bluuebunny/crossref_metadata_2025 huggingface dataset:
LPTO-03. IN-VITRO & IN-VIVO CULTURE OF PATIENT (PT) DERIVED CSF-CTCs IN LEPTOMENINGEAL DISEASE (LMDz) FROM MELANOMA TO IDENTIFY NOVEL TREATMENT STRATEGIES
Authors: Law Vincent , Evernden Brittany , Kenchappa Rajappa , Puskas John , Caceres Gisela , Ryzhova Elena , Smalley Inna , Etame Arnold , Sahebjam Solmaz , Magliocco Anthony , Smalley Keiran , Forsyth Peter
Published: August 2019

BACKGROUND: Approximately 5% of melanoma pts develop LMDz. There are essentially no models of LMDz available for therapeutic development. Here we report, the in-vitro & in-vivo culturing of CSF-CTCs. METHODS: CSF-CTCs were detected by the Veridex CellSearch® System. Cell-free DNA and cell-associated DNA were extracted, sequenced and profiled. Expanded ex-vivo CSF-CTCs were grown in-vitro and tested for drug sensitivity. CSF-CTCs were grown successfully in-vivo from 1 pt; labeled human Braf V600E WM164 cells were injected IT in as a control. RESULTS: CSF-CTCs: 12 LMDz pts and 8 melanoma pts without LMDz were studied. All but 1 LMDz pts (92%) had CSF-CTCs (avg: 2148.60; range 23 - 3055 CTCs/ml). In contrast, 3/8 (37%) melanoma Brain Mets pts without LMDz had CSF-CTCs but fewer of them (avg: 0.31; range 0.13 - 0.6 CTCs/ml CSF). CSF-CTCs Profile: These had BrafV600E (83%), and GNAQ Q209P & NRAS Q61R in 1 pt each. Ex-vivo culture of CSF-CTCs and PDX model: After lengthy optimization of conditions we successfully expanded CSF-CTCs in-vitro (~25% of pts), and in-vivo in immunodeficient mice from 1 pt (~10% of samples). Ceritinib, used as a FAK inhibitor, with MEKi was effective in-vitro (p=3.17e-6) and prolonged survival in-vivo in LMDz (median survival: >32 days vs control: 18 days; p=7.81e-5). CONCLUSIONS: Though the sample size is small, this is the first report of the successful in-vitro & in-vivo culture of CSF-CTCs from pts with LMDz. Single cell analysis to determine how representative these models are and further in-vivo testing are in progress.
LPTO-04. GENERATION AND CHARACTERIZATION OF PATIENT-DERIVED PRECLINICAL MODELS FROM TUMOR CELLS ISOLATED FROM CEREBROSPINAL FLUID
Authors: Offin Michael , Vojnic Morana , Liu Zebing , Lui Allan , Siau Evan , Gladstone Eric , Mattar Marissa , Khodos Inna , Drilon Alexander , Boire Adrienne , Rudin Charles , De Stanchina Elisa , Ladanyi Marc , Somwar Romel
Published: August 2019

BACKGROUND: CNS metastases occur in 20–50% of lung cancer patients during their disease; leptomeningeal disease (LMD) representing 5–8%, classically carries a poor prognosis with a median overall survival ranging from 1–11 months. There is a paucity of patient-derived preclinical disease models using tumor cells isolated from the CSF. Models that faithfully recapitulate the biology of CNS tumors would offer new insights into the biology of the disease as well as provide the basis for developing more effective therapy. METHODS: To create more representative preclinical models to study LMD we isolated tumor cells from CSF of 5 patients with cytologically proven LMD and implanted the cells into the subcutaneous flank of immune-compromised mice. Where possible, cell lines were also generated from PDX tissues. Models were characterized by next generation sequencing (NGS), growth rates, expression of driver oncogenes and sensitivity to small molecule inhibitors. RESULTS: To date, one PDX (LUAD-0048A) and cell line model were successfully derived from CSF samples (NSCLC patient with MET amplification) and 4 are pending. MET amplification and mRNA over-expression were confirmed by quantitative PCR in the PDX tissue and the cell line. Western blot analysis indicated that over-expressed MET was phosphorylated in both PDX tissue and cell line. These results were confirmed by immunohistochemistry. Growth of LUAD-0048A cells were unaffected by 3 MET inhibitors (crizotinib, cabozantinib, glesatinib). Similarly, MET inhibitors did not induce apoptosis in the cells. CONCLUSION: LMD represents an aggressive metastatic event in lung cancer patients. Here we were able to successfully establish a PDX from the CSF of a patient with LMD and trial targeted therapies in vivo. Translational collaborations where patients with clinical suspicion of LMD undergo CSF sampling, NGS/ctDNA analysis, and PDX modeling are crucial in improving our understanding of this metastatic compartment and investigating novel treatment paradigms.
LPTO-05. FACTORS INFLUENCING RISK OF LEPTOMENINGEAL METASTASIS IN BREAST CANCER PATIENTS RECEIVING STEREOTACTIC RADIOSURGERY FOR LIMITED BRAIN METASTASES
Authors: Zhang Michael , Chan Jason , Xu Chelsea , Anderson August , Lazar Ann , Villanueva-Meyer Javier , McDermott Mike , Melisko Michelle , Sneed Penny , Morin Olivier , Braunstein Steve
Published: August 2019

Leptomeningeal metastasis (LM) is a late stage manifestation of advanced breast cancer frequently managed with whole brain radiotherapy (WBRT) and/or intrathecal chemotherapy. A subset of breast cancer patients who undergo stereotactic radiosurgery (SRS) for limited brain metastases (BM) ultimately develop LM. We hypothesized that this subset of high-risk patients may be identified by patient, disease, and/or treatment parameters. Clinical records from 135 consecutive breast cancer patients from a single institution who underwent SRS for BM between February 2010 and March 2018 were retrospectively analyzed. Diagnosis of LM was determined radiographically and/or by cerebrospinal fluid analysis. Demographic data, clinical history, histopathology, BM features, systemic disease burden, and prior treatments were analyzed with Cox proportional hazards regression. In our cohort, 22 (16.3%) patients ultimately developed LM. With a median follow up of 18.9 (IQR 8.6–38.7) months after diagnosis of BM, the actuarial rate of LM at 18 months was 14.5% (95% CI, 7.0–21.4%). Median OS after diagnosis of LM was 7.3 (95% CI, 3.1–15.4) months. There was significantly increased risk of LM with ≥5 vs < 5 BM at BM diagnosis (33.0% vs 7.5% [18-month actuarial risk], HR 3.5, p=0.0045), and ≥7 vs < 7 cumulative number of BM treated (21.9% vs 11.1% [18-month actuarial risk], HR 2.7, p=0.023). Variables not significantly associated with the risk of LM included tumor receptor status (ER, PR, HER2, triple negative), graded prognostic assessment, KPS, extracranial metastases, total BM volume, prior WBRT, or prior surgical resection. In conclusion, patients with a larger number of brain metastases at BM diagnosis or ≥7 cumulative number of brain metastases treated appear to be at higher risk of developing LM and may benefit from stronger consideration of WBRT, intrathecal chemotherapy, and/or brain-penetrating systemic therapy.
LPTO-10. ASSESSMENT OF LEPTOMENINGEAL CARCINOMATOSIS DIAGNOSIS AND OUTCOMES FROM 2005 TO 2015 AT THE OHIO STATE UNIVERSITY
Authors: Williams Nicole , Rinehardt Hannah , Morgan Evan , Kassem Mahmoud , Palettas Marilly , Puduvalli Vinay , Giglo Pierre , Lustberg Maryam , Wesolowski Robert , Sardesai Sagar , Stover Daniel , Vandeusen Jeffrey , Bazan Jose , Ramaswamy Bhuvaneswari , Noonan Anne
Published: August 2019

BACKGROUND: Leptomeningeal carcinomatosis (LMC) is a complication of solid tumor malignancies where tumors metastasize to the leptomeninges. LMC complicates 4–15% of malignancies with incidence increasing as survival of patients with advanced cancer improves. Diagnostic methods include magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology. We assessed detection methods, incidence, and outcomes of LMC at The Ohio State University Comprehensive Cancer Center from 2005–2015. METHODS: This was a single-institution retrospective study of 160 patients with confirmed diagnosis of LMC. Patients with hematologic and central nervous system malignancies were excluded. Descriptive statistics were used to summarize demographic and clinical characteristics. Overall survival (OS) was defined as time from LMC diagnosis to death or last known follow-up, and was generated using Kaplan-Meier methods. RESULTS: Median age of LMC diagnosis was 55.8 years (range: 48, 62.5). 69 (43%) patients had primary breast cancer, 41 (26%) had lung cancer, and 17 (11%) had melanoma. 73 patients (46%) presented with stage IV disease at initial diagnosis of the primary cancer, 41 (26%) with stage III disease, and 26 (16%) with stage II disease. Median time from diagnosis of primary cancer to diagnosis of LMC was 2 years (range: 0, 31.2). 158 (99%) patients had metastases at the time of LMC diagnosis, predominantly in bone (36%) or brain (36%). Median OS was 1.9 months (CI: 1.3, 2.5). 160 (100%) patients had an MRI of the brain or spine and 155 (97%) had MRI findings consistent with LMC. 75 (47%) patients underwent lumbar puncture, and 39 (52%) had CSF cytology positive for malignancy. CONCLUSIONS: Despite treatment, prognosis remains poor and confirmation of diagnosis can be challenging. This study highlights the need for novel therapeutics and improved diagnostic techniques for patients with LMC.
TRLS-02. A PILOT STUDY OF EVALUATING EARLY TREATMENT RESPONSE OF BRAIN METASTASES AFTER STEREOTACTIC RADIOSURGERY USING DYNAMIC SUSCEPTIBILITY-WEIGHTED PERFUSION MAGNETIC RESONANCE IMAGING
Authors: Huang Jiayi , Rao Yuan , Milchenko Mikhail , LaMontagne Pamela , Abraham Christopher , Robinson Clifford , Wan Leping , Shimony Joshua , Rich Keith , Benzinger Tammie
Published: August 2019

PURPOSE: To determine if dynamic susceptibility-weighted perfusion magnetic resonance imaging (DSC-PMR) can be used to predict local recurrence (LR) of brain metastases after stereotactic radiosurgery (SRS). METHODS: This is a prospective observational study of adult brain metastasis patients treated with single-fraction SRS, who were imaged with DSC-PMRs before SRS and after 1 week. DSC-PMRs were performed with tracer method in which injection of gadolinium was followed by repeated T2*-weighted gradient echo-planar image acquisition. Regions of interests (ROIs) were generated based on the T1-enhancing tumors irradiated. Relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) parameter maps were calculated by dividing the top 5% of CBV or CBF values within a ROI by the contralateral normal thalamus. LR was determined according to the RECIST 1.1 criteria. Cox regression was conducted to identify factors associated with time to LR. LR rates were estimated with the Kaplan-Meier method and compared using log-rank test. RESULTS: Twenty-three patients were enrolled from 2013 through 2016, with 24 evaluable lesions from 17 patients. After a median follow-up of 12.8 months (range: 3.0–53.7), 5 lesions (21%) developed LR after a median of 3.4 months (range: 2.3–5.7). On univariable analysis, higher rCBV at week 1 (HR 1.06, 95% CI 1.01–1.11, p=0.02), lower SRS dose (HR 0.43, 95% CI 0.20–0.91, p=0.03), and larger tumor volume (HR 1.52, 95% CI 1.05–2.20, p=0.03) were significantly associated with LR, but not histology, rCBV at baseline, change of rCBV at week 1 from baseline, or any rCBF parameters. Higher rCBV at week 1 (above the median) was associated with significantly higher risk of LR than lower rCBV (44% vs 0% at 1 year, respectively, p=0.02). CONCLUSIONS: DSC-PMR and specifically rCBV at week 1 may be a promising imaging biomarker to predict treatment response of brain metastasis after SRS and warrant further investigation.
TRLS-03. PHASE II TRIAL OF GDC-0084 IN COMBINATION WITH TRASTUZUMAB FOR PATIENTS WITH HER2-POSITIVE BREAST CANCER BRAIN METASTASES (BCBM)
Authors: Leone Jose Pablo , Trippa Lorenzo , Milisits Lindsey , Andrews Chelsea , Ligibel Jennifer , Parsons Heather , Bi Wenya , Zhao Jean , Winer Eric , Lin Nancy
Published: August 2019

BACKGROUND: The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. GDC-0084 is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. METHODS: This is a single-center, phase II study to evaluate the efficacy of the combination of GDC-0084 with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive GDC-0084 (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to GDC-0084/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha < 10%. Cohort B will enroll 10 patients. The trial opened in February, 2019. NCT03765983.
THER-08. BRAIN METASTASES AS A FIRST SITE OF RECURRENCE IN PATIENTS RECEIVING CHEMOTHERAPY WITH CONTROLLED SYSTEMIC CANCER: A CRITICAL BUT UNDER-RECOGNIZED CLINICAL SCENARIO
Authors: O’Connell Kaelin , Romo Carlos , Grossman Stuart
Published: August 2019

BACKGROUND: As the treatment of non-central nervous system (CNS) malignancies has improved, brain metastases (BM) have been observed as a site of first recurrence in patients with controlled or responding systemic cancers. This suggests that while chemotherapy is effective for the systemic disease, drug concentrations in the CNS are likely subtherapeutic. These findings are in accord with data suggesting that over 98% of FDA-approved drugs are unable to penetrate the blood brain barrier (BBB). METHODS: A literature review was conducted to estimate the proportion of patients with non-small lung cancer (NSCLC), breast cancer, and melanoma with controlled systemic cancers who developed BM as initial site of recurrence. Only studies explicitly reporting BM with controlled extra-cranial (EC) disease or reporting the first site of recurrence after chemotherapy were included. RESULTS: Of 262 studies screened,13 contained adequate data regarding the status of systemic cancer and initial site of recurrence. These reported on 1,024 patients. Four studies in patients with NSCLC revealed that 11–43% developed BM as initial site of recurrence. Similar data was seen in patients with breast cancer (6 studies, 4–19%) and metastatic melanoma (3 studies, 4–25%). Approximately 15% of patients on chemotherapy with stable or responding systemic NSCLC, breast cancer, and melanoma developed isolated BM as initial site of relapse. CONCLUSIONS: This literature review included 1,024 patients with common and treatable metastatic cancers whose disease was controlled with chemotherapy. First recurrence in the brain was noted in 23% of those with NSCLC, 12% with breast cancer, and 12% with melanoma. These findings strongly suggest that, while systemic antineoplastic therapy controlled their systemic cancer, concentration of these drugs within the CNS was low, allowing disease progression in the CNS. Reducing the incidence of BM requires novel therapeutic approaches designed to facilitate drug entry through an intact BBB early in treatment.
THER-09. IMPACT OF KRAS MUTATION STATUS ON THE EFFICACY OF IMMUNOTHERAPY IN LUNG CANCER BRAIN METASTASES
Authors: Lauko Adam , Ali Assad , Sagar Soumya , Barnett Addison , Li Hong , Chao Samuel , Pennell Nathan , Stevens Glen , Peereboom David , Yu Jennifer , Murphy Erin , Angelov Lilyana , Mohammadi Alireza , Suh John , Barnett Gene , Ahluwalia Manmeet
Published: August 2019

BACKGROUND: Immunotherapy is increasingly used in patients with non-small cell lung cancer brain metastases (NSCLCBM). KRAS mutations are associated with worse prognosis and there is no FDA approved targeted therapy. KRAS mutations are associated with increased expression of PD-L1. We evaluated the outcomes of NSCLCBM with KRAS mutations treated with immune checkpoint inhibitors (ICI). METHODS: We reviewed 800 patients with NSCLCBM treated at our tertiary care center. 226 had known KRAS mutational status, 121 of which received immunotherapy. Overall survival (OS) was calculated from either the start of immunotherapy (when both groups received immunotherapy) or from the date of diagnosis of brain metastasis. Kaplan-Meier method and Cox Proportional hazard model were utilized to determine differences in OS and the Chi-square test was utilized to determine differences in PD-L1 expression. RESULTS: In 109 patients where both KRAS and PD-L1 status were known, KRAS mutations had greater PD-L1 expression (80.1% vs 61.9% positive, p=0.04). There was no difference in OS between KRAS mutant vs KRAS wild-type patients treated with immunotherapy. Median survival from the start of immunotherapy was 15.6 vs 15.5 months respectively (p=0.7), after adjusting for age, KPS, lesion number and extra-cranial metastasis (HR = .91, p=.7). Patients with KRAS mutations treated with immunotherapy versus those who received chemotherapy had a 1-year OS from the diagnosis of brain metastasis of 60.9% vs 38.7% respectively (trending towards significance, p=0.05). KRAS wild-type patients treated with immunotherapy versus those who did not receive immunotherapy had a 1-year OS from the diagnosis of brain metastasis of 61.9% vs 62.5% (p=0.85), respectively. DISCUSSION: KRAS mutations are associated with increased PD-L1 expression. Use of immunotherapy negates the poor outcomes seen traditionally in patients with NSCLCBM and KRAS mutations and it improves survival compared to use of chemotherapy. Our experience supports the use of immunotherapy in these patients.
THER-10. IMPACT OF BRAF MUTATIONAL STATUS ON THE EFFICACY OF IMMUNOTHERAPY FOR MELANOMA BRAIN METASTASES
Authors: Lauko Adam , Sagar Soumya , Barnett Addison , Wei Wei , Chao Samuel , Stevens Glen , Peereboom David , Yu Jennifer , Murphy Erin , Angelov Lilyana , Mohammadi Alireza , Suh John , Barnett Gene , Ahluwalia Manmeet
Published: August 2019

BACKGROUND: BRAF mutations occur in 50% of melanoma patients. Targeted agents – BRAF and MEK inhibitors and immunotherapy improve survival of melanoma patients with BRAF mutations. These agents have intracranial efficacy as shown in clinical trials. However, the efficacy of immunotherapies (immune checkpoint blockade) in melanoma brain metastases and the correlation with BRAF status is not as well characterized. METHODS: We reviewed 351 patients with melanoma brain metastases treated at our tertiary care center between 2000 and 2018, 75 of which received immunotherapy with known BRAF mutational status. Two-year, 5-year, and median overall survival (OS) was calculated from the start of immunotherapy to compare the efficacy of immunotherapy in BRAF mutant and BRAF wild type patients using the log-rank test. RESULTS: At the time of diagnosis of brain metastasis, the median age was 61 (23–87) years, median KPS was 80 (50–100), number of intracranial lesions was 2 (1–15), and 79% had extra-cranial metastases. Sixty-three patients were treated with stereotactic radiosurgery (SRS), 27 underwent whole brain radiation (WBRT) and 21 underwent surgery. When treated with immunotherapy, BRAF mutant and BRAF wild type median survival was 15.7 months (95% CI=9.4 – 42.4) and 6.9 (95% CI=4.1– 26.7) months (p-value=0.205), respectively. Two-year BRAF mutant and BRAF wild type survival was 35% (95% CI=21 – 58) and 28% (95% CI=16 – 51), and 5-year survival was 22% (95% CI=10 – 46) and 23% (95% CI=11 – 47), respectively. CONCLUSIONS: Twenty percent of patients with BRAF mutant and BRAF wild-type patients treated with immunotherapy derive a long-term benefit from immunotherapy and multimodality treatment and are alive 5 years from diagnosis of brain metastases. This was rarely seen in the pre-immunotherapy era in melanoma brain metastases. There was no difference in outcome based on the BRAF mutational status with use of immunotherapy in melanoma brain metastases.
THER-11. PEPTIDE-MEDIATED PERMEABILIZATION OF THE BLOOD-BRAIN BARRIER IMPROVES DRUG DELIVERY TO BRAIN METASTASIS
Authors: Aasen Synnøve Nymark , Espedal Heidi , Holte Christopher , Keunen Olivier , Karlsen Tine Veronika , Tenstad Olav , Maherally Zaynah , Miletic Hrvoje , Hoang Tuyen , Eikeland Anne Vaag , Baghirov Habib , Olberg Dag Erlend , Pilkington Geoffrey J , Sarkar Gobinda , Jenkins Robert , Sundstrøm Terje , Bjerkvig Rolf , Thorsen Frits
Published: August 2019

BACKGROUND: Melanoma patients have a high risk of developing brain metastases, which is associated with a poor prognosis. The blood-brain barrier (BBB) inhibits sufficient drug delivery into metastatic lesions. We investigated the ability of a synthetic peptide (K16ApoE) to permeabilize the BBB for more effective drug treatment. METHODS: DCE-MRI was performed to study the therapeutic window of BBB opening facilitated by K16ApoE. In vivoand in vitroassays were used to determine K16ApoE toxicity and also to obtain mechanistic insight into its action on the BBB. The therapeutic impact of K16ApoE on melanoma metastases was determined together with dabrafenib, which is otherwise known not to cross an intact BBB. RESULTS: DCE-MRI exhibited an effective K16ApoE-mediated BBB opening for up to 1h. Mechanistic studies displayed a dose-dependent effect of K16ApoE caused by induction of endocytosis. At higher concentrations, the peptide also showed unspecific disturbances on plasma membranes. Combined treatment with K16ApoE and dabrafenib reduced the brain metastatic burden in mice compared to dabrafenib. We also showed by PET/CT that the peptide facilitated the delivery of compounds up to 150 kDa into the brain. CONCLUSIONS: We demonstrate a transient opening of the BBB, caused by K16ApoE, that facilitates improved drug-delivery into the brain. This improves the efficacy of drugs that otherwise do not cross the intact BBB.
MLTI-03. FIRST-LINE STEREOTACTIC RADIOSURGERY COMBINED WITH SYSTEMIC TARGETED AND IMMUNE CHECKPOINT INHIBITOR THERAPY IN MELANOMA PATIENTS WITH NEWLY DIAGNOSED BRAIN METASTASES
Authors: Heumann Thatcher , Ye Rebecca , Wu Peter , Habibi Akram , Sansosti Alexandra , Beaudreault Cameron , Kryger Marc , Bernstein Kenneth , Pavlick Anna , Kondziolka Douglas
Published: August 2019

BACKGROUND: Of solid tumors, melanoma has the highest propensity for CNS spread with historic median survivals of 5–8 months following brain metastasis diagnosis. We evaluated the impact of systemic BRAF targeted and immune checkpoint inhibitor (ICI) therapies on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM) and assessed patient treatment burden associated with prolonged survival. METHODS: We retrospectively reviewed the demographics, disease characteristics, therapeutic regimens, overall survival, and first-year cumulative incidence of comorbid disease for patients with de novo MBM treated between 2013 and 2017 at a major melanoma referral center. RESULTS: Among 123 newly diagnosed MBM patients: 65% were male, 24% were 50 years old or less, 50% were BRAF mutated, 63% had multiple intracranial lesions at diagnosis. Locally, 73% received SRS as first-line treatment. Systemically, 73% received ICI, 46% received BRAF targeted therapy, and 12% received neither. With a median follow up of 11 months (mo), total cohort median OS was 13.2 mo. Median OS for first-line SRS combined with ICI and BRAF targeted therapy was 31.0 mo (47% 3-year OS), 17.5 mo (31% 3-year OS) with ICI monotherapy, and 6.1 mo (22% 3-yr OS) alone. SRS and BRAF targeted therapy were associated with improved OS. At one-year follow-up, comorbid conditions with the greatest cumulative incidence were fatigue, nausea, intracranial hemorrhage, deep vein thrombosis, major depressive disorder, and pneumonia. Patients averaged one inpatient visit every 4.5 mo (1 week average length of stay), and 2 advanced imaging studies (MR/CT/PET-CT) per month following MBM diagnosis. CONCLUSIONS: In one of the largest reported MBM series, survival has improved markedly for patients receiving first-line SRS combined with targeted and immunotherapies. Simultaneously, longer life expectancy comes with increasing incidences of comorbid conditions reflecting an evolving complexity of and need for coordination of care for patients with MBM.
MLTI-08. AN EXCEPTIONAL INTRACRANIAL RESPONSE TO REPEAT RADIATION AND IMMUNOTHERAPY IN A PATIENT WITH METASTATIC, POORLY DIFFERENTIATED ADENOCARCINOMA OF THE LUNG
Authors: Sumrall Ashley , Burri Stuart , Asher Anthony
Published: August 2019

We report an unusual case of a long-term survivor of metastatic, poorly differentiated adenocarcinoma of the lung (EGFR- ALK-) who developed intracranial disease after definitive treatment of a stage IIIB lung cancer. He received a complex course of RT which began with SRS to his intracranial disease in 2012 and included: brainstem (pontine) mass, left parietal mass, left frontal, left lateral temporal, and left insular lesions. The left temporal mass progressed and was resected. Subsequently, SRS was given to a right anterior frontal lesion. Additional SRS was given to progressive right superior frontal mass & left temporal tumor bed was given fractionated RT to the left temporal tumor bed. Later, he developed bilateral cerebellar masses and right-sided progression. More SRS was given to right frontal area, and then to bilateral cerebellar lesions. Surprisingly, he did well neurologically until seizures developed. His repeat biopsy was sent for NGS and noted to be PDL1+, APC mutated, and KRAS mutated. This gentleman was started on pembrolizumab in May 2016. Due to colitis, his therapy stopped in January 2017. His colitis progressed such that immunotherapy could not be restarted. Now, after observation only for the past 2.5 years. his disease has disappeared. He is doing well neurologically. We propose that the use of radiation and immunotherapy worked to produce an exceptional, durable response.
MLTI-17. DIFFERENTIATION OF RADIATION INJURY FROM RECURRENT BRAIN METASTASIS USING COMBINED FET PET/MRI RADIOMICS
Authors: Lohmann Philipp , Kocher Martin , Ceccon Garry , Bauer Elena , Stoffels Gabriele , Viswanathan Shivakumar , Ruge Maximilian , Neumaier Bernd , Shah Nadim , Fink Gereon , Langen Karl-Josef , Galldiks Norbert
Published: August 2019

BACKGROUND: The aim of this study was to investigate the potential of combined radiomics textural feature analysis of contrast-enhanced MRI (CE MRI) and static O-(2-[18F]fluoroethyl)-L-tyrosine(FET) PET for the differentiation of recurrent brain metastasis from radiation injury. PATIENTS AND METHODS: Fifty-two patients with newly diagnosed or progressive contrast-enhancing brain lesions on MRI after radiotherapy (predominantly radiosurgery, 84% of patients) of brain metastases were additionally investigated using FET PET. Based on histology (n=19) or clinicoradiological follow-up (n=33), local recurrent brain metastases were diagnosed in 21 patients (40%) and radiation injury in 31 patients (60%). Forty-two features (shape-based, first and second order features) were calculated on both unfiltered and filtered CE MRI and summed FET PET images (20–40 min p.i). After feature selection, logistic regression models using a maximum of five features to avoid overfitting were calculated for each imaging modality separately and for the combined FET PET/MRI features. The resulting models were validated using cross-validation. Diagnostic accuracies were calculated for each imaging modality separately as well as for the combined model. RESULTS: For differentiation between radiation injury and brain metastasis recurrence, textural features extracted from CE MRI had a diagnostic accuracy of 81%. FET PET textural features revealed a slightly higher diagnostic accuracy of 83%. However, the highest diagnostic accuracy was obtained when combining CE MRI and FET PET features (accuracy, 89%). CONCLUSION: Our findings suggest that combined FET PET/MRI radiomics using textural feature analysis offers a great potential to contribute significantly to the management of patients with brain metastases. SUPPORT: This work was supported by the Wilhelm-Sander Stiftung, Germany
OTHR-01. USING COGNITION TO PREDICT RISK OF MEDICAL DECISION-MAKING IMPAIRMENT IN BRAIN CANCER
Authors: Gerstenecker Adam , Triebel Kristen
Published: August 2019

BACKGROUND: Medical decision-making capacity refers to the ability to make informed decisions about medical treatment. Understanding is the most cognitively demanding aspect of medical decision-making and requires the ability to comprehend medically-related information and then use that information to make decisions about diagnosis, prognosis, and treatment options. In previous papers, we have shown that knowledge about specific cognitive abilities that affect understanding in brain cancer could be used to construct actuarial equations designed to help clinicians identify persons with brain cancer or brain metastases at risk of understanding impairment. METHODS: In total, 184 participants (67 with brain metastasis, 41 with non-brain metastasis, 29 with malignant glioma, and 47 healthy controls) were recruited. All participants were administered a neuropsychological battery that included a performance-based measure of medical decision-making capacity. Impairment cutoffs were calculated from control group performance. Using the cognitive scores that were most highly associated with understanding, logistic and linear regression models were used to construct actuarial equations designed to predict intact/impaired understanding and understanding scores, respectively. RESULTS: As expected, both brain cancer groups had poorer understanding than controls and approximately 50% of both brain cancer groups exhibited impaired understanding. Over 24% of the non-brain metastasis group exhibited impaired understanding. Significant associations were found between understanding and all administered cognitive variables, with the strongest correlations noted as between understanding and measures of executive function, verbal memory, and verbal fluency. Using these cognitive variables, we were able to construct predictive equations that showed strong psychometric properties. CONCLUSIONS: These data demonstrate how cognitive measures can estimate medical understanding in persons with cancer. Clinically, these findings suggest that poor verbal memory, executive function, and/or phonemic fluency function could serve as “red flags” for reduced consent capacity in this patient population, and thus signal that a more comprehensive medical decision-making capacity evaluation is warranted.
OTHR-04. INCIDENCE AND SURVIVAL OUTCOMES IN UROTHELIAL CARCINOMA BRAIN METASTASES
Authors: Kavouridis Vasileios , Harary Maya , Smith Timothy , Braun David , Iorgulescu Bryan
Published: August 2019

INTRODUCTION: Urothelial carcinoma is a common malignancy with ~79,000 new cases diagnosed annually. However, urothelial brain metastases (UBM) are encountered uncommonly. Herein we evaluate their national prevalence, predictors, and treatment outcomes in the contemporary era. METHODS: The characteristics, management, and overall survival (OS) of UBM patients (2010–2015) were evaluated using the National Cancer Database, which comprises >70% of all newly diagnosed cancers in the U.S. OS was analyzed with Kaplan-Meier methods and log-rank tests. National outcomes were compared to our institutional cohort of UBMs. RESULTS: Out of 208,600 patients diagnosed with urothelial carcinoma, 8.4% presented with stage IV disease--of these only 216 (1.2%) had BMs at the time of diagnosis. Patients presenting with bone, liver, or lung metastases were more likely to present with synchronous BMs. Brain involvement demonstrated significantly worse median OS (3.9mos, 95%CI: 3.1–4.9) than non-BM stage IV disease (10.9mos, 95%CI: 10.6–11.2, p< 0.001). Compared to non-BM stage IV disease, UBMs were more likely to have surgery for metastatic disease and receive radiotherapy (p< 0.001); but were less likely to have primary resection or chemotherapy. In multivariable analysis of stage IV urothelial cancer, BMs demonstrated significantly worse OS (HR 1.43, 95%CI: 1.20–1.72, p< 0.001). In our institutional data, 10 urothelial cancer patients developed BMs; of which 7 were male, median age and KPS at diagnosis were 64.9yo (IQR 56.4–72.0) and 85 (IQR 75–100). Four patients had synchronous metastases; the median number of BM lesions was 2 (IQR 1–2), with a median size of 2.6cm (IQR 1.6–3.3). All 10 underwent GTR, 3 also with SRS and 7 with WBRT, associated with a median OS of 16.5mos. CONCLUSION: Our results confirm the rarity of UBMs and suggest that BM screening may only be indicated in stage IV patients with neurological symptoms. Systemic therapies demonstrate improved OS in these patients.
OTHR-09. IDENTIFYING EPIGENETIC SIGNATURES IN LUNG ADENOCARCINOMAS THAT PREDICT DEVELOPMENT OF BRAIN METASTASIS
Authors: Zuccato Jeffrey , Mamatjan Yasin , Aldape Kenneth , Zadeh Gelareh
Published: August 2019

INTRODUCTION: Metastases are the most common adult brain tumor with half spreading from lung cancers and they reduce median overall survival from 26 to 12 months. There are no robust patient-specific predictors of brain metastasis. Epigenetic signatures predict disease recurrence in other cancers and identifying brain metastasis methylation-based signatures may allow for treatment approaches to high-risk patients that prevent their development. METHODS: In 207 lung adenocarcinomas, multivariate cox time to brain metastasis analyses including clinically-relevant variables (lung tumor size and TNM nodal score) along with significant covariates on univariate analyses were performed. DNA was extracted from 142 of these tumors and profiled on the Illumina Infinium EPIC array. A generalized boosted regression classification model used differentially methylated CpG sites significantly predicting time to brain metastasis in a 70% training cohort cox analysis (p< 0.05). Resulting methylation-based risk scores were compared to size and nodal status in a multivariate analysis of the independent 30% testing cohort. RESULTS: Of 207 patients with 72 brain metastatic events, tumor size (HR=1.5, 95%CI 1.1–2.0, p=0.01), N status (N3 vs. N0, HR=9.9, 95%CI 3.1–31, p=0.0001), EGFR status (HR=0.4, 95%CI 0.2–0.8, p=0.014), and age (HR=0.7, 95%CI 0.5–1.0, p=0.039) independently predicted their development. Methylation-based risk scores significantly predicted time to brain metastasis in a univariate analysis of the testing cohort (p=0.03). A multivariate analysis of testing cohort patients identified methylation score as the only independent predictor of brain metastasis (HR=4.3, 95%CI 1.1–17, p=0.038) accounting for tumor size and N score. CONCLUSIONS: Genome-wide DNA methylation signatures predict brain metastasis development in lung adenocarcinomas independent of tumor size and nodal disease. The design of a nomogram combining methylation profile other clinical factors may be used to determine patient specific brain metastasis risk values to guide patient counselling, extent of treatment, and screening.
OTHR-12. DRIVING RECOMMENDATIONS IN PATIENTS WITH NEWLY DIAGNOSED BREAST CANCER BRAIN METASTASES
Authors: Swartz Leigh , Egloff Heidi , Morikawa Aki , Van Poznak Catherine
Published: August 2019

BACKGROUND: Approximately 5% of all patients with breast cancer develop breast cancer brain metastases (BCBM). Medical and legal guidance on health conditions associated with driving may vary by state. The paucity of data to guide clinicians’ recommendations on driving in the setting of BCBM prompted this review of clinical practice. The primary objective is to determine the frequency of provider-documented driving recommendations with secondary objectives to define associated clinical factors. METHODS: University of Michigan’s (UM) DataDirect tool retrospectively searched records dated 11/30/2012 to 11/30/2018 using ICD 9 and 10 codes for breast cancer (C50.912, C50.911, C50.919, 174.9, 175.9) and for brain metastases (C79.31, D49.6, D43.2, 198.3, 239.6). Eligibility criteria were: age ≥ 18, BCBM, UM pathology confirmation of breast cancer, CNS imaging at time of diagnosis performed or reviewed at UM, and UM consultation with medical oncology, radiation oncology, neuro-oncology, neurosurgery, or neurology within 4 weeks of BCBM diagnosis. Chart abstraction included clinical and demographic factors for descriptive analysis. RESULTS: Only 87 of the 188 identified subjects (46%) met eligibility criteria. The most common exclusions were non-breast cancer brain lesion (n=40), neither UM imaging nor pathology (n=23) and no intra-parenchymal brain metastases (n=22). Of the 87 eligible subjects, 21 (24%) had documented recommendations against driving. Five of the 7 subjects with documented seizure history within 4 weeks of diagnosis also had documented recommendations against driving. There were 32 of 87 subjects on anti-epileptics of which 13 had documented driving recommendations. CONCLUSIONS: The minority of patients (24%) with newly diagnosed BCBM had a documented recommendation against driving. Seizure activity was strongly associated with documentation of driving recommendations. Other than seizure activity, general parameters regarding the safety of driving with newly diagnosed BCBM are not well defined. Prospective study is indicated to provide data supported recommendations regarding driving with BCBM.
RADI-02. SINGLE-SESSION VERSUS MULTISESSION GAMMA KNIFE RADIOSURGERY FOR LARGE BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER: RETROSPECTIVE ANALYSIS
Authors: Kim Jin Wook , Park Kawngwoo
Published: August 2019

PURPOSE: To evaluate the efficacy of Gamma Knife radiosurgery (GKS) in patients with large brain metastases by comparing single-session radiosurgery (S-GKS) and multisession radiosurgery (M-GKS), the authors retrospectively analyzed the clinical outcomes of the patients who underwent GKS for brain metastases from non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Between January 2010 and December 2016, 66 patients with 74 lesions >=10 cm3 from large brain metastases from only NSCLC were included. Fifty-five patients with 60 lesions were treated with S-GKS; 11 patients with 14 lesions were treated with M-GKS. Median doses were 16 Gy (range, 11–18 Gy) for the S-GKS group and 8 Gy (range, 7–10 Gy) in three fractions for the M-GKS group. RESULTS: With a mean follow-up period of 13.1 months (range, 1.3–76.4 months), the median survival duration was 21.1 months for all patients. Median tumor volume was 14.3 cm3 (range, 10.0–58.3). The local control rate was 77.0% and the progression-free survival rate was 73.6% at the last follow-up. There were no significant between-group differences in terms of local control rate (p = 0.10). Compared with S-GKS, M-GKS did not differ significantly in radiation-induced complications (38.1% versus 45.4%, p = 0.83). While eight patients who underwent S-GKS experienced major complications of grade >=3, no toxicity was observed in patients treated with M-GKS. CONCLUSIONS: M-GKS may be an effective alternative for large brain metastases from NSCLC. Specifically, severe radiation-induced toxicity (≥ grade 3) did not occur in M-GKS for large-volume metastases. Although the long-term effects and results from larger samples remain unclear, M-GKS may be a suitable palliative treatment to preserve neurological function.
RADI-08. A SURVEY BASED STUDY OF BRAIN METASTASES MANAGEMENT FOR PATIENTS WITH NON-SMALL CELL LUNG CANCERS OR MELANOMA
Authors: Fong Chin Heng , Leighl Natasha , Butler Marcus , Doherty Mark , Kruser Timothy , Shultz David
Published: August 2019

INTRODUCTION: The standard of care for 1–4 brain metastases (BrM) is stereotactic radiosurgery (SRS), whereas whole brain radiation remains the standard treatment for extensive BrM, and surgical resection is appropriate in certain scenarios. Some newer systemic therapies such as tyrosine kinase inhibitors and immunotherapy have impressive CNS activity and are used by some practitioners either alone or in combination with other modalities as first-line treatment for BrM. We conducted a survey to ascertain current real-world practices for the treatment of BrM from NSCLC and melanoma. OBJECTIVES: Our study aimed to assess practice patterns of oncologists who treat BrM from NSCLC or melanoma. We also investigated the extent to which various clinical factors influence decision making. METHODOLOGY: We created 2 sets of surveys: one for Medical-/Clinical-/Neuro- oncologists and another for Radiation oncologists/Neurosurgeons. Surveys were conducted online or on-line. Following administration, data was tabulated and analyzed. Statistical analyses were performed using Fisher’s exact test. RESULTS: Of 361 respondents, 250 were Radiation oncologists/Neurosurgeons, and 111 were Medical-/Clinical-/Neuro- oncologists. For patients with 1–3 brain lesions, all < 2cm, 34% of respondents recommended systemic therapy alone as first-line treatment. In contrast, only 15% recommend systemic therapy alone for >9 lesions, at least one > 2cm. Medical-/Clinical-/Neuro- oncologists were more likely to recommend systemic therapy alone compared to Radiation oncologists/ Neurosurgeons for 1–3 lesions, all < 2cm (53% vs. 28%, p< .0001). For patients with > 9 BrM, one >2cm diameter, Medical-/Clinical-/Neuro- oncologists were not significantly more likely to recommend systemic therapy alone (20% vs 13%, p=.11). DISCUSSION: Our results reveal that significant numbers of physicians recommend systemic therapy alone as first-line therapy in BrM and that management decisions correlate with a physician’s type of practice. These findings underscore the need for prospective clinical trials to direct appropriate BrM management.
RADI-10. THERAPEUTIC EFFECTS OF fSRS IN 44 CASES OF BRAIN METASTASES OF NSCLC WITH A MAXIMUM DIAMETER ≥ 4CM AND ANALYSIS OF ITS PROGNOSTIC FACTORS
Authors: Mingyao Lai , Zhen Junjie , Li Juan , Zhou Jiangfen , Hu Qingjun , Ye Minting , Li Shaoqun , Xiao Xiao , Wang Lichao
Published: August 2019

OBJECTIVE: To analyze the therapeutic effects of fSRS on brain metastases of NSCLC with a maximum diameter ≥ 4 cm, and explore the prognostic factors. METHODS: A retrospective analysis was conducted on the clinical data of 44 cases of brain metastases of NSCLC with a maximum diameter ≥ 4 cm in Guangdong Sanjiu Brain Hospital from January 2006 to December 2016. RANO criteria were adopted for imaging evaluation at 3 months after completion of radiotherapy. One- and 2-year survival rates were calculated and the differences in survival rates between groups were analyzed with Log-rank test. Kaplan-Meier method was used in univariate analysis to investigate the effects of KPS, RPA classification, number of metastases, total lesion volume, systemic treatment and surgery on prognosis; and Cox regression model in multivariate analysis. RESULTS: The postoperative imaging evaluation showed that there were 5 cases of CR, 20 of PR, 12 of SD and 7 of PD. The median PFS, OS, 1- and 2-year survival rates were 6 months, 16 months, 65.9% and 20.5%, respectively. KPS, RPA classification, number of metastases and surgery had no significant correlations with prognosis. However, systemic treatment and the maximum lesion volume ＜28.3cc were considered as favorable factors related to prognosis (P=0.046, 0.027). Moreover, the maximum lesion volume ＜28.3cc was found to be the independent prognostic factor for the survival (P=0.035). CONCLUSION: Treatment of brain metastases of NSCLC with a maximal diameter ≥4 cm with fSRS is proved to be feasible. The maximum lesion volume is related to prognosis. Systemic treatment (chemotherapy, TKI treatment, etc.) may improve prognosis, but more cases are needed to investigate the prognostic significance.
RADI-14. FRAMELESS STEREOTACTIC RADIOSURGERY ON THE GAMMA KNIFE ICON: EARLY EXPERIENCE FROM 42 PATIENTS WITH BRAIN METASTASES
Authors: Vulpe Horia , Save Akshay , Xu Yuanguang , Elliston Carl , Garrett Matthew , Wu Cheng-Chia , Cheng Simon , Jani Ashish , Bruce Jeffrey , McKhann Guy , Sisti Michael , Wang Tony
Published: August 2019

BACKGROUND: The Gamma Knife (GK) Icon uses a Cone-Beam CT (CBCT) scanner and an infrared camera system to support the delivery of frameless radiosurgery. There are limited data on patients treated with frameless GK radiosurgery (GKRS) for brain metastases. OBJECTIVE: To describe the early experience, process, technical details, and short-term outcomes with frameless GKRS for brain metastases at our institution. METHODS: We describe our patient selection and workflow for frameless GKRS in detail. Because of the short interval of follow-up, we provide crude rates of local control. RESULTS: 42 patients had a total of 96 brain metastases. Median age was 69. 77 intact lesions were treated definitively, 18 cavities postoperatively, and 1 had GKRS for recurrence after resection. 11 patients underwent repeat GKRS to the same area. Median dose was 20Gy in 1 fraction (range: 14–21), 24Gy in 3 fractions (range: 19.5–27), and 25Gy in 5 fractions (Range: 25–30). Median treatment time was 23.7 minutes (Range: 7.3 – 85.5). 29 patients had a follow-up MRI in our records after completing GKRS. Median follow-up time was 105 days (Range: 16 – 314). 16 local recurrences (LR) were identified in 9 patients. An additional 6 patients had distant brain recurrence without LR. Crude mean time between GKRS and LR was 101 days (range 44–161 days). There were 6 patients with grade 1, 3 with grade 2, 2 with grade 3, and 1 with grade 4 toxicity. We found an improvement in workflow and a greater number of patients eligible for GKRS due to the ability to fractionate treatments. CONCLUSION: We report a large cohort of consecutive patients with brain metastases treated with frameless GKRS. We look forward to studies with longer follow-up to provide valuable data on clinical outcomes and to further our understanding of the radiobiology of hypofractionation in the brain.