Brain Metastases In Patients Research Articles

TMET-34. PYROPTOSIS IS AN ACQUIRED VULNERABILITY OF BRAIN METASTASES

Abstract Metastasis, the spread of cancer cells from one part of the body to another, is a leading cause of death among cancer patients. Three particularly dangerous forms of metastases are the spread of lung, skin, and breast cancers to the brain. On average survival time of all brain metastasis (BM) patients is around 4 months, which is accompanied by a failing and undefined standard of care. We have strived to bridge the gap between novel safe therapeutics and brain metastasis patients by discovering and targeting metabolic vulnerabilities in brain metastases. Here, we conducted comparative metabolomic screening in patient-derived BM lines versus normal brain cells to identify dihydroorotate dehydrogenase (DHODH) as a cancer-selective targetable vulnerability. DHODH is an essential enzyme that is located within the inner membrane of the mitochondria which has a primary role in producing pyrimidine metabolites through the de novo uridine synthesis pathway and also contributes to the proper functioning of the electron transport chain. Through this, DHODH has been implicated in the essential functioning of energy metabolism, DNA and RNA synthesis, and most recently in the modulation of the immune system. In our studies we have elucidated the significant effect DHODH inhibitors and the induction of DHODH CRISPR knock-out has against the cell viability, sphere formation, and proliferation of patient derived BM samples in vitro and in vivo. Furthermore, through metabolomics we have discovered that following DHODH perturbation, there is a significant increase in a signaling lipid (D-ethryo-Dihydrosphingosine) that specifically inhibits Protein Kinase C (PKC) and initiates Gasdermin E (GSDME) mediated pyroptosis. By uncovering this mechanism we have discovered GSDME mediated pyroptosis is an aquired vulnerability of brain metastases. Overall, this study highlights the translational potential of DHODH inhibitors in BM and elucidates novel mechanistic underpinnings of nucleotide deprivation within the context of cell death.

RADT-43. RADIOSURGERY FOR BRAIN METASTASES FROM GYNECOLOGICAL PRIMARIES: AN INSTITUTIONAL PERSPECTIVE OF 58 METASTATIC LESIONS

Abstract Stereotactic radiosurgery (SRS) is being increasingly employed in the treatment of brain metastases. The evidence of radiological response of metastatic lesions from gynecological primary is lacking in literature. To assess the response rate of metastatic lesions to gamma knife SRS over a longitudinal follow-up period, a single centre prospectively maintained database was analysed retrospectively from 2014 to 2024. Lesion volumes were contoured at each follow up scan using Leksell Gammaplan software. Response assessment in neuro-oncology (RANO) criteria was used to assess radiological tumor response rates. Fifteen patients with 58 lesions were included. Average duration of radiological follow-up available was 16.7 months. The primary gynecological source of brain metastases in patients were cervical(n=4), ovarian(n=7), endometrial(n=3) and vulvar (n=1). Single fraction SRS was used for 49 lesions (range 16-20 Gy) and hypofractionated SRS for 9 lesions (8Gy x 3 to 9Gy x3). Average time to complete response was 9.01 months (range 1-25.7). The average follow-up for lesions with partial response was 12.2 months (range 1 -32) As per RANO criteria, complete response was seen in 33(56.9%) lesions and partial response in 25(43.1%). At 6month follow up, complete response was seen in 58.49% (n=31) of the lesions available(n=53) for assessment and partial response in 41.51%(n=22). At 18-months, complete response was seen in 66.67%(n=22) and partial response in 33.33%(n=11). Within pathological subgroups, endometrial (60%,n=3) primary showed higher rate of complete response at 6months than ovarian (52.7%,n=19), vulvar (50%, n=1) and cervical (40%,n=6) subgroups. Brain metastases from ovarian primary source were most encountered and endometrial metastases showed highest response rates to SRS. Six month and 18-month response rates were better than previously reported literature.

RADT-29. ASSOCIATION OF ANATOMIC PROXIMITY OF BRAIN PARENCHYMAL METASTASIS TO THE CSF SPACE AND UPFRONT STEREOTACTIC RADIOSURGERY TO SUBSEQUENT LEPTOMENINGEAL METASTASIS DEVELOPMENT IN BRAIN METASTATIC NSCLC

Abstract OBJECTIVE The most common solid systemic malignancies that metastasize to the leptomeninges are lung cancer, especially non-small cell lung cancer (NSCLC). Generally, patients develop leptomeningeal metastasis (LM) subsequent to brain parenchymal metastases (BM). However, its predictors remain unknown. Hence, the present study was carried out to explore the predictors of LM in brain metastatic NSCLC patients. METHODS The final analysis included 112 pathologically definite NSCLC patients with BMs treated in our center between July 1, 2014, and December 30, 2020. Of 112, one-half had LM. Three radiologists analyzed radiologic images independently. Anatomic proximity of BMs to the CSF space (dural-based metastases, periventricular or major CSF cisterns such as basal cisterns and cisterna magna) was measured and stratified into CSF space invading/bordering and detached lesions. The endpoint was the occurrence of LM or death, whichever occurred first. Univariable and multivariable logistic regressions were performed to identify potential predictors for LM. RESULTS Of 112, 48 (42.8%) were males, and 64 (57.2%) were females. Most patients (90.2%) had adenocarcinoma histology. The median follow-up time was 10.1 months (IQR, 4.2-18.4 months) following BM diagnosis. Univariate logistic regression analysis demonstrated that histology (OR 0.084, 95%CI 0.004-0.461, P=0.020), EGFR/ALK/ROS1 mutation (OR 3.868, 95%CI 1.583-10.079, P=0.003), CSF space invading/bordering lesion (OR 10.278, 95%CI 4.203-27.375, P=0.000), extracranial metastasis control (OR 2.7, 95%CI 1.191-6.309, P=0.019), upfront stereotactic radiosurgery (SRS) (OR 0.024, 95%CI 0.001-0.12, P=0.000), and target therapy (OR 4.476, 95%CI 1.877-11.464, P=0.001) were the potential predictor. CSF space invading/bordering lesion (OR 7.443, 95%CI 2.099-32.853, P=0.003) and upfront SRS (OR 0.035, 95%CI 0.002-0.212, P=0.003) remained statistically significant in the multivariate logistic regression analysis. CONCLUSION CSF space invading/bordering BMs may increase the risk of LM development in brain metastatic NSCLC patients, while upfront SRS targeting BM potentially decreases the risk. A prospective study is warranted to affirm.

EPID-37. PROGNOSIS OF BRAIN METASTASES PATIENTS WITH WHOLE BRAIN RADIATION THERAPY (WBRT) VS NON-WBRT AT THE NATIONAL CANCER CENTER OF INDONESIA, DHARMAIS HOSPITAL

Abstract BACKGROUND Limited treatment options for brain metastases (BM) remain a challenge for many cancer centers in Indonesia. To improve overall survival, Whole Brain Radiation Therapy (WBRT) is still widely used in many Indonesian cancer centers This study aims to evaluate the effectiveness of WBRT vs non-WBRT for overall survival of brain metastases patients. METHOD This retrospective study observed 148 brain metastasis patients admitted to our hospital from January 1st, 2021 to December 31st, 2022 and we followed their overall survival up to July 1st, 2023. The brain metastasis is confirmed by brain MRI. In addition to overall survival, we collected information on age, sex, primary tumor types, sides of metastasis, and treatment received (WBRT, non-WBRT, and surgery). To examine the overall survival among treatment received and tumor characteristics, we present median survival time, Kaplan-Meier curves, and its log-rank statistics using Stata program version 17. Additionally, we use Cox regression for further analysis. RESULTS The overall median survival of these patients was 4.3 months. Patients receiving WBRT exhibit higher survival rates than non-WBRT as presented in their median survival rates (1.5 months vs 6.9 months). The primary tumors (breast, lung, and others) have no difference in the median survival rates. The survival rate trends using Kaplan-Meier showed a significant difference between patients with WBRT vs non-WBRT (log-rank p=0.0). A Cox regression shows hazard rates(HR) for patients receiving WBRT =0.40 and it shows only a small change when adjusted for surgery and other variables. CONCLUSIONS Brain metastasis patients who received WBRT have better survival than non-WBRT patients who could reduce HR to 0.4. This means that WBRT patients are protected 60% of the risk for overall survival.

NCOG-02. ASSESSING THE INFLUENCE OF ADJUVANT INTERSTITIAL BRACHYTHERAPY ON MALIGNANT BRAIN TUMOR PATIENTS: INSIGHTS FROM THE NATIONAL READMISSION DATABASE

Abstract Interstitial brachytherapy (IB) is a form of surgically administered radiotherapy involving the implant of radioactive seeds into the resection cavity after tumor excision. Advances in IB for brain cancers have revived interest in this treatment platform. However, the impact of this therapy on hospital quality measures remains poorly characterized. Here we utilized the National Readmission Database (NRD) to address this gap in knowledge. We identified patients with malignant brain tumors who had undergone either craniotomies (C) for tumor resection or craniotomies augmented with adjuvant interstitial brachytherapy (C+IB) in the National Readmission Database (NRD, 2010-2018). Propensity-score weighting and survey regression techniques were used for analysis. Over the study period, the number of craniotomies with adjuvant interstitial C+IB steadily decreased. For brain metastasis (BM) patients, C+IB and C patients exhibited comparable length of hospital stay (IRR:0.95, CI95:0.61-1.50, p=0.838) and routine discharge to home or self-care (OR:1.01, CI95:0.86-1.18, p=0.918). However, primary brain tumor (PBT) patients who underwent C+IB showed longer hospital stay (IRR:1.43, CI95:1.03-1.99, p=0.032) and are less likely to undergo routine discharge (OR: 0.38, CI95:0.20-0.74, p=0.005) relative to the C cohort. Despite these differences, C+IB and C patients showed comparable 30- or 90- day readmission risk. The profile of readmission diagnoses was also similar. Cost-analysis suggests that IB increased the median total charge by $19,184 (p=0.003). Our analysis suggests that adjuvant interstitial brachytherapy did not alter hospital course/readmission risk for brain metastasis patients. However, PBT patients who underwent this therapy showed longer hospitalization and increased likelihood for non-routine discharge.

BIOS-01. MACHINE LEARNING-BASED PREDICTION OF INPATIENT CARE COSTS FOR PATIENTS WITH BRAIN METASTASES: A REAL-WORLD ANALYSIS

Abstract INTRODUCTION Brain metastases (BMs) are increasingly a cause of significant cancer-related morbidity, mortality, and economic burden. While BM-related healthcare costs have been previously described, predictive analytics based on contemporary cohorts, particularly for inpatient care, remain unavailable. This study sought to evaluate inpatient care costs (IPCC) and associated reimbursements for patients with BMs and perform predictive modeling through supervised machine learning (sML) using a contemporary, commercial US claims database. METHODS This retrospective study, reported following STROBE and TRIPOD+AI reporting guidelines, included adult patients (aged 18-65 years) in the United States (US) with BMs included in the MarketScan Commercial Claims and Encounters Database who received inpatient care during January 2016 to December 2021. Eligible patients were identified using ICD-10 codes. IPCC measures were adjusted using the Medical Care component of the 2023 Consumer Price Index. The primary study outcome was total IPCC, represented by adjusted gross total payments. After log-transformation performed due to data skew, sML was carried out using Random Forest algorithm with 1000 iterations with a 70:30 training-test data split, followed by residual analysis and evaluation of predictive performance using root-mean-squared error (RMSE), out-of-bag error (OOBE), and calibration curve. Multivariable linear regression was carried out for sensitivity analyses. RESULTS A total of 25117 unique inpatient admissions across 13477 BM patients were included, with median (IQR) age of 57 years (51-61). Gross median (IQR) CPI-medical-care-adjusted values per admission were: total payments $28,119.51 (16847.45-55111.67); hospital payments $24,678.74 (14601.66-47864.84); and payments to principal physician $884.80 (441.07-2434.15), being 3.6% (IQR 1.9-6.8) of total payment. Median inpatient length of stay was 4 days (IQR 2-8). ML model had an OOBE of 0.61 and, using test data, RMSE of 0.85, indicating robust performance. No major deviations were found on residual analysis. CONCLUSIONS Contemporary IPCCs for BM patients in US are substantial but driven minimally by payments to principal physician. sML may be utilized to successfully predict IPCC for BM patients.

ANGI-06. CEREBROSPINAL FLUID MAY BE THE MOST IMPORTANT PATHWAY FOR BRAIN METASTASES: A DATA-DRIVEN HYPOTHESIS AND CLINICAL IMPLICATIONS

Abstract INTRODUCTION Hematogenous spread of brain metastases represents conventional wisdom. However, compelling physiologic evidence suggests that brain metastases may reach the CNS by way of the CSF either via the choroid plexus or directly from the bone marrow. We provide clinical evidence that invasion of brain parenchyma occurs through the CSF, and we model the therapeutic implications of this novel hypothesis. METHODS First, we assessed whether brain metastases were contiguous with a CSF space in 204 consecutive patients using pre-treatment MRI. Then, CSF was examined for malignant cells in 66 consecutive brain metastasis patients. Next, we contoured normal brain MRIs of 3 patients to calculate the percentage of brain within 5 mm of a CSF space. Finally, we queried an international neoplastic meningitis registry for patients with brain metastases to evaluate response to intra-CSF chemotherapy alone. RESULTS In 204 consecutive patients with brain metastases, the mean number of metastases was 4.63 (SD 6.26), and 85% of metastases touched a CSF space. In 67% of patients, all metastases touched a CSF space. In our consecutive cohort of 66 patients with CSF analysis, 44% with one, 46% with two, 63% with three, and 71% with >3 metastases had malignant cells in the CSF (R2=0.93, p=0.04). Brain contouring revealed that up to 75% of the brain parenchyma lies within 5 mm of a CSF space. Seven of 10 patients with both brain and CSF metastases receiving only intrathecal chemotherapy experienced disappearance or substantial reduction in the size of their metastases. CONCLUSIONS This data suggest that brain metastases may access the CNS through the CSF. Intrathecal chemotherapy can reach most brain metastases and can produce objective responses. We suggest that the CSF should be monitored in all patients with, or at risk for, brain metastases, and true cures may require treatment of the CSF space.

RBIO-06. STEREOTACTIC RADIOSURGERY ENHANCES T-CELL RECEPTOR REPERTOIRES AND INDUCES IMMUNOGENICITY IN BRAIN METASTASIS

Abstract BACKGROUND Brain metastasis is a frequent and deadly complication of systemic malignancy. The incidence rate is increasing and the prognosis remains poor, in contrast to recent advances in the management of systemic malignancy. Our previous work revealed an immunosuppressive microenvironment in brain metastasis and correlation between T-cell status and patient outcomes, shared across the primary tumor histologies. Therefore, we hypothesize that induction of immunogenicity has potential to improve brain metastasis patient outcome. METHODS Pre-operative stereotactic radiosurgery (SRS) (n = 44) and post-operative SRS (n = 47) brain metastasis specimens were collected from an ongoing clinical trial (MDACC protocol 2018-0552) designed to determine optimal timing of SRS for the treatment of brain metastasis. The patient materials were extracted DNA and RNA, and subjected to T-cell receptor (TCR) repertoire sequencing and mRNA-seq to interrogate radiation-induced immunogenicity. RESULTS In a preliminary analysis of the first 21 specimens, Gene Set Enrichment Analysis revealed that SRS significantly enhanced multiple immune-related signaling pathways including interferon response, along with apoptotic pathways, in brain metastasis. We also found that TCR signaling and PD-1 signaling was upregulated by radiotherapy. TCR repertoire analysis further identified increased density and diversity of TCRs induced by SRS treatment. Profiling of the remaining sample set is currently ongoing. CONCLUSIONS In light of our previous finding regarding the correlation between immune status and outcomes of patients with brain metastases, reversing immunosuppression in brain metastasis could be a key factor on patient prognosis and treatment. Our TCR repertoire and mRNA sequencing analyses with pre-operative and post-operative SRS brain metastasis cohorts support a role for radiation-induced immunogenicity, pointing to a prospective therapeutic approach for brain metastasis management.

EPID-31. IMPACT OF THE COVID-19 PANDEMIC ON THE UTILIZATION OF STEREOTACTIC RADIOSURGERY AMONG RACIAL MINORITIES DIAGNOSED WITH BRAIN METASTASES

Abstract OBJECTIVES Brain metastases (BM) is the most common form of adult brain tumors and one of the devastating consequences of cancer. Stereotactic radiosurgery (SRS) is an established and effective treatment for oligometastatic BMs. We examined how COVID-19 pandemic impacted clinical utilization of SRS in BM treatment and generalize such impact to outpatient care for patients with all cancer types. METHODS Three national-scale datasets were used: National Cancer Database (NCDB,N=5,238), the National COVID Cohort Collaborative database (N3C, N=13,106 for BM, N=203,706 for all cancer types), and SEER. Multivariable logistic regression models were performed to determine whether the pandemic affected clinical utilization of SRS in BM treatment and chemotherapy initiation for all cancer types. RESULTS Prior to 2019 (pre-pandemic), we observed no racial disparity in the odds of receiving SRS between non-Hispanic white (NHWs) and non-Hispanic black (NHBs) BMs in both NCDB and N3C. Between 2020 and 2021 (pandemic), however, NHBs were significantly less likely to receive SRS comparing to NHWs in both NCDB (NHB:aOR-0.77,p=0.002) and N3C (NHB:aOR-0.78,p<0.001). In SEER, the age-adjusted incidence rate of BM remained unchanged when comparing pre- and post-pandemic periods. Further substantiating the impact of COVID-pandemic on racial disparity in outpatient care for all cancer patients, we showed that NHB patients were more likely to receive delayed chemotherapy (>60 days since diagnosis of cancer) compared to NHWs during the pandemic (aOR-1.10, p<0.001), but such association was not detected before pandemic. Ratio of odds ratio (ROR) analysis confirmed that NHB patients comparing to NHWs during pandemic experienced 1.11-fold difference in the odds of delayed chemotherapy between NHBs and NHWs before pandemic [ROR=1.11, p<0.001]. CONCLUSION Racial disparity in SRS-receipt for BM patients has been exacerbated during COVID-19 pandemic and such impact could be generalized to outpatient care for all cancer types. Understanding the determinants giving rise to this disparity should augment the readiness of our cancer care infrastructure in anticipation of future pandemics or other public health crises.

RTID-03. A MULTICENTER, RANDOMIZED, CONTROLLED TRIAL OF FOCUSED-ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER DISRUPTION PLUS SYSTEMIC PEMBROLIZUMAB FOR PATIENTS WITH NSCLC BRAIN METASTASES (LIMITLESS)

Abstract BACKGROUND Systemic therapy for brain metastases (BM) is hindered by blood-brain barrier (BBB). Low-intensity focused ultrasound (LIFU), combined with IV microbubble oscillators, leads to non-invasive BBB disruption, which could enhance intracranial delivery of systemic immune checkpoint inhibitors. This randomized controlled trial (RCT) aims to evaluate safety and efficacy of LIFU-mediated BBB disruption plus systemic pembrolizumab for NSCLC BM. METHODS LIMITLESS (NCT05317858) is an ongoing, multicenter, parallel-arm, open-label RCT that randomizes NSCLC BM patients on standard-of-care pembrolizumab monotherapy to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in a 2:1 ratio. Included patients have age ≥18 years, normal organ function, KPS ≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM with ≥1 BM meeting RANO-BM measurable disease criteria. All patients receive standard-of-care therapy, while those on arm 1 undergo LIFU before each pembrolizumab dose (200mg IV q3weeks). Patients undergo pre-treatment brain MRI, followed by IV microbubbles for enhanced sonication effects. MR-guided BBB disruption is performed using transcranial 220kHz LIFU device with real-time acoustic-feedback-based power control for maintaining effective microbubble activation. Pembrolizumab is infused immediately after sonication, and repeat MRI is done 24-48 hours later to assess treatment effects. Primary study outcome is overall objective response rate (ORR) at 6 months as assessed using RANO-BM. Using Bayesian design for power analysis, a superior ORR of 60% is assumed for LIFU arm versus 30% for control arm for total sample size of N=96 (64 participants in LIFU and 32 in control arm), for 80% power using two-sided chi-square test with alpha=0.05. For upper-bound estimate, ORR of 45% in LIFU arm and 30% in control arm, the study needs N=369 participants (246 in LIFU arm and 123 in control arm). Secondary outcomes are best ORR and median time-to-response. Exploratory outcomes are median progression-free survival (PFS), overall survival (OS), median intracranial PFS, median extracranial PFS, and quality of life. Patient enrollment commenced in 2022 and remains ongoing.

Bridging the gap: unlocking the potential of emerging drug therapies for brain metastasis.

Brain metastasis (BrM) remains an unmet clinical need in advanced cancers with an increasing incidence and poor prognosis. The limited response to various treatments is mainly derived from the presence of the substantive barrier, blood-brain barrier (BBB) and brain-tumor barrier (BTB), which hinders the access of potentially effective therapeutics to the metastatic tumor of brain. Recently, the understanding of the structural and molecular features of the BBB/BTB has led to the development of efficient strategies to enhance BBB/BTB permeability and deliver drugs across the BBB/BTB to elicit the antitumor response against BrM. Meanwhile, novel agents capable of penetrating the BBB have rapidly developed and evaluated in pre-clinical studies and clinical trials, with both targeted therapies and immunotherapies demonstrating impressive intracranial activity against BrM. In this review, we summarize the recent advances in the biological properties of the BBB/BTB, and the emerging strategies for BBB/BTB permeabilization and drug delivery across the BBB/BTB. We also discuss the emerging targeted therapies and immunotherapies against BrM tested in clinical trials. Additionally, we provide our viewpoints on accelerating clinical translation of novel drugs into clinic for patients of BrM. Although still facing challenges, we expect this review to benefit the future development of novel therapeutics specifically from clinical perspective.

Expert consensus on the prevention of brain metastases in patients with HER2-positive breast cancer

Expert consensus on the prevention of brain metastases in patients with HER2-positive breast cancer

Treatment of brain metastases from non-small cell lung cancer: preclinical, clinical, and translational research.

Lung cancer is the second most common type of cancer and is the leading cause of cancer-related deaths in the United States. Approximately 10-40% of patients with solid tumors develop brain metastases, with non-small cell lung cancer accounting for approximately 50% of all cases of patients with brain metastases. Many management options are available which can include surgery, radiation, and systemic therapy. A variety of factors go into the selection of management of brain metastases. In this review, we will focus on the treatment strategies and optimizing the management of brain metastases in patients with non-small cell lung cancer.

Quality of life after stereotactic radiosurgery for brain metastasis: an assessment from a prospective national registry.

Stereotactic radiosurgery (SRS) is frequently used in the management of brain metastasis patients. However, there is an urgent need to evaluate post-treatment outcomes and quality of life metrics for patients undergoing SRS for brain metastases. The NeuroPoint Alliance (NPA) SRS Quality Registry conducted prospective enrollment of patients undergoing SRS from 2017 to 2024. Patients with brain metastases from lung cancer, breast cancer, and melanoma were included in the analysis. Outcomes of interest included quality of life metrics, as captured by the five-dimension Euro-QOL (EQ-5D) at 6-12 months and last record follow-up, overall survival, local progression, out-of-field progression, and overall intracranial progression. 522 patients comprised our analytic cohort, and 315 patients had available EQ-5D data at the time of SRS and final follow-up. 264 (47.8%), 197 (35.7%), and 91 (16.5%) patients had 1, 2-4, and 5-14 lesions pre-SRS, respectively. The median overall survival time from diagnosis was 27.3 months. The median time-to-local progression was not reached. At final follow-up, 107 (34.0%) patients had improvement, 51 (16.2%) patients had stable, and 113 patients (35.9%) had worsening EQ-5D scores when compared to baseline. For 44 (13.9%) patients mixed responses across the EQ-5D indices were reported. Linear regression analysis showed that male sex, smoking status, primary tumor type, time-to-overall progression, cumulative intracranial tumor volume (CITV), and baseline EQ-5D were statistically significantly associated with EQ-5D single index at the final follow-up. Real-world data from the SRS NPA Registry demonstrated that most patients with brain metastasis had no change or improvement in quality of life after SRS. Baseline EQ-5D was predictive of EQ-5D single index at final follow-up, and, as such, EQ-5D at baseline would be a valuable assessment measure for brain metastasis patients undergoing SRS.

P27.24.A SYSTEMIC AND LOCAL THERAPIES BEFORE AND AFTER DIAGNOSIS OF LEPTOMENINGEAL DISEASE IN PATIENTS WITH BRAIN METASTASES: AN EXPLORATIVE, SINGLE-CENTER RETROSPECTIVE COHORT STUDY

Abstract BACKGROUND Leptomeningeal metastasis (LMD), the dissemination of cancer cells into leptomeninges and/or cerebrospinal fluid, is believed to increase in incidence due to improved survival of oncological patients. Real-world data on therapies before and after diagnosis of LMD in brain metastasis patients are still limited. We aimed to characterize local and systemic therapies before and after diagnosis of LMD in these patients. MATERIAL AND METHODS We included 120 patients (treated from 2012 to 2023) with underlying solid malignancy, presence of brain metastasis together with leptomeningeal spread, either confirmed by MRI, cerebrospinal fluid sampling, or both modalities. Data on demographics, radiological, and therapy-related characteristics were collected. Kaplan-Meier estimates and Cox model regression analysis were performed to identify factors associated with survival. RESULTS Breast cancer (35.8%), NSCLC (20.8%), melanomas (16.7%), and gastric cancer (5.7%) were among the most common entities. In 56% of cases, the diagnosis was made by MRI, in 5% by cerebrospinal fluid puncture (LP) alone, and in 39% by both MRI and LP. The median overall survival (OS) of the cohort was 2.77 months [95% CI: 2.27 - 4.20]. Patients who received systemic after diagnosis of LMD, either chemotherapy (n=26), targeted therapies (n=21) or checkpoint inhibitors (n=9) showed increase survival as compared to respective control patients. The only independent prognostic factors at diagnosis of LMD were presence of lung cancer (HR: 2.36 [95% CI: 1.28 - 4.4], p=0.006) and melanoma (HR: 2.30 [95% CI: 1.27 - 4.2], p=0.006). Local or systemic treatment modalities before LMD diagnosis were not associated with survival. CONCLUSION This study provides insights into the complex treatment modalities for LMD patients, both in terms of prior therapies and therapies after diagnosis of LMD. These results underscore the need for large prospective multi-center registries and interventional studies to further improve interdisciplinary and personalized therapy for these patients.

P17.01.A ANAMNESTIC RADIOLOGICAL METASTASES OUTCOME SURGICAL SCORE (ARMO-S). A PURPOSE OF A PREDICTIVE SCORING SYSTEM FOR SURGICAL BRAIN METASTASES

Abstract BACKGROUND Several risk stratification scores have been suggested to aid prognostication and guide treatment strategies for brain metastases (BMs). However, the current scores do not focus on the specific neurosurgical population, therefore not predicting short-term mortality and postoperative performance status. MATERIAL AND METHODS This retrospective observational study of 362 consecutive patients treated with surgery for BMs aims to identify the factors associated with post-surgical outcomes and propose a surgery-specific prognostic score for patients with BMs candidate for open surgery. RESULTS Factors significantly associated with OS and performance status in multivariate analysis were age, KPS, surgical site, synchronous debut of BM, number, tumor volume, seizure, extra-cranial metastases, and deep-seated location. The variables were incorporated into the Anamnestic Radiological Metastases Outcome Surgical score (ARMO-S). The values range between 0 and 10. Patients were divided into two groups (low-risk and high-risk) based on each significant subgroup’s median survival and performance status with an optimal cutoff value determined as 4. The two groups have significant differences in OS (9.6 versus 14 months, p = 0.0048) postoperative KPS (90 versus 70, p=0.012) and KPS at last follow-up evaluation (75 versus 30, p<0.001) CONCLUSION ARMO-S is a simple and comprehensive score for BM patients selected for neurosurgery, as it incorporates the main factors of the most important prognostic scores, implementing them with more surgery-specific predictive elements such as tumor location and volume, presence of seizures at onset, and involvement of eloquent brain areas.

Multiomics-Based Outcome Prediction in Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy (PULSAR).

Objectives: This retrospective study aims to develop a multiomics approach that integrates radiomics, dosiomics, and delta features to predict treatment responses in brain metastasis (BM) patients undergoing PULSAR. Methods: A retrospective study encompassing 39 BM patients with 69 lesions treated with PULSAR was undertaken. Radiomics, dosiomics, and delta features were extracted from both pre-treatment and intra-treatment MRI scans alongside dose distributions. Six individual models, alongside an ensemble feature selection (EFS) model, were evaluated. The classification task focused on distinguishing between two lesion groups based on whether they exhibited a volume reduction of more than 20% at follow-up. Performance metrics, including sensitivity, specificity, accuracy, precision, F1 score, and the area under the receiver operating characteristic (ROC) curve (AUC), were assessed. Results: The EFS model integrated the features from pre-treatment radiomics, pre-treatment dosiomics, intra-treatment radiomics, and delta radiomics. It outperformed six individual models, achieving an AUC of 0.979, accuracy of 0.917, and F1 score of 0.821. Among the top nine features of the EFS model, six features came from post-wavelet transformation and three from original images. Conclusions: The study demonstrated the feasibility of employing a data-driven multiomics approach to predict treatment outcomes in BM patients receiving PULSAR treatment. Integrating multiomics with intra-treatment decision support in PULSAR shows promise for optimizing patient management and reducing the risks of under- or over-treatment.

IMMUNE AND MOLECULAR CORRELATES OF RESPONSE TO IMMUNOTHERAPY REVEALED BY BRAIN-METASTATIC MELANOMA MODELS.

Despite the promising results of immune checkpoint blockade (ICB) therapy, outcomes for patients with brain metastasis (BrM) remain poor. Identifying resistance mechanisms has been hindered by limited access to patient samples and relevant preclinical models. Here, we developed two mouse melanoma BrM models that recapitulate the disparate responses to ICB seen in patients. We demonstrate that these models capture the cellular and molecular complexity of human disease and reveal key factors shaping the tumor microenvironment and influencing ICB response. BR1-responsive tumor cells express inflammatory programs that polarize microglia into reactive states, eliciting robust T cell recruitment. In contrast, BR3-resistant melanoma cells are enriched in neurological programs and exploit tolerance mechanisms to maintain microglia homeostasis and limit T cell infiltration. In humans, BR1 and BR3 expression signatures correlate positively or negatively with T cell infiltration and BrM patient outcomes, respectively. Our study provides clinically relevant models and uncovers mechanistic insights into BrM ICB responses, offering potential biomarkers and therapeutic targets to improve therapy efficacy.

Predictors of brain metastases in patients with oligometastatic solid tumours treated with stereotactic body radiation therapy.

In patients with oligometastatic disease (OMD) treated with stereotactic body radiation therapy (SBRT), those who develop brain metastases (BrM) may have poor outcomes. We aimed to investigate variables associated with BrM development in this population. Patients with ≤ 5 extracranial metastases from solid tumors treated with SBRT from 2008 to 2016 at Sunnybrook Odette Cancer Centre were included. We investigated the association between covariates and CIBrM (cumulative incidence of BrM) using Fine-Gray analysis, and progression-free survival (PFS) and overall survival (OS) using Cox regression. We investigated the association between extracranial progression and CIBrM using time-based conditional analysis. Among 404 patients, the most common primary sites were lung, colorectal, prostate, breast and kidney. Median follow-up was 49 months. Median PFS was 25 months. Median OS was 70 months. 58 patients developed BrM, and 5-year CIBrM was 16%. On multivariable analysis, number of extracranial metastases, location of metastases, total planning target volume (PTV), and time from primary diagnosis to OMD were not associated with CIBrM, although several of these variables were associated with extracranial PFS and OS. Primary site was associated with CIBrM, with colorectal and prostate cancer associated with lower CIBrM compared to lung cancer. Widespread extracranial progression (≥ 5 sites) within 24, 36, 48 and 60 months of OMD diagnosis was independently associated with higher CIBrM. In patients with OMD treated with SBRT, baseline variables related to extracranial disease burden and distribution were not associated with BrM development, while primary site and widespread extracranial progression were associated with BrM development.

MTAS-02 PREDICTORS OF BRAIN METASTASIS IN CANCER PATIENTS IN CAMEROON

Abstract BACKGROUND Cancer still remains one of the leading causes of death globally, with higher burden faced by low- and middle-income countries. A third of all brain tumors are attributed to metastatic disease. However, in Cameroon, there is scarcity of data assessing predicting factors associated with brain metastasis patients. METHODS We conducted a review of patient records from the 1/1/2020 to 31/12/2023 at the oncology center in Douala, Cameroon. Multivariate logistic regression was used to assess for potential predictors associated with brain metastasis. RESULTS Overall, 1500 patient charts were reviewed. A total of 229 charts (15.3%) were complete. Majority of patients were female 159(69.4%), and the mean age was 52.2 (SD=15.7). The proportion of cancer patients with brain metastasis was 15.7%(n=36), with breast cancer accounting most for metastasis 17(47.2%). Age and primary tumor size were the factors significantly (p =0.033 and p= 0.037 respectively) associated with brain metastasis. CONCLUSION Brain metastasis was common in patients with breast cancer. Age and primary tumor size play a key role in predicting development of brain metastasis in this study group. LIMITATIONS 1. Majority of reviewed charts had incomplete information. 2. Retrospective nature of the study. 3. Single center study.