Incidence Of Brain Metastases Research Articles

Characterizing metastatic uveal melanoma patients who develop symptomatic brain metastases.

Metastatic uveal melanoma (mUM) is an advanced ocular malignancy characterized by a hepatotropic pattern of spread. As the incidence of brain metastases (BM) in mUM patients has been thought to be low, routine CNS surveillance has not been recommended. Notably, no formal assessment of BM incidence in mUM has to date been published to support this clinical practice. We aimed to determine the true rate of BM in mUM and to clarify the clinical and genomic risk factors associated with BM patients through a collaborative multicenter, retrospective research effort. Data collected from 1,845 mUM patients in databases across four NCI-designated comprehensive cancer centers from 2006-2021 were retrospectively analyzed to identify patients with BM. Brain imaging in most cases were performed due to onset of neurological symptoms and not for routine surveillance. An analysis of demographics, therapies, gene expression profile, tumor next generation sequencing (NGS) data, time to metastasis (brain or other), and survival in the BM cohort was completed. 116/1,845 (6.3%) mUM patients were identified with BM. The median age at time of UM diagnosis was 54 years old (range: 18-77). The median time to any metastasis was 4.2 years (range: 0-30.8). The most common initial metastatic site was the liver (75.9%). 15/116 (12.9%) BM patients presented with BM at the time of initial metastatic diagnosis. Median survival after a diagnosis of BM was 7.6 months (range: 0.4-73.9). The median number of organs involved at time of BM diagnosis was 3 (range: 1-9). DecisionDX-UM profiling was completed on 13 patients: 10-Class 2, 2-Class 1B, and 1-Class 1A. NGS and cytogenetic data were available for 34 and 21 patients, respectively. BM was identified in 6.3% of mUM cases and was associated with high disease burden and a median survival of under 8 months once diagnosed. Since most patients in this cohort were symptomatic, the incidence of asymptomatic BM remains unknown. These data suggest the use of routine brain imaging in all mUM patients at risk for developing BM for early detection.

P11.61.B Capecitabine treatment of CNS metastases from breast cancer: intracranial response and survival

Abstract Background 20-30% of breast cancer patients develop brain metastases (BM) and 5% leptomeningeal metastases (LM). Incidence of BM and/or LM is dependent on breast cancer subtype. Treatment of BM consists of local treatment (resection and/or radiotherapy) and if possible systemic therapy. LM can be treated with radiotherapy of the symptomatic location of the nervous system and/or systemic therapy. Capecitabin is effective for both systemic metastases and BM of HER2-positive breast cancer. The effect of capecitabine in the non-HER2-positive breast cancers and in the LM group is largely unknown. The goal of this study is to determine the intracranial response of capecitabine and survival in HM and/or LM of the various breast cancer subtypes. Material and Methods breast cancer patients with HM and/or LM treated with capecitabine were selected retrospectively from a breast cancer patient cohort treated at the Netherlands Cancer Institute - Antoni van Leeuwenhoek between 2005 and 2020. Follow-up MRI scans of the brains were performed in all patients. The primary endpoints were intracranial response, intracranial progression-free survival (PFS) and overall survival (OS). Subgroup analyses for breast cancer subtypes and BM and LM patient groups were done. Results 93 of 381 patients treated for CNS metastases of breast cancer fulfilled the inclusion criteria. Sixty-one patients (66%) had HM only, 13 (14%) had LM only and 19 patients (20%) had both HM and LM. Forty-six percent of patients had HER2-positive breast cancer, 26% had hormone receptor-positive breast cancer and 28% of patients had a triple negative subtype. After three months of capecitabine treatment intracranial response was 53%. Median OS in the patient group with intracranial response was 16.5 months versus 4.5 months in the non-response group. The hazard ratio (HR) for the median OS, corrected for radiotherapy and concurrently administered, other systemic therapy was 0.33 (95% CI: 0.17-0.67). Median intracranial PFS was 7.3 months in the response group versus 1.4 months in the non-response group (p<0.001).The corrected HR for median intracranial PFS 0.13 (95% CI 0.06-0.27). The HER2-positive subtype group showed the longest median OS (22 months) as compared to the other subtypes (OS in hormone-receptor positive and triple negative subtype both 12 months) Conclusion Fifty-three percent of breast cancer patients with HM and/or LM treated with capecitabine demonstrate an intracranial response after three months of treatment. HER2+ breast cancer patients with HM and/or LM have a longer survival than patients with hormone receptor-positive or triple negative breast cancer subtypes.

MA04.09 The Incidence and Predictors of Unsuspected Brain Metastases in Patients with Stage IA NSCLC

Pretreatment evaluation for brain metastases with brain MRI is not routinely recommended for patients diagnosed with clinical T1N0 non-small cell lung cancer (NSCLC). However, the incidence of brain metastases in this patient population is not well known. In this study, we used two large U.S. clinical databases to examine the incidence and predictors of brain metastases among patients with stage IA NSCLC.

EP08.02-166 Brain Metastases in Patients with ALKrearranged or ROS1-fusion Non-small-Cell Lung Cancers in China

Brain metastases (BM) are common in ALK rearranged or ROS1-fusion non-small-cell lung cancer (NSCLC) and are usually associated with a poor outcome, but the baseline incidence and evolution of BM over time in those NSCLCs are seldom reported. In this study, we evaluated the frequency of BM in patients with anaplastic lymphoma kinase (ALK)-rearranged or c-ros oncogene 1(ROS1)-fusion NSCLC.

Outcomes of first-line anti-PD-L1 blockades combined with brain radiotherapy for extensive-stage small-cell lung cancer with brain metastasis.

Anti-programmed cell death-ligand 1 (Anti-PD-L1) blockades have become the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC) from CASPIAN and IMpower133 trials. SCLC has a high incidence of brain metastasis (BM) and brain radiotherapy (BRT) is the main local treatment method, but there is limited data on the BRT-immunotherapy scheme. The aim of the retrospective study is to investigate the clinical efficacy and safety of the first-line anti-PD-L1 blockades combined with BRT in ES-SCLC with BM. Patients with newly diagnosed ES-SCLC with baseline BMs at Shandong Cancer Hospital and Research Institute between 2017 and 2021 were selected. Patients were divided into the anti-PD-L1+BRT group and BRT group. We also assessed the leukoencephalopathy in both groups. A total of 46 patients were selected. Fifteen were divided into anti-PD-L1+BRT group and 31 to BRT group. The median overall survival (OS) was not reached (NR) vs 15.9m (P = 0.172). Progression-free survival (PFS) was numerically prolonged with anti-PD-L1 blockades, but the significance was not reached (median: 9.4m vs 7.4m, P = 0.362). The median intracranial PFS was not improved, neither (median: 8.2m vs 8.9m, P = 0.620). Objective response rate (ORR) in the two groups was 73.33% vs 77.42% (P = 0.949) and disease control rate (DCR) was both 100%. Intracranial ORR and DCR were 53.33% vs 70.97% (P = 0.239) and 73.33% vs 80.65% (P = 0.855), respectively. There was no significant difference in leukoencephalopathy incidence between the two groups. The combination of first-line anti-PD-L1 blockades with BRT did not confer a significant survival benefit in ES-SCLC with BM, without enhancing cranial neurotoxicity.

Incidence of Brain Metastases in Women Treated With Neoadjuvant Chemotherapy for Breast Cancer: Implications for Screening

PurposePatients with metastatic breast cancer may develop brain metastases. Our study identified high-risk patients to refine selection criteria for BM screening approaches. PatientsWe reviewed breast cancer patients treated with neoadjuvant chemotherapy (NAC) at a single university center between 2005 and 2019. MethodsCompeting risks analysis was performed with the Fine and Gray model to analyze the cumulative incidence of BM and loco-regional recurrence. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier and log-rank tests. Multivariable analysis was performed with Cox proportional hazards regression to identify factors predictive for development of BM. Statistical significance was determined as a 2-sided P value of <.05. ResultsIn total, 112 patients experienced distant failure (DF) and 49 patients developed BM. Twenty patients with BM (41%) presented with symptoms requiring craniotomy +/- whole brain radiation treatment. Patients with BM were significantly more likely to have local (P < .01) and regional (P < .01) failure. On multivariable analysis, age <40 years (P = .011), presence of lung metastases (P < .0001), and residual nodal disease with >4 lymph nodes positive after NAC (P = .024) all predicted for increased likelihood of BM. Patients with these criteria had higher likelihoods of having BM (P = .013) and worse PFS (P = .044). On multivariable analysis for OS, presence of lung metastases was the most significant predictor of poor outcome (P < .0001). ConclusionWe propose a study of screening brain MRI for young (<40 years) patients with breast cancer receiving NAC and patients who develop metastatic disease post-NAC, especially those with lung involvement.

Diagnostic and prognostic nomograms for newly diagnosed intrahepatic cholangiocarcinoma with brain metastasis: A population-based analysis.

Brain metastasis (BM) is one of the rare metastatic sites of intrahepatic cholangiocarcinoma (ICC). ICC with BM can seriously affect the quality of life of patients and lead to a poor prognosis. The aim of this study was to establish two nomograms to estimate the risk of BM in ICC patients and the prognosis of ICC patients with BM. Data on 19,166 individuals diagnosed with ICC were retrospectively collected from the Surveillance, Epidemiology, and End Results (SEER) database. Independent risk factors and prognostic factors were identified by the logistic and the Cox regression, respectively. Next, two nomograms were developed, and their discrimination was estimated by concordance index (C-index) and calibration plots, while the clinical benefits of the prognostic nomogram were evaluated using the receiver operating characteristic (ROC) curves, the decision curve analysis (DCA), and the Kaplan-Meier analyses. The independent risk factors for BM were T stage, N stage, surgery, alpha-fetoprotein (AFP) level, and tumor size. T stage, surgery, radiotherapy, and bone metastasis were prognostic factors for overall survival (OS). For the prognostic nomogram, the C-index was 0.759 (95% confidence interval (CI) = 0.745-0.773) and 0.764 (95% CI = 0.747-0.781) in the training and the validation cohort, respectively. The calibration curves revealed a robust agreement between predictions and actual observations probability. The area under curves (AUCs) for the 3-, 6-, and 9-month OS were 0.721, 0.727, and 0.790 in the training cohort and 0.702, 0.777, and 0.853 in the validation cohort, respectively. The DCA curves yielded remarkable positive net benefits over a wide range of threshold probabilities. The Kaplan-Meier analysis illustrated that the nomogram could significantly distinguish the population with different survival risks. We successfully established the two nomograms for predicting the incidence of BM and the prognosis of ICC patients with BM, which may assist clinicians in choosing more effective treatment strategies.

Spatial oriented single-cell proteomic assay of low grade serous ovarian carcinoma identifies tumor oncogenic pathways associated with brain metastases (233)

Objectives: As the systemic treatment of epithelial ovarian cancer (EOC) has improved, and the survival is longer, the incidence of brain metastases (BM) in EOC patients has increased to about 2-6% and invariably results in death. In order to better understand the molecular mechanisms involved in the development of EOC BM and to characterize the BM architecture and heterogeneity, we recently used multiplex cyclic-immunofluorescence (Cyc-IF) to characterize a set of matched samples from a single ovarian cancer patient. Methods: The samples included a primary tumor, a peritoneal tumor collected at recurrence, and a BM. Cyc-IF is a spatial oriented single-cell proteomic assay that allows the quantification of over 60 proteins in a single FFPE slide. Results: Our analyses indicated that tumor architecture and heterogeneity were highly altered in the BM compared to the primary and recurrent tumors in this patient. Indeed, the primary and recurrent intraperitoneal tumors showed extensive heterogeneity with cancer cells in different cell states related to the cell cycle (cyclins), hormone receptors (PR and ER) and signaling pathways. In contrast, the BM was overall more homogeneous, with no PR receptor expression and low expression of cyclins. EOC cells from the BM harbor higher oncogenic MAPK and PI3K-AKT signaling pathway activity, higher estrogen receptor expression and displayed immunosuppressive properties including increased expression of PD1 and the presence of tumor-associated macrophages (TAM) and regulatory T cells (Tregs). Importantly, we were able to identify cell populations in the primary tumor that had phenotypes similar to that of cells found in the BM. Conclusions: These findings are consistent with the concept that EOC cells with a predilection for BM are present early during the disease course. Therefore, this represents an opportunity to develop a molecular signature for BM prevention and treatment. Objectives: As the systemic treatment of epithelial ovarian cancer (EOC) has improved, and the survival is longer, the incidence of brain metastases (BM) in EOC patients has increased to about 2-6% and invariably results in death. In order to better understand the molecular mechanisms involved in the development of EOC BM and to characterize the BM architecture and heterogeneity, we recently used multiplex cyclic-immunofluorescence (Cyc-IF) to characterize a set of matched samples from a single ovarian cancer patient. Methods: The samples included a primary tumor, a peritoneal tumor collected at recurrence, and a BM. Cyc-IF is a spatial oriented single-cell proteomic assay that allows the quantification of over 60 proteins in a single FFPE slide. Results: Our analyses indicated that tumor architecture and heterogeneity were highly altered in the BM compared to the primary and recurrent tumors in this patient. Indeed, the primary and recurrent intraperitoneal tumors showed extensive heterogeneity with cancer cells in different cell states related to the cell cycle (cyclins), hormone receptors (PR and ER) and signaling pathways. In contrast, the BM was overall more homogeneous, with no PR receptor expression and low expression of cyclins. EOC cells from the BM harbor higher oncogenic MAPK and PI3K-AKT signaling pathway activity, higher estrogen receptor expression and displayed immunosuppressive properties including increased expression of PD1 and the presence of tumor-associated macrophages (TAM) and regulatory T cells (Tregs). Importantly, we were able to identify cell populations in the primary tumor that had phenotypes similar to that of cells found in the BM. Conclusions: These findings are consistent with the concept that EOC cells with a predilection for BM are present early during the disease course. Therefore, this represents an opportunity to develop a molecular signature for BM prevention and treatment.

Prophylactic cranial irradiation for limited-stage small-cell lung cancer in the magnetic resonance imaging era.

We investigated the role of prophylactic cranial irradiation (PCI) in limited-stage small-cell lung cancer (LS-SCLC) according to tumor response in the magnetic resonance imaging (MRI) era. We retrospectively evaluated patients with LS-SCLC without brain metastases (BMs) on MRI who achieved either complete response (CR) or partial response (PR) after initial chemoradiotherapy at our center from 2006 to 2017. This study comprised 116 patients (median age, 58 years; men, 92; women, 24). After initial chemoradiotherapy, 53 patients achieved CR, while 63 patients achieved PR. Eighty-three patients received PCI. Patients who received PCI had better overall survival (OS, 5-year: 52.5% vs. 35.1%; p=0.012) and progression-free survival (PFS, 5-year: 45.0% vs. 28.2%; p=0.001) and a lower incidence of BMs (5-year: 18.3% vs. 39.4%; p=0.010). In the subgroup analysis, PCI improved OS (5-year: 67.8% vs. 46.7%, p=0.005) and PFS (5-year: 65.2% vs. 35.0%, p=0.021) and decreased BM risk (5-year: 12.1% vs. 52.4%, p=0.002) for patients with CR. However, PCI had no benefit (5-year OS: 40.5% vs. 35.6%, p=0.763; 5-year BMs: 24.6% vs. 31.9%, p=0.561) for patients with PR. Tumor response remained an important factor for selecting patients for PCI in the MRI era. PCI should be recommended for patients with LS-SCLC who achieve CR after initial thoracic chemoradiotherapy.

Prostate Cancer Brain Metastasis: Review of a Rare Complication with Limited Treatment Options and Poor Prognosis.

Brain metastases (BM) are perceived as a rare complication of prostate cancer associated with poor outcome. Due to limited published data, we conducted a literature review regarding incidence, clinical characteristics, treatment options, and outcomes of patients with prostate cancer BM. A literature analysis of the PubMed, MEDLINE, and EMBASE databases was performed for full-text published articles on patients diagnosed with BM from prostate cancer. Eligible studies included four or more patients. Twenty-seven publications were selected and analyzed. The sources of published patient cohorts were retrospective chart reviews, administrative healthcare databases, autopsy records, and case series. BM are rare, with an incidence of 1.14% across publications that mainly focus on intraparenchymal metastases. Synchronous visceral metastasis and rare histological prostate cancer subtypes are associated with an increased rate of BM. Many patients do not receive brain metastasis-directed local therapy and the median survival after BM diagnosis is poor, notably in patients with multiple BM, dural-based metastases, or leptomeningeal dissemination. Overall, prostate cancer BM are rare and associated with poor prognosis. Future research is needed to study the impact of novel prostate cancer therapeutics on BM incidence, to identify patients at risk of BM, and to characterize molecular treatment targets.

The Significance of MicroRNAs in the Molecular Pathology of Brain Metastases.

Simple SummaryBrain metastases are increasingly common in cancer patients and hurt survival and quality of life. Therefore, efforts are increasingly devoted to research into brain metastases and discovering new diagnostic approaches and therapeutic targets. MicroRNAs, which are involved in regulating most cellular processes, including metastasis, appear to be promising molecules in this regard. The number of studies on microRNAs is constantly increasing. This review aims to summarize the current knowledge on the importance of microRNAs in the pathobiology of brain metastases and to suggest possibilities for their use in diagnostic and therapeutic practice.Brain metastases are the most frequent intracranial tumors in adults and the cause of death in almost one-fourth of cases. The incidence of brain metastases is steadily increasing. The main reason for this increase could be the introduction of new and more efficient therapeutic strategies that lead to longer survival but, at the same time, cause a higher risk of brain parenchyma infiltration. In addition, the advances in imaging methodology, which provide earlier identification of brain metastases, may also be a reason for the higher recorded number of patients with these tumors. Metastasis is a complex biological process that is still largely unexplored, influenced by many factors and involving many molecules. A deeper understanding of the process will allow the discovery of more effective diagnostic and therapeutic approaches that could improve the quality and length of patient survival. Recent studies have shown that microRNAs (miRNAs) are essential molecules that are involved in specific steps of the metastatic cascade. MiRNAs are endogenously expressed small non-coding RNAs that act as post-transcriptional regulators of gene expression and thus regulate most cellular processes. The dysregulation of these molecules has been implicated in many cancers, including brain metastases. Therefore, miRNAs represent promising diagnostic molecules and therapeutic targets in brain metastases. This review summarizes the current knowledge on the importance of miRNAs in brain metastasis, focusing on their involvement in the metastatic cascade and their potential clinical implications.

Usefulness of pro-gastrin-releasing peptide as a predictor of the incidence of brain metastasis and effect of prophylactic cranial irradiation in patients with limited-stage small-cell lung cancer

Prophylactic cranial irradiation (PCI) is recommended for patients with limited-stage small-cell lung cancer (LS-SCLC) who respond well to initial treatment. However, PCI is often omitted because of its potential neurotoxicity in the era of modern diagnostic imaging devices. In the present study, we aimed to investigate the risk factors for brain metastasis (BM) in patients eligible for PCI and who may benefit more from it. Patients with LS-SCLC who responded well to definitive thoracic chemoradiotherapy were included in the present study. Competing risk regression was used to identify factors associated with BM, and the Kaplan–Meier method was used to assess overall survival (OS). Between 2004 and 2017, 62 patients were eligible for PCI and were analyzed. Of these, 38 (61.3%) underwent PCI. Overall, 17 patients (27.4%) developed BM, with a 2-year cumulative incidence of 22.8%. Multivariate analysis (MVA) revealed that pretreatment elevated pro-gastrin-releasing peptide (ProGRP) levels were associated with an increased risk for BM (HR, 7.96, P = 0.0091). PCI tended to reduce the risk of BM (HR, 0.33; P = 0.051). The use of PCI was associated with improved OS in patients with ProGRP levels > 410 pg/mL (P = 0.008), but not in those with ProGRP ≤ 410 pg/mL (P = 0.9). Pretreatment ProGRP levels may be useful in predicting the development of BM in patients with LS-SCLC who achieved a good response to initial therapy and to determine which patients should undergo PCI.

The occurrence and associated risk factors of brain metastases in well differentiated grade 1 and 2 bronchial neuroendocrine tumours: A single centre retrospective analysis of 280 patients

Typical and atypical bronchial carcinoid account for around 2% of all neuroendocrine neoplasms of pulmonary origin. Fewer than 5% of patients with these cancers are thought to develop brain metastases, and hence routine intracranial imaging is not currently included in staging investigations. In this study, retrospective case note analysis was performed on 280 patients diagnosed with either typical carcinoid (TC) or atypical carcinoid (AC) at a large, single-site cancer centre. None of the 219 patients with TC developed brain metastases during the course of their disease, whereas seven of the 61 AC (11.5%) were found to have intracranial spread, four of which were present at the point of diagnosis. A Cox proportional hazard model showed that a Ki-67 expression ≥18%, patient age ≥65 years and disease stage at diagnosis were all independently and significantly associated with the development of brain metastases in AC. This study has found new evidence that the incidence of brain metastases in AC is significantly higher than previously thought. Of all the variables reviewed, Ki-67 expression was most strongly associated with the development of intracranial disease in AC and could be readily translated into clinical practice. Predictive factors such as age, disease stage and Ki-67 expression could be used to identify patients at particularly increased risk of brain metastases, who would benefit from early intracranial imaging. This could allow for earlier detection and treatment of metastases, with the potential to improve clinical outcomes and patient quality of life.

Abstract 976: Interrogating the pre-metastastic gene signature to block brain metastases

Abstract BACKGROUND: The incidence of brain metastases (BM) is tenfold higher than that of primary brain tumors. BM predominantly originate from primary lung, breast, and melanoma tumors with a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need to identify novel therapies against BM. The goal of this work is to uncover the molecular factors that drive the formation of BM and investigate whether we can slow down and ultimately block BM formation. METHODS: The Singh lab has generated a large in-house biobank of patient-derived BM cell lines that are established from BM patient tumor samples. We use these BM cell lines to generate murine orthotopic xenograft models of BM and interrogate the biological processes that lead to BM. These models have successfully recapitulated all the stages of their respective BM cascades and additionally captured a “pre-metastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. Pre-metastatic cell populations are impossible to detect in human patients but represent a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable and difficult to treat brain tumors. RESULTS: RNA sequencing of pre-metastatic BM cells revealed a unique deregulated transcriptomic profile that is specific to pre-metastatic cells despite the tumor of origin. Subsequent Connectivity Map analysis revealed compounds that we biologically characterized in vitro for selective anti-BMIC phenotypes. This effort led to a lead compound that exhibits anti-BM activity in vitro, while remaining ineffective against normal brain cell controls. Preliminary in vivo work has shown that following both orthotopic and intracardiac injection of BM cells, treatment with this lead compound reduces the tumor burden compared to mice being treated by a vehicle control, while providing a significant survival advantage. Ongoing mechanistic investigations aim to delineate the protein target of this compound in the context of the observed selective anti-BM phenotype. CONCLUSION: Identification of novel small molecules that target premetastatic BM cells could slow or prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients. Citation Format: Agata Kieliszek, Blessing Bassey-Archibong, Chitra Venugopal, Sheila Singh. Interrogating the pre-metastastic gene signature to block brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 976.

Abstract 2190: Brain-seeking extracellular vesicles derived from metastatic breast cancer cells modulate brain endothelial cell metabolism

Abstract Breast cancer, particularly the triple-negative subtype, is the primary cause of brain metastasis in women and affects ~10-16% of breast cancer patients. Breast cancer patients diagnosed with brain metastasis have limited therapeutic options and, therefore, a dismal prognosis with a median survival time of ~10 months. Recent studies have suggested that metastatic cells extravasate and grow along the blood-brain barrier (BBB) in a favorable microenvironment called the pre-metastatic niche. However, the early steps leading to the onset of breast-to-brain metastasis are poorly understood, limiting the development of strategies to prevent, detect and treat premetastatic or early-stage lesions. It is now well accepted that extracellular vesicles (EVs), nanoparticles secreted from cancer cells, can travel to distant organs, activate resident cells and promote the remodeling of the extracellular matrix and significantly impact organ-specific metastatic spread. Using our mouse model of breast to brain metastasis, we have demonstrated, for the first time, that EVs derived from brain-seeking breast cancer cells (Br-EVs) breach the intact BBB via transcytosis, are taken up by astrocytes and cause a significantly increased incidence of brain metastasis. Within this context, we are studying the interactions between Br-EVs and brain endothelial cells (ECs), the latter being a key functional component of the BBB. Utilizing primary human ECs and using a transwell assay established in our laboratory as an in vitro model of the BBB, we have identified the mechanism(s) through which Br-EVs modulate EC endocytic metabolism in favor of increased vesicle recycling and transcytosis. Our mechanistic studies demonstrate that ECs treated with Br-EVs show a significant decrease of multiple target proteins, all of which are involved in the long-recycling loop of the endocytic vesicles. Br-EVs mediate, at least in part, their effect through the delivery to the target cells of a specific subset of micro RNAs. As a result, Br-EVs upregulate EC basal transcytosis rate promoting their transfer to the brain parenchyma. These findings indicate that Br-EVs can alter BBB basal metabolism and help to prepare a microenvironment, better known as the pre-metastatic niche, that promotes and sustains the survival and growth of breast cancer metastases in the otherwise hostile brain microenvironment. These results increase our understanding of the early events that facilitate breast-to-brain metastasis and have the potential to identify key regulators in the early steps of brain metastasis formation. Our mechanistic studies will also inform and contribute to the development of EV-based diagnostic and therapeutic strategies for the early management of breast cancer patients with brain metastasis. (This work was supported by NIH R21 CA253051-01 and the Breast Cancer Research Foundation). Citation Format: Sara Busatto, Golnaz Morad, Marsha Moses. Brain-seeking extracellular vesicles derived from metastatic breast cancer cells modulate brain endothelial cell metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2190.

A case of radical resection for brain metastases of pancreatic cancer after curative chemotherapy for para-aortic lymph node metastases

BackgroundThe incidence of brain metastasis of pancreatic cancer has been reported to be approximately 0.3%. The blood–brain barrier of the central nervous system restricts the transfer of substances, including chemotherapeutic agents, from the bloodstream. It is hypothesized that brain metastasis may occur despite successful chemotherapy for the primary tumor. Herein, we report a case of brain metastases of pancreatic cancer that occurred after chemotherapy and discuss relevant literature.Case presentationA 64-year-old man underwent distal pancreatectomy with D2 lymph node dissection for resectable pancreatic tail cancer. Invasive ductal carcinoma of pancreas, pT3N2M0 pStageIII (TNM Classification of Malignant Tumors, UICC 8th edition) was diagnosed. S-1 adjuvant chemotherapy was initiated. Three months postoperatively, CA19-9 had increased to 619 U/mL. Additionally, contrast-enhanced computed tomography (CT) and fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT revealed local recurrence in the para-aortic lymph nodes. Chemotherapy was revised to a combined regimen of gemcitabine and nab-paclitaxel. After 4 cycles, tumor markers were normalized. After 5 cycles, recurrence could not be identified on contrast-enhanced CT; therefore, the patient was adjudged to be in complete remission. However, after 29 cycles of chemotherapy, the patient had symptoms of raised intracranial pressure. Magnetic resonance imaging showed two metastatic lesions of 20 mm and 32 mm in the left frontal lobe and cerebellum, respectively. Quasi-emergency resection of the metastatic brain tumors was performed. Pathological examination revealed that the resected specimens originated from primary pancreatic cancer. The patient was discharged on postoperative day 12, without any complications. Postoperatively, a total of 53 Gy of local brain radiation therapy was added. On postoperative day 30, blood carcinoembryonic antigen level had decreased to 5.4 ng/dl and all other tumor markers were negative. Additionally, tumor markers of the cerebrospinal fluid were markedly reduced and the cytology was negative for tumor cells. These results suggested complete resection of the metastatic brain tumors.ConclusionsAggressive resection and salvage stereotactic radiotherapy for metastatic brain tumors may lead to complete cure and a good long-term prognosis.

Real-world outcomes among patients with HER2+ metastatic breast cancer with brain metastases.

BACKGROUND: Among patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC), incidence of brain metastases (BMs) is relatively high and increasing. Despite the high unmet need for patients with HER2+ MBC and BMs, real-world data on treatment patterns and outcomes for these patients are limited. OBJECTIVE: To compare treatment patterns and overall survival (OS) among patients with HER2+ MBC with and without BMs in the United States. METHODS: This was a real-world retrospective cohort study in which adults diagnosed with HER2+ MBC between January 1, 2016, and May 31, 2019, were identified in the Flatiron Health electronic health records database. The cohort was stratified by presence of BMs at MBC diagnosis (baseline) and before the initiation of each line of therapy (LOT). Key outcomes were OS and systemic therapy/regimen used within each LOT. An adjusted Cox proportional hazards model was used to evaluate the impact of BMs on OS. RESULTS: Of 1,755 included patients, 173 (9.9%) had BMs at baseline. Trastuzumab+ pertuzumab-based regimens were the most common first- (n = 689, 44.3%) and second-line (n = 316, 35.3%) treatments for all patients. Among patients with BMs, trastuzumab emtansine was the most common third-line regimen (n = 18, 23.4%). Lapatinib-based regimens were used more frequently among patients with BMs but were used by less than 20% of patients with BMs within any LOT. Median OS was 22.3 and 37.3 months for patients with and without BMs at baseline, respectively. Patients with BMs had a higher risk of death compared with patients without BMs (HR, 3.2; 95% CI = 2.6-3.8). CONCLUSIONS: BMs are associated with an increased risk of mortality among patients with HER2+ MBC. Further studies are needed to evaluate the extent to which novel systemic therapies for HER2+ MBC address the unmet need among patients with BMs. DISCLOSURES: This study was funded by Seagen Inc. Andres Forero-Torres is an employee of and owns stock in Seagen Inc. Kendra DeBusk is an employee of Seagen Inc. and owns stock in Seagen Inc. and Roche. Andy Surinach and Yutong Liu are employees of Genesis Research, which received funding from Seagen Inc. in connection with this study. At the time of this study, Chimeka Ike was an employee of Seagen Inc. and owns stock in Seagen Inc. At the time of this study, Nicolas Lindegger was an employee of Seagen Inc., Seagen International GmbH, and owns stock in Seagen Inc. and Roche. At the time of this study, Naomi Schwartz was a paid consultant to Seagen Inc.; she currently is an employee of and owns stock in Seagen Inc.

P-64 Incidence of brain metastases in a potentially high-risk group of patients with metastatic colorectal cancer: Results from a pilot study

Brain metastases (BM) are an uncommon presentation of metastatic colorectal cancer (mCRC) and routine imaging of the brain is not recommended. The majority of patients with BM undergo a palliative treatment course with an expected survival of few months. However, appropriately selected patients could be candidates for metastasis-directed treatment with a potential for a curative outcome. In a registry-based CRC cohort study patients undergoing curatively intended treatment of BM had more frequently rectal cancers with lung metastases.

Clinical and molecular characteristics of advanced esophageal/GEJ cancer with brain metastasis.

e16092 Background: Brain metastasis (BRM) in gastroesophageal (GE) cancer is uncommon, but contributes to poor prognosis and significant symptom burden. While HER2 overexpression has been suggested as a potential driver of BRM, clinicopathologic and molecular determinants of BRM in GE cancer and their impact on clinical outcome remain incompletely understood. Methods: We retrospectively analyzed clinicopathologic data from 323 advanced esophageal/GEJ patients (pts) at Johns Hopkins from 2003 to 2021. Univariate and multivariate logistic regression were performed to investigate the association between several clinical and molecular features and the occurrence of BRM, with particular focus on HER2 overexpression (by IHC and FISH) and PD-L1 expression (by IHC) as measured by the combined positive score (CPS). Overall survival was estimated using the Kaplan-Meier method. Results: Median age was 64 and most pts were white (90.4%). Tumors were 73.7% esophageal primary, 82.7% adenocarcinoma, 43.8% HER2+, and 11.1% CPS ≥ 1. Cumulative incidence of BRM in overall cohort and within HER2+ subgroup was 14.6% (47 pts) and 25.4% (16 pts), respectively. Pts with BRM (not already present at time of stage IV diagnosis) had median onset of 10.8 months. Seventeen (36.2%) pts had a solitary brain lesion and 10 (21.7%) were asymptomatic. On univariate analysis, adenocarcinoma and HER2 overexpression were associated with increased risk of BRM (OR 3.45; 95% CI 0.09-0.96; p = 0.043 and OR 2.72; 95% CI 1.11-6.67; p = 0.028, respectively). Notably, the HER2 association was strengthened when HER2 equivocal tumors were re-classified as positive in an exploratory analysis (OR 3.55; 95% CI 1.38-9.14; p = 0.009). Adenocarcinoma and HER2 overexpression were collinear in the multivariate model. In pts with BRM, OS was improved in HER2+ pts (16.72 months; 95% CI 12.3-21.1 months; log-rank p = 0.039 and OR 0.33; 95% CI 0.11-0.99; Cox regression p = 0.049). CPS and primary tumor location were not associated with increased BRM. Conclusions: HER2 overexpression identifies an esophageal/GEJ molecular subtype that is significantly associated with increased risk of BRM; though with improved OS (compared to non-HER2+ BRM) and later onset CNS progression, likely reflecting durable extra-CNS control on targeted systemic therapy and a potential HER2+ subgroup with relatively indolent biology. Prevalence of asymptomatic and solitary brain lesions supports increased brain surveillance for this population.

The role of RARRES2 in regulating lipic metabolic reprogramming in the development of brain metastases in triple negative breast cancer.

e13047 Background: Triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is characterized by a high incidence of brain metastases (BM) and a poor prognosis. As the most lethal form of breast cancer, brain metastases remains a major clinical challenge due to its rising incidence and lack of effective treatment strategies. Recent evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastases (BCBM), but the underlying mechanisms are far from been fully elucidated. Methods: Using public datasets and our single-cell transcriptome sequencing data, we identified and verified the specific down-regulation of RARRES2, a multifunctional adipokine and chemokine, in brain metastases of triple negative breast cancer. We investigated the effect of aberrant RARRES2 expression on brain metastases in both in vitro and in vivo studies. Key signaling pathway components were evaluated using qPCR and Western blot analysis. Lipidomics were performed to elucidate the regulation of lipid metabolic reprogramming of RARRES2. Results: We show for the first time that down-regulation of RARRES2 is specifically associated with BCBM, and that RARRES2 promoted BCBM through lipid metabolic reprogramming. Mechanistically, reduced expression of RARRES2 in brain-tropic triple negative breast cancer cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols (TAGs) by regulating PTEN-PI3K-SREBP1 signaling pathway to facilitate the survival of breast cancer cells in the unique brain microenvironment. Conclusions: Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of brain metastases, thereby offering potential therapeutic targets for BCBM in TNBC.