Patients Developed Brain Metastases Research Articles

Pedunculated Neoplasm of the Vulva.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy, typically presenting as eczema-like lesions in areas rich in apocrine glands such as the perineum. Here, we report a case of EMPD presenting as a prominent pedunculated neoplasm in a 65-year-old woman. Despite initial misdiagnosis and treatment, biopsy confirmed EMPD infiltration. Following surgical excision, the patient developed brain metastases, indicating a poor prognosis. EMPD's pathogenesis remains unclear, but distinguishing primary from secondary forms is crucial for prognosis and treatment. Our case underscores the importance of recognizing atypical EMPD presentations for timely intervention and improved outcomes.

Overall Survival after Radiotherapy for Brain Metastases According to ECOG Status-A Prospective Study of 294 NSCLC Patients.

Up to 40% of non-smallcell lung cancer (NSCLC) patients develop brain metastases (BMs). The potential benefits of radiotherapy (RT) in patients with poor performance status (PS) are questionable, with considerable risk for futile treatment. We analyzed overall survival after initial radiotherapy in NSCLC patients with BMs, focusing on the relationship between PS and survival after RT. This study reports a prospective observational study including consecutive 294 NSCLC patients with first-time BMs. Overall survival (OS) was calculated from the start of RT to death or last follow-up (1 June 2023). Overall, in the 294 included patients (median age 69 years), the median OS was 4.6 months; 2.5 months after WBRT (n = 141), and 7.5 months after SRT (n = 153). After WBRT, mOS was equally poor for patients with ECOG 2 (1.9 months) and ECOG 3-4 (1.2 months). After SRT, mOS for patients with ECOG 2 was 4.1 months; for ECOG 3 patients, mOS was 4 1.6 months. For NSCLC patients with ECOG 2 diagnosed with BMs who are not candidates for surgery or SRT, WBRT should be questioned due to short survival.

Abstract CT292: Phase II study of pembrolizumab in combination with lenvatinib in patients with triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other tumor types and brain metastases

Abstract Background: Many patients develop brain metastasis during the course of their disease and it represents the cause of death in more than half of them. The prognosis and survival of patients with brain metastases remains poor with limited palliative treatment options. Thus, there is a need to develop new strategies for the therapeutic management of patients with brain metastases. Inflammatory stimuli originating from CNS tumors may increase the permeability of the blood-brain barrier and promote immune cell activation and infiltration into tumors. Several studies have demonstrated now the efficacy of immune checkpoint inhibitors in patients with melanoma with active brain metastases. The modulation of VEGF-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. Lenvatinib is an oral, potent multiple receptor tyrosine kinase inhibitor that selectively inhibits VEGFRs, VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other pro-angiogenic and oncogenic pathway-related receptor tyrosine kinases. The combination of lenvatinib and pembrolizumab is approved for patients with metastatic endometrial carcinoma and renal cancer, and it is investigated in other tumor types with promising preliminary results. We hypothesize that pembrolizumab and lenvatinib will be an effective treatment for TNBC, NSCLC, and other solid tumor types with brain metastases by decreasing angiogenic tumor activity and improving antitumor T-cell activity. Methods: This is a single-center, open-label, multi-cohort Phase II study evaluating the efficacy and safety of pembrolizumab in combination with lenvatinib in patients with solid tumors and brain metastases. The study has 3 cohorts: triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other solid tumor types with established or preliminary clinical evidence of efficacy of programmed cell death-1 (PD-1) and angiogenesis inhibitors. Eligible patients will have at least 1 unirraditated or progressing brain metastasis of 0.5-2 cm on brain MRI. The study is conducted using a Simon’s optimal two-stage design, and approximately 87 patients will be enrolled concurrently (n=29 per cohort). Pembrolizumab (200 mg intravenously on Day 1 of each cycle) and lenvatinib (20 mg orally once daily) are administered in 21-day cycles for a maximum of 24 months. The primary endpoint is intracranial objective response rate at 4 months as assessed by the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Exploratory analyses will include evaluation of tissue and blood-based immune-related correlates of response to the pembrolizumab and lenvatinib combination. The first patient was enrolled in January 2022 and accrual of patients is ongoing (NCT05064280). Citation Format: Ecaterina E. Dumbrava, Emma J. Montazari, Uyen M. Vu, Tiantian Cai, Mehmet Altan, Nuhad K. Ibrahim, Debra N. Yeboa, Jing Li, Frederick F. Lang, Gisela Sanchez, Isabella C. Glitza, Barbara J. O'Brien, Rashmi K. Murthy, Jianbo Wang, Tanisha T. Darko, Denisse Velazquez, Komal Shah, Funda Meric-Bernstam, Hussein Tawbi, Jordi Rodon. Phase II study of pembrolizumab in combination with lenvatinib in patients with triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other tumor types and brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT292.

Primary cardiac myxofibrosarcoma of the left atrium and pericardium: a case report

BackgroundPrimary cardiac myxofibrosarcoma is rare and commonly occurs in the left atrium. Myxofibrosarcoma is aggressive and has a high mortality rate due to its high rate of recurrence. Complete surgical resection is considered important; however, effective treatment options have not been established.Case presentationWe report the case of a 75-year-old woman who developed a myxofibrosarcoma spreading to the left atrium and pericardium. We performed surgical resection of the tumor to prevent sudden death due to mitral valve obstruction or cerebral infarction due to embolism of the scattered mass. However, we were unable to complete the resection of the tumors. The patient developed brain metastasis 2 months after surgery and eventually died due to brain hemorrhage 3 months after surgery.ConclusionsIn this report, we described a rare case of primary cardiac myxofibrosarcoma located not only in the left atrium but also in the pericardium. Considering preoperative laboratory findings, surgical and adjuvant therapy, and the patient’s wishes are important for the best therapeutic course for an individual.

BSBM-22 CHARACTERIZATION OF CIRCULATORY SHEAR STRESS-INDUCED MOLECULAR CHANGES IN LUNG ADENOCARCINOMA CELLS AND IMPLICATIONS IN BRAIN METASTASIS

Abstract INTRODUCTION Lung cancer is the most common tumor to metastasize to the brain, as 40% of patients develop brain metastasis (BM). Once diagnosed, survival is only 6.5-10 months. A potential target to prevent BM is circulating tumor cells (CTCs). The mechanisms that mediate a CTCs adaptation to the harsh environment of circulation and BM have not been elucidated. We have demonstrated that primary lung cancer cells (LCCs) subjected to circulation have increased migration across brain endothelial cell monolayers, increased side population, and decrease survival in rodents when injected intracardially vs plated controls. METHODS We engineered a microfluidic device capable of subjecting tumor cells to prolonged circulatory shear stress (CSS) that allows the isolation/modeling of CTC-like cells. Primary LCCs (A549, H1563) were subjected to circulation, suspension, or plated (2D) for 72h as controls. At this time point, LCCs were collected, and total mRNA was extracted. Samples were submitted for RNA sequencing. Weighted gene co-expression network analysis (WCGNA) and Ingenuity Pathway Analysis were performed. (FC >2 and p-value <0.05). RESULTS Transcriptomic analysis indicates that cells subjected to CSS activate specific gene networks involved in cell survival, migration, invasion, adhesion of tumor cells, and cytoskeletal reorganization (z-score: >2, p-value: 0.05). Canonical pathways in CTCs included ILK-signaling and Xenobiotic Metabolism. LCCs exposed to CSS had increased expression of multidrug resistance pumps ABCC2, ABCF2 (P:<0.001), and side population on flow cytometry (P: <0.05). The top differentially expressed genes in CTC-like cells (MMP1, ANGPTL4, and CEMIP) were involved in the invasion, angiogenesis, and pre-metastatic niche (PMN) formation of BM. CONCLUSION LCCs that survive CSS have increased expression of genes associated with migration, invasion, and chemoresistance compared to 2D controls. Targeting genes in CTCs that mediate survival and preparation of the PMN may be useful in preventing BM.

Long-term survival of breast cancer patients with brain metastases: subanalysis of the BMBC registry

Up to 30% of metastatic breast cancer (BC) patients develop brain metastases (BM). Prognosis of patients with BM is poor and long-term survival is rare. Identification of factors associated with long-term survival is important for improving treatment modalities. A total of 2889 patients of the national registry for BM in BC (BMBC) were available for this analysis. Long-term survival was defined as overall survival (OS) in the upper third of the failure curve resulting in a cut-off of 15 months. A total of 887 patients were categorized as long-term survivors. Long-term survivors compared to other patients were younger at BC and BM diagnosis (median 48 versus 54 years and 53 versus 59 years), more often had HER2-positive tumors (59.1% versus 36.3%), less frequently luminal-like (29.1% versus 35.7%) or triple-negative breast cancer (TNBC) (11.9% versus 28.1%), showed better Eastern Cooperative Oncology Group (ECOG) performance status (PS) at the time of BM diagnosis (ECOG 0-1, 76.9% versus 51.0%), higher pathological complete remission rates after neoadjuvant chemotherapy (21.6% versus 13.7%) and lower number of BM (n= 1, BM 40.9% versus 25.4%; n= 2-3, BM 26.5% versus 26.7%; n ≥4, BM 32.6% versus 47.9%) (P < 0.001). Long-term survivors had leptomeningeal metastases (10.4% versus 17.5%) and extracranial metastases (ECM, 73.6% versus 82.5%) less frequently, and asymptomatic BM more often at the time of BM diagnosis (26.5% versus 20.1%), (P < 0.001). Median OS in long-term survivors was about two times higher than the cut-off of 15 months: 30.9 months [interquartile range (IQR) 30.3] overall, 33.9 months (IQR 37.1) in HER2-positive, 26.9 months (IQR 22.0) in luminal-like and 26.5 months (IQR 18.2) in TNBC patients. In our analysis, long-term survival of BC patients with BM was associated with better ECOG PS, younger age, HER2-positive subtype, lower number of BM and less extended visceral metastases. Patients with these clinical features might be more eligible for extended local brain and systemic treatment.

Clinical Outcome in Patients With Early-Stage Small Cell Lung Cancer Treated With Surgery or Radiation in the Absence of Prophylactic Cranial Irradiation: A Single-Center Retrospective Study

As screening chest computed tomography for patients at high risk for cancer has become more widely accepted, increasing numbers of patients with early-stage small cell lung cancer (SCLC) are being diagnosed. Although surgery is an accepted option for patients with early-stage SCLC, for patients who decline or cannot undergo surgery, stereotactic body radiation treatment (SBRT) is an alternative. Although prophylactic cranial irradiation (PCI) improves survival in patients with limited-stage SCLC, PCI for early-stage SCLC (stage T1-T2) has not been explored. This study defines survival and recurrence patterns in patients with early-stage SCLC who were treated with surgery or SBRT in the absence of PCI. In this single-institution retrospective study, 14 patients diagnosed with early-stage SCLC (stage T1-T2) between July 2015 and May 2021 at a single tertiary care hospital were treated with SBRT or surgery with no PCI. Primary outcomes were locoregional cancer recurrence, distant recurrence, recurrence-free survival, and overall survival. The secondary outcome was development of brain metastasis. Analyses included Cox regression, Kaplan-Meier survival, and log-rank tests. A total of 14 patients (5 women and 9 men) were included in the study: 9 with stage T1 and 5 with stage T2 SCLC. Six patients (43%) received SBRT and 8 (57%) had surgical treatment. All patients except 1 received adjuvant chemotherapy. Median follow-up was 14.3 months (range, 2.4-64.4 months), and the median age at diagnosis was 71.5 years (range, 54-81 years). Cox regression and log-rank tests showed no significant differences in any outcomes between the surgery and SBRT groups, and no patients developed brain metastases during the study period. Data are lacking regarding the benefit of PCI in early-stage SCLC. Although the sample size in this study was too small to draw any conclusions, the findings add to the ongoing dialogue regarding the importance of PCI in this patient population. No difference was identified in survival and cancer recurrence in patients who received either surgery or SBRT in the absence of PCI.

Outcome predictors of breast cancer patients developing brain metastasis

Outcome predictors of breast cancer patients developing brain metastasis

Upfront and Repeated Stereotactic Radiosurgery in Patients With Brain Metastases From NSCLC

IntroductionApproximately 40% of non-small-cell lung cancer (NSCLC) patients develop brain metastases (BM). Stereotactic radiosurgery (SRS) instead of whole-brain radiotherapy (WBRT) is increasingly administered as an upfront treatment to patients with a limited number of BM. We present outcomes and validation of prognostic scores for these patients treated with upfront SRS. MethodsWe retrospectively analyzed 199 patients with a total of 268 SRS courses for 539 brain metastases. Median patient age was 63 years. For larger BM, dose reduction to 18 Gy or hypofractionated SRS in 6 fractions was applied. We analyzed the BMV-, the RPA-, the GPA- and the lung-mol GPA score. Cox proportional hazards models with univariate and multivariate analyses were fitted for overall survival (OS) and intracranial progression-free survival (icPFS). ResultsSixty-four patients died, 7 of them of neurological causes. Thirty eight patients (19,3%) required a salvage WBRT. Median OS was 38, 8 months (IQR: 6-NA). In univariate analysis as well as multivariate analysis, the Karnofsky performance scale index (KPI) ≥90% (P = 0, 012 and P = 0, 041) remained as independent prognostic factor for longer OS. All 4 prognostic scoring indices could be validated for OS assessment (BMV P = 0, 007; RPA P = 0, 026; GPA P = 0, 003; lung-mol GPA P = 0, 05). ConclusionIn this large cohort of NSCLC patients with BM treated with upfront and repeated SRS, OS was markedly favourable, in comparison to literature. Upfront SRS is an effective treatment approach in those patients and can decidedly reduce the impact of BM on overall prognosis. Furthermore, the analysed scores are useful prognostic tools for OS prediction.

P12.09.B Extracellular vesicle derived-miR-146a increases melanoma brain metastasis progression via Notch signalling pathway dysregulation

Abstract Background Melanoma has the highest tropism of any cancer to metastasize to the brain, and 40% of late-stage patients develop brain metastasis. Invasion, survival, and progression of tumors is dependent on the support of the surrounding microenvironment; therefore, modulation of neighboring cells is a key factor in metastasis. Extracellular vesicles (EVs) are important in cell-to-cell signalling, shuttling proteins, RNA and DNA to alter the surroundings into a favorable tumor microenvironment. Our aims were to investigate the role of melanoma brain metastasis (MBM) derived EVs in MBM development to find possible contributing mechanisms to cancer progression for eventual therapeutic targeting. Material and Methods MBM-EVs isolated via sequential ultracentrifugation were injected into mice as a pre-treatment prior to intracardial injection of MBM cells. EVs were co-cultured with normal human astrocytes (NHA) to investigate phenotypic changes. MiRNA sequencing was performed on EVs collected from MBM cells and compared to NHA and melanocytes to determine a candidate miRNA for targeting. In situ hybridization was utilized to evaluate the level of miRNA in clinical patient MBM samples. Functional in vivo validation was performed by injecting miRNA knockout MBM cells into mice. Sequencing of NHA in the presence or absence of target miRNA mimic was used to determine downstream targets. Results Mice primed with EVs had a significant increase in MBM tumor burden, compared to non-primed mice. Co-culture with MBM-EVs resulted in NHA activation in vitro, with increased proliferation, invasion, cytokine production, and upregulation of GFAP. MiR-146a was highly upregulated in MBM EVs, and miR-146a mimics activated NHA. Patient samples had a significant increase in miR-146a expression, compared to healthy brain controls. MiR-146a knockdown in MBM mice models reduced MBM burden and prolonged animal survival. Sequencing of NHA determined NUMB, an inhibitor of the Notch signalling pathway, as a target of miR-146a. Numb and other downstream Notch proteins expression was significantly altered in NHA in the presence of both MBM-EVs and miR-146a. Conclusion In conclusion, EVs are important regulators of MBM and establish tumor-supporting reactive astrocytes by delivery of miR-146a. MiR-146a alters Notch signalling in astrocytes via inhibition of the tumor suppressor gene NUMB. Elevated miR-146a levels in patients suggests a potential clinical intervention is possible via miR-146a targeting.

Immunotherapy in NSCLC Patients with Brain Metastases.

Approximately 40% of unselected non-small cell lung cancer (NSCLC) patients develop brain metastases (BMs) during their disease, with considerable morbidity and mortality. The management of BMs in patients with NSCLC is a clinical challenge and requires a multidisciplinary approach to gain effective intracranial disease control. Over the last decade, immune checkpoint inhibitors (ICIs) have emerged as a game-changer in the treatment landscape of advanced NSCLC, with significant improvements in survival outcomes, although patients with BMs are mostly underrepresented in randomized clinical trials. Moreover, the safety and activity of ICIs and radiotherapy combinations compared with single-agent or sequential modalities is still under evaluation to establish the optimal management of these patients. The aim of this review is to summarize the state-of-the-art of clinical evidence of ICIs intracranial activity and the main challenges of incorporating these agents in the treatment armamentarium of NSCLC patients with BMs.

Abstract 1841: MRTX849 inhibits P-gp and demonstrates CNS exposure in mouse models and cancer patients and demonstrates antitumor activity in intracranial mouse models of lung cancer brain metastasis

Abstract MRTX849 is a covalent, mutant selective, KRAS G12C inhibitor in development for cancer patients harboring this mutation. KRAS G12C is mutated in ~14% of lung adenocarcinoma and KRAS G12C inhibitors adagrasib and sotorasib have demonstrated clinical activity. While early data are encouraging, approximately one-third of KRAS-mutant non-small cell lung cancer (NSCLC) patients develop brain metastases and this remains a significant unmet medical need. P-glycoprotein 1 (P-gp)-mediated efflux is a major mechanism for the active transport of small molecules out of the CNS. MRTX849 is a P-gp inhibitor and inhibits its own efflux at plasma exposure levels achieved in humans at the 600 mg BID dose level resulting in achieving appreciable drug levels in cerebrospinal fluid (CSF). Total and free-fraction adjusted plasma concentrations of MRTX849 were 8.6 μM and 43 nM; respectively, 8 hours post administration of a clinically relevant oral dose of 200 mg/kg to mice. In addition, the CSF concentration, a measure of the free brain concentration, was 52 nM, which is above the cellular pERK1/2 IC50 value measured at 24 hours in cancer cell lines (~5 nM). Administration of 100 mg/kg MRTX849 to mice also resulted in CSF exposure above the cellular IC50 and a CSF/plasma (free-fraction adjusted) partition coefficient (Kp,uu) value of 0.4. To evaluate the tumor growth inhibition following oral administration of MRTX849 in an orthotopic model of lung cancer brain metastasis, immunocompromised mice were intracranially implanted with luciferase-labeled human NSCLC LU99 cells. Lower bioluminescence imaging (BLI)-based tumor flux was observed for the 100 mg/kg BID MRTX849-treated mice compared to vehicle and an 88% reduction in bioluminescence signal compared to baseline was observed suggesting strong tumor regression and consistent with significantly longer survival in treated mice. In addition, MRTX849 treated brain tumors demonstrated 85% reduced ERK phosphorylation. Similarly, treatment with MRTX849 resulted in potent tumor regression and significant survival extension in another intracranial KRAS G12C model of NSCLC using LU65 cells. CSF levels were determined at steady-state in two patients in the MRTX849-001 Phase1/2 clinical trial. The CSF/plasma (free fraction adjusted) Kp,uu value was 0.47 with patient CSF levels achieved consistent with CSF levels observed in responding mouse models (24-35 nM). These data demonstrate MRTX849 crosses the blood brain barrier in preclinical models and cancer patients. In addition, antitumor activity observed in mouse models of brain metastases provides rationale for exploring the utility of MRTX849 for the treatment of patients harboring KRAS G12C mutant lung cancer with brain metastases. Citation Format: Kazuhide Shimizu, Jill Hallin, Mohini Singh, Naema Nayyar, Matthew R. Strickland, Aaron C. Burns, Cornelius Cilliers, Lauren Hargis, Peter A. Olson, Matthew A. Marx, Priscilla K. Brastianos, Hiroaki Wakimoto, James G. Christensen. MRTX849 inhibits P-gp and demonstrates CNS exposure in mouse models and cancer patients and demonstrates antitumor activity in intracranial mouse models of lung cancer brain metastasis [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 1841.

Single-Cell Proteomics Analysis of Recurrent Low-Grade Serous Ovarian Carcinoma and Associated Brain Metastases.

Between 2% and 6% of epithelial ovarian cancer (EOC) patients develop brain metastases (brain mets), which are incurable and invariably result in death. This poor outcome is associated with a lack of established guidelines for the detection and treatment of brain mets in EOC patients. In this study, we characterize an unusual case of low-grade serous ovarian carcinoma (LGSOC) that metastasized to the brain. Using a spatially oriented single-cell proteomics platform, we compared sequential biopsies of a primary tumor with a peritoneal recurrence and brain mets. We identified several targetable oncogenic pathways and immunosuppressive mechanisms that are amplified in the brain mets and could be involved in the progression of LGSOC to the brain. Furthermore, we were able to identify cell populations that are shared between the primary tumor and the brain mets, suggesting that cells that have a propensity for metastasis to the brain could be identified early during the course of disease. Taken together, our findings further a path for personalized therapeutic decisions in LGSOC.

A Clinical Analysis and Literature Review of Six Cases with Primary Pulmonary Lymphoepithelioma-Like Carcinoma.

Methods The clinical data of six patients with primary pulmonary lymphoepithelioma-like carcinoma treated in Zhejiang Taizhou Hospital of Taizhou Enze Medical Center (Group) from May 2014 to December 2018 were summarized and analyzed. Combined with the relevant literature, the primary pulmonary lymphoepithelioma-like carcinoma was analyzed retrospectively. Results The main manifestations of six patients were respiratory symptoms, and cough was the most common. The imaging features of six patients were mainly round-like high-density mass shadow or nodule shadow. All patients were diagnosed by pathology. Microscopically, the cancer cells were nested, with large nuclei and vacuoles and abundant lymphocyte infiltration in the tumor stroma. The positive rates of EBER, p63, CK5/6, and Ki-67 were high, and TTF-1 was negative. Five patients received surgical treatment. One patient developed brain metastasis 12 months after operation and received craniocerebral radiotherapy. The other patients did not receive radiotherapy and chemotherapy, and one patient did not receive treatment. After follow-up, four patients survived so far, the longest survival time was 82 months, one patient lost follow-up, and one patient died of lung metastasis 24 months after operation. Conclusion Primary pulmonary lymphoepitheliomatoid-like carcinoma is a rare lung malignant tumor, whose pathogenesis is related to Epstein-Barr virus infection. The clinical manifestations are nonspecific, but with unique pathological characteristics. Surgical resection is the proper treatment for early-stage patients, and comprehensive treatment with surgery as the main treatment is suitable for late-stage patients. The prognosis is good.

Immune suppressive microenvironment in brain metastatic non-small cell lung cancer: comprehensive immune microenvironment profiling of brain metastases versus paired primary lung tumors (GASTO 1060)

ABSTRACT Lung cancer is one of the most common causes of brain metastases and is always associated with poor prognosis. We investigated the immunophenotypes of primary lung tumors and paired brain metastases, as well as immunophenotypes in the synchronous group (patients with brain metastases upon initial diagnosis) and metachronous group (patients developed brain metastases during the course of their disease). RNA sequencing of eighty-six samples from primary lung tumors and paired brain metastases of 43 patients was conducted to analyze the tumor immune microenvironment. Our data revealed that matched brain metastases compared with primary lung tumors exhibited reduced tumor infiltrating lymphocytes (TILs), a higher fraction of neutrophils infiltration, decreased scores of immune-related signatures, and a lower proportion of tumor microenvironment immune type I (high PD-L1/high CD8A) tumors. Additionally, we found a poor correlation of PD-L1 expression between paired brain metastases and primary lung tumors. In addition, gene set enrichment analysis (GSEA) showed that some gene sets associated with the immune response were enriched in the metachronous group, while other gene sets associated with differentiation and metastasis were enriched in the synchronous group in the primary lung tumors. Moreover, the tumor immune microenvironment between paired brain metastases and primary lung tumors displayed more differences in the metachronous group than in the synchronous group. Our work illustrates that brain metastatic tumors are more immunosuppressed than primary lung tumors, which may help guide immunotherapeutic strategies for NSCLC brain metastases.

Transcriptomic analyses of esophageal cancer patients with brain metastases.

341 Background: Brain metastases from esophageal cancer are extremely rare with an estimated incidence of 1.7% but limited survival. Some reports highlight the rich microvascular density of such tumors and their distinctive degree of HER2, HIF1-a and EGFR expression, further emphasizing the potential role of angiogenesis in their neurotropic behavior. With this in mind, we aimed to illustrate the transcriptomic landscape of brain metastases from esophageal cancers and better understand the disease biology. Methods: Following IRB approval, we collected retrospective data on patients with a diagnosis of esophageal cancer with histology-proven brain metastases treated at our institution between 2008 and 2020. We identified 10 adequate, paired samples with available tissue for RNA extraction. Expression data was generated using NanoString TS 360 panels to characterize gene signatures of interest and analyzed using GSEA_4.1.0. Results: All 10 patients were Caucasian, 90% were male. Median age was 63 years. All had adenocarcinoma with G2-G3 histology. Median follow-up was 39.4 mos (95%CI, 27.4 to 51.4). At data cutoff, 6 patients had died. Median OS was 24.6 mos. Median time from curative surgery to CNS recurrence was 8.3 mos. Ninety percent of patients developed brain metastases within 24 mos of surgery. Median time from brain metastases to death was 4.7 mos. Almost a third of patients had HER2 positive disease. 48 gene signatures were analyzed; 5 being significantly enriched between metastatic and primary site accounting for cell cycle, DNA damage repair, MYC, mTOR signaling and immortality and stemness. Out of a pool of 760, significant overlap was seen between 12 genes across the 5 signatures of interest: POLE, LIG1, FEN1 (involved in DNA repair and replication); AURKA and PLK1 (cell proliferation and triggers for G2/M transition), BUB1 (establishment of the mitotic spindle checkpoint and chromosome congression), MCM2 and MCM4 (initiation of genome replication); BRIP1 and RAD51 (critical in homologous recombinational repair); CCNE1 (cell cycle G1/S transition) and WRAP53 (dual role as p53 regulator and protein involved in telomere elongation and DNA repair). ERBB2 was similarly enriched in primary and metastatic sites. Conclusions: These preliminary data demonstrate that the genomic basis of brain metastases in esophageal cancer goes beyond EGFR/ERBB2 signaling. A complex genomic interaction is present in brain metastases as compared to primary site that offers these cells the advantage for neurotropism. To our knowledge this is the first study attempting to illustrate genomic differences between primary and matched brain metastasis sites in esophageal cancer.

HER2-low breast cancer could be associated with an increased risk of brain metastasis.

The HER2-low breast cancer is a newly recognized entity with the clinical characteristics is yet to be defined. We hypothesized that HER2-low breast cancer could lead to an increased rate of brain metastases in patients with localized breast cancer. We tested this hypothesis in a large cohort of breast cancer patients with long follow-up. We included 2686 adult breast cancer patients followed up in Hacettepe University Cancer Center. Patients with 1 + positive HER2 expression and 2 + HER2 expression with a negative FISH were categorized as HER2-low disease. We evaluated the brain metastasis risk withbinary logistic regression analyses and reported odds ratios (OR) with 95% confidence intervals (CI). During a median 95.4 (IQR 72.6-123.1)month follow-up, 184 patients developed brain metastasis (6.9%). The brain metastases were developed in 5.1% of the patients with HER2-negativedisease, 8.5% of the patients with HER2-low disease, and 10.1% of the patients with HER2-positive disease. A multivariable binary logistic regression model demonstrated an increased risk of brain metastasis in patients with HER2-low disease (OR: 1.611, 95% CI 1.055-2.460, p = 0.027) and in HER2-positive patients (OR: 1.837, 95% CI 1.308-2.580, p < 0.001). Additionally, HR + -HER2-low disease was associated with a decreased DFS compared to HR + -HER2-negative disease (p = 0.008). In this study, we observed an increased risk of brain metastasis in localized breast cancer patients with HER2-low disease. We think that a high level of vigilance and a low threshold for brain imaging could benefit HER2-low breast cancer patients similar to the patients with HER-positive disease.

Estimating population-based incidence of brain metastases – a comprehensive incident cohort study

Abstract Aims Brain metastases are the most common intracranial tumour and affect approximately 20% of adult cancer patients, most commonly from lung, breast, melanoma, and kidney cancer. However, the true incidence of brain metastasis is unknown. England’s cancer registration system only reliably captures brain metastases present at diagnosis (rather than those that develop later), and the same is true for US-based data. Although it is relatively easy to identify patients receiving some treatments for brain metastases (surgery, stereotactic radiosurgery (SRS) and whole-brain radiation therapy (WBRT)), identifying those receiving chemotherapy or no treatment is much harder. As a result, the existing literature is heavily biased towards reporting treated populations. This study attempts to find an unbiased estimate of the true number of patients developing brain metastases, based on data from a single centre. Method Cases of brain metastasis were retrospectively identified from the radiology information system database (SolitonTM). We performed a Boolean search for specific keywords in the radiology reports of all CT and MRI head scans performed at the trust between 1st January 2018 and 31st December 2019. The following keywords were searched for “metastases”, “metastatic“, “metastasis”, “mets”, “deposit”, “deposits”, “secondaries”, “secondary” and “disseminated”. Duplicate cases were then removed and the subsequent list was manually reviewed We identified all patients who received any treatment for brain metastases who were diagnosed at our centre. We only included patients with newly diagnosed brain metastases (included: leptomeningeal; excluded: skull-based metastases). We excluded patients who were diagnosed in other centres and treated here or diagnosed outside the study period. We then extracted data on primary diagnosis, admissions, and survival. Results 1192 patients had a CT or MRI of the head with a mention of “brain metastases” in the report; of these 305 were newly diagnosed with brain metastases during the study period (432 had metastases; 127 diagnosed earlier). Of these 305 patients, 217 (71.1%) were treated locally (SRS = 88; WBRT = 74; surgery = 88; systemic therapy = 16; multiple treatments = 45) and 10 (3.3%) were referred elsewhere. 78 (25.6%) patients received no treatment. Of the 217 treated patients, 124 were female, and the median age was 61. Of the 78 untreated patients, 38 were females, and the median age was 70 years old. The commonest primary diagnoses in both groups were lung (39%) and breast (21%) cancer. 16 (21%) of the untreated patients had an unbiopsied primary tumour. Median survival for patients having (any) treatment was 52 weeks compared to 5 weeks for those not having treatment. Conclusion We have presented an unbiased single-centre estimate of brain metastases occurrence. Unlike previous work, we manually reviewed all imaging reports that suggested metastasis, and included all patients diagnosed with brain metastases at any timepoint. We reduced the bias associated with being a tertiary centre by only including patients who were diagnosed here, rather than referred from other centres. 25% of our cohort received no treatment, and survival in this group is poor. This is broadly in line with the only other study on this topic (Bentley, 2019) that reported a large minority (39%) of untreated patients. Our key conclusions are: When assessing the incidence of brain metastases, studies that do not account for untreated patients are likely to significantly underestimate incidence, and over-estimate survival. Improving outcomes in patients with brain metastases might be best achieved by addressing earlier identification and intervention in those who currently receive no treatment

444 CORRELATION BETWEEN PATHOLOGIC COMPLETE RESPONSE TO NEOADJUVANT THERAPY AND RECURRENCE IN PATIENTS WITH ESOPHAGEAL CANCER

Abstract Multimodal treatment options in carcinoma esophagus include neoadjuvant chemoradiotherapy or chemotherapy followed by surgery. The degree of pathologic response to different neoadjuvant options and its impact on the oncologic outcome is a matter of debate. With this background we carried out this study to analyze the rate of pathologic complete re-sponse (pCR) and its effect on recurrence in patients with carcinoma esophagus treated with various combinations of neoadjuvant chemotherapy/radiotherapy and surgery. Methods The records of all patients with carcinoma esophagus registered in our clinics between June 2012 and December 2014 were retrieved from a prospectively maintained database and were analyzed. of the 70 patients with histologically proven esophageal cancer who were treated with curative intent during this period, those with pCR (15) were followed up for a minimum of 5 years. These 15 patients are the subjects of this study. Results Forty eight (48) patients received neoadjuvant chemotherapy (NACT), 16 were treated with short course radiotherapy (SRT), and 3 patients received neoadjuvant chemoradiation (CRT). Four patients developed metastatic disease on neoadjuvant therapy. 66 patients (63 after neoadjuvant therapy and 3 upfront) underwent transthoracic esophagect-omy. Pathological CR was seen 12 patients (25%) in NACT-surgery arm, 2 (12%) in SRT-surgery and 1 (33%) in CRT-surgery groups. Three patients had postoperative mortality due to pulmo-nary complications. At 5 yrs, 14 out of 15 patients with pathological CR are alive and disease free. One patient developed brain metastases after 3 years and died. Conclusion Neoadjuvant therapy followed by radical surgery is a safe and effective treatment option for the management of carcinoma esophagus. Pathologic CR strongly correlates with recurrence-free survival. The relative significance of pCR after different types of neoadjuvant therapies need to be tested in future studies.

780 ISOLATED BRAIN METASTASIS OF ESOPHAGEAL CARCINOMA AFTER MINIMALLY INVASIVE ESOPHAGECTOMY MIGHT NOT HAVE A DISMAL PROGNOSIS

Abstract After esophagectomy for esophageal carcinoma, 2–13% of patients develop brain metastases (BM) which are associated with a poor prognosis. Further investigation into treatment and prognosis is beneficial given the scarce publications and varying outcomes. Methods Case files of all 339 patients who underwent esophagectomy in a single high-volume centre between January 2015 and December 2020 were retrospectively reviewed, all procedures were minimally invasive esophagectomies (MIE). Patients with BM and isolated brain metastases (iBM) were identified and a Kaplan–Meier analysis was performed. Results 15 out of 339 patients (4,4%) undergoing MIE developed BM of which 9 (60,0%) were iBM. Most patients were diagnosed with squamous cell carcinoma (55,6%), localised in the middle third of the esophagus (66,7%) and had a pathologic complete response (66,7%). Treatment consisted of gamma knife (GK) radiosurgery (44,4%), surgical resection (22,2%), GK and surgical resection (11,1%) and best supportive care (22,2%). Median time to diagnose iBM was 8,4 months (95% CI 0,0–17,2) and survival after recurrence was 14,3 months (95% CI 0,0–45.9). 2 patients (22,2%) remain disease-free after at least 2 years of follow-up. Conclusion iBM after esophagectomy for esophageal carcinoma is rare, but when encountered should be treated with a curative intent in selected cases. More research should be conducted on the benefits of screening for iBM after esophagectomy, especially in patients diagnosed with a squamous cell carcinoma in the middle third of the esophagus with a pathological complete response.