bluuebunny/crossref_metadata_2025 huggingface dataset:
BSCI-04. TARGETING TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES WITH A RE-ENGINEERED LUPUS AUTOANTIBODY
Authors: Zhang Shenqi , May Christopher , Shirali Anupama , Dubljevic Valentina , Campbell James , Zhou Jiangbing , Hansen James
Published: August 2019

An unusual lupus anti-DNA autoantibody, 3E10, has potential to be used against triple-negative breast cancer (TNBC) brain metastases. 3E10 penetrates live cell nuclei, inhibits DNA repair, and is selectively toxic to cancer cells with the PTEN and/or DNA-damage response (DDR)-deficiencies that are associated with brain metastases in TNBC. The ENT2 nucleoside transporter that 3E10 uses to cross cell membranes is highly expressed in tumors and in brain endothelial cells (BECs) at the blood-brain barrier (BBB), and 3E10 has previously delivered cargo proteins to ischemic brain in a rat stroke model. We have re-engineered 3E10 into an optimized fragment, called Deoxymab-1 (PAT-DX1), that has increased effect on PTEN/DDR-deficient tumor cells. In the present study we tested the ability of PAT-DX1 to cross the BBB and improve outcomes in a mouse model of TNBC brain metastases. PAT-DX1 crossed from apical to basolateral chambers in an hCMEC/D3 Transwell filter model of the BBB, and penetrated the nuclei of and was toxic to the brain-seeking 231-BR subclone of MDA-MB-231 TNBC cells, which harbors a loss of PTEN compared to parental cells. Brain metastases were generated in nude mice by intracardiac injection of 1.75x105 231-BR cells engineered for expression of luciferase, as confirmed by IVIS one week after injection. Mice with brain metastases were treated by tail vein injection of control (PBS, n=7) or DX1 (20 mg/kg, n=7) 3x/week for 4 weeks. Mice were observed for behavior and weights, and brain radiance efficiency was monitored by weekly IVIS to track metastatic tumor growth. PAT-DX1 significantly suppressed growth of brain metastases based on absolute and relative radiance efficiencies in the brain, increased the median survival of the mice from 38 to 52 days (P< 0.02), and was well tolerated. These results provide proof of concept for use of a re-engineered autoantibody against brain metastases.
BSCI-07. BONE MARROW T-CELL SEQUESTRATION IN THE SETTING OF BRAIN METASTASES
Authors: Chongsathidkiet Pakawat , Woroniecka Karolina , Dechant Cosette , Kemeny Hanna , Cui Xiuyu , Wilkinson Daniel , Lorrey Selena , Fecci Peter
Published: August 2019

INTRODUCTION: Brain metastases remain one of the most dreaded consequences of late stage cancer, yet their incidence has risen as survival from primary cancers has improved. We have recently reported that tumors harbored within the brain, specifically, sequester T-cells within the bone marrow as a novel mechanism of immune evasion. Sequestration results from tumor-imposed loss of S1P1 receptor from the T-cell surface. Stabilization of the receptor on T-cells frees T-cells from sequestration and licenses T-cell activating therapies for intracranial tumors. While this phenomenon was initially uncovered in glioblastoma, its role in promoting immune-evasion in brain metastases remains less clear. METHODS: Blood, bone marrow, and tumors were collected from mice bearing intracranial tumors commonly metastatic to the brain, including lung carcinoma (LLC), melanoma (B16F10), or breast carcinoma (E0771) and analyzed by flow cytometry. T-cell S1P1 levels, as well as total T-cell counts were assessed in each compartment. Correlation analyses were conducted between T-cell counts and S1P1 levels on T-cells in the bone marrow across intracranial and subcutaneous murine tumor models. RESULTS: T-cell lymphopenia and accompanying accumulation of T-cells in the bone marrow were observed in the murine models of lung carcinoma, melanoma, and breast carcinoma, but only when these tumor lines were implanted intracranially. Sequestered T-cells in tumor-bearing mice showed decreased surface S1P1 levels in a manner correlating with their sequestration. CONCLUSION: S1P1-mediated bone marrow T-cell sequestration is a novel mode of cancer-induced T-cell dysfunction in intracranial tumors. Preventing receptor internalization abrogates T-cell sequestration and licenses T-cell activating therapies in glioblastoma. Sequestration is now observed in models of brain metastases. Pharmacologic strategies to stabilize S1P1, reverse sequestration, and restore circulating T-cell numbers are anticipated to improve immunotherapeutic efficacy for brain metastases.
BSCI-11. STROMAL PLATELET DERIVED GROWTH FACTOR RECEPTOR-β (PDGFRβ) PROMOTES BREAST CANCER BRAIN METASTASIS
Authors: Thies Katie , Hammer Anisha , Hildreth Blake , Russell Luke , Sizemore Steven , Trimboli Anthony , Kladney Raleigh , Steck Sarah , Das Manjusri , Bolyard Chelsea , Pilarski Robert , Cuitino Maria , Koivisto Christopher , Schoenfield Lynn , Otero Jose , Chakravarti Arnab , Ringel Matthew , Li Zaibo , Kaur Balveen , Leone Gustavo , Ostrowski Michael , Sizemore Gina
Published: August 2019

Stromal platelet-derived growth factor receptor-beta (PDGFRβ) has emerged as an actionable mediator of breast tumor-stromal communication. As a receptor tyrosine kinase, PDGFRβ is activated by its ligand, PDGFB, which is released by neighboring tumor epithelium and endothelium. However, how PDGF signaling mediates breast cancer (BC) initiation, progression, and metastasis remains unclear. To evaluate PDGFRβ in this disease, we developed a mouse model of stromal-specific PDGFRβ activation using the Fsp-cre transgene previously published by our group. Mesenchymal-specific activation of PDGFRβ promotes preferential experimental brain metastasis of PDGFB-expressing mammary tumor cells when injected intravenously and accelerates intracranial tumor growth of these cells. Mammary tumor cells expressing low levels of PDGFB do not exhibit a similar increase in brain metastases in PDGFRβ mutant mice. To our knowledge, this is the first example where genetic manipulation of the stroma leads to an increased incidence of BCBM. Our pre-clinical data suggests that primary breast tumors that express high PDGFB could preferentially metastasize to the brain. To test this in patients, we analyzed PDGFB protein expression in a tissue microarray comprised of HER2-positive and triple negative BC primary tumors. While high PDGFB did not correlate with site-independent metastatic recurrence, it was prognostic of brain metastasis, mirroring our mouse data. Our findings suggest that high primary tumor PDGFB expression defines a subset of BC patients predisposed to brain metastases. These patients may benefit from therapeutic intervention of PDGFRβ signaling. To test this pre-clinically, we treated mice harboring intracranial tumors with the PDGFR-specific inhibitor, crenolanib. Excitingly, crenolanib treatment significantly inhibited the brain tumor burden in these mice. Combined, our findings (1) advocate that primary tumor expression of PDGFB is a novel prognostic biomarker for the development of BCBM and (2) support clinical trial evaluation of PDGFR inhibitors for the prevention and treatment of BCBM.
BSCI-13. TUMOR-SPECIFIC tGLI1 TRANSCRIPTION FACTOR MEDIATES BREAST CANCER BRAIN METASTASIS VIA ACTIVATING METASTASIS-INITIATING CANCER STEM CELLS AND ASTROCYTES IN THE TUMOR MICROENVIRONMENT
Authors: Sirkisoon Sherona , Carpenter Richard , Rimkus Tadas , Doheny Daniel , Zhu Dongqin , Aguayo Noah , Anguelov Marlyn , Arrigo Austin , Regua Angelina , Xing Fei , Chan Michael , Metheny-Barlow Linda , Watabe Kounosuke , Lo Hui-Wen
Published: August 2019

Breast cancer is the second leading cause of brain metastases in women; patients with breast cancer brain metastasis (BCBM) survive only 6–18 months after diagnosis. Mechanisms for BCBM remain unclear, which contributes to ineffective treatments and dismal prognosis. Truncated glioma-associated oncogene homolog 1 (tGLI1) belongs to the GLI1 family of zinc-finger transcription factors and functions as a tumor-specific gain-of-function mediator of tumor invasion and angiogenesis. Whether tGLI1 plays any role in metastasis of any tumor type remains unknown. Using an experimental metastasis mouse model, via intracardiac implantation, we showed that ectopic expression of tGLI1, but not GLI1, promoted preferential metastasis to brain. Conversely, selective tGLI1 knockdown using tGLI1-specific antisense oligonucleotides led to decreased brain metastasis of intracardially inoculated breast cancer cells. Furthermore, intracranial implantation mouse study revealed tGLI1 enhanced intracranial colonization and growth of breast cancer cells. Immunohistochemical staining of patient samples showed that tGLI1, but not GLI1, was increased in lymph node metastases compared to matched primary tumors, and that tGLI1 was expressed at higher levels in BCBM specimens compared to primary tumors. Whether tGLI1 plays any role in radioresistance is unknown; we found radioresistant BCBM cell lines and patient specimens expressed higher levels of tGLI1 than radiosensitive counterparts, and that tGLI1 promotes radioresistance. Since cancer stem cells (CSCs) are highly metastatic and radioresistant, we examined whether tGLI1 promotes BCBM and radioresistance through activating CSCs. Results showed that tGLI1 transcriptionally activates stemness genes CD44, Nanog, Sox2, and OCT4, leading to stem cell activation. Furthermore, we observed that tGLI1-positive CSCs strongly activated and interacted with astrocytes, the most abundant brain tumor microenvironmental cells known to promote tumor growth, in vitro and in vivo. Collectively, our findings establish a novel role of that tGLI1 plays in promoting breast cancer preferential metastasis to brain, radioresistance, and astrocytes in the metastatic niche.
BSCI-15. METASTATIC BRAIN TUMOR TARGETING PEPTIDES ISOLATED THROUGH PHAGE DISPLAY BIOPANNING AGAINST BRAIN METASTASIS-INITIATING CELLS
Authors: Kim JongMyung , Liu James
Published: August 2019

To effectively target metastatic brain tumors (MBTs), the paradigm of treating MBTs after visualization on clinical imaging needs to be shifted to an understanding of the mechanisms that drive the formation and maintenance of brain metastasis-initiating cells (BMICs). Targeting this tumor sub-population, which may form as a result from activation of epithelial-mesenchymal transition, may allow for more effective means of isolating and targeting brain metastasis. In order to isolate BMICs, we have harvested cells from patient derived MBTs originating from lung cancer and cultured the cells using serum-free media conditions. In vivo phage display biopanning was used to isolate 12-amino acid length peptides that specifically target BMICs. Of the peptides recovered, one peptide, LBM4, was tested for specificity of binding to MBTs through in vitro and in vivo binding assays. When comparing patient derived metastatic brain tumors cells against brain metastasis cell lines, we found that both types of cells demonstrated similar morphology when grown in serum media conditions, but when grown in serum-free media, both demonstrated a tumor sphere morphology, similar to a stem cell-like state. LBM4 demonstrated specific binding to MBT cells over primary lung cancer cells in vitro through flow cytometry analysis and immunocytochemistry. Fluorescent tagged LBM4 intravenously injected into mice harboring intracranial BM demonstrated peptide localization to the tumor within the intracranial cavity visualized with live animal imaging. In vivo phage display biopanning is an effective tool that is able to isolate cell specific targeting peptides. MBT targeting peptides can potentially result in a shifting of the clinical treatment paradigm of brain metastases, through the development of more effective targeted therapeutics aimed at BMICs, as well as improving detection of MBT cells which may result in earlier tumor visualization as well as delineation of tumor recurrence versus radiation effects.
TRLS-01. RADIOSURGERY FOLLOWED BY TUMOR TREATING FIELDS (TTFIELDS) FOR BRAIN METASTASES (1–10) FROM NSCLC IN THE PHASE 3 METIS TRIAL
Authors: Mehta Minesh , Gondi Vinai , Ahluwalia Manmeet , Brown Paul
Published: August 2019

Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment comprising alternating electric fields that have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The METIS study [NCT02831959] investigates the efficacy and safety of TTFields in NSCLC patients with brain metastases. NSCLC patients (N=270) with 1–10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, > 18 hours/day) within 7 days of SRS or supportive care. The TTFields portable device delivers TTFields to the brain using 4 transducer arrays, while patients receive the best standard-of-care for their systemic disease. Patients are followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; KPS ≥70; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57. In August 2018, an independent Data Monitoring Committee (DMC) performed a review of the METIS trial data collected to that point. The DMC concluded that no unexpected safety issues have emerged on the study, and recommended to continue the METIS study as planned.
THER-07. DEVELOPMENT OF A NEW MOLECULAR PREDICTOR FOR RISK OF BRAIN METASTASES AND EFFICACY OF TARGETED THERAPY IN MELANOMA
Authors: Colman Howard , Boucher Ken , Stehn Chris , Kircher David , Holmen Sheri
Published: August 2019

Despite therapeutic advances in the treatment of melanoma, development of brain metastases (BM) continues to be a major manifestation of treatment failure. The ability to identify those patients who are at highest risk of developing brain metastases is limited with current methods. Development of sensitive and specific biomarkers to predict which stage II-III melanoma patients are at highest risk of BM would enable initiation of prospective clinical trials focused on both intensive surveillance and therapeutic prevention. To accomplish this goal, we embarked on an effort to optimize a combined molecular/clinical/pathologic predictor of BM risk. We firstanalyzed multiple gene expression datasets including TCGA (n = 437) and an independent series from Australia (n = 183) and identified a list of 60 consensus genes that is robustly predictive of development of melanoma BM (p < 0.05; FDR 5%). Next, we performed a similar analysis of association of miRNAs and melanoma BM risk which identified a set of miRNAs with significant predictive power. An optimized combined set of mRNA and miRNA markers was a better predictor of BM risk than either mRNA or miRNA list alone when applied to the TCGA data set. The combined predictor was most sensitive in separating patients with no metastases from those with either BM or systemic metastases. Current efforts are focused on optimizing miRNA and mRNA separation of patients specifically with BM from those with other mets, and with integrating the expression classifier with other clinical and pathologic predictive factors including: age, stage, thickness, location, histology, ulceration, gender. The sensitivity and specificity of the resulting clinical/molecular predictor will be validated in an independent retrospective cohort, and subsequently implemented in a prospective BM screening trial to determine real-world utility of this approach in preparation for prospective BM adjuvant/chemoprevention trials utilizing both immunotherapy and targeted therapy approaches.
THER-12. PRECLINICAL EVALUATION OF NERATINIB PLUS T-DM1 IN ORTHOTOPIC PDX MODELS OF HER2-POSITIVE BREAST CANCER BRAIN METASTASES
Authors: Ni Jing , Wang Yanzhi , Diala Irmina , Kabraji Sheheryar , Freedman Rachel , Lin Nancy , Zhao Jean
Published: August 2019

Breast cancer brain metastases (BCBM) are a major cause of morbidity and mortality, despite multimodal management including surgery, radiotherapy, and systemic therapies. There is an urgent need to develop novel, efficacious alternatives. Neratinib is an orally bioavailable, irreversible pan-HER tyrosine kinase inhibitor that is FDA-approved in the extended adjuvant treatment setting for HER2-positive, early breast cancer (NCT00878709). Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate with reported single-agent activity against HER2-positive BCBM. Here, we used HER2-positive orthotopic patient derived xenograft (PDX) models of BCBM to test if combining neratinib with T-DM1 could improve tumor response. PDX cells are labelled with luciferase to allow tumor growth measurement in vivo. We found that neratinib is able to reduce phosphorylated HER2 in an orthotopic PDX tumor derived from HER2-positive BCBM, indicating that neratinib can cross the BBB and inhibit HER2 activation in BCBM PDX tissues. However, in both HER2-positive DF-BM354 and DF-BM355 PDX models, single agent neratinib did not block orthotopic tumor growth compared to vehicle control as monitored by bioluminescence measurements. In contrast, combined treatment of neratinib with T-DM1 significantly reduced tumor growth compared to single agent treatment with neratinib or T-DM1 at earlier time points in both models. At later time points, the combined treatment is comparable to T-DM1 alone in DF-BM354 model, but significantly prolong the survival of mice bearing DF-BM355 tumors. These data warrant further testing of neratinib alone and in combination with T-DM1 in additional BCBM PDX models to better understand drivers of resistance and susceptibility to HER2-inhibitors in HER2-positive BCBMs. Furthermore, they support the launch of a prospective clinical trial (NCT01494662) to test the efficacy and tolerability of T-DM1 in combination with neratinib in patients with progressive HER2-positive BCBM.
THER-16. EFFICACY OF UPFRONT IMMUNE CHECKPOINT INHIBITORS IN LUNG CANCER BRAIN METASTASIS
Authors: Barnett Addison , Lauko Adam , Ali Assad , Li Hong , Sagar Soumya , Chao Samuel , Pennell Nathan , Peereboom David , Stevens Glen , Angelov Lilyana , Yu Jennifer , Murphy Erin , Mohammadi Alireza , Suh John , Barnett Gene , Ahluwalia Manmeet
Published: August 2019

INTRODUCTION: Immune checkpoint inhibitors (ICI) have resulted in improved outcomes in a subset of patients with lung cancer. However, data describing the efficacy of ICI in lung cancer brain metastasis (LCBM) is limited. We analyzed overall survival (OS) in patients with LCBM treated with upfront ICI, defined as having received ICI within 90 days of LCBM diagnosis, compared to non-ICI therapies. METHODS: We reviewed 665 patients with LCBM who were diagnosed between 2000 and 2018 at a major tertiary care institution. Of those patients, 240 received ICI, 164 of which received ICI after 90 days and 76 received ICI within 90 days. Propensity score (PS) was calculated using a logistic regression model including age, KPS, number of baseline brain lesions, and presence of extra-cranial metastasis (ECM) at the time of BM diagnosis. OS from BM diagnosis between PS matched cohorts were compared using Kaplan-Meier, the Log-Rank test, and Cox proportional hazards model. RESULTS: Prior to PS matching, median survival between ICI and non-ICI cohorts was not significantly different (10.9 months for both, p=0.81), although more ICI patients had ECM (57.1% vs 40.9%, p=0.006). Following PS matching, the ICI (n=76) and non-ICI (n=76) cohorts had a median age (62.4 vs 62.3 years), KPS (80 for both), lesion number (2 for both), and ECM (56.6% for both). Of matched patients, 94% received SRS, 52% received WBRT, and 29% underwent surgical resection. Compared to non-ICI, the ICI cohort has a 2-year OS hazard ratio, HR=0.87 (95% CI=0.58–1.31, p=0.51). Median and 1-year survival were not significantly different between ICI and non-ICI cohorts (median: 10.9 vs 9.1 months; 1-yr: 43.0% vs 42.4%). CONCLUSION: Patients with BM from primary lung cancer who received ICI within 90 days of their BM diagnosis did not have improvement in OS compared to patients who received non-ICI therapies.
MLTI-04. EVOLUTION OF TREATMENT PARADIGMS FOR PATIENTS WITH ≥1 BRAIN METASTASES FROM PRIMARY NON-SMALL-CELL LUNG CANCER – A SYSTEMATIC REVIEW
Authors: Brar Karanbir , Ellenbogen Yosef , Warsi Nebras , Badhiwala Jetan , Mansouri Alireza
Published: August 2019

BACKGROUND: Brain metastases (BM) are common in non-small cell lung cancer (NSCLC), with approximately 10% of patients presenting with BM at the time of diagnosis. The aim of this systematic review was to critically evaluate the evolution of management paradigms for BM from NSCLC. METHODS: We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, and CENTRAL for randomized controlled trials (RCTs) published until October 2018. Comparative RCTs based on ≥ 50 patients were selected. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS). RESULTS: Among 3188 abstracts, 14 RCTs (2494 patients) met inclusion criteria. Median sample size was 97 (range 59–538). Most trials were open-label, parallel, superiority trials. All included patients aged ≥18 with histologically proven NSCLC and ≥1 BM proven on CT/MRI. The majority of trials (11/14) excluded patients with non-favorable performance status (ECOG, KPS, or WHO scales), prior SRS or WBRT, and/or leptomeningeal metastases. Interventions assessed included WBRT (11/14), SRS (3/14), targeted therapies (e.g. EGFR inhibitors, 5/14), and various chemotherapeutic regimens (12/14). Most trials (12/13) reported no significant difference in OS between interventions. 4/10 trials reported a difference in PFS, two of which only included patients with EGFR-mutant NSCLC; these showed a significant increase in PFS in patients managed with EGFR inhibitors. The other two trials reported longer PFS with sodium glycididazole + WBRT vs. WBRT alone (p=0.038) and temozolomide + SRS vs. SRS alone (p=0.003). The incidence of adverse events was consistent across most treatment groups. CONCLUSIONS: Most trials showed no significant improvement in OS; however, improvement in PFS was seen in several trials, most notably in EGFR-positive patients treated with EGFR inhibitors. Given the long-standing merit of radiation-based therapies for BM management, these data support the need for an in-depth meta-analysis assessing the comparative efficacy of current management paradigms for specific patient populations.
MLTI-05. IDENTIFYING BRAIN METASTATIC CASES FROM FREE TEXT CLINICAL NARRATIVES WITH REFINEMENT OF SEMANTIC HETEROGENEITY USING MACHINE LEARNING
Authors: Wells Michael , Robin Adam , Poisson Laila , Noushmehr Houtan , Snyder James
Published: August 2019

INTRODUCTION: Brain metastatic disease (BM) is ripe for discovery using computational tools like machine learning (ML) due to disease complexity and multidimensional critical data (imaging, genomics, primary disease, drug exposures)1. Leveraging real-world-evidence’ (RWE) from routine health data to inform clinical management is hindered by fragmented unstructured data and semantic heterogeneity2. Clinical data in EHR and institutional registries are typically free text narratives absent common data elements (CDE). Curating existing data into CDE with machine learning (ML) may inform contemporary approaches (RWE, N-of-1 trials, and precision medicine) that are dependent on large high-quality datasets. Harvesting existing institutional registries may expand demographic representation, confirm benchmarks of established treatments, and provide test environment for prospective ML applications. METHOD: An R-based deep convoluted neural network (DNN) using keras and an API for Tensorflow python was trained on physician narratives of 2000 BM cases and 8000 other CNS conditions labeled by diagnosis spanning 17 years3,4. The ML model was tested with 405 non-labeled narratives to: A) Identify BM from other CNS conditions (i.e. glioma, meningioma, non-tumor). B) Evaluate word embedding using GLoVe5 to standardize abbreviations and misspellings by assigning terms to CDE by training the model to plot “mets”, “metastases” and “spine” with the 20 most similar contextual words. RESULTS: DNN architecture achieved 97% accuracy in distinguishing BM (n=178) for others (n=227). “Mets” and “metastasis” have a connected contextual network suggesting shared meaning, whereas spine did not share a network. CONCLUSIONS: ML can identify BM cases in free-text registries which can serve as a quality control measure and aid data aggregation. Standardizing shorthand terminology to CDE with DNN trained in word embedding can possibly address semantic heterogeneity and facilitate data automation. Solutions are needed to compile and automate quality BM data across institutions to achieve the volume and complexity required for contemporary analysis using ML.
MLTI-06. BEVACIZUMAB VERSUS SURGICAL INTERVENTION FOR RADIATION NECROSIS IN PREVIOUSLY IRRADIATED BRAIN METASTASES
Authors: Hong Christopher , Sujijantarat Nanthiya , Chiang Veronica
Published: August 2019

INTRODUCTION: Both medical management with bevacizumab and surgical management via craniotomy or more recently with laser interstitial thermal ablation (LITT) have been shown to be efficacious in the management of radiation necrosis (RN) after radiosurgery for brain metastases (BM). Indications for how to choose medical versus surgical management however remains unclear. METHODS: Single-institution chart review was performed of all patients with biopsy or radiographically confirmed RN after radiosurgery for BM between 2011 and 2017. Progression-free survival (PFS) and overall survival (OS) were compared between those treated using bevacizumab versus surgical intervention. RESULTS: 15 patients underwent craniotomy, 18 patients underwent LITT, and 18 patients were treated with bevacizumab. Those treated with bevacizumab had significantly higher number of regrowing lesions (n >1) at time of intervention (50.0%) versus those treated with surgery (15.2%) (p< 0.05). Likewise, pre-treatment KPS was lower in the bevacizumab cohort (median: 60) vs the surgery cohort (median: 90) (p< 0.05). Patients treated with bevacizumab demonstrated significantly decreased PFS (%PFS at 1-year 16.7% vs 86.7% and 87.8% for craniotomy and LITT, respectively; %PFS at 2-years 0% vs 86.7% and 73.2% for craniotomy and LITT, respectively, p < 0.05). Similar results were observed for OS (%OS at 1-year for bevacizumab 33.3% vs 93.3% and 73.8% for craniotomy and LITT, respectively; %OS at 2-years for bevacizumab 11.1% vs 64.6% and 63.2% for craniotomy and LITT, respectively, p< 0.05). CONCLUSIONS: Preliminary analysis shows that bevacizumab therapy in our institution is being chosen for patients with lower KPS and multiple regrowing lesions while surgical intervention is being chosen for patients with good KPS and single, symptomatic regrowing lesions. While the comparative outcomes after bevacizumab appear to be significantly worse than surgical management, it remains unknown if the difference is more related to its true efficacy or the significant discrepancy between the comparison groups.
MLTI-11. IMPLANTABLE POLYMERIC BCNU AS AN ADJUNCT TO SURGERY FOR METASTATIC INTRACRANIAL DISEASE
Authors: Ryken Timothy , Evans Linton
Published: August 2019

SUMMARY: One hundred and thirty cases of craniotomy for tumor utilizing BCNU implantable chemotherapy were performed by the authors between including 23 cases for metastatic intracranial disease. The series included 12 woman and 11 men with an average age of 56.9 years. The diagnoses were as follows: non-small lung carcinoma (13), breast cancer (6), small-cell lung cancer (1), colon cancer (1), unknown primary (2). Patients undergoing resection plus implantable chemotherapy following whole brain radiotherapy (5 patients) or following stereotactic radiosurgery (5 patients) were the most common. Only patient developed possible local recurrence (3%). Complications included two cerebrospinal fluid leaks with associated complications requiring reoperations (11%) both following whole brain radiotherapy and 3 patients (17%) with thromboembolic episodes (3 deep venous thromboses, one with a pulmonary embolus and sudural hematoma). In this challenging population, local implantable chemotherapy appears relatively safe and a reasonable consideration as a surgical adjunct.
MLTI-12. TIMING OF SYSTEMIC THERAPY ADMINISTRATION RELATIVE TO STEREOTACTIC RADIOSURGERY AND DEVELOPMENT OF RADIATION NECROSIS IN PATIENTS WITH BRAIN METASTASES
Authors: Hammoudeh Lubna , Cagney Daniel , Aizer Ayal
Published: August 2019

PURPOSE: The mainstay of oncologic therapy for patients with brain metastases involves brain-directed radiation, increasingly given via stereotactic radiosurgery (SRS), and systemic therapy for extracranial disease control. We sought to investigate the association between the timing of systemic therapy and SRS administration on development of radiation necrosis among patients with brain metastases. METHODS: We retrospectively identified 429 patients treated at Brigham and Women’s Hospital/Dana-Farber Cancer Institute with SRS for newly-diagnosed brain metastases between 2001–2015. Systemic therapy was tiered into 4 categories: chemotherapy, immunotherapy, hormonal therapy, and targeted therapy. All images were manually reviewed by two radiation oncologists specializing in brain tumors to assess the presence versus absence of radiographic necrosis. Patients with radiographic necrosis who harbored associated neurologic symptoms or were managed with steroids/bevacizumab/resection were considered to have symptomatic radiation necrosis. Data were analyzed using univariable Cox regression in SAS v9.4. The median follow-up in surviving patients was 1.79 years. RESULTS: In total, 252/429 and 361/429 patients received systemic therapy pre and/or post SRS, respectively. Patients receiving systemic therapy ≤5 days before SRS displayed higher rates of radiographic (HR 2.48, 95% CI 1.06–5.81, p=.04) and symptomatic (HR 3.74, 95% CI 1.08–12.98, p=.04) necrosis; a similar association was seen in patients receiving systemic therapy ≤5 days after SRS (HR 1.72, 95% CI 0.84–3.53, p=.14 and HR 4.42, 95% CI 1.75–11.14, p=.002, respectively). Trends towards increased necrosis risk were noted when comparing systemic therapy administration 1–5 days versus 6–10 days before/after SRS. The above 4 associations were significant when restricting the cohort to patients receiving targeted systemic therapy (HR-range 3.57–21.49, p-range 0.01–0.04). CONCLUSIONS: Our results suggest that a reasonable delay between SRS and systemic therapy administration may reduce rates of radiation necrosis, even among patients receiving targeted therapies. Validation in an independent data set would lend further support to this concept.
MLTI-13. RESPONSE ASSESSMENT OF MELANOMA BRAIN METASTASES TREATED BY STEREOTACTIC RADIOTHERAPY OR IMMUNOTHERAPY OR BOTH: A COMPARISON OF RECIST 1.1, RANO AND iRANO CRITERIA
Authors: Le Rhun Emilie , Wolpert Fabian , Fialek Maud , Devos Patrick , Andratschke Nicolaus , Reyns Nicolas , Dummer Reinhard , Mortier Laurent , Weller Michael
Published: August 2019

BACKGROUND: The evaluation of response for brain metastases (BM) may be challenging in the context of treatment by stereotactic radiotherapy (SRT) or immunotherapy or both. METHODS: We reviewed clinical and neuroimaging data of 62 melanoma patients with newly diagnosed BM treated by the combination of immunotherapy and SRT (n=33, group A), immunotherapy alone (n=10, group B) or SRT alone or in combination with other systemic therapies (n=19, group C). Response was assessed using RECIST 1.1, RANO or iRANO criteria. RESULTS: BRAF mutations were noted in 26 patients. 54 patients (87%) had 1–3 metastases. The median DS-GPA was 3. After a median follow-up of 30.5 months, 39 patients have experienced CNS progression, 16 (48.5%) in group A, 9 (90%) in group B, 14 (73.5%) in group C. Median PFS was 129.5 days (range 82–532) in group A, 75 days (range 35–203) in group B, 136 days (range 59–514) in group C. Forty-seven patients (76%) had died at the time of the analysis, 22 (66.5%) in group A, 7 (70%) in group B, 18 (94.5%) in group C. Median OS was 345 days (range 65–1824) in group A, 174.5 days (range 50–1361) in group B, 409 days (range 102–1244) in group C. 52 MRI scans were available for central review: pseudoprogression was documented in 9 patients (29%) in group A, 0 (0%) in group B, 5 (29.5%) in group C. Response rates were similar with all three sets of response criteria. Progressive disease was less often called when applying iRANO to assess SRT target lesions. CONCLUSIONS: Despite the retrospective nature and the small sample size, these data may indicate that the omission of SRT from first-line treatment may compromise outcome. Pseudoprogression is uncommon with immunotherapy alone; pseudoprogression rates were similar after SRT alone or in combination with immunotherapy or other systemic treatment.
OTHR-06. ANALYSIS OF GENOMIC ALTERATIONS IN 154 BRAIN METASTASES
Authors: Ostorga Antonio Dono , Hines Gabriella , Moghadamtous Soheil Zorofchian , Esquenazi Yoshua , Ballester Leomar Y
Published: August 2019

Brain Metastases (BM) are associated with poor prognosis. Understanding the genomic alterations (GA) that drive tumor metastasis to the brain will increase our ability to identify patients at risk for BM, and provide better opportunities to implement targeted therapies. We performed a retrospective review of genomic alterations in 154 patients with BM from various primary sites (80 Lung, 22 Breast, 16 Melanoma, 5 Kidney, 4 Colorectal, 4 Prostate, and 23 carcinomas from unknown primary (UP). All cases were analyzed by a next generation sequencing assay the detects mutations in the coding region of 327 genes and rearrangements involving 37 genes. The most commonly mutated genes were; TP53, CDKN2A/B, KRAS, MYC, RB1, NF1, PIKC3A, STK11, and PTEN. A comparison of GA in our BM cases with unmatched primary tumors from COSMIC revealed differences in the frequency of mutated genes: TP53 (Lung 85% vs 38%, Breast 63.6% vs 26.0%) CDKN2A/B (Lung 33.7% vs 7%, Melanoma 56.2% vs 18%, Kidney 40% vs 2%, UC 34.7% vs 9%), ERBB2 (Breast 36.3% vs 4%), MYC (Breast 36.36% vs 0.3%), TERT (Melanoma 62.5% vs 25%, Kidney 40% vs 2%), APC (Colon 100% vs 48%), KRAS (Colon 100% vs 31%), PTEN (Prostate 50% vs 7%), TSC1 (Kidney 40% vs 2%), STK11 (UC 26.0% vs 6%). Our results demonstrate a higher frequency of TP53 mutations (p=0.001) in metastatic lung cancer, and a higher frequency of MYC amplification (p=0.01) in metastatic breast cancer, when compared to primary tumors. The present study demonstrates significant differences in the frequency of mutations between primary tumors and BM. Such differences may play an important role in the pathogenesis of BM and may allow for targeted strategies utilizing existing therapies.
OTHR-10. THE NATIONAL DISTRIBUTION OF NEWLY-DIAGNOSED BRAIN METASTASES IN ADULTS VARIES WIDELY BY PATIENT DEMOGRAPHICS
Authors: Kavouridis Vasileios , Torre Matthew , Harary Maya , Smith Timothy , Iorgulescu Bryan
Published: August 2019

INTRODUCTION: Metastases are oft-cited as comprising approximately half of all adult intracranial neoplasms, and their national composition remains unclear. METHODS: The patient demographics and histologic distribution of newly-diagnosed brain metastasis (BM) patients aged > 18yo without a prior history of cancer (2010–2015) were evaluated using the National Cancer Database, which comprises > 70% of all newly-diagnosed cancers in the U.S. RESULTS: 91,686 adults presented with a newly-diagnosed BM between 2010–2015. The most common sites of brain metastases overall were lung (82% of metastatic cases), breast (4.1%), melanoma (3.2%), kidney (2.9%), and colorectal (1.8%). The overall 1-year and 5-year OS rates for all BMs were 27.0% (95% CI [26.7%-27.3%]) and 5.3% (95% CI [5.1%-5.5%]), respectively. The distribution of primary sites for newly-diagnosed BMs varied by sex, age, and race. Compared to males, more females had BMs from breast (8.4% versus 0.8%) and fewer had BMs from kidney (1.9% versus 3.8%), melanoma (1.9% versus 4.5%), and esophagus (0.3% versus 2.0%). In young adults, particularly those 20-29yo, BMs were more likely from melanoma, genitourinary (in males), and soft tissue than adults in middle and advanced age. Lung carcinomas comprised fewer BMs in Hispanics (66%) compared to Whites (82%), Blacks (83%), and Asian/Pacific Islanders (85%). BMs from kidney and genitourinary primaries were higher in Hispanics (7.3% and 2.4% of BMs, respectively) than in Whites (2.8% and 0.3%, respectively), Blacks (1.8% and 0.1%, respectively), and Asian/Pacific Islanders (2.6% and 0.2%, respectively). Melanoma was more frequent in Whites (3.8% of BMs) and Hispanics (2.5%) compared to Blacks (0.3%) and Asian/Pacific Islanders (0.6%). CONCLUSION: Our results illustrate the national distribution of newly-diagnosed BMs and investigates how the distribution varies by patient demographics.
OTHR-15. PATIENTS WITH LIMITED STAGE SMALL CELL LUNG CANCER THAT RECUR WITH ISOLATED BRAIN METASTASES HAVE PROLONGED SURVIVAL
Authors: Bonder Bryan , Larijani Fatemeh Ardeshir , Dowlati Afshin , Rogers Lisa
Published: August 2019

INTRODUCTION: Small cell lung cancer (SCLC) frequently metastasizes to the brain. In patients with limited-stage disease (disease confined to one radiation portal), the incidence of brain metastasis after 3 years is 50–60%. We reviewed patients with SCLC and hypothesized that isolated brain recurrence has a unique natural history. METHODS: 471 adult SCLC patients seen at University Hospitals Case Medical Center from 1998 to 2014 were screened. Patients were separated by those with isolated brain metastases and those with other patterns of metastasis. Demographic data including age, race, sex, smoking history and clinical data such as TNM classification, stage, treatment, and time to relapse and death were collected. Median overall survival (mOS) and progression free survival (mPFS) were compared using log-rank tests and Kaplan-Meier plots were constructed. In a separate cohort of metastatic SCLC we examined differences in next generation sequencing (NGS) of targeted exomes between primary and metastatic sites including the brain. RESULTS: 281 extensive-stage patients and 40 limited-stage patients were included. 12% (30/281) of the extensive-stage patients and 25% (10/40) of limited-stage patients had isolated brain metastases. Patients with limited-stage disease who developed isolated brain metastases had significantly improved mOS as compared to those who developed other sites of metastasis (OS = 38.7 months vs. 20.2 months, p=0.033). Furthermore, mPFS for limited-stage patients with isolated brain metastases was improved compared to other patterns of metastases (PFS = 17.9 months vs. 10.1 months, p = 0.03). NGS demonstrated that NOTCH1 mutations were infrequent in biopsies from all metastatic sites but were common in primary lung tumors. CONCLUSION: In our single center review, patients with limited-stage SCLC who recurred only in the brain had improved survival as compared to those who had other patterns of metastases. Our initial work demonstrates differences in oncogenic gene mutations between the metastatic and primary tumors.
RADI-06. SINGLE- VERSUS MULTI-FRACTION STEREOTACTIC RADIOSURGERY FOR BRAINSTEM METASTASES
Authors: Jacobs Corbin , Woldemichael Kehali , Williamson Hannah , Abisheva Zhanerke , Howell Elizabeth , Abdelgadir Jihad , Dechant Cosette , Floyd Scott , Fecci Peter , Kirkpatrick John , Adamson Justus , Torok Jordan
Published: August 2019

BACKGROUND: For intracranial metastases with planning target volume (PTV) overlap of the brainstem (BSmet), the radiosurgical dose-fractionation that optimizes the therapeutic window is unknown. MATERIALS/METHODS: A retrospective review of brain metastases (BM) with/without BSmets treated with single-fraction stereotactic radiosurgery (SRS) or hypofractionated (2–5 fractions) radiosurgery (HF-SRS) between 2012–2016 was performed. Brainstem biologically effective doses (BED) and single-fraction equivalents of brainstem V10/V12 were calculated using α/β=3. Characteristics were compared between patients with/without BSmet and between SRS/HF-SRS cohorts using Wilcoxon rank sum, chi-square, or Fisher’s exact tests. Radiographic progression (RP) was assessed in patients with post-treatment contrasted MRI and defined as BSmet enlargement regardless of etiology (progression, radionecrosis, indeterminate). Kaplan-Meier estimates were compared between cohorts using log-rank test. RESULTS: 634 SRS/HF-SRS courses were identified, of which 59 (9.3%) treated ≥1 BSmet in 55 patients. BSmets occurred more commonly in patients with >4 BM (31% vs 10%, p< 0.001) and intracranial recurrence (39% vs 20%, p=0.003). BSmets were treated in 1 (22/59; 37%), 2 (1/59; 2%), or 5 (36/59; 61%) fractions. Age, KPS, and primary tumor site were balanced between SRS/HF-SRS cohorts. The HF-SRS cohort had significantly larger BSmet PTV (median 1.39cc vs 0.39cc, p=0.021), marginal dose (median 25Gy vs 15Gy, p< 0.001), brainstem V10 (median 1.60cc vs 0.47cc, p< 0.001), brainstem V12 (median 0.78cc vs 0.06cc, p< 0.001), and mean brainstem BED (median 9.27Gy3 vs 6.55Gy3, p=0.019). The SRS cohort was more likely to have prior whole brain radiotherapy (50% vs 14%, p=0.005) and restart steroids post-treatment (78% vs 41%, p=0.019). RP occurred in 6/17 vs 2/25 patients in the SRS vs HF-SRS cohorts, respectively (p=0.045). HF-SRS trended to higher freedom from RP (93% vs 74% @12mo; p=0.072). There was no overall survival difference (p=0.36). CONCLUSIONS: HF-SRS was associated with decreased RP and decreased likelihood of restarting steroids despite treating larger BSmets.
RADI-11. NRG ONCOLOGY CC001: A PHASE III TRIAL OF HIPPOCAMPAL AVOIDANCE IN ADDITION TO WHOLE-BRAIN RADIOTHERAPY (WBRT) PLUS MEMANTINE TO PRESERVE NEUROCOGNITIVE FUNCTION IN PATIENTS WITH BRAIN METASTASES (BM)
Authors: Tomé Wolfgang , Deshmukh Snehal , Gondi Vinai , Brown Paul , Wefel Jeffery , Armstrong Terri , Bruner Deborah , Bovi Joseph , Robinson Clifford , Khuntia Deepak , Grosshans David , Konski Andre , Roberge David , Kundapur Vijayananda , Devisetty Kiran , Shah Sunjay , Usuki Kenneth , Anderson Bethany Marie , Mehta Minesh , Kachnic Lisa
Published: August 2019

BACKGROUND: NRG CC001, a phase III trial of WBRT+memantine (WBRT+M) with or without Hippocampal Avoidance (HA), sought to assess the neuro-protective effects of lowering the radiation dose received by the hippocampus. METHODS: Patients (pts) with brain metastases were stratified by RPA class and prior radiosurgery/surgery and randomized to either WBRT+M or HA-WBRT+M (30Gy/10 fractions). Standardized neurocognitive function (NCF) tests were performed at baseline, 2, 4, 6, and 12 months (mos.). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence estimated NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory with Brain Tumor module and analyzed using mixed effects models and t-tests. RESULTS: From 7/2016 to 3/2018, 518 patients were randomized. Median follow-up was 7.9 mos. HA-WBRT+M was associated with lower NCF failure risk (adjusted HR=0.74, p=0.02) due to lower risk of deterioration in executive function at 4 mos. (p=0.01); and encoding (p=0.049) and consolidation (p=0.02) at 6 mos. Age≤61 predicted for lower NCF failure risk (HR=0.60, p=0.0002); non-significant test for interaction indicated independent effects of HA and age. Patient-reported fatigue (p=0.036); difficulty speaking (p=0.049); and problems remembering things (p=0.013) at 6 mos. favored the HA-WBRT+M arm. Imputation models accounting for missing data also favored the HA-WBRT+M arm for patient-reported cognition (p=0.011) and symptom interference (p=0.008) at 6 mos. Treatment arms did not significantly differ in toxicity; intracranial progression or overall survival. CONCLUSIONS: While achieving similar intracranial control and survival; Hippocampal Avoidance during WBRT+M for brain metastases better preserves NCF and patient-reported symptoms. Supported by UG1CA189867 (NCORP) and DCP from the NCI.
RADI-29. BIOLOGIC SUBTYPES OF BREAST CANCER BRAIN METS AS A PREDICTOR OF LOCAL CONTROL AFTER STEREOTACTIC RADIOSURGERY
Authors: Salgado Lucas Resende , Smith Andrew , Cohen Alexandra , Tseng Tzu-Chi , Lin Jung-Yi , Moshier Erin , Green Sheryl , Germano Isabelle
Published: August 2019

INTRODUCTION: Brain metastases (BM) are diagnosed in approximately 15% of breast cancer (BC) patients. Biologic subtype is predictive of loco-regional recurrence following breast conserving therapy and/or mastectomy with the highest risk in the ER-/PR-/HER2- (TN) subtype. The aim of this study is to determine whether biologic subtype is predictive of local control (LC) in BC patients with BM treated with Stereotactic Radiosurgery (SRS). MATERIALS/METHODS: All patients underwent LINAC-based SRS at our institution. Patients were subdivided into three biologic subtypes: ER+/Her2- (Luminal), Her2+, and TN (Basal). Kaplan Meier method was used to estimate the overall survival (OS). Cox proportional hazard model was used to analyze association of local failure (LF) with biologic subtypes. This is an IRB-approved single center retrospective study. RESULTS: 108 BC BM in 50 consecutive patients were included in this study with a median follow up of 11.1 months. The median disease-specific GPA was 2.0, and all patients received systemic chemotherapy and/or hormonal therapy. The 12 month LC rates for the entire cohort were 85%, 87%,49% for Luminal, Her2+ and Basal, respectively, with a significantly shorter LC for the basal sub-type (p=0.014). The 12 month OS rates were 83%, 88%, 80% for Luminal, Her2+ and Basal, respectively with a no significant difference in OS among the subgroups. 24% of the lesions were treated with salvage whole brain radiation therapy. CONCLUSIONS: This study shows that in BC patients with BM treated with SRS, biologic subtype impacts LC but not OS. Consideration of radiation treatment intensification or altered fractionation to improve LC may be indicated for the TN subtype. Further multi-center studies are necessary to corroborate our results.