bluuebunny/crossref_metadata_2025 huggingface dataset:
BSBM-16 GLIOBLASTOMA AS A METASTATIC DISEASE: A POSSIBLE MOLECULAR PATHWAY OF METASTATIC SPREAD ACCORDING TO THE GENE MUTATION PROFILE
Authors: Jancalek Radim , Hendyrch Michal , Sana Jiri
Published: August 2024

Glioblastoma (GBM) is the most common glial brain tumor in adults. It accounts for nearly 50 % of malignant primary brain tumors and represents a disease with a dismal prognosis. GBM is characterized by rapid infiltrative spread within the central nervous system; however, its metastases are considered sporadic. The molecular background of primary and secondary GBM is yet to be discovered, making it difficult to describe the possible molecular pathway/s of metastatic spread. Due to increasing overall survival rates in GBM patients, extracranial metastasis is becoming more common, making this topic increasingly relevant. We screened a case of spinal GBM metastasis and its molecular background and searched for differences in gene mutation profile between the primary and metastatic disease to outline possible molecular pathways of metastatic spread. In this study, we discovered that the alteration of NF1, NOTCH3, and ARID1A could explain, at least in part, the acquired invasiveness and metastatic potential in a GBM case. This finding underscores the importance of genetic testing in understanding tumor progression and its potential impact on patient oncological management. The project was supported by the NU23-03-00100 grant from the Ministry of Health, Czech Republic.
BSLM-02 SPATIAL TRANSCRIPTOMICS ANALYSIS IDENTIFIES A UNIQUE TUMOR-PROMOTING FUNCTION OF THE MENINGEAL STROMA IN MELANOMA LEPTOMENINGEAL DISEASE
Authors: Alhaddad Hasan , Ospina Oscar , Khaled Mariam , Ren Yuan , Vallebuona Ethan , Boozo Mohammad Baraa , Forsyth Peter , Pina Yolanda , Macaulay Robert , Law Vincent , Tsai Kenneth , Cress Douglass , Fridley Brooke , Smalley Inna
Published: August 2024

Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. The inaccessible nature of the disease site and lack of understanding of the biology of this unique metastatic site are major barriers to developing efficacious therapies for patients with melanoma LMD. Here, we characterize the tumor microenvironment of the leptomeningeal tissues and patient-matched extra-cranial metastatic sites using spatial transcriptomics analyses in clinical specimens, with extensive in vitro and in vivo validation. We show the spatial landscape of melanoma LMD to be characterized by a lack of immune infiltration and instead exhibit a higher level of stromal involvement. We show that the tumor-stroma interactions at the leptomeninges activate pathways implicated in tumor-promoting signaling, mediated through upregulation of SERPINA3 at the tumor-stroma interface. Our functional experiments establish that the meningeal stroma is required for melanoma cells to survive in the CSF environment and that these interactions lead to a lack of MAPK inhibitor sensitivity in the tumor. We show that knocking down SERPINA3 or inhibiting the downstream IGR1R/PI3K/AKT axis results in re-sensitization of the tumor to MAPK-targeting therapy and tumor cell death in the leptomeningeal environment using in vitro and in vivo models. Our data provides a spatial atlas of melanoma LMD, identifies the tumor-promoting role of meningeal stroma, and demonstrates a mechanism for overcoming microenvironment-mediated drug resistance unique to this metastatic site.
BSLM-03 BRANCHED-CHAIN KETO ACIDS PROMOTE AN IMMUNE-SUPPRESSIVE AND NEURODEGENERATIVE MICROENVIRONMENT IN LEPTOMENINGEAL DISEASE
Authors: Khaled Mariam , Ren Yuan , Kundalia Ronak , Alhaddad Hasan , Chen Zhihua , Wallace Gerald , Evernden Brittany , Ospina Oscar , Hall MacLean , Liu Min , Darville Lancia , Izumi Victoria , Chen Y Ann , Pilon-Thomas Shari , Stewart Paul , Koomen John , Corallo Salvatore , Jain Michael , Robinson Timothy , Locke Fredrick , Forsyth Peter , Smalley Inna
Published: August 2024

Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omic analyses of CSF from patients with melanoma, breast cancer and lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment dominated by inactive, dysfunctional T cells and alternatively activated macrophages. These findings were confirmed in mouse models of LMD. We identified dysregulations in proteins and lipids indicating neurodegenerative processes and reactive gliosis. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD. Functionally, BCKA disrupted the viability and function of T lymphocytes, chimeric antigen receptor (CAR) T cells, neurons, and meningeal cells. These findings support the severe neurological decline, deficiency in the anti-tumor immune environment, and lack of response to immune therapies observed in patients clinically. Sodium phenylbutyrate is an FDA-approved BCKA-lowering therapy with exceptional safety profile and CNS penetration. We show that sodium phenylbutyrate improved neurological function and survival outcomes in murine models of breast cancer, lymphoma and melanoma LMD. In lymphoma LMD models, sodium phenylbutyrate also improved the efficacy of CAR T cell therapy. This work provides the preclinical rationale for repurposing BCKA-lowering therapies such as sodium phenylbutyrate for patients with LMD.
BSLM-06 PROGNOSTIC SIGNIFICANCE OF CEREBROSPINAL FLUID GLUCOSE AND PROTEIN LEVELS IN METASTATIC BREAST CANCER PATIENTS WITH LEPTOMENINGEAL DISEASE: A RETROSPECTIVE STUDY
Authors: Niraula Sujan , Gauli Sugam , Baran Andrea M , Tyburski Haley , Zhang Huina , O’Regan Ruth , Mohile Nimish , Anders Carey K , Hardy Sara , Dhakal Ajay
Published: August 2024

BACKGROUND

The prognostic significance of cerebrospinal fluid (CSF) glucose and protein levels among patients with leptomeningeal disease (LMD) is unknown. This single-institution retrospective study aims to investigate the association of CSF glucose and protein levels with overall survival (OS) among metastatic breast cancer (MBC) patients with LMD.

METHODOLOGY

MBC patients diagnosed with LMD between Jan 1st, 2010, and Jan 1st, 2023, were included. Patients without known CSF glucose or protein levels at the time of LMD diagnosis were excluded. OS was evaluated using the Kaplan-Meier method and compared using the log-rank test. For multivariate analysis, a step-wise model selection was performed after the inclusion of sub-type of interest, and variables meeting entry (p<0.10) and staying criteria (p<0.05). Median glucose and protein levels were compared using the Wilcoxon rank-sum test.

RESULTS

28 patients met inclusion criteria. Positive CSF cytology samples (CSF+) had significantly lower glucose levels vs CSF cytology negative samples (CSF-) [median (IQR) 40 (18-58) vs. 64 (53-92) mg/dl, p=0.006]. Prior study from this data set had shown that the CSF- group was associated with better OS vs the CSF+ group. Hence, four groups were created based on the CSF (+/-) and glucose (Low vs High/Normal). Median OS (months), 95% confidence Interval (CI) for CSF+/Glucose_Low, CSF+/Glucose_Normal/High, CSF-/Glucose_Low and CSF-/Glucose_High/Normal were 3.4(0.23-NE), 16.5(2.9-NE), 3.1(1.28-NE), 51.5(4.9-NE), p=0.03. Glucose_Low overall was associated with shorter OS in multivariate analysis [hazard ratio (HR), 95%CI 4.64 (1.71, 13.2)]. Median CSF protein was not different between CSF+/– groups. Median OS (months), 95%CI for Protein_High and Protein_Low /Normal groups were 28.5 (2.9, 51.5) vs. 6.5 (0.85, 8.0), p=0.36. In multivariate analysis, CSF protein level was not associated with OS.

CONCLUSION

The association between low CSF glucose level and worse survival among patients with MBC LMD was observed.
BSLM-07 A FIRST IN HUMAN PHASE 1 TRIAL OF DOSE ESCALATING INTRATHECAL (IT) DENDRITIC CELLS (CDC1S) PRIMED AGAINST HER2/HER3 IN PATIENTS (PTS) WITH LEPTOMENINGEAL DISEASE (LMD) FROM TRIPLE NEGATIVE (TNBC) OR HER2+ BREAST CANCER (BC)
Authors: Forsyth Peter , Gandhi Shipra , Wilcox Jessica , Law Vincent , Mo Qianxing , Chen Zhihua , Ahmed Kamran , Piteo Cecily , Evernden Brittany , Pina Yolanda , Boire Adrienne , Kalinski Pawel , Czerniecki Brian
Published: August 2024

BACKGROUND

Leptomeningeal disease (LMD) is a devastating complication of BC has a dismal prognosis. The CSF of LMD pts have an innate (PMID:34035069), but not adaptive, immune response (bioRxiv 2023.03.17.533041; doi: https://doi.org/10.1101/2023.03.17.533041) that is insufficient to combat LMD. We used IT cDC1 to elicit an adaptive response in LMD and found they were safe, induced a Th1 response, cured most HER2+ LMD, and prevented LMD recurrence (PMCID: 9354231). Responses were CD4+ and B cell dependent. cDC1s induce Th1 responses in HER2/HER3 tumors (PMID: 35710296; PMID: 34785506). And there are trials of cDC1s in BC patients (e.g.NCT03384914, NCT03387553, etc.) We hypothesized that a RP2D would be found and the CSF would be remodeled to have a Th1 immunological profile.

METHODS

Phase I single-arm, dose escalation multicenter study to establish 1) safety of IT cDC1s, and 2) associations between clinical outcomes & translational CSF studies (e.g. scRNAseq, cytokine arrays). Eligibility includes TNBC or HER+ LMD pts, prior pCSpRT/WBRT, ECOG ≤2, normal organ function, life expectancy of ≥ 8 weeks, and an Ommaya. IT cDC1s were administered weekly x 12 wks at one of 4 dose levels (1 X 106 – 5 X 107 cDC1s) until PD, DLT or withdrawal. Primary Endpoints were 1) safety and DLTs, 2) association between clinical endpoints and immune profiles. We used the BOIN design for the MTD. Response was measured using RANO-LM (PMID: 30715514). DLTs were defined as ≥ gr. 3 not due to LMD, resistant to medical intervention/CSF removal. Final pre & post cDC1 treatment cyto/chemokine & scRNAseq will be determined. As of 04 01 2024, 4 pts were treated [3 pts cohort 1 @ 1 X 106 & 1 pt cohort 2 @ 2 X 106]. NCT05809752. Sponsor: Department of Defense
BMRK-01 EXTERNALLY VALIDATED PREDICTIVE NOMOGRAM FOR BRAIN METASTASIS IN EARLY-STAGE BREAST CANCER
Authors: Jennings Kristofer , Raghavendra Akshara Singareeka , Kotecki Nuria , Amato Ottavia , Tripathy Debu , Awada Ahmad , Ibrahim Nuhad
Published: August 2024

BACKGROUND

Brain metastasis presents a significant concern for early-stage breast cancer (ESBC) patients, impacting their survival and overall well-being. Constructing a predictive nomogram based on primary tumor characteristics offers a way to anticipate the likelihood of brain metastasis. The objective is to create tools aiding in the identification of high-risk patients, enriching clinical trial cohorts to prevent or delay brain metastasis onset early in the disease.

METHODS

We reviewed 40,290 ESBC cases (stages I-III) at the University of Texas MD Anderson Cancer Center, Houston, spanning January 1, 1997, to May 8, 2020. Validated the model with Institut Jules Bordet, Belgium, patient data for accuracy and reproducibility analyzing 1,644 cases with the same inclusion criteria.Statistical models considered patient age, tumor features (grade, hormone receptor, HER2 status), and treatments (chemotherapy, endocrine therapy). Using these, our multivariate model predicted brain metastasis occurrence over 1, 2, and 5 years, evaluated through Receiver Operating Characteristic (ROC) analysis.

RESULTS

Key predictors for brain metastasis included younger age, high estrogen and progesterone receptor percentage, higher tumor size; use of aromatase inhibitor therapy, and use of selective estrogen receptor modulator therapy were associated with a decreased risk of brain metastasis. Higher grade, Ki-67 levels, HER2-positive status, lymphovascular invasion and the use of chemotherapy was associated with an increased risk. The AUC values for the prediction of brain metastasis at various time intervals in the test cohort were 0.81 at 4 years, 0.80 at 5 years, and 0.77 at 10 years. In the validation cohort, the AUCs were 0.81 at 4 and 5 years, decreasing to 0.70 at the 10-year mark.

CONCLUSIONS

This tool offers valuable support to clinicians in personalized patient care decisions regarding brain metastasis risk. Continuous validation and research will enhance these models, bolstering reliability and applicability in clinical and research settings.
BMRK-05 ASSOCIATION BETWEEN HER2-LOW STATUS AND TIME TO DEVELOPMENT OF BRAIN METASTASES AMONG PATIENTS WITH BREAST CANCER: A RETROSPECTIVE COHORT STUDY
Authors: Yijun Fan Kevin , Chehade Rania , Fernandes Italo , Moravan Veronika , Jerzak Katarzyna
Published: August 2024

BACKGROUND

Brain metastases (BrM) develop in a high proportion of patients with breast cancer. We aimed to investigate the association between HER2 status (HER2-0, HER2-low, HER2+) and time to BrM development in patients treated for breast cancer BrM.

METHODS

We investigated a cohort of 188 women with metastatic breast cancer (MBC) treated for BrM at Sunnybrook Odette Cancer Centre from 2008-2018, for whom HER2 status was available in either the primary breast cancer (PBC) or metastatic site. We investigated: (1) association between HER2 status of the PBC (when available) and time from PBC to BrM diagnosis (PBC-TTBM), and (2) association between HER2 status of either PBC or metastatic site (the higher level of HER2 expression was utilized when >1 sample was available) and time from MBC to BrM diagnosis (MBC-TTBM).

RESULTS

Median age was 50 years and 54% of patients had >1 BrM. 40 patients had triple-negative breast cancer (TNBC), 77 had HER2+ disease, and 70 had HR+(hormone receptor+)/HER2- disease. Among 129 patients for whom PBC HER2 status was available, median PBC-TTBM was 44 months. HER2-low (n=29) status was associated with shorter PBC-TTBM compared to HER2-0 (n=60) and HER2+ (n=40) status (33 vs. 50 vs. 52 months, p=0.045). Among patients with HR+/HER2- disease, HER2-low status (n=21) was associated with shorter PBC-TTBM compared to HER2-0 status (n=29) (34 vs. 95 months, p<0.001). Among patients with TNBC, PBC-TTBM was similar among patients with HER2-low (n=8) and HER2-0 (n=31) status (24 vs. 27 months, p=0.79). In all patients, median MBC-TTBM was 21 months. MBC-TTBM was similar among patients with HER2-0 (n=58), HER2-low (n=53) and HER2+ (n=77) disease (15 vs.19 vs. 22 months, p=0.75); no differences were observed within the HR+/HER2- and TNBC subgroups.

CONCLUSIONS

HER2-low status is associated with shorter PBC-TTBM, particularly among patients with HR+/HER2- disease.
BMRK-08 TRENDS IN BREAST CANCER BRAIN METASTASES INCIDENCE AND MORTALITY: DISPARITIES BY MOLECULAR SUBTYPES, AGE, AND RACE
Authors: Thierheimer Marisa , Armashi Abdul Rahman Al , Martin James M
Published: August 2024

Brain metastases represent a critical complication of breast cancer, with a significant impact on patient prognosis. Understanding the variations in incidence and mortality across molecular subtypes, races, and age groups is crucial to enhance risk stratification and guide resource allocation. Identifying these trends can inform treatment and prognostication efforts. Utilizing the Surveillance, Epidemiology, and End Results 17 database, this study examined trends in synchronous breast cancer brain metastasis (BCBM) incidence and mortality from 2010-2020. The National Cancer Institute’s Joinpoint Regression Program was employed to estimate annual percent changes (APCs). Results were considered significant if the 95% confidence interval excluded zero, and trends were identified using JoinPoint software to delineate variations across demographic and molecular distinctions. There was a significant overall increase in BCBM incidence (APC=2.3%) between 2010-2020. Analysis by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status revealed incidence increases across all four subtypes, with Non-White patients experiencing a significant decrease in BCBM incidence in HR-/HER2+ tumors (APC=-7.7%). After accounting for observation-time bias, mortality rates demonstrated statistically significant upward trends overall (APC=4.0%) and across several biomarker groups, particularly HR+/HER2+ (APC=7.3%), HR-/HER2+ (APC=5.6%), and HR+/HER2- (APC=4.4%). While the increase in HR-/HER2- was more modest (APC=2.7%), it contributes to the evolving landscape of BCBM mortality. Disparities in mortality rates were also pronounced among age and racial groups within these individual subtypes. Representing the largest population-based study to evaluate trends in BCBM incidence and mortality, our analysis uncovers varying patterns across molecular subtypes, age, and race. These disparities suggest underlying biological differences and inherent healthcare barriers, highlighting the urgent need for targeted interventions in at-risk populations. Our findings lay crucial groundwork for further research into these disparities and tailored clinical and policy measures to improve BCBM outcomes.
BMRK-09 PROGNOSTIC ROLE OF TUMOR-INFILTRATING LYMPHOCYTES AND TERTIARY LYMPHOID STRUCTURES IN BRAIN METASTASIS
Authors: Mughal Sadaf Shabbir , Reiss Yvonne , Felsberg Jörg , Meyer Lasse , Macas Jadranka , Schlue Silja , Starzetz Tatjana , Köhrer Karl , Fehm Tanja , Müller Volkmar , Lamszus Katrin , Helfrich Iris , Wikman Harriet , Berghoff Anna , Brors Benedikt , Plate Karlheinz , Reifenberger Guido
Published: August 2024

Brain metastases (BrMs) constitute the most common type of brain cancer with abysmal prognosis. Given the high incidence and poor prognosis of BrM, understanding the tumor microenvironment (TME) architecture across BrM subtypes is increasingly crucial, especially with the emergence of novel immunotherapeutic agents like immune checkpoint inhibitors, which have demonstrated efficacy in melanoma and lung cancer BrM. Tertiary lymphoid structures (TLS) are spatially organized lymphoid aggregates in the TME that mediate antitumor immunity. Despite being established as prognostic and predictive markers in various cancers, their significance in BrM lacks extensive investigation. We performed gene expression profiling using paired-end RNA sequencing and multiplex immunofluorescence combined with spatial imaging on 149 human BrM samples. Cell type deconvolution analysis revealed that BrMs from non-small cell lung carcinoma (NSCLC) and malignant melanoma exhibited significantly higher immune cell infiltration compared to BrMs from breast carcinoma. Furthermore, B cell infiltration was detected in some patients, suggesting potential TLS formation. We created a metagene signature comprising TLS hallmarks in BrMs using transcriptomic profiling, allowing us to categorize BrM patients into TLS-positive and TLS-negative groups. This finding was corroborated by multiplex immunofluorescence staining of corresponding BrM tissue sections, which confirmed TLS-like aggregate formation in 40% of the BrM patients. Differential gene expression analysis highlighted the presence of activated lymphocyte-mediated immunity as well as increased immunoglobulin production signature in TLS-positive tumors. Additionally, a higher TLS signature score was associated with improved overall survival of lung carcinoma patients after BrM diagnosis. Our results underscore the heterogeneity of the tumor microenvironment in BrM, and the identification of intratumoral TLS may guide patient stratification for therapeutic interventions.
BMRK-12 THE CNSIDE CSF TUMOR CELL DETECTION PLATFORM IS A FEASIBLE, CLINICALLY RELEVANT AND SCALABLE PLATFORM FOR DISEASE MANAGEMENT FOR PATIENTS WITH LEPTOMENINGEAL DISEASE
Authors: Tripathy Arushi , Corkos Perry , Blouw Barbara , Moore Melissa , LaFrance Norman , Hedrick Marc , Kumthekar Priya
Published: August 2024

CNSide is a platform that analyzes Cerebrospinal Fluid (CSF) of patients with solid tumors having Leptomeningeal Disease for presence of tumor cells (CSF-TCs) and expression of different biomarkers via Fluorescent In Situ Hybridization (FISH), Next-Generation Sequencing (NGS) and Immunocytochemistry (ICC). CNSide was offered as a commercial test in a CAP accredited CLIA certified Laboratory and ordered at each physician’s discretion. Retrospective analysis of test results between January 2020 and October 2022 showed that the test was ordered by 19 physicians from 5 unique health systems totaling 613 tests on 218 individual patients. Of these, 162 (74.3%) were female; ages ranged from 19-99 years with a median age of 58. A range of cancer pathologies were sent for CNSide analysis, of which breast (n=105) and lung (n=65) were most common. CSF-TCs were detected in 67% (412/613) samples of which 66% (195/294) were from breast cancer patients and 76% (175/229) from lung cancer patients. In lung cancer patients, ALK was detected in 14% (17/118) and CMET in 61% (78/128). In breast cancer patients, HER2 was detected in 39% (65/168) patients, ER in 26% (44/168) and PR in 4% (5/120). Furthermore, 73% (16/22) lung cancer patients had HER positive CSF. Tumor cell detection with CNSide was more frequently seen than positive cytology and provided a more reliable quantitative measure of CNS malignant disease. This data shows that CNSide is viable from a feasibility perspective across many different tumor types. Furthermore, it is scalable and detects clinically relevant biomarkers. Analysis of the prospective FORESEE clinical trial to determine the impact of CNSide on clinical decisions is ongoing.
IMUN-03 IT-IO: INTRATHECAL ADMINISTRATION OF NIVOLUMAB AND IPILIMUMAB IN COMBINATION WITH SYSTEMIC COMBINATION OF NIVOLUMAB AND IPILIMUMAB IN PATIENTS WITH NSCLC OR MELANOMA AND NEWLY DIAGNOSED LEPTOMENINGEAL METASTASIS, A MULTICENTRIC PHASE I STUDY - PRELIMINARY DATA
Authors: Le Rhun Emilie , Dummer Reinhard , Gramatzki Dorothee , Kraehenbuehl Lukas , Britschgi Christian , Wicki Andreas , Migliorini Denis , Weindler Susanne , Weiss Tobias , Dafni Urania , Weller Michael
Published: August 2024

The EANO ESMO guidelines recommend the use of intrathecal pharmacotherapy in patients with leptomeningeal metastases with circulating tumor cells in the cerebrospinal fluid or linear leptomeningeal disease on MRI. Phase I studies have established that doses of intrathecal nivolumab of up to 50 mg Q2W combined with systemic nivolumab (240 mg Q2W) are safe (NCT03025256). The superiority of the combination of systemic nivolumab and ipilimumab over nivolumab alone or chemotherapy has been shown in patients with advanced NSCLC or melanoma. The objective of IT-IO is to determine the feasibility of intrathecal double immune checkpoint inhibition for patients with newly diagnosed LM from NSCLC or melanoma. IT-IO (NCT05598853) is a prospective phase I, multicentre, open label, interventional clinical study aiming at determining the recommended phase 2 dose (RP2D) of intrathecal nivolumab and ipilimumab. The diagnosis of LM must be confirmed or probable by EANO ESMO criteria, steroid dose must be stable or decreasing and <4 mg dexamethasone equivalent per day in the last 7 days. Co-existing oligosymptomatic brain metastases are allowed if <2 cm diameter or if planned to be treated by stereotactic radiosurgery. Planned whole brain radiotherapy and planned or prior craniospinal irradiation are not allowed. The treatment regimen within the IT-IO study consists of intrathecal administration of nivolumab/ipilimumab in combination with systemic nivolumab/ipilimumab. Patients are treated with a fixed dose of IT nivolumab (50 mg) and increasing doses of IT ipilimumab. Three dose levels of IT ipilimumab are planned: 5 mg at dose level 1, 10 mg at dose level 2 and 20 mg at dose level 3. The RP2D is determined in a 3 + 3 design. Secondary endpoints will explore compartmental efficacy and survival. The dose escalation phase has been completed without dose limiting toxicity. Enrolment in the expansion phase has started in January 2024
IMUN-05 PHASE II STUDY OF NIVOLUMAB (NIVO) IN COMBINATION WITH RELATLIMAB (RELA) IN PATIENTS WITH ACTIVE MELANOMA BRAIN METASTASES (MBM)
Authors: Phillips Suzanne , Burton Elizabeth , Oliva Isabella Claudia Glitza , McQuade Jennifer , Amaria Rodabe , Diab Adi , Wong Michael , Chung Caroline , Milton Denái , Malke Jared , Simon Julie , Wefel Jeffrey , Li Jing , Davies Michael , Tawbi Hussein
Published: August 2024

BACKGROUND

More than half of patients diagnosed with metastatic melanoma (MM) will develop brain metastases. Despite this prevalence, these patients are excluded from most clinical trials. The CheckMate 204 study combining ipilimumab (3mg/kg) plus nivo (1mg/kg) for patients with asymptomatic MBM revealed an intracranial (IC) response in 54% of patients. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 55% of patients. RELATIVITY-047, a global phase II/III randomized study, reported on the fixed-dose combination of nivo/rela (480 mg/160 mg) compared to nivo (480 mg) alone for patients with advanced unresectable and untreated melanoma. This combination demonstrated significantly improved PFS compared to anti-PD-1 monotherapy. Grade 3/4 TRAEs occurred in 21% of patients in the combination group compared to 11% in the monotherapy group with no new safety signals. The nivo/rela combination has FDA approval for the treatment of patients with MM but has not been studied in patients with MBM.

METHODS

This single arm, single center phase II trial evaluates the safety and efficacy of nivo/rela in patients with MBM. 30 MBM patients who are asymptomatic and treatment naïve to anti-PD-1 therapy will be enrolled. Patients are treated with nivo/rela (480 mg/160 mg) every 4 weeks for up to 25 cycles, disease progression, or unacceptable toxicity. The primary objective is to evaluate IC response (CR + PR) by MRI per modified RECIST 1.1 criteria. Monitoring for futility will be performed using the Bayesian Optimal Phase 2 design. Longitudinal research blood, tissue, and microbiome samples will be collected along with neurocognitive assessments and quality of life surveys.

RESULTS

This study is actively enrolling. Eight of planned 30 subjects have been treated. At a median follow-up of 8 months, IC response was seen in 43% of patients. Grade 3 TRAEs occurred in 12% of patients with no new safety signals.
IMUN-07 TIMING AND OUTCOME OF BRAIN METASTASES FOLLOWING FIRST-LINE IPILIMUMAB PLUS NIVOLUMAB THERAPY FOR METASTATIC MELANOMA IN A COMMUNITY ONCOLOGY PRACTICE
Authors: Victoria Ong Claire , Samlowski Wolfram
Published: August 2024

Melanoma brain metastases (MBM) are a frequent complication of advanced stage disease. MBM are an important cause of morbidity and mortality during disease progression. We report a retrospective cohort study of patients treated with combined ipilimumab and nivolumab as initial therapy for metastatic melanoma to identify and evaluate the clinical course of patients who developed brain metastases in the “real world setting.” The aim of our study was (1) to determine the frequency and timing of brain metastases onset and (2) to characterize the incidence and timing of brain metastases following first line combined ipilimumab-nivolumab therapy. We evaluated 73 patients. Only 20 (27.4%) patients developed MBM. The majority of these patients were identified at initial evaluation of metastatic disease (20.5%), while the rate of CNS progression during immunotherapy was low (6.9%). Patient treatment response, progression-free survival (PFS), overall survival, and neurologic progression-free survival (CNS PFS) were evaluated. We observed that patients with MBM at diagnosis of metastatic disease had improved PFS and CNS PFS, compared to patients who progressed in the CNS following treatment. Despite the presence of symptomatic MBM at diagnosis, 27% of patients with MBM at diagnosis achieved a durable complete remission (NED). Of note, all responding patients presented with neurologic symptoms associated with their brain metastases, and half of them were receiving systemic steroids at the time of treatment. In contrast, patients with delayed onset of brain metastases had an extremely poor outcome, with a median PFS of only 4.8 months. Thus, in patients presenting with MBM at diagnosis of metastatic disease, combined ipilimumab/nivolumab therapy has significant clinical activity. Furthermore, checkpoint inhibitor therapy appears to reduce the frequency of delayed onset brain metastases. However, novel treatment options need to be developed to more effectively treat patients who progress in the CNS following initial combination therapy.
MMOD-07 CONSORTIUM FOR INTRACRANIAL METASTASIS ACADEMIC RESEARCH (CIMARA): INTERNATIONAL INTERDISCIPLINARY COLLABORATIONS TO IMPROVE OUTCOMES OF PATIENTS WITH CNS METASTASES
Authors: Van Swearingen Amanda , Anders Carey , Tawbi Hussein , members CIMARa
Published: August 2024

Brain metastases, including both parenchymal lesions and leptomeningeal disease, impact hundreds of thousands of patients annually worldwide, and are increasing in incidence as systemic anticancer therapies, and thus survival, improves. While historically patients with brain metastases were excluded from clinical trials, after much advocacy by patients and physicians over the past decade this has changed. More effective design of clinical trials for patients with brain metastases is needed, and a multidisciplinary team spanning local and systemic therapies is critical. CIMARa (Consortium for Intracranial Metastasis Academic Research) was formalized in June 2021, and is now a multidisciplinary, international group of clinical investigators, research scientists, and advocates who share the collective goal of improving outcomes for patients with brain metastases. As of April 2024, CIMARa includes nearly 110 members from 50 institutions and 8 countries in North America and Europe. CIMARa aims to improve outcomes through the awareness and coordination of multi-institutional clinical trials testing novel therapeutic strategies for this unique patient population, as well as through retrospective clinical studies and translation of preclinical work to the clinical setting. CIMARa collaborations thus far have led to multi-institutional and international preclinical collaborations and clinical studies, including 2 retrospective case series already published. Several more initiatives and studies are in progress, including developing consensus language around symptomatic vs asymptomatic brain metastases, a multisite retrospective study on PARP inhibitors in patients with breast cancer CNS metastases, and a large multisite retrospective on the efficacy and safety of bevacizumab for radiation necrosis in patients with brain metastases. Anyone interested in CIMARa can reach out to cimarainfo@gmail.com for more information or to be added to the membership list and receive communications about meetings and studies. Patient and caregiver advocates are especially welcome and encouraged to participate in CIMARa.
MMOD-09 PINEAL GERMINOMA RECURRENCE AND DISTANT METASTASIS IN A POST-CHEMOTHERAPY AND POST-RADIOTHERAPY ADULT FILIPINO: A CASE REPORT
Authors: Balanquit Loiue Stihl , De Roxas-Bernardino Ranhel
Published: August 2024

Pineal Germinomas are rare tumors comprising approximately less than one percent of brain tumors seen mostly in children or young adults and in males. Its recurrence is even more rare especially with local recurrence or leptomeningeal dissemination which is around 15%. We report a case of a 25 year old female which initially presents as frontal headache with associated photophobia and doubling of vision. Persistence of symptoms prompted consult upon which an MRI was done revealing a mass lesion. Surgical biopsy was done with histopathology revealing germinoma. Four cycles of chemotherapy and one session of radiotherapy were done. Serial MRI showed regression in size and complete resolution of the initial symptoms hence patient was able to return to work. One month thereafter, patient had sudden onset left sided weakness hence readmission. Radiation Necrosis and Pineal Germinoma Recurrence were entertained. MRI perfusion revealed interval increase of the intracranial mass. Additionally, MRI of the whole spine with contrast revealed Multifocal intradural mass on the cervical, lumbar and sacral region upon which surgical removal was done. Histopathology revealed Germinoma. The patient was then also started on corticosteroid therapy and eventual Partial Laminectomy. After which, radiation therapy and other treatment modalities were also considered. Hence, in this paper, we aim to report an extremely rare case of Pineal Germinoma with recurrence and distant metastasis in a Female Adult Filipino and to provide novel insight on the treatment modalities for Pineal Germinoma Recurrence.
MMOD-10 BRAIN METASTASIS, MENINGIOMA, AND GLIOMA: A RARE CASE OF MULTIPLE PRIMARY MALIGNANCIES
Authors: Li Boyi , Higgins Dominique
Published: August 2024

Multiple primary malignancies is a rare occurrence in which a single patient has multiple tumors of different origins. This occurs more commonly in patients with genetic conditions such as Li- Fraumeni disease or NF1. Here we present a case of a 78 year-old woman with no known family history of cancer or underlying genetic condition, who was found to have three different types of brain tumors, two of which presented simultaneously. The patient initially underwent resection of a right frontal WHO grade 2 meningioma in 2021. She elected not to pursue adjuvant radiation and subsequent serial MRIs up to September 2023 showed no recurrence. The patient was also found to have stage IIIa serous endometrial carcinoma, with genetic profile revealing a TP53 mutation. She underwent a hysterectomy in March 2023 and 6 cycles of paclitaxel/carboplatin with good systemic control. She then presented in March 2024 with status epilepticus and was found on new MRI to have two new lesions: an irregular enhancing cortical right occipitotemporal lesion with leptomeningeal involvement and a small round well-circumscribed heterogeneously enhancing periventricular mass along the atrium of the left lateral ventricle. The patient was taken for stereotactic biopsy of both lesions given the difference in radiologic appearance. Pathology results revealed the left lesion to be metastatic high-grade serous carcinoma and the right lesion an infiltrating high grade glioma, positive for TERT promotor mutation and MGMT promotor methylation positive. Germline testing is pending. To our knowledge, this is the first case of a patient with three distinct types of brain tumors: meningioma, metastasis, and glioma. Further understanding of this patient’s unique presentation and genetic profile will contribute to our understanding of the diagnosis and treatment of patients with multiple brain tumors.
MMOD-16 THE CHALLENGES IN ASSIGNING THE PRIMARY SOURCE OF METASTATIC FOCUS: PATHOLOGY POINT OF VIEW
Authors: Almurshed Maryam
Published: August 2024

Metastasis to the central nervous system is the most common cause of brain lesions, mostly in adults and mostly in the posterior fossa. Assigning the primary source of metastasis in a patient as a first presentation/ unknown primary is challenging to the pathologist. The diagnosis, in pathology point of view depends primarily on three factors: tumour morphology, the immunohistochemical expression, and clinical correlation to definitely specify the primary site of the metastasis. Missing one of thses factors may mislead the final diagnosis. The morphology of the metastasis may differ from the primary site as the metastasis may include “only” the tiny aggressive variant in the primary site, leading to mis- directing the pathological investigation. In addition, the immuno-expression is highly overlapping over different pathological entities, not mentioning the lab quality of stain. In cases of complex tumors, only one component of the tumor can metastasis leading to mis-labelling of the tumor entity. In conclusion, precise pathological diagnosis on tumor metastatic focus as a primary diagnosis can not be achieved without minding these factors, which are essential information to be delivered to the assigning pathologist.
NIRL-01 DEEP LEARNING-BASED VOLUMETRIC SEGMENTATION ENABLES RESPONSE ASSESSMENT AFTER LASER INTERSTITIAL THERMAL THERAPY
Authors: Haskell-Mendoza Aden , Reason Ellery , Gonzalez Ariel , Jackson Joshua , Sankey Eric , Srinivasan Ethan , II James Herndon , Fecci Peter , Calabrese Evan
Published: August 2024

BACKGROUND

Laser interstitial thermal therapy (LITT) allows for definitive tissue diagnosis, surgical cytoreduction, and faster post-operative return to systemic therapies for patients with brain tumors or radiation necrosis. Ablated tissue remains in situ following LITT, resulting in characteristic post-LITT lesion expansion. Post-LITT edema may be associated with transient clinical worsening and complicates subsequent response assessment.

METHODS

All patients receiving LITT at a single center for tumors or radiation necrosis from 2015 – 2023 with ≥ 9 months of MRI follow-up were retrospectively reviewed. A 3D U-net segmentation model implemented in nnU-Net was developed for automated segmentation of Contrast-enhancing Lesion Volume (CeLV) of LITT-treated lesions on T1-weighted post-contrast MR images. CeLVs were analyzed to establish volumetric post-LITT response assessments.

RESULTS

Sixty-one LITT-treated lesions and 6 control cases of medically-managed radiation necrosis were analyzed across 384 unique MRI exams. Automated segmentation was qualitatively accurate in 367/384 (95.6%) images. CeLV increased to a median of 68.3% (IQR 35.1 – 109.2%) from baseline at 1 – 3 months from LITT (P = 0.0012) and subsequently returned to baseline. Median overall survival (mOS) for LITT-treated patients was 39.1 (9.2 – 93.4) months. Using previously established volumetric thresholds, volumetric disease progression was defined as lesion expansion ≥ 40% from volumetric nadir or baseline. Twenty-one of 56 (37.5%) patients experienced volumetric progression with a progression-free survival of 21.4 (6.0 – 93.4) months. Patients with volumetric progression had lower mOS (17.3 vs 62.1 months, P = 0.0015).

CONCLUSION

We observed a nearly 70% increase in CeLV at 1 – 3 months post-LITT, which characteristically resolved within 6 months of the procedure. Development of response assessment criteria that account for transient post-LITT lesion expansion is feasible and should be considered for clinical trials. Automated lesion segmentation may facilitate adoption of volumetric response assessment into clinical practice.
NIRL-04 BRAIN METASTASES DISTRIBUTION WIDTH (BMDW): A NOVEL METRIC TO PREDICT DISTANT BRAIN FAILURE FOLLOWING STEREOTACTIC RADIOSURGERY IN PATIENTS WITH MULTIPLE BRAIN METASTASES
Authors: Gal Omer , Yarlagadda Sreenija , Hall Matthew D , Press Robert H , Wieczorek D Jay , Lee Yongsook C , Bejarano Tatiana , Tolakanahalli Ranjini , Gutierrez Alonso N , McDermott Michael W , Mehta Minesh P , Kotecha Rupesh
Published: August 2024

INTRODUCTION

We introduce a method of predicting clinical outcomes in newly diagnosed brain metastases (BM) patients after upfront stereotactic radiosurgery (SRS), based on a novel metric - brain metastases distribution width (BMDW) – which measures the amount of variation in BM volume.

METHODS

BMDW was defined as the coefficient of variation of mean BM volume (mBMV) per patient and was calculated by dividing the standard deviation of the mBMV (SD-mBMV) by the mBMV and multiplying by 100, to yield a percentage value representing BM volume heterogeneity. Patients were classified by BMDW into low (≤100) and high (>100) risk groups and the distant brain failure (DBF)-free and overall survival (OS) outcomes were summarized using the Kaplan-Meier method and compared between the two risk groups using the log-rank test.

RESULTS

The study cohort included 99 patients, the median age was 67 years (Range: 18-88) and 51% were female. The high- and low-risk groups included 63 (64%) and 36 (36%) patients, respectively. At a median follow-up of 20 months, a low BMDW predicted for a statistically significant prolonged DBF-free survival with a median of 21.4 months (95% confidence interval [CI]: 8.7-34.1 months) versus 4.9 months (95% CI: 3.3-6.5 months) for the high-risk group (p=0.023). OS was not significantly different between the groups (p=0.159). Multivariate analysis showed that BMDW was a dominant predictor of DBF, with a hazard ratio (HR) of 2.45 for the high-risk group (95% CI: 1.26-4.77, p=0.008), in addition to performance status (HR=2.16, 95% CI: 1.29-3.62, p=0.003) and presence of >10 lesions at diagnosis (HR=1.95, 95% CI: 1.01-3.77, p=0.046).

CONCLUSIONS

BMDW is a novel predictor of DBF in this cohort of newly diagnosed lung cancer patients with multiple brain metastases. It may be considered as a metric for patient selection between SRS and alternative options, such as hippocampal-avoidance whole brain radiotherapy.
NIRL-06 IS THE PRESENCE OF NEOPLASTIC MENINGITIS ASSOCIATED WITH A WORSE PROGNOSIS IN REAL-WORLD PATIENTS WITH BREAST CANCER AND BRAIN METASTASES?
Authors: Cacho-Díaz Bernardo , Cabrera Paula , Arrieta Oscar
Published: August 2024

BACKGROUND

Central nervous system (CNS) metastases are a severe and frequent scenario in patients with breast cancer; CNS metastases can be divided into parenchymal metastases (brain metastases) or neoplastic meningitis (leptomeningeal disease). The occurrence of both in the same patient is a common picture but scantly reported.

OBJECTIVE

To measure the association of brain metastases with or without meningeal involvement in patients with breast cancer and brain metastases.

METHODS

A prospectively acquired database from patients with breast cancer and central nervous system metastases was retrospectively analyzed.

RESULTS

In 659 patients, 292 (44%) had brain metastases (BM), 169 (26%) had neoplastic meningitis (NM), and 198 (30%) had both (BM+NM). The median overall survival (MOS) in the whole cohort was 9.59 months (95%CI 8.0 – 11.2); in those with BM, the MOS was 12.2 months (95%CI 10 – 14.5); in the NM group, the MOS was 5.8 months (95%CI 4.3 – 7.2 months); and for those on the group with both BM and NM (BM+NM) the MOS was 10.3 months (95%CI 8.0 – 26.7), P <0.001. After statistical adjustment, the difference in survival between BM and BM+NM persisted.

CONCLUSION

The presence of meningeal involvement in patients with breast cancer and brain metastases is associated with a worse prognosis.
NIRL-12 UNDERSTANDING LESION RESPONSE ON MRI AFTER LASER INTERSTITIAL THERMAL THERAPY (LITT) IN METASTATIC BRAIN TUMOR PATIENTS
Authors: Robert Stephanie , Sirota Madison , Sotoudeh Mahdi Salimi , Kaur Manpreet , Merkaj Sara , Aboian Mariam , Chiang Veronica
Published: August 2024

Laser-interstitial thermal therapy (LITT) at the time of radiographic regrowth after stereotactic radiosurgery (SRS) of brain metastases allows lesions to be biopsied and treated simultaneously. While excellent post-LITT responses have been reported, indications for use remain unclear. This study describes the variability seen in post-LITT imaging changes, especially FLAIR, reflecting perilesional edema, and examines clinical and treatment variables that may affect post-LITT response. Using a novel 3D-segmentation tool created at our institution, we analyzed volumetric changes in both FLAIR and contrast-enhancing lesions before and for 12-months post-LITT across 23 patients. Over half (57%, 13/23) of patients demonstrated an initial increase in FLAIR volume at 2 weeks post-LITT and 43% demonstrated stable or decreased FLAIR. For those with an initial decrease, their percentage volume change from 0 to 0.5 months ranged from 21% to 67%, while those with an initial increase, percentage volume change varied from 2.6% to 254%. Of the 13 patients with an initial increase in FLAIR, 6 had FLAIR resolution over the subsequent 6-12 weeks. Four patients did not show FLAIR resolution until 12 months. Of the 10 patients with initial decrease, 6 had resolution of FLAIR signal abnormality by 3 months and 9 by 6 months. At 12 months, in those patients with an initial FLAIR increase, only 54% showed a decrease in enhancing lesion volume compared to 70% of patients with an initial decrease in FLAIR. No clinical or treatment factors were statistically associated with any pattern of lesional change although trends were seen with pre-LITT size and immunotherapy use. Survival was found to be associated with biopsy pathology. This study demonstrates FLAIR changes after LITT can be even more variable than for contrast enhancing lesion volumes. A larger study is needed to determine clinical and treatment factors that contribute to early favorable responses to LITT.
NVTG-05 LONGITUDINAL OBSERVATION OF THE TREATMENT RESPONSE TO INTRATHECAL CHEMOTHERAPY WITH PEMETREXED VIA CIRCULATING TUMOR DNA FROM CEREBROSPINAL FLUID OF NON-SMALL CELL LUNG CANCER LEPTOMENINGEAL METASTASES
Authors: Hong Weiping , Yang Yanying , Wang Hui , Liu Qiongyao , Zhen Junjie , Lai Mingyao , Cai Linbo
Published: August 2024

Approximately 5% of patients with advanced non-small cell lung cancer may develop leptomeningeal metastasis (LM). 1,2 Patients with LM may have a poor prognosis; the median overall survival (OS) of LM NSCLC patients was only 3.6 to 11 months2,3. Although targeting therapies, particularly tyrosine-kinase inhibitors (TKI), are effective against primary tumors, the blood-brain barrier may limit their intracranial performance, resulting in variable patient survival outcomes. 4 LM patients have been shown to benefit from a variety of treatments, including surgery, radiation, systematic chemotherapy, targeted chemotherapy, immunotherapy, and intrathecal injection, but there is still a lack of conventional treatment paradigms for LM patients’ care. In patients with NSCLC, intrathecal administration, which delivers medications directly into the subarachnoid space via cerebrospinal fluid (CSF), was reported to be highly effective in controlling LM. 5,6 However, evaluating the efficacy of treatment for LM remains difficult and lacks standardization. Due to the diffusion of LM lesions, it is challenging to quantify tumor size using imaging techniques. Karnofsky performance score (KPS) is a commonly used assessment tool for functional impairment of LM 7, but it cannot disclose the tumor change in a quantifiable manner. Response Assessment in Neuro-Oncology (RANO) is a generally accepted response criterion that evaluates treatment response by incorporating a novel radiographic scorecard, CSF cytology or flow cytology, and neurological examination, while it was limited on measuring lesions for response assessment. 8,9 Recent research has demonstrated that circulating tumor DNA released by tumor apoptosis can be used as a biomarker to track treatment responses and tumor evolution. 10 Ct-DNA from cerebrospinal fluid (CSF) has also demonstrated superior intracranial response prediction performance compared to plasma. 11 In this study, patients with leptomeningeal metastasis (LM) who had undergone multiple courses of therapy received intrathecal pemetrexed (IP). Then, we monitored the dynamic changes in CSF-ctDNA to assess their response.