bluuebunny/crossref_metadata_2025_split huggingface dataset:
BSCI-19. EFFECT OF STEREOTACTIC RADIOSURGERY ON NON-SMALL CELL LUNG CANCER BRAIN METASTASIS: CORRELATIVE RADIOBIOLOGIC ANALYSIS FROM PHASE-II CLINICAL TRIAL NCT03398694
Authors: Huff Wei , Shireman Jack , Monaco Gina , Agrawal Namita , Park Cheol , Saathoff Miranda , Henriquez Mario , Watson Gordon , Ahmed Atique , Dey Mahua 
Published: August 2019

Abstract
BACKGROUND: Stereotactic radiosurgery (SRS) is an increasingly common modality used with or without surgery for brain metastases (BM). However, biological effect of SRS to tumors in vivois not known. METHODS: Patients were treated with SRS prior to surgery as per the clinical trial protocol. The resected tumor was divided into two groups: ‘center’ and ‘periphery’ with respect to the center of SRS treatment with periphery within 50%-isodose-line. Tissue was analyzed by whole exome sequencing (WES) and compared between the two groups as well as to non-radiated control tissues. RESULTS: All sequenced samples contained greater than 95% clean reads with an average read density of 100 base pairs and mapping efficiency of &gt;99%. Preliminary analysis focused on SNP and Indel detection. In pooled groups with n=7 replicates there was no statistically significant differences in total mutation burden in either SNP’s or Indels compared between controls and both treatment locations. Delving deeper intronic, frameshift, missense, and nonsense mutations all also showed insignificant changes between controls and center or peripheral tumor locations (p &gt;0.5, p &gt;0.1, p &gt;0.4, p &gt;0.3 respectively) hinting that at a pooled biological level there are not significant mutational burdens between treatment locations. However, at the individual level, matched comparison of SRS samples originating from the center or periphery of the same tumor showed total mutational burden differences. 6 out of 7 (86%) patients showed decreased total number of indels in peripheral vs. center and 5 out of 7 (71%) patients showed decreased number of SNP’s in peripheral vs. center locations. CONCLUSION: Ultimately, these data demonstrate the power of matched patient controls over bulk analysis in order to elucidate smaller but possibly biologically meaningful effects, and point to a possible location dependency in treatment associated mutation burden within a single patient and single tumor that may be masked at a population level.
BSCI-22. IDENTIFICATION OF ACTIONABLE TYROSINE KINASE-REGULATED NETWORKS REQUIRED FOR LUNG AND BREAST CANCER BRAIN METASTASIS
Authors: Pendergast Ann Marie , McKernan Courtney , Hoj Jacob , Anders Carey , Force Jeremy , Fecci Peter 
Published: August 2019

Abstract
Brain metastases are a common consequence of advanced lung and breast cancer resulting in functional impairment, cranial neuropathies, and decline in quality of life. Current therapies for brain metastasis, such as whole brain radiation therapy, can result in cognitive impairment, while targeted therapies and chemotherapy are largely ineffective due, in part, to the emergence of resistance and inability to reach effective concentrations in the central nervous system (CNS). We have uncovered a role for the Abelson (ABL) family of tyrosine kinases, ABL1 and ABL2, in lung and breast cancer metastasis to the brain. We show that cancer cells increase ABL expression upon colonization of the brain. Notably, we found that genetic inactivation or pharmacological inhibition of the ABL kinases suppressed lung and breast cancer metastasis to the brain. ABL allosteric inhibitors effectively cross the blood-brain barrier (BBB), inhibit ABL kinases and downstream targets in brain metastases, and markedly impair metastatic colonization of the brain. Further, treatment with an ABL allosteric inhibitor increased recruitment of Iba1+ macrophages/microglia to breast cancer brain metastases. Current studies are aimed at identifying the molecular mechanisms by which ABL kinase signaling regulates the crosstalk between cancer cells and macrophages/microglia, with the aim of disrupting metastatic colonization of the brain parenchyma. These data reveal, for the first time, a role for ABL kinases in promoting brain colonization by metastatic tumors, and demonstrate that ABL allosteric inhibitors efficiently penetrate the BBB and inhibit intracranial growth of breast and lung cancer metastases.
BSCI-23. TISSUE FACTOR SIGNALING ENHANCES METASTATIC BRAIN CANCER MALIGNANCY
Authors: Unruh Dusten , Mirkob Snezana , James C David , Horbinski Craig 
Published: August 2019

Abstract
Brain metastases are on the rise and remain one of the most refractory malignancies worldwide. Currently, the standard approach for therapy involves surgery and radiation. However, this approach usually produces only a modest increase in survival. We recently discovered that Tissue Factor (TF) strongly enhances the malignancy of gliomas via protease-activated receptor 2 (PAR2) signaling, though its role in brain metastases is not as well understood. In this study, we further explored the significance of TF in lung cancer brain metastases, showing that genetic and pharmacological targeting of TF-PAR2 signaling may decrease malignancy and increase the efficacy of radiotherapy. Studies were performed using patient-derived brain metastases coming from lung carcinoma. Markers of malignancy were measured by BrdU incorporation for cell proliferation, Matrigel-coated transwell migration, soft agar colony formation for anchorage-independent growth, limiting dilution assay for tumor initiation capacity, and clonogenic cell survival assay to measure radiation sensitivity. Low transcription of the TF gene is a favorable prognostic marker for overall survival in TCGA lung cancer patients (54.7 vs 41.9 months, P=0.0053), with 74% longer progression-free survival (102.7 vs 59.1 months, P=0.0012). TF knockdown significantly reduced tumor malignancy as determined by cell proliferation, invasion, colony formation, and in vivo growth. Conversely, TF overexpression increased tumor malignancy and promoted cancer stem-like behavior, as indicated by CD44 and CD133 expression, extreme limiting dilution assay, and anchorage-independent growth. A PAR2 antagonist, I-191, inhibited TF-mediated signaling and reduced cell proliferation by 51.3% (P&lt; 0.001). TF knockdown and I-191 increased radiation sensitivity. Exogenous treatment of lung cancer cells with recombinant TF suppressed radiation-induced apoptosis, and this effect was blocked with I-191. These data show that TF-PAR2 signaling may represent a novel therapeutic strategy to reduce the malignancy of brain metastasis and increase the efficacy of radiation.
BSCI-26. COMPARATIVE METHYLATION PROFILING OF EGFR MUTANT LUNG ADENOCARCINOMA AND PAIRED BRAIN METASTASIS
Authors: Mamatjan Yasin , Zuccato Jeffrey , Karimi Shirin , Cabanero Michael , Weiss Jessica , Sorotsky Hadas , Tsao Ming , Shepherd Frances , Aldape Kenneth , Zadeh Gelareh 
Published: August 2019

Abstract
BACKGROUND: Adenocarcinomas (ADC) are the most common lung tumours and EGFR-mutant lesions have a higher risk of brain metastasis development, which confers poorer survival. Genetic and epigenetic signatures of brain metastasis have not been comprehensively identified. The aim of this study is to compare the methylome of EGFR-mutant primary lung tumor and matched brain metastasis to identify mechanisms of brain metastasis and new treatment targets. METHOD: Seven matched primary to brain metastasis tumours were profiled using the Illumina Infinium MethylationEPIC BeadChip array. Hierarchical clustering and principal component analyses (PCA) were performed using most variable CpG sites. Supervised analyses were performed between lung and brain tumour samples. Copy number variation (CNV) plots identified alterations between pairs along with Leukocytes unmethylation for purity (LUMP) score and prediction lymphocyte proportion analyses to measure immune infiltration. RESULTS: Unsupervised clustering showed that the fourteen tumours clustered according to patient with similar methylation profiles between each of seven matched pairs. On the supervised analysis using 83K significant CpG sites, the fourteen samples clustered into two groups based on tumour site being lung or brain. Of these 83K CpG sites, 2.4K were either hypermethylated or hypomethylated in all lung samples. One quarter of these 2.4K CpG sites were located in promoter regions. CNV analyses showed losses of FGFR1, C19MC, CDKN2A, PTCH1, and MYCN genes with higher deep deletions in brain versus lung primary samples. Immune infiltration measures were similar between lung and brain metastasis pairs (LUMP-score=0.64) consistent with high immune cell infiltration. CONCLUSION: In this EGFR-mutant lung adenocarcinomas and matched brain metastases, differentially methylated CpG sites and CNV alterations are identified that distinguish lung from brain samples. Further work with additional matched samples may further elucidate signatures specific to brain metastasis and aid in our understanding of the mechanisms of brain metastasis.
LPTO-07. CARCINOEMBRYONIC ANTIGEN OF CEREBROSPINAL FLUID PREDICT PROGNOSIS OF LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER
Authors: Zhen Junjie , Wen Lei , Li Shaoqun , Lai Mingyao , Zhou Cheng , Cai Linbo 
Published: August 2019

Abstract
BACKGROUND: Leptomeningeal metastasis (LM) is a detrimental complication of patients with non-small cell lung cancer (NSCLC) and its incidence has increased due to recent improvements in survival. The aim of this study was to identify the clinicolpathological features and prognostic factors related to overall survival in NSCLC patients with LM. METHODS: Seventy-four consecutive patients diagnosed with LM from NSCLC between 2009 and 2018 in Guangdong Sanjiu Brain Hospital were retrospectively reviewed. RESULTS: Median KPS at diagnosis of LM were 60 (range, 20–90). Forty-seven (63.5%) patients harboring epidermal growth factor receptor (EGFR) or anaplasticlymphoma kinase (ALK) mutation while other twenty-seven patients (36.5%) were wild type or unknown status. Local treatment for LM consisted of whole-brain radiotherapy (WBRT) (52.7%), ventriculoperitoneal (VP) shunt (6.8%) and external drainage (6.8%). Systematic therapy for LM included EGFR or ALK tyrosine kinase inhibitors (TKI) (59.5%), chemotherapy (40.5%) and bevacizumab (8.1%). The median overall survival from diagnosis of LM to death was 8.1 months (95% confidence interval: 5.2 to 11.0). Patients with high Cerebrospinal Fluid (CSF) carcinoembryonic antigen (CEA) level (＞50ng/ml) had worse prognosis compared with those low CSF CEA level (≤50ng/ml) ones (p=0.02). However, there was no significant difference in survival between patients with high serum CEA and those with low serum CEA (p=0.645). EGFR/ALK mutation and EGFR/ALK TKI after LM were also identified as variables that had prognostic influence on survival, while KPS, concurrent brain metastasis, WBRT and chemotherapy had no prognostic value for survival. CONCLUSION: Median overall survival was higher than historical experience in this retrospective analysis. It is CSF CEA level, but not serum CEA level that correlated with prognosis for LM from NSCLC.
TRLS-10. MITIGATING NEUROCOGNITIVE DEFICITS FROM WHOLE-BRAIN RADIOTHERAPY IN PATIENTS WITH NUMEROUS BRAIN METASTASES VIA A NOVEL SUPEROXIDE DISMUTASE MIMETIC: RATIONALE & DESIGN OF A CLINICAL TRIAL
Authors: Kirkpatrick John , Franklin Heather , Torok Jordan , Floyd Scott , Anders Carey , Fecci Peter , Salama April , Clarke Jeffrey , George Daniel , Crapo James , Peters Katherine 
Published: August 2019

Abstract
BACKGROUND: Patients with a large number of brain metastases (BM) and/or micrometastatic disease in the brain present a clinical challenge. While technical innovations in stereotactic radiosurgery (SRS) have extended the number of BM that can be effectively treated, SRS does not treat occult disease and distant brain failure (DBF) post-SRS remains high. Immuno- and targeted therapies show promise in treating metastatic disease to the brain, though response rates are variable. In contrast, whole-brain radiotherapy (WBRT) provides high rates of local control and, compared to SRS, reduces the risk of distant brain failure. Unfortunately, WBRT is also associated with substantial neurocognitive deficits and neither altered fractionation nor the use of available neuroprotectants has adequately addressed this issue. An agent that safely minimizes the adverse effects of WBRT while preserving or enhancing tumor control would provide meaningful clinical benefit. TRIAL DESIGN: BMX-001, a novel Mn-porphyrin superoxide dismutase mimetic, has been shown to protect normal tissues from ionizing radiation in preclinical trials, reducing neurocognitive adverse effects as well as enhancing tumor response. Based on the first-in-human trial of this agent in patients with high-grade gliomas, we have instituted a clinical trial of WBRT +/- BMX-001 in adult patients with more than 10 BM from melanoma, non-small-cell lung, breast and renal cancer. Following a safety lead-in of 5 patients, all of whom will receive WBRT and BMX-001, 69 patients will be randomized to WBRT (3Gy/fraction x 10 fractions) with or without BMX-001 administered subcutaneously before, twice weekly during and once after WBRT (6 injections total.) The primary endpoint is cognition, as measured by the Hopkins Verbal Learning, Trailmaking A/B and Controlled Oral Word Association tests. Secondary endpoints include health-related quality-of-life, overall and progression-free survival, rates of radiation necrosis, DBF and neurologic death. Enrollment began January 2019. (ClinicalTrials.gov Identifier: NCT03608020.)
THER-02. IMPACT OF SYSTEMIC THERAPY IN MELANOMA BRAIN METASTASIS
Authors: Sagar Soumya , Lauko Adam , Barnett Addison , Wei Wei , Chao Samuel , Peereboom David , Stevens Glen , Angelov Lilyana , Yu Jennifer , Murphy Erin , Mohammadi Alireza , Suh John , Barnett Gene , Ahluwalia Manmeet 
Published: August 2019

Abstract
BACKGROUND: Melanoma brain metastasis is associated with a median overall survival (OS) of approximately 9 months. In recent years, management of melanoma brain metastases (MBM) by surgery and radiation [stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT)] has been bolstered by targeted therapy and immune checkpoint inhibitors (ICI). METHODS: 351 patients, who underwent treatment for MBM at our tertiary care center from 2000 to 2018, were grouped into those that received chemotherapy, ICI, or targeted therapy. Thirty-four percent of patients treated with ICI had received other systemic therapies as well as part of their management. OS was calculated from the date of diagnosis of the brain metastases. The Kaplan Meier analysis was utilized to determine median OS and difference in OS was determined by utilizing the Cox proportional hazard model. RESULTS: The median survival after the diagnosis of brain metastasis was 10.4, 11.96, and 7.06 months in patients who received ICI, chemotherapy and targeted therapy respectively. A multivariate model was developed including the type of systemic therapy, presence of extracranial metastases, age, KPS and number of intracranial lesions. 114 patients underwent SRS alone, 56 underwent SRS and WBRT, 43 underwent SRS and surgical removal, 28 had surgical removal, SRS and WBRT, and 78 had no intracranial therapy. Compared to patients who received chemotherapy, patients who received immunotherapy had a hazard ratio, HR = 0.628 (confidence interval = 0.396 – 0.994, p-value = 0.047). Presence of EC metastases (HR= 1.25, p-value &lt; .001), lower KPS (HR = .97, p-value &lt; .0001) and multiple brain lesions (HR = 1.117, p-value &lt; .0001) were associated with significantly worse OS. CONCLUSIONS: Addition of ICI significantly improves the OS in MBM compared to chemotherapy. Lower performance status, multiple brain metastases, and EC metastases are associated with poor OS.
THER-03. USING SUCCESSIVE EGF RECEPTOR ANTAGONISTS TO TREAT A PATIENT WITH EXTENSIVE METASTATIC DISEASE: CASE REPORT AND REVIEW OF THE LITERATURE
Authors: Megyesi Joseph , Macdonald David 
Published: August 2019

Abstract
INTRODUCTION: EGFR-targeted agents can be useful in the treatment of systemic metastatic cancer including that which has spread to the brain. We present the case of a patient with two different EGFR mutations that responded to receptor blockade. CASE REPORT: A 38 year old right-handed female presented with a one week history of progressive left-sided weakness and focal seizures. Neuroimaging revealed multiple enhancing brain lesions and a lesion in the left maxillary antrum. Body imaging revealed a right lung mass, hilar and mediastinal nodes and multiple bony lesions. Biopsy of the maxillary antrum lesion showed metastatic poorly differentiated adenocarcinoma, TTF-1 positive, suggesting a lung primary. ALK was not mutated but there was an EGFR mutation (exon 19 deletion). The patient underwent treatment with dexamethasone, levetiracetam, whole brain radiation and afatinib, an oral EGFR-targeted agent. Most of the brain lesions responded completely with only two small residual lesions. Seizures were controlled. There was major partial response from the systemic lesions. Two years later the patient was clinically well but the lung lesion, mediastinal nodes and bony lesions were all enlarging. A new pituitary lesion was identified on brain MRI. A liquid biopsy (blood) revealed a T790M mutation and the patient underwent stereotactic body radiation and EGFR-targeted therapy with osimertinib. All lesions responded to treatment and four years after initial diagnosis the patient is clinically well with stable disease. DISCUSSION: Successful treatment of widespread metastatic disease is possible with the use of multiple EGFR-targeted agents in certain patients.
THER-06. GENOMIC AND IMMUNE CHARACTERIZATION OF TRIPLE NEGATIVE BREAST CANCER BRAIN METASTASES
Authors: Vincent Benjamin , Sambade Maria , Chai Shengjie , Siegel Marni , Cuaboy Luz , Holye Alan , Parker Joel , Perou Charles , Anders Carey 
Published: August 2019

Abstract
INTRODUCTION: Approximately 50% of patients with metastatic triple negative breast cancer (TNBC) will develop brain metastases (BM). Routinely treated with radiotherapy and/or surgery, survival is generally less than one year. There are no approved systemic therapies to treat TNBC BM. We characterized the genomic and immune landscape of TNBC BM to foster the development of effective brain permeable anti-cancer agents, including immunotherapy. EXPERIMENTAL PROCEDURES: A clinically-annotated BCBM biobank of archival tissues was created under IRB approval. DNA (tumor/normal) and RNA (tumor) were extracted from TNBC primaries and BM; whole exome (WES) and RNA sequencing (RNASeq) was performed. Mutations were determined from WES as those co-identified by two variant callers (Strelka|Cadabra). Immune gene signature expression, molecular subtype identification, and T cell receptor repertoires were inferred from RNAseq. RESULTS: 32 TNBC patient tissues (14 primaries, 18 BCBM, 6 primary-BCBM matched), characterized as basal-like by PAM50, were analyzed. Top exome mutation calls included ten genes in ≥19% of BCBMs including TP53, ATM, and PIK3R1, and four genes in ≥18% of primaries including TP53 and PIK3R1. Many immune gene signatures were lower in BM compared to primaries including B cell, dendritic cell, regulatory T cell, and IgG cluster (p&lt; 0.05). A signature of PD-1 inhibition responsiveness was higher in BM compared with primaries (p&lt; 0.05). BCBM T cell receptor repertoires showed higher evenness and lower read count (both p &lt; 0.01) compared to primaries. CONCLUSIONS: TNBC BM compared to primaries that metastasize to the brain show lower immune gene signature expression, higher PD-1 inhibition response signature expression, and T cell receptor repertoire features less characteristic of an active antigen-specific response. Mutations common to TNBC BM and primaries include TP53 and PIK3R1. Given that non-BCBM (i.e. lung and melanoma) show response to checkpoint inhibitors, these findings collectively support further study of immunotherapy for TNBC BM.
THER-13. IMMUNOTHERAPY VERSUS STANDARD OF CARE IN MELANOMA BRAIN METASTASES WITH KNOWN BRAF STATUS
Authors: Barnett Addison , Sagar Soumya , Lauko Adam , Wei Wei , Chao Samuel , Peereboom David , Stevens Glen , Angelov Lilyana , Yu Jennifer , Murphy Erin , Mohammadi Alireza , Suh John , Barnett Gene , Ahluwalia Manmeet 
Published: August 2019

Abstract
BACKGROUND: A mutation of the BRAF protein is seen in approximately 50% of melanoma patients. Immune checkpoint inhibitors (ICI) are standard therapy in melanoma patients independent of a patient’s BRAF status. The primary objective of this study is to investigate the impact of BRAF status in patients treated with ICI compared to non-ICI systemic therapy on overall survival (OS) in patients with melanoma brain metastasis (MBM). METHODS: We reviewed 351 patients with MBM treated at our tertiary care center between 2000 and 2018. Of these, 144 had known BRAF status, 71 of which were BRAF mutant and 73 were BRAF wild-type. OS was calculated from the date of diagnosis of brain metastasis to compare the efficacy of ICI to other systemic therapies. Many of these patients received multiple lines of treatment including targeted therapies at some point during their care. The log-rank test and Cox proportional hazard model was utilized to determine differences in OS. RESULTS: Eighty-four percent of patients received local therapy that included either surgery, stereotactic radiosurgery or whole brain radiation therapy. In BRAF wild-type patients, 40 received ICI and 33 underwent non-ICI systemic therapy with a median survival (5.6 vs 7.1 months) and 2-year survival (28% vs 32%), respectively (p=0.64). Of the BRAF mutant patients, 33 received ICI and 38 did not with a median survival (17.1 vs 9.0 months) and 2-year survival (36% and 19%), respectively (p=0.014). When controlling for age, KPS, ECM, and number of lesions, BRAF mutant MBM patients treated with ICI compared to non-ICI had an OS hazard ratio, HR=0.4 (95% CI=0.21 – 0.78, p=0.0069). CONCLUSIONS: ICI therapy in BRAF mutant MBM patients results in improved OS compared to those with non-ICI systemic therapy. No such difference was observed in the BRAF wild-type cohort.