Incidence Of Brain Metastases Research Articles

The incidence of brain metastases in breast cancer according to molecular subtype and stage: a 10-year single institution analysis.

Breast cancer (BC) is the second most common etiology of brain metastases (BrM). We aimed to examine the incidence of BrM among all BC patients presenting to a large tertiary cancer centre over one decade. We included all BC patients presenting consecutively between 2009 and 2019 and cross referenced that cohort to a radiotherapy database, identifying patients treated for BrM at any time following their initial presentation. Cumulative incidences (CI) of BrM diagnoses were calculated using death as a competing risk and compared using the Fine-Gray method. Overall survival was estimated using the Kaplan Meier method. We identified 12,995 unique patients. The CI of BrM in patients who initially presented with Stage 0-4 disease was 2.1%, 3.7%, 9.4%, 10.6%, and 28.7%, respectively at 10years. For 8,951 patients with available molecular subtype data, 6,470 (72%), 961 (11%), 1,023 (11%), and 497 (6%) had hormone-receptor (HR)-positive/ERBB2-, HR-negative/ERBB2-, HR-positive/ERBB2 + , and HR-negative/ERBB2 + disease, respectively; the CI of BrM in each was 7.6%, 25.3%, 24.1%, and 26.6%, at 10years following BC diagnosis, respectively. Median overall survival (OS) following BC diagnosis and BrM diagnosis was 28years 95% CI [25, 32] and 10months 95% CI [9, 12], respectively. From a large, registry-based study, we observed that patients with ERBB2 + and triple negative BC have the highest incidence of BrM. Our data supports prospective surveillance brain MRI studies. Given advancements in BrM treatment, clinicians should have a low threshold for brain imaging in BC patients with high risk subtypes.

Abstract PO2-27-09: Clinical impact of routine MRI screening for brain metastases in patients with HER2 positive or triple negative metastatic breast cancer

Abstract Background: Routine screening for brain metastases (BMs) is currently not recommended in patients with metastatic breast cancer (BC). There is a growing consensus on the need for the screening of BMs in HER2 positive and triple negative breast cancer (TNBC) because 40% of patients experience BMs throughout the disease course and systemic treatment options with intracranial efficacy are now available. However, there is a lack of prospective study data on this matter. We conducted a prospective cohort study to evaluate the role of brain MRI screening for the patient with metastatic BC. Methods: Patients who newly diagnosed metastatic HER2+ or TNBC were eligible. Screening brain MRI was planned at diagnosis and failure from first line and second line of systemic therapy. All patients underwent complete physical examination and comprehensive neurologic assessment at baseline and thereafter. Patients who diagnosed symptomatic BMs were dropped from the study and subsequent treatment including local therapies and survival data were collected. Primary endpoint was the percentage of patients diagnosed with asymptomatic BMs. Results: A total of 147 patients were enrolled between Sep 2018 and Aug 2023 at Yonsei Cancer Center. The median age was 51 years (range, 29-80) and most patients (92.5%, n=136) had good performance status (ECOG 0-1). The tumor subtypes were as follows: TNBC, 51.0%; HER2 (ER-, HER2+), 29.3%; luminal-HER2 (ER+, HER2+), 19.7%. The cumulative incidence of asymptomatic BMs was 20.4% for overall patients; 24.0% for TNBC (18/75), 14.0% for HER2 (6/43), and 20.7% for luminal HER2 (6/29). Symptomatic detection of BMs during study period was 14.7% for TNBC, 18.6% for HER2, and 6.9% for luminal-HER2. Initial local treatment was stereotactic radiosurgery in 30 patients (58.8%), whole-brain radiation therapy in 14 patients (27.5%), surgical resection in 2 patients (3.9%) and 6 patients (11.8%) did not receive any treatment for BMs. After a median follow-up of 20.1 months, the median overall survival following a diagnosis of BMs was 23.7 vs 7.3 months (hazard ratio 0.41; 95% CI, 0.17 to 0.95; P = .04) in patients with asymptomatic and symptomatic BMs, respectively. Conclusions: We identified approximately 20% of patients with HER2+ or TNBC as asymptomatic BMs. Emerging systemic therapies showed promising intracranial response would warrant the detection of asymptomatic BMs through routine MRI screening. Incidence of brain metastases by subtypes Citation Format: Gun Min Kim, Joo Hyuk Sohn, Min Hwan Kim, Seul-Gi Kim, Hyung Soon Park, Jong Hee Jang, Yong Bae Kim, Seung-koo Lee. Clinical impact of routine MRI screening for brain metastases in patients with HER2 positive or triple negative metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-27-09.

Abstract PS11-01: Brain metastases in metastatic breast cancer: prevalence per line of treatment and cumulative incidence in a cohort of 18075 real-world patients

Abstract BACKGROUND Historic data suggest that incidence of brain metastasis (BM) is relatively distributed over time in HER2-positive (HER2+) breast cancer (BC), occurs early in triple negative BC (TNBC), and occurs late in hormone receptor-positive (HR+) metastatic BC (mBC). However, the timing of BM relative to line of therapy has not been well described. We describe the prevalence per line of therapy and cumulative incidence of BM in a large real-world cohort of patients (pts) with mBC, by BC subtype and line of therapy. METHODS This analysis used data from the longitudinal US Flatiron Health de-identified database, which provides unstructured and structured electronic health record-derived data from >2.6 million pts with cancer in ~800 unique sites of care. Eligible pts had initiated a first line of treatment (index data) for mBC up to March 1, 2021, to allow for ≥2 years potential follow-up time. Baseline characteristics were assessed, and pts categorized by HER2 and HR status: 1) HR+, HER2+; 2) HR+, HER2–, 3) HR–, HER2+ and 4) TNBC (i.e., negative for HR and HER2). For the last two categories, HER2-low subsets were defined based on immunohistochemistry results (1+, 2+, or equivocal). Lines of therapy were derived using both treatment regimens and progression data. The primary outcome was the first diagnosis of BM. The prevalence of BM was evaluated by subtype, at the index date, and by the line of therapy. The cumulative incidence function (CIF) of BM was used to estimate the risk of BM in pts free of BM at the index date, and death was treated as a competing event. RESULTS Overall, 18075 pts were included (HR+, HER2+: 3062 pts [16.9%]; HR–, HER2+: 902 pts [5.0%]; HR+, HER2–: 12331 pts [68.2%] [HR+, HER2-low: 7062 (39.1%)]; TNBC: 1780 pts [9.8%] [HR–, HER2-low: 725 pts (4.0%)]). Median age at the index date was 64 years (interquartile range: 54, 73) and 10271pts (56.8%) had visceral metastasis. In total, 5951 pts (32.9%) had de novo disease, 12090 (66.9%) had recurrent disease, and 34 (0.2%) did not have available data for mBC type. The table shows the number of pts by line of therapy, prevalence of BM, and cumulative incidence of BM from the index date. Of the included pts, 1306 (7.2%) had a BM at the index date; the CIF was run on the remaining 16973 pts. Overall, 2248 pts (13.2%) had an incident BM event during follow-up (HR+, HER2+: 578 events; HR–, HER2+: 237 events; HR+, HER2–: 1119 events [HR+, HER2-low: 619 events]; TNBC: 314 events [HR–, HER2-low: 124 events]), 9314 had a competing event, and 5411 were censored. By fourth-line therapy, the prevalence of BM was 26.1% in HR+, HER2+; 37.1% in HR–, HER2+; 24.7% in TNBC (HR–, HER2-low: 27.9%); but remained low at 7.2% in HR+, HER2– (HR+, HER2-low: 9.4%). The cumulative incidence of BM at 60 months was 23% in HR+, HER2+, 34% in HR–, HER2+, 10% in HR+, HER2–, and, 22% in TNBC. Overall, the HER2-low subsets had BM prevalence and cumulative incidence that were very close to those that were HER2–. CONCLUSIONS This large analysis of real-world data demonstrates that the prevalence of BM across pts with mBC differs by tumor subtype and by line of therapy. Conversely, HER2-low status may have limited impact. The cumulative incidence of BM was highest in the HR–, HER2+ and TNBC subgroups, and lowest in the HR+, HER2– subgroup; despite this, due to the high proportion of HER2–, HR+ mBC cases, the HR+, HER2– group represented the largest number of BM events. These data emphasize the need for clinical and biologic predictors of BM and for strategies to prevent their onset, and provide information on the impact of BM inclusion and exclusion criteria in clinical trials for pts with mBC. Number of patients by line of therapy, prevalence of BM, and cumulative incidence of BM from the index date BM, brain metastasis; HR, hormone receptor, pts, patients; TNBC, triple negative breast cancer. Citation Format: Sarah Sammons, Jose Leone, Thibaut Sanglier, Peter Lambert, Filippo Montemurro, Raf Poppe, Eleonora Restuccia, Sara Tolaney, Nancy Lin. Brain metastases in metastatic breast cancer: prevalence per line of treatment and cumulative incidence in a cohort of 18075 real-world patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-01.

Abstract PO5-07-11: Use of 64Cu-DOTA trastuzumab -PET to predict response to trastuzumab-deruxtecan (TDXd) in patients with metastatic disease to the brain: Study in Progress

Abstract Background: We have utilized 64Cu-DOTA trastuzumab-PET imaging in patients with advanced breast cancer. In our experience, uptake on 64Cu-DOTA trastuzumab-PET correlated with the qualitative assessment of HER2 by IHC. In women treated with the antibody-drug conjugate (ADC), ado-trastuzumab emtansine (TDM1), we identified a threshold level of 64Cu-DOTA trastuzumab-PET uptake that predicted for lack of response to TDM1. As patients are living longer with advanced breast cancer, the incidence of brain metastasis has increased. The ADC, trastuzumab-deruxtecan (T-DXd) has demonstrated activity in patients with metastatic HER2 positive breast cancer with brain metastases. The DESTINY 04 trial included patients with HER2 1+ and 2+ disease and demonstrated superior survival compared to standard of care. It is not feasible to biopsy all brain metastases to determine tumor markers. Given the increased incidence of brain metastases in this population and the efficacy of T-DXd in patients with HER2+ metastatic disease to the brain, we initiated a study of 64Cu-DOTA trastuzumab-PET/MRI of the brain prior to institution of T-Dxd. Endpoints Primary: 1. 64Cu-DOTA-trastuzumab PET-CT will identify tumor heterogeneity of trastuzumab uptake in women with metastatic breast cancers. 2. The degree of uptake of 64Cu-DOTA-trastuzumab PET-CT will predict for response to Enhertu. Secondary: 1. Uptake of 64Cu-DOTA-trastuzumab PET-CT will be predictive of response duration to Enhertu. Eligibility: Patients must have documented recurrent breast cancer that is HER2 1+, 2+ or 3+, evidence of brain metastases by CT or MRI of the brain and are candidate for treatment with trastuzumab-deruxtecan. The CNS disease must be stable and not in need of intervention. Methods: Prior to treatment staging workups includes pathologic review of HER2 status, disease staging with 18FDG-PET or CT of the chest/abdomen/pelvis and bone scan, and 64Cu-DOTA-trastuzumab PET/MRI of the brain. After initiation of T-Dxd, MRI of the brain is repeated every 6 weeks for the first 24 weeks and every 9 weeks thereafter. Progress: We have enrolled 1 patients to date, received PET and dynamic contrast-enhanced MRI. Four lesions were analyzed in this patient. The mean values of Ktrans (volumetric perfusion to tumor, s−1) in these lesions near a prior resection cavity were 0.210 s−1, indicating sufficient perfusion for ADC uptake. Corresponding to this perfusion data, the mean SUVmax of these lesions on the 64Cu-DOTA-trastuzumab PET scans was 5.38. Citation Format: Joanne Mortimer, Kofi Poku, Jessica Liu, Russell Rockne, Chen Bihong, Ryan Woodall, Vikram Adhikarla. Use of 64Cu-DOTA trastuzumab -PET to predict response to trastuzumab-deruxtecan (TDXd) in patients with metastatic disease to the brain: Study in Progress [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-07-11.

Abstract PO5-16-01: Clinicogenomic analysis reveals genomic associations of brain metastatic tropism in breast cancer

Abstract Introduction: Recent progress in imaging and therapeutics has led to improvements in the treatment of advanced breast cancer. However, the incidence of brain metastasis (BM) in breast cancer is increasing and continues to be associated with poor prognosis and significant morbidity. Herein, we describe genomic enrichments associated with brain tropism from a large institutional clinico-genomic cohort. Methods: Patients who underwent tumor and matched normal sequencing utilizing hybridization-capture based targeted exonic sequencing (MSK-IMPACT) from April 2014 to March 2023 were included in this analysis; this cohort included 6,377 samples from 5,135 patients. We analyzed genomic data to inform the full spectrum of somatic and germline mutations, copy number changes and structural variants enriched in samples in resected BM specimens (n = 179), compared to primary tumors (n = 2980), stratified by receptor status. Enrichment analysis was conducted using a Fisher exact test for each respective receptor status. Similar analyses were conducted between extracranial metastatic (ECM) sites (n = 3186) and primary tumors, to differentiate the unique genomic features driving the emergence of BM as compared to general metastatic propensity. Multiple hypothesis testing was performed using Benjamini-Hochberg. Further genomic analysis, including allele specific copy number changes and mutational signatures will be reported at the 2023 SABCS meeting. Results: Oncogenic alterations in several genes were found to be enriched in BM samples compared to primary tumor, with an odds ratio exceeding that of the corresponding ECM comparison. For example, in the HR+/HER2- subset (4329 samples from 3476 patients), pathogenic variants in the following genes were enriched in BM:Primary analysis: NF1 (OR 6.4 [2.9 – 13.7], q = 0.001, 15.5% of BM), MYC (OR 3.9 [2.0 – 7.4], q = 0.001, 24.4% of BM), AGO2 (5.2 [2.4 – 10.9], q= 0.002, 15.5% of BM), CDKN2A (OR 3.9 [1.6 – 9.4], q = 0.06, 10.3% of BM), ERBB2 (OR 3.6 [1.5 – 8.6], q = 0.06, 10.3% of BM), RB1 (OR 4.2 [1.5 – 11.4], q = 0.06, 8.6% of BM), TP53 (OR 2.0 [1.1 – 3.5], q = 0.07, 40% of BM). In contrast, ESR1 variants were enriched in BM:Primary (OR 14.0 [6.7 – 28.2], but at the same level as ECM:Primary (OR 12.3 [8.7 – 17.7]). When considering HER2+ tumors (919 samples from 739 patients), only NKX.3 was enriched in the BM:Primary comparison (OR 11.5 [3.2 – 42.3], q = 0.004, 11.6% of BM). Although no TNBC samples met significance thresholds after adjustment for multiple hypothesis testing, CDH1, NTRK1, EGFR, and TP53 emerged as putatively significant. Conclusions: In a large cohort of genomically-profiled breast cancer samples, we find recurrent involvement of genes involved in cell cycle regulation (RB1, CDKN2A, TP53); these have been found to be enriched in brain metastases from other cancer types and are implicated in resistance to common lineage-directed therapies. Our approach also uncovered several targets for which therapies are actively in development (ERBB2, MYC). Further study of genomic evolution of breast cancer in the context of brain metastasis and therapeutic resistance will uncover conserved site-specific genomic changes and will identify novel, rational therapeutic targets. Citation Format: Anton Safonov, Deborah Smith, Emanuela Ferraro, Junchao Shen, Ishaani Khatri, Rahul Kumar, Julia An, Mark Robson, Sarat Chandarlapaty, Adrienne Boire, Nikolaus Schultz, Nelson Moss, Luke Pike, Pedram Razavi. Clinicogenomic analysis reveals genomic associations of brain metastatic tropism in breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-16-01.

Incidence of hippocampal and perihippocampal brain metastases and impact on hippocampal-avoiding radiotherapy: A systematic review and meta-analysis

Background and PurposeIn patients requiring prophylactic cranial irradiation (PCI) or whole-brain radiotherapy (WBRT) for brain metastases (BMs), hippocampal avoidance (HA) has been shown to preserve neurocognitive function and quality of life. Here, we aim to estimate the incidence of hippocampal and perihippocampal BMs and the subsequent risk of local undertreatment in patients undergoing hippocampal sparing radiotherapy. Materials and MethodsMEDLINE, Embase, and Scopus were searched with the terms “Hippocampus”, “Brain Neoplasms”, and related terms. Trials reporting on the incidence of hippocampal and/or perihippocampal BMs or hippocampal failure rate after PCI or WBRT were included. ResultsForty records were included, encompassing a total of 5,374 patients with over 32,570 BMs. Most trials employed a 5 mm margin to define the HA zone. In trials reporting on BM incidence, 4.4 % (range 0 − 27 %) and 9.2 % (3 − 41 %) of patients had hippocampal and perihippocampal BMs, respectively. The most common risk factor for hippocampal BMs was the total number of BMs. The reported failure rate within the HA zone after HA-PCI or HA-WBRT was 4.5 % (0 − 13 %), salvageable with radiosurgery in most cases. SCLC histology was not associated with a higher risk of hippocampal failure (OR = 2.49; p = 0.23). In trials comparing with a conventional (non-HA) PCI or WBRT group, HA did not increase the hippocampal failure rate (OR = 1.90; p = 0.17). ConclusionThe overall incidence of hippocampal and perihippocampal BMs is considerably low, with a subsequent low risk of local undertreatment following HA-PCI or HA-WBRT. In patients without involvement, the hippocampus should be spared to preserve neurocognitive function and quality of life.

Abstract 5521: Nicotine promotes perineural brain metastasis of lung cancer by activating GABAergic neurons

Abstract Tobacco smoking significantly increases the incidence of brain metastasis. However, the pathological mechanism by which smoking promotes brain metastasis through modulating brain microenvironment is yet poorly understood. We previously showed that the incidence of brain metastasis is associated with nicotine intake. Nicotine enhanced polarization of M2 pro-tumor microglia, which promoted brain metastasis. In addition to the immune surveillance role, microglial cells also control neuronal synapse formation. Microglial cells promote neuron synapse formation in the developing brain, whereas microglia depletion suppresses synapse density. Furthermore, microglia-secreted microRNAs (miRNAs) have been shown to promote synaptic formation by targeting synapse-related genes of the DKK-Wnt family. Neurons are one of the most abundant cell types in the brain, and they are highly specialized for cell-to-cell signal activation. However, little is known about the roles of neurons in brain metastasis of lung cancer. We hypothesize that nicotine stimulates microglia to secrete exosomal miR-32-3p, which promotes brain metastasis by augmenting GABAergic synaptic formation and hence releasing GABA that serves as a metabolic substrate to fuel tumor cell growth. We also hypothesize that inhibiting the GABA transporter of tumor cells suppresses brain metastasis by blocking the GABA shunt. We found that lung cancer patients with a smoking history had significantly higher synaptic formation and the expression of GABA transporter in brain metastasis. To investigate the effect of smoking and nicotine intake on brain metastasis in vivo, mice were intracardially transplanted with lung cancer brain metastasis cells (H2030BrM and PC9BrM) followed by administration of nicotine or cigarette smoke exposure in a smoking chamber. We found that smoking and nicotine increased M2 microglia polarization, synaptic formation, and the expression of GABA in mouse brain metastasis. Furthermore, nicotine increased the secretion of miR-32-3p from nicotine-pretreated microglia, which promoted GABA release from GABAergic neurons. Treating H2030BrM and PC9BrM cells with conditioned medium (CM) obtained from neurons exposed to CM derived from nicotine-treated microglia exosomes resulted in increased tumor growth through the activation of the GABA shunt pathway. Blocking GABA transporter 1 (GAT1) by CRISPR/Cas9 or a small molecule of GAT1 inhibitor suppressed the GABAergic neuron-induced tumor progression. Our results indicate that nicotine-activated microglia enhanced GABA release from neurons followed by the promotion of GABA shunt in tumor cells and that a GAT inhibitor serves as a promising therapeutic tool for the treatment of lung cancer patients with brain metastasis. Citation Format: Shih-Ying Wu, Abhishek Tyagi, Ravindra Pramod Deshpande, Kerui Wu, Eleanor Cecile Smith, Kounosuke Watabe. Nicotine promotes perineural brain metastasis of lung cancer by activating GABAergic neurons [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5521.

Abstract 4139: Prolyl 4-hydroxylase subunit alpha 1 acts as a novel target for lung adenocarcinoma brain metastasis

Abstract Lung cancer is the most lethal cancer worldwide, with a high incidence of distant metastasis. Many lung adenocarcinoma (LUAD) patients experience brain metastasis during the disease process with unfavorable prognosis. Our previous study has discovered that P4HA1 was exclusively upregulated in brain metastatic cells. Through the analysis of single-cell RNA sequencing of LUAD samples, we found that the expression of P4HA1 in brain metastatic tumor cells is higher than that in primary tumor cells. This finding was further confirmed by immunohistochemical staining. Significantly, a strong presence of P4HA1 in primary tumors is associated with a reduced duration of disease-free survival in individuals with LUAD. Overexpression of P4HA1 in A549 and PC9 cell lines significantly increased the incidence of brain metastasis in BALB/c nude mice, whereas knockdown of P4HA1 in high brain metastatic cells significantly decreased the incidence of brain metastasis and reduced the tumor foci in brain with improved survival. Utilization of DHB, a P4HA1 inhibitor, exerts both therapeutic and preventive effects in relieving brain metastases in nude mice. Furthermore, remarkable inhibition of tumor growth by DHB was observed in patient derived xenograft (PDX) models. RNA sequencing analysis demonstrated that the reduction of P4HA1 expression had a substantial impact on cell adhesion and extracellular matrix (ECM)-receptors interactions. Western blotting analysis verified that the decrease in P4HA1 expression led to a drop in the expression of adhesion molecules ICAM1, VCAM1, NCAM1, as well as integrin molecules ITGA2 and ITGA3. Furthermore, when endothelial cells were co-cultured with conditioned medium from tumor cells, it was observed that the expression of the tight junction molecule ZO1 was reduced after co-culturing with conditioned medium from P4HA1 knockdown A549 cells. The results from the in vitro blood-brain barrier (BBB) model and in vivo biofluorescence imaging indicate that P4HA1 promoted brain metastasis of LUAD via modulating the ability of tumor cells to cross the blood-brain barrier. In conclusion, our study reveals that overexpression of P4HA1 promotes metastatic spread to the brain, and targeting P4HA1 could be a promising therapeutic strategy for the treatment of lung adenocarcinoma brain metastasis. Citation Format: Yan He, Zhenyu Luo, Yucheng Dong, Rui Wan, Xue Zhang, Hua Bai, Jie Wang. Prolyl 4-hydroxylase subunit alpha 1 acts as a novel target for lung adenocarcinoma brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4139.

Abstract 4798: MRI screening for brain metastases (BrM) versus SYMptom-directed brain imaging for patients with triple negative (TN) or HER2+ metastatic breast cancer (MBC): An ad-hoc interim analysis of a randomized phase II pilot study

Abstract Background: Patients with HER2+ or TN MBC are at high risk of developing BrM, but the role of MRI screening for early detection of asymptomatic BrM has not yet been established. Methods: We conducted a multicentre phase II pilot study, which randomized patients with TN or HER2+ MBC to 1 year of BrM screening (contrast enhanced brain MRI at baseline, 4, 8, and 12 months) versus a control arm of symptom directed brain imaging (MRI only if symptoms of BrM develop). The primary goal was to determine the feasibility of a future randomized trial of BrM screening versus symptom-directed imaging in this patient population. Key inclusion criteria were age ≥18; TN MBC diagnosed ≤12 weeks prior to study entry or HER2+ MBC with no restrictions regarding time of diagnosis; no symptoms of BrM or known asymptomatic BrM; ECOG ≥ 1 and no MRI contraindications. Overall (EORTC QLQ BN20) and neurologic-specific (FACT-BR tools) quality-of-life as well as cancer-related anxiety (NCI PRO-CTCAE) were assessed at baseline, 6 and 15 months. Criteria rendering a future trial “not feasible” were defined a-priori as: <30% of eligible patients enroll in the study, <50% complete the study protocol, and/or >50% of patients allocated to the control arm during the 1 year study period are screened for asymptomatic BrM with CT or MRI. Results: Between 2018 and 2023, 44 patients from 3 participating centres enrolled in the study. Thirty-five participants (80%) had HER2+ and 9 (20%) had TN MBC. Of the 22 patients randomized to each of the study arms; 3 patients (8%) in each arm withdrew prior to study completion. Reasons for withdrawal included claustrophobia (n=3) or discontent with their randomised arm (n=3) or follow-up requirements (n=1). Metrics regarding the proportion of eligible patients who enrolled in the study were only collected from the Sunnybrook Odette Cancer Centre site; of 91 patients approached, 38 (42%) enrolled in the study. Within the 12-month study period, the incidence of BrM among patients in the screening arm was n=3 (14%) versus n=4 (18%) in the control arm. To-date among patients in the study arm, 11 (50%) completed the 12-month screening protocol, 5 (23%) remain on study and 6 (27%) did not complete the protocol due to either death or early study withdrawal. Among patients in the control arm, 10 (45%) completed 12-month follow-up, 4 (18%) remain on study and 8 (36%) did not complete follow-up due to either death or early study withdrawal. In total, 13 patients (59%) in the control arm had brain imaging, 4 in the absence of neurological symptoms. Conclusion: A large randomized trial to investigate the utility of MRI-based surveillance for asymptomatic detection of BrM in the proposed patient population is likely feasible, although episodic brain imaging in the control arm was common. Analysis of patient reported outcomes is ongoing. Citation Format: Katarzyna Joanna Jerzak, Megan Shum, Gregory Pond, Orit Freedman, Gursimran Chandhoke, Tatiana Conrad, Priscilla Brastianos, Gregory Stanisz, Arjun Sahgal, Ellen Warner. MRI screening for brain metastases (BrM) versus SYMptom-directed brain imaging for patients with triple negative (TN) or HER2+ metastatic breast cancer (MBC): An ad-hoc interim analysis of a randomized phase II pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4798.

Abstract 5551: Targeted nanoparticles co-delivering PARP inhibitor and other immune modulators overcome the immunosuppressive tumor microenvironment

Abstract Several mutations have been identified that are associated with an increased risk of triple-negative breast cancer (TNBC), including those that are deleterious in the BRCA gene. TNBC is associated with the worst prognosis and the highest incidence of brain metastasis (30%) among all subtypes of BC. Despite objective responses to poly (ADP-ribose) polymerase (PARP) inhibition and improvements in progression-free survival (PFS) compared to standard chemotherapy in patients with BRCA-mutated TNBC, benefits are transitory. Furthermore, our understanding of the effect of PARP inhibitors (PARPi) in treating breast cancer brain metastasis (BCBM) and modulating its tumor microenvironment (TME) is still lacking. To this end, we analyzed the brain TME of BRCA-mutated BCBM in the absence or presence of treatment with PARPi. Interestingly, we found that the immune TME of the brain hinder the antitumor activity of PARPi by upregulating multiple immunosuppressive molecules, including PD-L1. Furthermore, we found that BCBM overexpress P-selectin through its interaction with the tumor-associated microglia, bone marrow-derived macrophages and endothelial cells in the TME. Thus, we designed a novel nanoparticle (NP) targeting P-selectin to serve as a brain-penetrant delivery system for the treatment of BCBM. In order to target BRCA-mutated BCBM, we harnessed our novel P-selectin-targeted NPs to entrap PARPi and other immune modulators that we found to exert synergistic activity when combined. To evaluate the antitumor activity of our P-selectin-targeted NPs, we established 3-dimensional (3D) ex vivo and in vivo BRCA-mutated BCBM models. Importantly, we saw favorable effects of the P-selectin-targeted NPs in comparison to the combination of the free drugs, suggesting that out targeted-NPs overcome the TME-mediated resistance to PARPi through the modulation of the immunosuppressive microenvironment of the brain. Citation Format: Rami Khoury, Ron Kleiner, Eilam Yeini, Daniel Rodriguez Ajamil, Sahar Israeli Dangoor, Tamer Sanalla, Iris Barshack, Roni Satchi-Fainaro. Targeted nanoparticles co-delivering PARP inhibitor and other immune modulators overcome the immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5551.

Surgical excision and radiotherapy for brain metastasis from colorectal cancer: How frailty and comorbidity indices influence outcome.

The incidence of brain metastasis (BM) from colorectal cancer (CRC) is increasing. This study aims to identify the clinical prognosticators and evaluate the prognostic validity of common comorbidity indices in patients with BM from CRC. This retrospective single-center study analyzed 93 patients with BM from CRC who received surgical excision and/or radiotherapy. The clinical characteristics and prognostic indices including the 5-item modified frailty index (mFI-5) and prognostic nutritional index (PNI) were calculated from the collected patient data and analyzed. In this study, 66 (71.0%), 10 (10.8%), and 17 (18.3%) patients received whole-brain radiotherapy (WBRT) alone, surgery alone, and surgery plus WBRT, respectively. The median survival of all patients was 3.98 months (IQR: 1.74-7.99). The 2- and 3-year survival rates were 7.4% and 3.7%, respectively. Controlled primary tumor (p = 0.048), solitary BM (p = 0.001), surgery + radiation (p < 0.001), and greater PNI (p = 0.001) were independent predictors of favorable survival. In surgically treated patients, uncontrolled primary tumor (p = 0.006), presence of multiple BM (p < 0.001), and MFI-5 ≥ 2 (p = 0.038) were independent prognosticators. For patients who received WBRT, the presence of two (p = 0.004) or multiple (p < 0.001) BM and PNI (p < 0.001) were independent survival predictors MFI-5, multiple BM, and the status of the primary tumor were independent prognosticators for patients who underwent surgery for CRCBM. For patients who received WBRT, the PNI and the number of BM were independent survival predictors.

O-Glycome Profiling of Breast Cancer Cell Lines to Understand Breast Cancer Brain Metastasis.

Breast cancer is the second leading cause of cancer-related death among women and a major source of brain metastases. Despite the increasing incidence of brain metastasis from breast cancer, the underlying mechanisms remain poorly understood. Altered glycosylation is known to play a role in various diseases including cancer metastasis. However, profiling studies of O-glycans and their isomers in breast cancer brain metastasis (BCBM) are scarce. This study analyzed the expression of O-glycans and their isomers in human breast cancer cell lines (MDA-MB-231, MDA-MB-361, HTB131, and HTB22), a brain cancer cell line (CRL-1620), and a brain metastatic breast cancer cell line (MDA-MB-231BR) using nanoLC-MS/MS, identifying 27 O-glycan compositions. We observed significant upregulation in the expression of HexNAc1Hex1NeuAc2 and HexNAc2Hex3, whereas the expression of HexNAc1Hex1NeuAc1 was downregulated in MDA-MB-231BR compared to other cell lines. In our isomeric analysis, we observed notable alterations in the isomeric forms of the O-glycan structure HexNAc1Hex1NeuAc1 in a comparison of different cell lines. Our analysis of O-glycans and their isomers in cancer cells demonstrated that changes in their distribution can be related to the metastatic process. We believe that our investigation will contribute to an enhanced comprehension of the significance of O-glycans and their isomers in BCBM.

Treatment outcomes and prognostic factors in patients with driver mutant non-small cell lung cancer and de novo brain metastases

Central nervous system (CNS) metastases can be seen at a rate of 30% in advanced stages for patients with non-small cell lung cancer (NSCLC). Growing evidence indicates the predictive roles of driver gene mutations in the development of brain metastases (BM) in recent years, meaning that oncogene-driven NSCLC have a high incidence of BM at diagnosis. Today, 3rd generation targeted drugs with high intracranial efficacy, which can cross the blood–brain barrier, have made a positive contribution to survival for these patients with an increased propensity to BM. It is important to update the clinical and pathological factors reflected in the survival with real-life data. A multi-center, retrospective database of 306 patients diagnosed with driver mutant NSCLC and initially presented with BM between between November 2008 and September 2022 were analyzed. The median progression-free survival (mPFS) was 12.25 months (95% CI, 10–14.5). While 254 of the patients received tyrosine kinase inhibitor (TKI), 51 patients received chemotherapy as first line treatment. The median intracranial PFS (iPFS) was 18.5 months (95% CI, 14.8–22.2). The median overall survival (OS) was 29 months (95% CI, 25.2–33.0). It was found that having 3 or less BM and absence of extracranial metastases were significantly associated with better mOS and iPFS. The relationship between the size of BM and survival was found to be non-significant. Among patients with advanced NSCLC with de novo BM carrying a driver mutation, long-term progression-free and overall survival can be achieved with the advent of targeted agents with high CNS efficacy with more conservative and localized radiotherapy modalities.

Abstract B004: Clinico-genomic characteristics of breast cancer brain metastasis: A multi-institutional analysis from AACR Project GENIE BPC

Abstract Purpose: The presence of Her2 amplification is associated with an increased risk of developing brain metastases. Brain metastases in breast cancer can be particularly challenging and have significant implications for prognosis and treatment. Common Her2-targeted therapies and small tyrosine kinase inhibitors have demonstrated the ability to penetrate the blood brain barrier and be effective in treating brain metastases. We investigated the clinico-genomic characteristics and the prognosis of brain metastasis in patients with breast cancer. Experimental design: Patients with breast cancer whose tumors underwent targeted sequencing from 2013-2018 at age 56 years old or younger at three institutions from the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (AACR Project GENIE BPC) registry were selected for data curation. The PRISSMM data model was used for real world outcomes including overall survival. We analyzed clinical and genomic characteristics, treatment, and clinical outcome data among patients with and without brain metastases, stratified by Her2 amplification and hormone-receptor status (Her2+ vs. Her2-/HR+ vs. triple-negative breast cancer (TNBC)). We explored the top 20 most frequently altered genes that were included on at least 20% of sequencing panels. Results: A total of 1019 patients with breast cancer along with their receptor subtype information were included in the study (110 patients were excluded due to either post- mortem sequencing or unknown receptor subtype). Among them, 336 (33%) patients were identified to have developed brain metastasis (n=87 with Her2+; n=181 with Her2-/HR+; and n=68 with TNBC). At time of advanced disease, the brain was the first and only distant site of disease in 41/336 (12%) and detected with extracranial sites of disease in 22/336 (7%) patients. For patients presenting with stage I-III breast cancer, the cumulative incidence of brain metastasis at 5 years from breast cancer diagnosis was higher in those with TNBC (35%; 95% CI: 25, 50) as compared to 24% (95% CI: 16, 37) and 21% (95% CI: 15, 29) for those with Her2+ and Her2-/HR+ subtypes, respectively. Median overall survival from brain metastasis was significantly longer (log-rank p&amp;lt;0.001) for those with Her2+ disease (19m, 95% CI: 13, 36) compared to those with Her2-/HR+ (8.9m, 95% CI: 6.3, 15) or TNBC (7.4m, 95% CI: 4.6, 11). Among patients who ever developed brain metastases, IKZF3 alterations occurred in 71% (20/28) of Her2+ patients but did not occur in either Her2- subtype. Additionally, frequencies of CDK12, MYC, and PTEN alterations differed across subtypes. Conclusions: Brain involvement at metastatic presentation conferred a higher risk of death than brain-sparing metastases. Triple negative and Her2+ histologies were associated with higher risk of brain involvement at metastasis presentation. Further exploration by treatment received across receptor subtypes and genomic alterations will be presented. Citation Format: Samantha Brown, Hannah E. Fuchs, Jessica A. Lavery, Katherine S. Panageas, Nelson S. Moss. Clinico-genomic characteristics of breast cancer brain metastasis: A multi-institutional analysis from AACR Project GENIE BPC [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B004.

Clinical characteristics, outcomes and prognostic factors in KRAS mutant lung cancers: experience from a tertiary care cancer center in India.

Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations in lung cancers, long considered untargetable, have had a recent rise in interest due to promising data of agents targeting KRAS p.G12C. As Indian data are scarce, we sought to identify baseline clinical characteristics, prognostic factors and outcomes of lung cancer patients with KRAS mutations at our hospital. Patients with KRAS mutant lung cancers treated at our institute from 2016 to 2022 were analysed. 133 patients with KRAS mutant lung cancers were identified. Median age was 57 (interquartile range 28-78) years, and 58 (43.6%) were smokers. 17 (12.7%) had brain metastases. The commonest variant was p.G12C, seen in 53 (39.8%) patients. Six (4.5%) had programmed death ligand 1 (PDL-1) expression >50% by Ventana SP263 PDL-1 assay, and 13 (9.7%) had epidermal growth factor mutation. Of 92 patients with available treatment details, the majority received intravenous chemotherapy, nine (9.8%) received tyrosine kinase inhibitors and four (4.4%) received immunotherapy (pembrolizumab). Median progression-free survival (PFS) with first-line therapy was 6 (95% confidence interval (CI) 2.8-9.2) months and median overall survival (OS) was 12 (CI 9.2-14.8) months. The incidence of brain metastases was higher in patients with G12C mutations (p = 0.025). Brain metastases (HR: 3.57, p < 0.001), Eastern Cooperative Oncology Group performance status (PS) ≥ 2 (HR: 2.13, p = 0.002) and G12C mutation (HR: 1.84, p = 0.011) were associated with inferior PFS, while brain metastases (HR: 4.6, p < 0.001), PS ≥ 2 (HR: 2.33, p = 0.001) and G12C mutation (HR: 1.93, p = 0.01) were associated with inferior OS. This is the largest dataset of KRAS mutant lung cancers from India. Brain metastases were higher in patients with G12C mutations and associated with poorer PFS and OS. G12C mutation and PS ≥ 2 were also associated with inferior PFS and OS. Experience with targeted therapy for KRAS mutations remains an area of future exploration due to the unavailability of these agents in India.

Cumulative incidence and risk factors of brain metastases in metastatic non-small cell lung cancer without baseline brain metastasis: Pooled analysis of individualized patient data from IMpower130, IMpower131, and IMpower150.

The objective of this study was to explore the abilities of atezolizumab plus chemotherapy in preventing brain metastases (BMs) among metastatic non-small cell lung cancer (NSCLC) without initial BMs, as well as the risk factors of BMs. Individual patient data from three trials involving first-line atezolizumab for metastatic NSCLC (IMpower130, IMpower131, and IMpower150) were pooled. Among patients without baseline BMs and without epidermal growth factor receptor(EGFR) and/or anaplastic lymphoma kinase (ALK) mutations, those receiving atezolizumab+chemotherapy±bevacizumab were classified as the atezolizumabplus chemotherapy group and those receiving placebo+chemotherapy±bevacizumab were classified as the chemotherapy group. The cumulative incidences of BM (CI-BMs) between the two groups were compared. Other factors associated with the CI-BM were analyzed by Cox regression analyses. With a median follow-up of 17.6 months (range, 0.03-33.64 months), 74 (3.1%) of the 2380 enrolled patients developed BMs, including 50 (3.1%) and 24 (3.0%) in the atezolizumab plus chemotherapy group (n=1589) and the chemotherapy group (n=791), respectively. The CI-BMs at 6, 12, and 24months were 1.7%, 2.8%, and 3.3%, respectively. After taking competing risk events into account, there was no significant difference in the CI-BMs between the two groups (p=.888). Nevertheless, the use of bevacizumab and the histology of nonsquamous NSCLC were found to be independently associated with the risk of BMs. In patients with metastatic EGFR/ALK wild-type NSCLC without baseline BMs, adding atezolizumab in the first-line treatment might not reduce the CI-BM. However, the administration of bevacizumab may reduce the risk of BMs.

Proteomics-based Model for Predicting the Risk of Brain Metastasis in Patients with Resected Lung Adenocarcinoma carrying the EGFR Mutation.

Introduction: Epidermal growth factor receptor (EGFR) mutation is common in Chinese patients with lung adenocarcinoma (LUAD). Brain metastases (BMs) is high and associated with poor prognosis. Identification of EGFR-mutant patients at high risk of developing BMs is important to reduce or delay the incidence of BMs. Currently, there is no literature on the prediction and modeling of EGFR brain metastasis at the proteinomics level. Methods: We conducted a retrospective study of BMs in postoperative recurrent LUAD with EGFR mutation in the First Affiliated Hospital of Guangzhou Medical University. Tissue proteomic analysis was applied in the primary tumors of resected LUAD in this study using liquid chromatography-mass spectrometry (LC-MS/MS). To identify potential markers for predicting LUAD BM, comparative analyses were performed on different groups to evaluate proteins associated with high risk of BMs. Results: A combination of three potential marker proteins was found to discriminate well between distal metastasis (DM) and local recurrence (LR) of postoperative LUAD with EGFR mutation. Gene Ontology (GO) analysis of significantly altered proteins between BM and non-BM (NBM) indicated that lipid metabolism and cell cycle-related pathways were involved in BMs of LUAD. And the enriched pathways correlated with BMs were found to be quite different in the comparison groups of postoperative adjuvant therapy, tyrosine kinase inhibitor (TKI), and chemotherapy groups. Finally, we developed a random forest algorithm model with eight proteins (RRS1, CPT1A, DNM1, SRCAP, MLYCD, PCID2, IMPAD1 and FILIP1), which showed excellent predictive value (AUC: 0.9401) of BM in patients with LUAD harboring EGFR mutation. Conclusions: A predictive model based on protein markers was developed to accurately predict postoperative BM in operable LUAD harboring EGFR mutation.

Stereotactic Radiosurgery for Women Older than 65 with Breast Cancer Brain Metastases.

Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in older women, there are limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of older breast cancer patients ≥65 years old with BM compared to younger patients at our institution. An IRB-approved single-institutional retrospective review of biopsy-proven breast cancer patients with BM treated with 1- to 5-fraction stereotactic radiation therapy (SRS) from 2015 to 2020 was performed. Primary endpoint was intracranial progression-free survival (PFS) defined as the time interval between the end of SRS to the date of the first CNS progression. Secondary endpoints were overall survival (OS) from the end of SRS and radiation treatment patterns. Kaplan-Meier estimates and Cox proportional hazard regression method were used for survival analyses. A total of 112 metastatic breast cancer patients with BMs were included of which 24 were ≥65 years old and 88 were <65 years old. Median age at RT was 72 years (range 65-84) compared to 52 years (31-64) in younger patients. There were significantly higher number of older women with ER/PR positive disease (75% vs. 49%, p = 0.036), while younger patients were more frequently triple negative (32% vs. 12%, p = 0.074) and HER2 positive (42% vs. 29%, p = 0.3). Treatment-related adverse events were similar in both groups. Overall, 14.3% patients had any grade radiation necrosis (RN) (older vs. young: 8.3% vs. 16%, p = 0.5) while 5.4% had grade 3 or higher RN (0% vs. 6.8%, p = 0.7). Median OS after RT was poorer in older patients compared to younger patients (9.5 months vs. 14.5 months, p = 0.037), while intracranial PFS from RT was similar between the two groups (9.7 months vs. 7.1 months, p = 0.580). On univariate analysis, significant predictors of OS were age ≥65 years old (hazard risk, HR = 1.70, p = 0.048), KPS ≤ 80 (HR = 2.24, p < 0.001), HER2 positive disease (HR = 0.46, p < 0.001), isolated CNS metastatic disease (HR = 0.29, p < 0.001), number of brain metastases treated with RT (HR = 1.06, p = 0.028), and fractionated SRS (HR = 0.53, p = 0.013). On multivariable analysis, KPS ≤ 80, HER2 negativity and higher number of brain metastases predicted for poorer survival, while age was not a significant factor for OS after adjusting for other variables. Patients who received systemic therapy after SRS had a significantly improved OS on univariate and multivariable analysis (HR = 0.32, p < 0.001). Number of brain metastases treated was the only factor predictive of worse PFS (HR = 1.06, p = 0.041), which implies a 6% additive risk of progression for every additional metastasis treated. Although older women had poorer OS than younger women, OS was similar after adjusting for KPS, extracranial progression, and systemic therapy; and there was no difference in rates of intracranial PFS, neurological deaths, and LMD in the different age groups. This study suggests that age alone may not play an independent role in treatment-selection and that outcomes for breast cancer patients with BMs and personalized decision-making including other clinical factors should be considered. Future studies are warranted to assess neurocognitive outcomes and other radiation treatment toxicities in older patients.

Whole-Brain Radiotherapy Alone vs Preceded by Bevacizumab, Etoposide, and Cisplatin for Untreated Brain Metastases From Breast Cancer

The incidence of brain metastasis is increasing in patients with metastatic breast cancer. Treatments to extend the control of brain metastasis are urgently required. To investigate whether the addition of an induction treatment of bevacizumab, etoposide, and cisplatin (BEEP) improves brain-specific progression-free survival (PFS) after whole-brain radiotherapy (WBRT). This open-label, randomized, multicenter clinical trial assessed patients with brain metastases from breast cancer (BMBC) in Taiwan from September 9, 2014, to December 24, 2018, with survival follow-up until December 31, 2021. Key inclusion criteria included metastatic brain tumors not suitable for focal treatment, WBRT naivety, age 20 to 75 years, and at least 1 measurable brain metastatic lesion. The primary end point was brain-specific PFS, with an expected hazard ratio of 0.60, a 2-sided α ≤ .20, and power of 0.8. Eligible patients were randomly assigned at a ratio of 2:1 to the experimental arm, which involved 3 cycles of BEEP followed by WBRT, or the control arm, which involved WBRT alone. The primary end point was the determination of brain-specific PFS by local investigators according to the Response Evaluation Criteria in Solid Tumors, version 1.1, the initiation of other brain-directed treatment after WBRT, or death. Other key end points included brain-specific objective response rate after 8 weeks of BEEP treatment or WBRT and 8-month brain-specific PFS rate, PFS, and overall survival. A total of 118 patients with BMBC were randomized, with the intention-to-treat cohort comprising 112 patients. The median age was 56 years (range, 34-71 years), and 61 patients (54.5%) had ERBB2 (formerly HER2 or HER2/neu)-positive disease. The median (range) brain-specific PFS was 8.1 (0.3-29.5) vs 6.5 (0.9-25.5) months in the experimental and control arms, respectively (hazard ratio, 0.71; 95% CI, 0.44-1.13; P = .15; significant at predefined α ≤ .20). The brain-specific objective response rate at 2 months was not significantly different (BEEP treatment vs WBRT, 41.9% vs 52.6%), but the 8-month brain-specific PFS rate was significantly higher in the experimental group (48.7% vs 26.3%; P = .03). Adverse events were generally manageable with prophylactic granulocyte colony-stimulating factor treatment. The findings show that induction BEEP before WBRT may improve the control of BMBC compared with using upfront WBRT, which could address an unmet need for an effective systemic treatment for intractable brain and extracranial metastases from metastatic breast cancer. ClinicalTrials.gov Identifier: NCT02185352.

A Review of Recent Advances in the Molecular Mechanisms Underlying Brain Metastasis in Lung Cancer.

Brain metastasis from lung cancer is a prevalent mode of treatment failure associated with a poor prognosis. The incidence of brain metastasis has recently shown a dramatic increase. The early detection and risk stratification of lung cancer-related brain metastasis would be highly advantageous for patients. However, our current knowledge and comprehension of the underlying mechanisms driving brain metastasis in lung cancer pose significant challenges. This review summarizes the mechanisms underlying brain metastasis, focusing on the intricate interplay between lung cancer-derived tumor cells and the unique characteristics of the brain, recent advancements in the identification of driver genes, concomitant genes, epigenetic features, including miRNAs and long noncoding RNAs, as well as the molecular characterization of brain metastasis originating from other organs, which may further enhance risk stratification and facilitate precise treatment strategies.