formal analysis, and drafted the manuscript. A.K. contributed to the study design and Methodology and drafted the manuscript. 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Stereotact Funct Neurosurg 61(1):45–50. 10.1159/000100659 Williams J, Enger C, Wharam M, Tsai D, Brem H (1998) Stereotactic radiosurgery for brain metastases: Comparison of lung carcinoma vs. non-lung tumors. J Neurooncol 37(1):79–85. 10.1023/A:1005958215384 Kattaa AH, Persad AR, Hori YS, Harary PM, Izhar M, Ustrzynski L et al (2026) Peripheral neural crest tumor brain metastases management: a single-institution retrospective study. J Neurooncol 176(1):65. 10.1007/s11060-025-05247-y Izhar M, Kattaa AH, Hori YS, Lam FC, Tayag A, Ustrzynski L et al (2025) Hepatoblastoma brain metastasis treated with stereotactic radiosurgery: Illustrative case and literature search. Surg Neurol Int 16:526. 10.25259/SNI_806_2025 Kattaa AH, Hori YS, Harary PM, Akhavan-Sigari A, Zamarud A, Persad AR et al (2025) Adenoid cystic carcinoma brain metastases treated with stereotactic radiosurgery: A single institution retrospective cohort study and comprehensive literature review. Neurosurg Rev 48(1):618. 10.1007/s10143-025-03761-1 Izhar M, Kattaa AH, Hori YS, Lam FC, Kalra N, Zagzoog N et al (2026) Treatment outcomes of stereotactic radiosurgery for sarcoma brain metastases—systematic review. J Neurooncol 177(2):70. 10.1007/s11060-026-05542-2 Ding C, Saw CB, Timmerman RD (2018) Cyberknife stereotactic radiosurgery and radiation therapy treatment planning system. Plan Syst 43(2):129–140. 10.1016/j.meddos.2018.02.006 . Spec Issue 3D Treat Loo M, Pin Y, Thierry A, Clavier JB (2020) Single-fraction radiosurgery versus fractionated stereotactic radiotherapy in patients with brain metastases: a comparative study. Clin Exp Metastasis 37(3):425–434. 10.1007/s10585-020-10031-5 Schwartz LH, Litière S, De Vries E, Ford R, Gwyther S, Mandrekar S et al (2016) RECIST 1.1—Update and clarification: From the RECIST committee. Eur J Cancer 62:132–137. 10.1016/j.ejca.2016.03.081 Laue K, Pozzi S, Zerbib J, Bertolio R, Eliezer Y, Cohen-Sharir Y et al (2026) p53 inactivation drives breast cancer metastasis to the brain through SCD1 upregulation and increased fatty acid metabolism. Nat Genet 58(1):116–131. 10.1038/s41588-025-02446-1 Grote I, Poppe A, Lehmann U, Christgen M, Kreipe H, Bartels S (2024) Frequency of genetic alterations differs in advanced breast cancer between metastatic sites. Genes Chromosomes Cancer 63(1):e23199. 10.1002/gcc.23199 Bubb RS, Komaki R, Hachiya T, Milas I, Ro JY, Langford L et al (2002) Association of Ki-67, p53, and bcl-2 expression of the primary non-small-cell lung cancer lesion with brain metastatic lesion. Int J Radiat Oncol 53(5):1216–1224. 10.1016/S0360-3016(02)02861-4 Lasota J, Kaczorowski M, Chłopek M, Miłek-Krupa J, Szczepaniak M, Ylaya K et al (2025) An immunohistochemical and molecular genetic study of 60 colorectal carcinoma brain metastases in pursuit of predictive biomarkers for cancer therapy. Hum Pathol 155:105717. 10.1016/j.humpath.2025.105717 Chen X, Zhang T, Su W, Dou Z, Zhao D, Jin X et al (2022) Mutant p53 in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis 13(11):974. 10.1038/s41419-022-05408-1 Izhar M, Thakur A, Park DJ, Chang SD (2024) Ultrasound mediated blood-brain barrier opening increases brain tumor biomarkers: A review of preclinical and clinical trials. J Liq Biopsy 6:100277. 10.1016/j.jlb.2024.100277 Izhar M, Ahmad Z, Moazzam M, Jader A (2024) Targeted liquid biopsy for brain tumors. J Liq Biopsy 6:100170. 10.1016/j.jlb.2024.100170 Izhar M, Lesniak MS (2025) Role of Extracellular Vesicles in the Pathogenesis of Brain Metastasis. J Extracell Biol 4(5):e70051. 10.1002/jex2.70051 Sumou IK, Hui CV (2024) Case report: Efficacy of later-line fam-trastuzumab deruxtecan in a patient with triple-positive breast cancer with brain metastases. Front Oncol 14:1470560. 10.3389/fonc.2024.1470560 Leng JX, Su C, Carpenter DJ, Floyd W, Vaios E, Shenker R et al (2024) Impact of TP53 mutations on brain metastasis control in non-small cell lung cancer patients undergoing stereotactic radiosurgery. J Radiosurgery SBRT 9(2):91–99 PubMed PMID: 39087065; PubMed Central PMCID: PMC11288656 Kumamoto T, Yamazaki F, Nakano Y, Tamura C, Tashiro S, Hattori H et al (2021) Medical guidelines for Li–Fraumeni syndrome 2019, version 1.1. Int J Clin Oncol 26(12):2161–2178. 10.1007/s10147-021-02011-w Swaminathan M, Bannon SA, Routbort M, Naqvi K, Kadia TM, Takahashi K et al (2019) Hematologic malignancies and Li–Fraumeni syndrome. Mol Case Stud 5(1):a003210. 10.1101/mcs.a003210 Hendrickson PG, Luo Y, Kohlmann W, Schiffman J, Maese L, Bishop AJ et al (2020) Radiation therapy and secondary malignancy in Li-Fraumeni syndrome: A hereditary cancer registry study. Cancer Med 9(21):7954–7963. 10.1002/cam4.3427 Patchell RA (2003) The management of brain metastases. Cancer Treat Rev 29(6):533–540. 10.1016/S0305-7372(03)00105-1 Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC (1999) Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol 45(2):427–434. 10.1016/S0360-3016(99)00198-4 Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K et al (2006) Stereotactic Radiosurgery Plus Whole-Brain Radiation Therapy vs Stereotactic Radiosurgery Alone for Treatment of Brain Metastases: A Randomized Controlled Trial. JAMA 295(21):2483. 10.1001/jama.295.21.2483 Thariat J, Chevalier F, Orbach D, Ollivier L, Marcy PY, Corradini N et al (2021) Avoidance or adaptation of radiotherapy in patients with cancer with Li-Fraumeni and heritable TP53-related cancer syndromes. Lancet Oncol 22(12):e562–e574. 10.1016/S1470-2045(21)00425-3 Light N, Layeghifard M, Attery A, Subasri V, Zatzman M, Anderson ND et al (2023) Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis. Nat Commun 14(1):77. 10.1038/s41467-022-35727-y Gupta S, Dawood H, Giantini Larsen A, Fandino L, Knelson EH, Smith TR et al (2021) Surgical and Peri-Operative Considerations for Brain Metastases. Front Oncol 11:662943. 10.3389/fonc.2021.662943 Ene CI, Ferguson SD (2022) Surgical Management of Brain Metastasis: Challenges and Nuances. Front Oncol 12:847110. 10.3389/fonc.2022.847110 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 21 Apr, 2026 Reviews received at journal 16 Apr, 2026 Reviewers agreed at journal 09 Apr, 2026 Reviews received at journal 08 Apr, 2026 Reviewers agreed at journal 06 Apr, 2026 Reviewers agreed at journal 06 Apr, 2026 Reviewers agreed at journal 05 Apr, 2026 Reviewers agreed at journal 05 Apr, 2026 Reviewers invited by journal 02 Apr, 2026 Editor assigned by journal 02 Apr, 2026 Submission checks completed at journal 02 Apr, 2026 First submitted to journal 01 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9295398","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":619204591,"identity":"a5dbc780-5053-4b8a-99af-a09f9d9a335c","order_by":0,"name":"Muhammad Izhar","email":"","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"","lastName":"Izhar","suffix":""},{"id":619204594,"identity":"a8004665-02fb-4d78-bb7c-cb4a0c8931fd","order_by":1,"name":"Yusuke S. Hori","email":"","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"S.","lastName":"Hori","suffix":""},{"id":619204595,"identity":"7315a7c0-9d5d-4202-a7b3-6fee6cf7b215","order_by":2,"name":"Ahed H. Kattaa","email":"","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ahed","middleName":"H.","lastName":"Kattaa","suffix":""},{"id":619204596,"identity":"f4b95094-f2cb-43bc-a433-2654ccd86cfd","order_by":3,"name":"Paul M. Harary","email":"","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Paul","middleName":"M.","lastName":"Harary","suffix":""},{"id":619204597,"identity":"f6cbb4b6-f9ac-42e3-80bc-a960faf5b7e5","order_by":4,"name":"Fred C. Lam","email":"","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Fred","middleName":"C.","lastName":"Lam","suffix":""},{"id":619204598,"identity":"ababf7c0-59ea-4916-ace4-457dc0764afa","order_by":5,"name":"Neeraj Kalra","email":"","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Neeraj","middleName":"","lastName":"Kalra","suffix":""},{"id":619204599,"identity":"e56b637d-8f0a-402c-b2d5-3dce04f6e2cd","order_by":6,"name":"Nirmeen Zagzoog","email":"","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Nirmeen","middleName":"","lastName":"Zagzoog","suffix":""},{"id":619204600,"identity":"5369409e-8149-4419-9c2f-c5a821b9fc41","order_by":7,"name":"Armine Tayag","email":"","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Armine","middleName":"","lastName":"Tayag","suffix":""},{"id":619204601,"identity":"4fb4ae27-a4f6-4d2c-8f50-edb073940a13","order_by":8,"name":"Louisa Ustrzynski","email":"","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Louisa","middleName":"","lastName":"Ustrzynski","suffix":""},{"id":619204602,"identity":"162691bf-cf55-44bb-9157-b829647a45cf","order_by":9,"name":"Sara C. Emrich","email":"","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"C.","lastName":"Emrich","suffix":""},{"id":619204603,"identity":"cc9f8e46-d11a-48bc-a0c3-3af8340a91ed","order_by":10,"name":"David J. Park","email":"","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"J.","lastName":"Park","suffix":""},{"id":619204604,"identity":"068a04db-2279-4707-b9bc-cd2bd156a4f3","order_by":11,"name":"Steven D. Chang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYFCCBDYQKQdmVzAwMDYwMBgQpcWYAUSdIUVLYgPRWuTbk589+LmjNn3+/OZnDw5U3JNtYG/eJoFPi8GZZ+aGvWeO5244xmZucOBMsXEDz7Ey/FokctgkeNuO5W5gYzCT/tiWkNggkWOGV4v8jBw2yb9tx9Ll29i/SRwEaZF/g18Lw40cNmnetpoEhmM8ZhAtEjz4tQD9YiYt23bAcMOxnDKJA2cSjNt40oot8DoMGGKSb9vq5OWbj2+TOFCRINvPfnjjDbwOg4DDCCYbEcpBoI5IdaNgFIyCUTAiAQBDCkwgDHfjJQAAAABJRU5ErkJggg==","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Steven","middleName":"D.","lastName":"Chang","suffix":""}],"badges":[],"createdAt":"2026-04-01 19:08:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9295398/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9295398/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106536328,"identity":"e8ffdf51-e709-4b28-9f87-3baa4652f8c2","added_by":"auto","created_at":"2026-04-09 15:12:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":37081,"visible":true,"origin":"","legend":"\u003cp\u003ePatient screening and treatment flow diagram.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9295398/v1/f56ffc6ac75d0f0bde56e3a0.png"},{"id":106536301,"identity":"216f3802-4e74-4933-a0e2-e762a21cfea6","added_by":"auto","created_at":"2026-04-09 15:11:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":45583,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curve for overall survival following SRS in patients with Li-Fraumeni syndrome and brain metastases.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9295398/v1/02138c56782b6419d2524716.png"},{"id":106536294,"identity":"837c8272-391a-4dde-83bc-c1a25b6d72c0","added_by":"auto","created_at":"2026-04-09 15:11:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":53393,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curve for distant progression-free survival following SRS in patients with Li-Fraumeni syndrome and brain metastases.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9295398/v1/0b69f9efb51767f5bbaf3ca9.png"},{"id":106536416,"identity":"4bd1de7f-6824-4c2b-b3e4-74e099716ed9","added_by":"auto","created_at":"2026-04-09 15:12:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1047300,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9295398/v1/929ea7b6-b52b-4236-8247-7e58849a6d99.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Outcomes of CyberKnife Stereotactic Radiosurgery for the Brain Metastases in Patients with Li Fraumeni Syndrome","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eLi-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer predisposition syndrome characterized by a high risk of developing a wide range of malignancies, often at an early age. Most tumors in LFS are represented by five core cancer types: adrenocortical carcinoma, breast cancer (BC), central nervous system (CNS) tumors, osteosarcoma, and soft-tissue sarcomas. In addition, individuals with LFS are susceptible to several other malignancies, including leukemia, colorectal, gastric, and lung cancers, melanoma, pediatric head and neck tumors, as well as pancreatic and prostate cancers. Cancer survivors within this population remain at substantial risk for developing multiple primary malignancies and therapy-related secondary cancers. The estimated lifetime cancer risk approaches approximately 90% in women and 70% in men, with nearly half of all cancers occurring before the age of 40 years (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eApproximately 60\u0026ndash;80% of LFS cases are caused by germline mutations in the tumor suppressor gene \u003cem\u003eTP53\u003c/em\u003e, which regulates the cell cycle, DNA repair, and apoptosis (\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In contrast, LFS-like syndrome lacks detectable mutations within the coding regions of the gene (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This discordance between \u003cem\u003eTP53\u003c/em\u003e mutation status and the classic LFS phenotype suggests underlying biological complexity, potentially due to post-translational alterations of p53, complete gene deletions, the influence of modifier genes, or compensatory alterations in related molecular pathways that modulate phenotypic expression (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGiven the high lifetime burden of malignancy in LFS patients, many individuals develop aggressive extracranial cancers with metastatic potential. Consequently, the occurrence of brain metastases (BM) represents a clinically significant challenge in this population, particularly as improvements in systemic therapies continue to prolong survival. Despite this, there are currently no established treatment guidelines for the management of BM in LFS patients, and this clinical scenario remains largely unaddressed in the existing literature. To our knowledge, this study represents the first investigation specifically evaluating the safety and efficacy of stereotactic radiosurgery (SRS) for the treatment of BM in LFS patients. SRS for BM from primary cancers is associated with high rates of local tumor control (LTC) (\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e"},{"header":"2. METHODS","content":"\u003cp\u003e \u003cb\u003eParticipants\u003c/b\u003e \u003c/p\u003e \u003cp\u003e This retrospective study, approved by the Institutional Review Board of Stanford University Medical Center (protocol no. 3910), reviews all LFS patients with BM who underwent SRS at our institution. Electronic medical records were retrospectively screened to identify patients and collect their demographic, clinical, and radiological data. The inclusion criteria consisted of patients diagnosed with LFS who later developed BM and received SRS at Stanford Medical Center between 1998 and 2025. Patients were excluded if they lacked follow-up brain imaging or had incomplete clinical data.\u003c/p\u003e \u003cp\u003e \u003cb\u003eTarget Delineation and Planning\u003c/b\u003e \u003c/p\u003e \u003cp\u003eSRS was delivered using the CyberKnife robotic radiosurgery system (Accuray Inc., Sunnyvale, California, USA). Treatment planning involved high-resolution, contrast-enhanced magnetic resonance imaging (MRI) or computed tomography (CT) scans with thin slices through the region of interest. Following informed consent, patients underwent Aquaplast mask fabrication and acquisition of thin-section CT and contrast-enhanced T1-weighted MRI. These stereotactic scans were reviewed for completeness and adequacy for image fusion using the Precision system (Accuray Inc., Sunnyvale, CA, USA). They were then fused using the CK multi-plan treatment planning workstation for further analysis and planning. Target delineation was performed with gross tumor volumes defined based on contrast-enhancing lesions. Treatment plans were iteratively developed for each lesion, with dose prescription and delivery guided by previously established protocols (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eFollow-Up and Assessment\u003c/b\u003e \u003c/p\u003e \u003cp\u003ePatients were closely monitored following treatment, with scheduled follow-up visits every three months or sooner if new symptoms emerged. Radiographic assessments, including contrast-enhanced MRI, were performed every 3 months for the first 2 years and then every 6 months to evaluate treatment response and detect disease progression. Tumor response to CK SRS was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). According to RECIST guidelines, LTC was defined as complete response (CR), partial response (PR), or stable disease (SD), while progressive disease (PD) indicated local failure. Overall survival (OS) was defined as the time from the start of treatment to death from any cause or the last follow-up clinic date. Distant progression-free survival (DPFS) was defined as the time from the treatment to the development of a new lesion outside the previously irradiated field or the last follow-up.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical Analysis\u003c/b\u003e \u003c/p\u003e \u003cp\u003eStatistical analysis was performed using SPSS version 29 (IBM SPSS version 29.0, Chicago, IL). Descriptive statistics were used to summarize the demographic characteristics of the study population and treatment outcomes. Continuous variables were summarized as medians and ranges. Categorical variables were reported as frequencies and associated percentages. Survival outcomes were assessed using Kaplan-Meier analysis. OS and DPFS durations were reported with a 95% confidence interval (CI).\u003c/p\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003eAmong 800 patients screened, 152 were identified as having LFS. During their lifetime, 104 of these 152 LFS patients (68%) developed non-CNS primary cancers. 13 LFS patients with non-CNS primary cancers developed BM (12.5%). A total of five patients with 16 BM lesions were treated with CK SRS (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe cohort was predominantly female (80%), with a median age of 49 years (range, 37\u0026ndash;65) at the time of BM treatment. Most patients had a pre-treatment ECOG performance status of 1 (60%), while the remainder had ECOG scores of 2 or 3. All patients harbored germline \u003cem\u003eTP53\u003c/em\u003e mutations and had no history of primary CNS malignancy. One patient (20%) had a benign CNS tumor (pituitary adenoma). The median number of primary non-CNS malignancies was 3 (range, 2\u0026ndash;5). At the time of BM diagnosis, the primary disease was uncontrolled in most patients (80%), and extracranial metastases were present in 80% of cases (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient-level baseline characteristics and prior treatment history\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber (%) or Median (range)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal number of patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo. of lesions per patient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (80%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at BM treatment (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (37\u0026ndash;65)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-treatment ECOG score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (60%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo. of primary non-CNS cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary CNS Cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther benign CNS tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (80%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary disease controlled\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (80%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtracranial metastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (80%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior surgery for non-index lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior systemic therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior WBRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eBM: Brain metastases, WBRT: Whole-brain radiotherapy, CNS\u0026thinsp;=\u0026thinsp;Central Nervous System, a\u0026thinsp;=\u0026thinsp;one patient had Pituitary adenoma, LFS\u0026thinsp;=\u0026thinsp;Li Fraumeni Syndrome, NSCL\u0026thinsp;=\u0026thinsp;Non-Small Cell Lung Cancer,\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe median number of lesions per patient was 2 (range, 1\u0026ndash;7), with a median cumulative tumor volume per lesion of 26.9 cm\u0026sup3; (range, 4.66\u0026ndash;43.9). At the time of treatment, lesions were generally small, with a median maximum diameter of 6.1 mm (range, 3.2\u0026ndash;29.5). Most lesions were located in the supratentorial compartment (87.5%), with fewer infratentorial lesions (12.5%) and no involvement of the brainstem. Lesions were more frequently located in the right hemisphere (62.5%) compared to the left (37.5%). With respect to treatment parameters, the median individual lesion volume was 0.12 cm\u0026sup3; (range, 0.02\u0026ndash;18.9). The median prescribed dose was 24 Gy (range, 20\u0026ndash;27 Gy), with a median maximum dose of 33.6 Gy (range, 29.3\u0026ndash;35.3), delivered at a median isodose line of 72% (range, 68\u0026ndash;82%). Most lesions (93.7%) were treated with single-fraction SRS, while a small proportion (6.3%) received two fractions, and no lesions were treated with three fractions (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLesion-Level Characteristics and Radiosurgical Treatment Parameters\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber (%) or Median (range)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal number of lesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal volume of lesions (cm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.9 (4.66\u0026ndash;43.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximum diameter (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.1 (3.2\u0026ndash;29.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaterality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (62.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSupratentorial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (87.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfratentorial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrainstem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSRS treatment parameters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLesion volume (cm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.12 (0.02\u0026ndash;18.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrescribed dose (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25 CR26\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximum dose (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33.6 (29.3\u0026ndash;35.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsodose line (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 (68\u0026ndash;82)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of fractions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (93.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThree\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (6.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eSRS\u0026thinsp;=\u0026thinsp;stereotactic radiosurgery, wks\u0026thinsp;=\u0026thinsp;weeks\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe cohort demonstrated marked heterogeneity in histology and molecular profiles of primary tumors metastatic to the brain, reflecting the diverse oncologic spectrum associated with LFS. Histologies of primary tumors include non\u0026ndash;small cell lung cancer (NSCLC) (20%), pleomorphic sarcoma (20%), gastric adenocarcinoma (20%), leiomyosarcoma (20%), and one unknown primary (20%). Tumors were predominantly of moderate to poor differentiation, consistent with aggressive biological behavior.\u003c/p\u003e \u003cp\u003eAll evaluable cases harbored pathogenic \u003cem\u003eTP53\u003c/em\u003e alterations, including missense mutations (p.Arg174Trp, p.G245S, p.Arg282Trp) and a frameshift variant (p.R306fs). In addition to TP53 alterations, multiple co-occurring genomic aberrations of clinical significance were identified, suggesting complex oncogenic signaling networks (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. The NSCLC case demonstrated actionable EGFR alterations, including an exon 19 deletion and a p.T790M mutation, which are potential targets for tyrosine kinase inhibitors. The gastric adenocarcinoma case exhibited extensive genomic amplification, including \u003cem\u003eERBB2 (HER2), CCNE1\u003c/em\u003e, and \u003cem\u003eEGFR\u003c/em\u003e, along with \u003cem\u003ePIK3CA\u003c/em\u003e mutation and biallelic loss of \u003cem\u003eCDKN2A\u003c/em\u003e and \u003cem\u003eMTAP\u003c/em\u003e, reflecting a highly proliferative and genomically unstable phenotype. Similarly, the pleomorphic sarcoma case demonstrated amplification of cell-cycle and growth-regulatory genes (\u003cem\u003eCCND3, YAP1, TFEB\u003c/em\u003e) alongside biallelic deletion of \u003cem\u003eCDKN2A/B\u003c/em\u003e, further underscoring dysregulation of cell-cycle control. The leiomyosarcoma case also exhibited CCNE1 amplification.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHistologies and Molecular Alterations of Primary Cancer Metastatic to the Brain\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary Tumor Histology\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrading\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTP53 variants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGenomic alterations of Clinical Significance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMethod of BM diagnosis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNSCLC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModerately differentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.520A\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg174Trp)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEGFR E746_A750del, EGFR T790M (also positive on FISH for CSF)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBiopsy after surgical resection\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePleomorphic sarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUndifferentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.909_\u003c/p\u003e \u003cp\u003e916dupCACTAAGC (p.R306fs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCCND3 amplification, TFEB amplification, biallelic deletion in CDKN2A and CDKN2B, amplification of YAP 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBiopsy after surgical resection\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastric adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePoorly differentiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.733G.A (p.G245S)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eERBB2 (HER2) Amplification,\u003c/p\u003e \u003cp\u003eCCNE1 Amplification,\u003c/p\u003e \u003cp\u003eCDKN2A Biallelic Loss (Homozygous Deletion),\u003c/p\u003e \u003cp\u003eEGFR Amplification,\u003c/p\u003e \u003cp\u003eESR1 Amplification,\u003c/p\u003e \u003cp\u003eMTAP Biallelic Loss (Homozygous Deletion),\u003c/p\u003e \u003cp\u003ePIK3CA (H1047R)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBiopsy after surgical resection\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeiomyosarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGrade II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.844C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg282Trp)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCCNE1 amplifications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBiopsy after surgical resection\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eBM\u0026thinsp;=\u0026thinsp;Brain Metastases, CSF\u0026thinsp;=\u0026thinsp;Cerebrospinal fluid\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe median maximum lesion diameter decreased over time, measuring 4.31 mm (range, 0\u0026ndash;25.7) at 3 months, and reaching 0 mm at both 6-month follow-up (range, 0\u0026ndash;27) and last follow-up (range, 0\u0026ndash;29), reflecting substantial radiographic response. At 3 months, most lesions demonstrated either PR (43.7%) or SD (37.5%), with a CR observed in 18.7% of lesions and no cases of progressive disease. By 6 months, CR rates increased to 43.75%, with PR and SD each observed in 18.75% of lesions. At the last follow-up, CR was achieved in 56.3% of lesions, with the remainder demonstrating PR (18.6%) or SD (25.1%). Notably, no lesions exhibited radiographic progression at any time point (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePost-treatment Response Summary\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber (%) or Median (Range)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLesion maximum diameter (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3-month follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.31 (0\u0026ndash;25.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6-month follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0\u0026ndash;27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLast follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0\u0026ndash;29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiological response at 3 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (18.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (43.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiological response at 6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (53.84%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (23.08%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (23.08%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiological response at last follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (56.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (18.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (25.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNo local progression was observed among the 16 treated lesions, corresponding to a 100% LTC rate at 3 months, 6 months, and the last follow-up. All individuals were deceased at the time of analysis, with deaths attributed exclusively to systemic disease rather than neurological causes. The median follow-up duration was 45 weeks (range, 33.4\u0026ndash;503), and the median OS was 11.03 months (95% CI, 9.53\u0026ndash;12.54). The OS rates were 100% at 3 and 6 months, decreasing to 40% at 12 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median DPFS was 7.5 months (95% CI\u0026thinsp;=\u0026thinsp;7.3\u0026ndash;7.7), with DPFS rates of 80% at 3 and 6 months and 20% at 12 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Importantly, no adverse radiation-related outcomes were observed, including radiation necrosis or radiation-induced secondary malignancies (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of Patient- and Lesion-Level Outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber (%) or Median (Range)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal progression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFinal survival status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeceased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCause of death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeurological\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystemic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow up duration (wks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (33.4\u0026ndash;503)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian overall survival (months) (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.03 (9.53\u0026ndash;12.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival rate\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian DPFS (months) (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.5 (7.3\u0026ndash;7.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDPFS rate\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal tumor control rate*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLast follow up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation necrosis*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation-Induced Cancer#\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e* = Lesion-based, # = Patient-based, CI\u0026thinsp;=\u0026thinsp;confidence Interval,\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"4. DISCUSSION","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Incidence of BM in LFS\u003c/h2\u003e \u003cp\u003eThe prevalence of BM in LFS patients is not well-reported. However, \u003cem\u003eTP53\u003c/em\u003e perturbation and p53 pathway downregulation are strongly associated with BM across multiple carcinomas (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). For instance, Grote et al. (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) investigated the prevalence of AKT1, ERBB2, ESR1, PIK3CA, and TP53 mutations in 521 BC metastases of the four major metastatic sites, including bone, brain, liver, and lung, via next-generation sequencing and pyrosequencing. They found TP53 in 51% of BCBM. Across molecular subtypes of NSCLC, Laue et al. (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) reported that TP53 alterations were significantly more frequent in BM than in extracranial metastatic sites. Bubb et al. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) reported that 66% of BM samples had highly expressed TP53. Similarly, Lasota et al. (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) reported that TP53 mutations were identified in 69% of colorectal cancer BM. Moreover, in an in vivo study, Laue et al. (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) also demonstrated that TP53 knockdown in TP53-wild-type (WT) EMT6 murine BC cell lines, generating TP53-null EMT6 cells, selectively enhanced the development of BM compared to their TP53-WT counterparts. Furthermore, TP53-null cells produced larger tumors with many metastatic lesions in the brain relative to other organs (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Despite the established role of TP53 alterations in metastatic progression, it remains poorly defined whether germline TP53 mutations in LFS predispose to an increased incidence of BM or confer a distinct organotrophic bias toward the brain. However, in our study, we reported that 12.5% of the LFS patients with primary cancers develop BM in the disease course. Future investigations with larger, multicenter cohorts and integrated molecular profiling are warranted to determine whether germline TP53 status independently influences the frequency, timing, and organ-specific dissemination of metastatic disease.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e4.2 TP53 role in Radioresistance\u003c/h2\u003e \u003cp\u003ePreclinical evidence suggests that expression of mutant TP53 may be associated with increased resistance to chemotherapy and radiation across multiple tumor types (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e); however, robust clinical evidence supporting this association remains limited and inconsistent. In contrast, our findings demonstrated excellent response to SRS, with a 100% LTC rate at last follow-up, suggesting that high-dose, focal radiation may overcome potential mechanisms of radioresistance in this setting.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Diagnosis of BM in LFS\u003c/h2\u003e \u003cp\u003eThe clinical diagnosis of BM differs significantly between patients without LFS and those with LFS. In non-LFS patients, BM are typically suspected in the context of a known primary malignancy, most commonly lung, breast, or melanoma, and are often diagnosed following the onset of neurological symptoms such as headaches, seizures, or focal deficits, prompting neuroimaging. In contrast, patients with LFS frequently develop multiple primary malignancies over their lifetime and are commonly followed up in structured surveillance programs, including periodic whole-body and brain MRI. As a result, BM in LFS patients are more likely to be detected incidentally at an earlier, often asymptomatic stage, and may arise in the setting of multiple synchronous or metachronous primary cancers. This distinction has important clinical implications, as early detection in LFS may contribute to smaller lesion size at diagnosis and broaden the feasibility of focal treatment strategies such as SRS. However, in patients with multiple primary malignancies, the exact histological origin of BM cannot always be definitively determined. In our cohort, one patient with BM in the setting of multiple primary cancers underwent SRS without histopathological confirmation of the lesion origin, whereas the remaining four patients had surgical resection with biopsy-based determination of histology (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In such scenarios, minimally invasive approaches, such as cerebrospinal fluid (CSF)-based liquid biopsy, may serve as valuable diagnostic tools (\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Notably, in our cohort, CSF analysis in one patient identified EGFR mutations concordant with tissue biopsy findings, supporting the potential utility of liquid biopsy in guiding diagnosis and management.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e4.4 Current Literature on BM in LFS patients\u003c/h2\u003e \u003cp\u003eDespite the well-established cancer predisposition associated with LFS, the literature on the management of BM in this population remains strikingly deficient. To our knowledge, existing evidence is limited to a single case report, Sumou et al. (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), reporting a 23-year-old female with LFS who was diagnosed with bilateral triple-positive BC. She underwent multimodal treatment consisting of systemic chemotherapy, HER2-targeted therapy, total mastectomy, and locoregional radiotherapy. Four years later, she developed a BM in the left parieto-occipital region, which was treated with surgical resection and RT (40 Gy in 10 fractions). Despite subsequent treatment with capecitabine, lapatinib, a gonadotropin-releasing hormone (GnRH) agonist, and tamoxifen, disease progression occurred with the development of multiple new intracranial lesions after 14 months. A second-line regimen comprising capecitabine, neratinib, a GnRH agonist, and letrozole was initiated; however, further progression of brain metastases was observed after 7 months. Six years later, therapy with Fam-trastuzumab deruxtecan (T-DXd) was initiated, resulting in a favorable response at 4 months, characterized by a sustained decline in cancer antigen 15\u0026thinsp;\u0026minus;\u0026thinsp;3 levels, reduction in the size of the dominant brain lesion, and no evidence of new intracranial metastases. At the age of 30, the patient remains on T-DXd therapy with continued disease control.\u003c/p\u003e \u003cp\u003eSimilarly, Leng et al. (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) evaluated 225 non-LFS patients with NSCLC BM treated with SRS. On subgroup analysis, LTC rates were numerically higher in patients harboring pathogenic TP53 variants compared to those with TP53 wild-type tumors; however, this difference did not reach statistical significance.\u003c/p\u003e \u003cp\u003eIn contrast, our cohort demonstrated a 100% LTC rate following SRS for BM in LFS patients, suggesting a potentially enhanced radiosensitivity in this population. The high LTC rates observed in our LFS cohort may be attributable to several factors. First, BM in this population is often detected at a small size, as a result of intensive surveillance protocols following an LFS diagnosis, which facilitate early identification of intracranial disease. Second, the concurrent or sequential use of active systemic therapies may have contributed to improved intracranial disease control, potentially augmenting the therapeutic effect of SRS.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e4.5 Safety of SRS in BM\u003c/h2\u003e \u003cp\u003eRadiation therapy (RT) in patients with LFS is generally approached with caution due to the potential risk of treatment-related secondary malignancies (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Prior studies have reported the development of radiation-induced tumors and hematologic malignancies in this population (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). However, some evidence suggests that not all post-radiation malignancies represent de novo secondary cancers; for instance, a small series demonstrated that, among individuals with LFS who developed malignancies within prior radiation fields, a proportion were attributable to local tumor recurrence rather than new primary tumors (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). At our institution, one patient with LFS (unpublished data) was treated with surgical resection (SR) and adjuvant RT for an IDH-mutant anaplastic astrocytoma and later developed a recurrence within the irradiated field at the resection cavity. Interestingly, histopathological and molecular evaluation of the recurrent lesion demonstrated a glioma with an NTRK fusion and IDH wild-type status, indicating a potential shift in tumor biology and raising concern for either clonal evolution or a radiation-associated secondary neoplasm. In another patient with LFS (unpublished data), treatment with SR and adjuvant RT for an IDH-mutant anaplastic astrocytoma was followed by the development of a skull-based osteosarcoma, consistent with a likely radiation-associated secondary malignancy in this genetically susceptible population.\u003c/p\u003e \u003cp\u003eConsequently, while radiation exposure should be minimized when feasible, it should not be categorically withheld when clinically indicated. Instead, treatment decisions should be guided by a careful risk-benefit assessment, with priority given to oncologic control. In such cases, close longitudinal surveillance is recommended to monitor for the development of secondary malignancies within irradiated fields (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGiven the heightened susceptibility to radiation-induced malignancies in patients with LFS, a highly conformal, focal radiation to intracranial lesions with a steep dose fall-off delivered by SRS could potentially minimize radiation exposure to surrounding normal brain tissue compared to conventional RT (\u003cspan additionalcitationids=\"CR34\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). In addition, SRS is typically administered in a single or a limited number of fractions, resulting in limited radiation exposure. However, further studies are needed to establish whether SRS provides a clinically significant reduction in the risk of radiation-induced CNS malignancies (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Moreover, it is important to acknowledge that SRS planning typically involves CT-based imaging, which introduces additional radiation exposure. Nevertheless, the dose associated with diagnostic or planning CT is substantially lower than that delivered during therapeutic radiation. Future efforts should focus on optimizing and standardizing imaging protocols, particularly in patients with multiple lesions who may require repeated imaging, in order to minimize cumulative radiation exposure while maintaining accurate treatment planning.\u003c/p\u003e \u003cp\u003eIn our cohort of 16 lesions treated with CyberKnife SRS, predominantly delivered in a single fraction, no secondary intracranial malignancies were observed. However, the median follow-up duration was limited, and longer-term surveillance is necessary to adequately assess the risk of radiation-induced tumors in LFS patients with BM.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e4.6 Safety of Systemic Therapy\u003c/h2\u003e \u003cp\u003eSimilarly, the use of conventional cytotoxic chemotherapy may confer an increased risk of secondary cancers in LFS (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e); however, most experts advocate prioritizing treatment efficacy over potential long-term adverse effects, particularly in the setting of aggressive or life-threatening disease (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). However, the role of cytotoxic chemotherapy in BM is very limited. Therefore, targeted therapies and immunotherapies may represent attractive alternatives. For example, the presence of a BRAF V600E mutation could render a patient eligible for BRAF inhibitor therapy, tumors exhibiting hypermutation may be responsive to immune checkpoint blockade, and NF1 mutations could identify candidates for MEK inhibitor treatment (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Similarly, EGFR alterations identified in our cohort represent clinically actionable targets, supporting the potential role of tyrosine kinase inhibitors (TKIs) in the management of these patients. Also as given above, Sumou et al. (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) reported a 23-year-old female with LFS, treated for bilateral triple-positive BC BM with T-DXd therapy, and the lesions responded well. These precision-based approaches offer the potential for effective tumor control while minimizing exposure to DNA-damaging agents, which is particularly relevant in this genetically susceptible population.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e4.7 Role of Surgical Resection\u003c/h2\u003e \u003cp\u003eSurgical resection remains a standard treatment modality for BM, particularly for patients with large or symptomatic lesions causing significant mass effect, as it provides rapid decompression and histopathological diagnosis (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). However, its role becomes increasingly limited in the setting of multiple and small BM, where surgical intervention is often impractical or infeasible due to the need for multiple craniotomies and associated morbidity (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). In patients with LFS, BM are typically multiple and small due to early detection through surveillance. Therefore, surgical resection may be appropriate for larger or symptomatic lesions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e4.8 Limitations and Future Directions\u003c/h2\u003e \u003cp\u003eThis study has several limitations that warrant consideration. First, its retrospective design, relatively small sample size, and limited follow-up duration restrict the generalizability of our findings and preclude definitive conclusions regarding long-term outcomes. In particular, the short follow-up limits the ability to assess late adverse effects, including the risk of radiation-induced secondary malignancies in this genetically susceptible population.\u003c/p\u003e \u003cp\u003e Future studies should focus on prospective, multicenter collaborations to better define the prevalence of BM in patients with LFS and to establish standardized neuro-oncological management guidelines. Additionally, subgroup analyses based on primary tumor histology and underlying molecular profiles, including specific TP53 alterations and co-mutations, are needed to understand differential treatment responses better and optimize patient selection for SRS.\u003c/p\u003e \u003cp\u003eFinally, extended longitudinal follow-up will be essential to evaluate the long-term safety of SRS, particularly with respect to the incidence of radiation-induced secondary neoplasms, and to further clarify its role as a potentially safer, focal therapeutic approach in this high-risk population.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eIn this study, SRS demonstrated excellent LTC and a favorable safety profile for the management of BM in patients with LFS. In our cohort, all treated lesions achieved durable local control without evidence of radiation necrosis or secondary malignancies during the follow-up period. Given the tendency for BM in LFS to be multiple and small, often detected early through intensive surveillance, SRS represents a particularly suitable and minimally invasive therapeutic option. However, the risk of radiation exposure should not be underestimated. Nevertheless, given the limited sample size and follow-up, further prospective, multicenter studies with longer surveillance are warranted to validate these findings, better define long-term risks, and establish evidence-based guidelines for the optimal management of brain metastases in patients with Li-Fraumeni syndrome\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate:\u0026nbsp;\u003c/strong\u003eThis study was conducted with prior approval from the Stanford University Institutional Review Board (no. 3910) panel on Medical Human Subjects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAI tools:\u003c/strong\u003e During the preparation of this manuscript, the author(s) used Grammarly AI to improve the grammar and readability of the manuscript. No AI-generated idea has been used in this manuscript. The authors have reviewed and edited the output and take full responsibility for the content of this publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of supporting data:\u0026nbsp;\u003c/strong\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM.I. contributed to conceptualization, study design, and Methodology, performed data collection and formal analysis, and drafted the manuscript. A.K. contributed to the study design and Methodology and drafted the manuscript. Y.H., D.P., and S.C. contributed to conceptualization and supervised the manuscript. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSchneider K, Zelley K, Nichols KE, Levine AS, Garber J (2025) Li-fraumeni syndrome. GeneReviews\u0026reg;[Internet]\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCognigni V, Capelletto E, Bordi P, Pavese V, Carf\u0026igrave; FM, Gelsomino F et al (2024) A case series of non-small cell lung cancer patients with \u003cem\u003eEGFR\u003c/em\u003e or \u003cem\u003eHER2\u003c/em\u003e exon 20 insertion in Li Fraumeni syndrome. 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Front Oncol 12:847110. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fonc.2022.847110\u003c/span\u003e\u003cspan address=\"10.3389/fonc.2022.847110\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Li Fraumeni Syndrome, CyberKnife, Brain Metastases, Radiosurgery, Gamma Knife","lastPublishedDoi":"10.21203/rs.3.rs-9295398/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9295398/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eLi-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline \u003cem\u003eTP53\u003c/em\u003e mutations and an increased risk of radiation-induced malignancies, posing significant challenges in the management of brain metastases (BM). Data regarding the safety and efficacy of stereotactic radiosurgery (SRS) for BM in this population remain limited.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe performed a retrospective analysis of patients with LFS who underwent SRS for BM at our institution. Patient-level, lesion-level, and treatment-related data were collected. Outcomes assessed included local tumor control (LTC), overall survival (OS), distant progression-free survival (DPFS), radiographic response, and treatment-related adverse events.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 5 patients with 16 BM lesions were treated with SRS. The median age at treatment was 49 years (range, 37\u0026ndash;65). Lesions were typically small (median diameter 6.1 mm) and predominantly supratentorial (87.5%). Most lesions (93.7%) were treated with single-fraction SRS with a median prescribed dose of 24 Gy. LTC was 100% at 3 months, 6 months, and at last follow-up. Median OS and DPFS were 11.03 months (95% CI, 9.53\u0026ndash;12.54) and 7.5 months (95% CI, 7.3\u0026ndash;7.7), with all deaths attributable to systemic disease rather than neurological progression. Importantly, no cases of radiation necrosis or radiation-induced secondary malignancies were observed during a median follow-up of 45 weeks.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eSRS demonstrated excellent local control and a favorable safety profile for the treatment of BM in patients with LFS. Given the tendency for lesions to be small and multifocal, along with the need to minimize radiation exposure, SRS represents a rational, focal treatment approach in this high-risk population. However, longer follow-up and prospective studies are needed to better define long-term safety, particularly regarding the risk of radiation-induced malignancies.\u003c/p\u003e","manuscriptTitle":"Outcomes of CyberKnife Stereotactic Radiosurgery for the Brain Metastases in Patients with Li Fraumeni Syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-09 15:09:48","doi":"10.21203/rs.3.rs-9295398/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-21T11:48:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-16T20:48:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"25376668973013796757520633851350247250","date":"2026-04-09T12:38:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-08T08:33:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"228528952221324209882839010392561418047","date":"2026-04-06T16:55:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"299941921769591243751162869362560521100","date":"2026-04-06T16:23:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"216614754732146821065092665099816519986","date":"2026-04-06T00:17:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"295285107486118715086510099373054598414","date":"2026-04-05T20:28:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-02T17:45:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-02T17:24:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-02T17:23:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2026-04-01T18:58:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"bfd2b8b2-4510-4c9d-aedf-460a921918aa","owner":[],"postedDate":"April 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T08:55:25+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-09 15:09:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9295398","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9295398","identity":"rs-9295398","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}