bluuebunny/crossref_metadata_2025 huggingface dataset:
BSLM-04 INTRATHECAL DELIVERY OF PEPTIDE-PULSED TYPE 1 CONVENTIONAL DENDRITIC CELL VACCINE IS HIGHLY EFFICACIOUS FOR THE TREATMENT OF BREAST CANCER-ASSOCIATED LEPTOMENINGEAL DISEASE IN PRECLINICAL MODELS
Authors: Law Vincent , Snyder Colin , Chen Zhihua , Kalinski Pawel , Czerniecki Brian , Forsyth Peter
Published: August 2024

BACKGROUND

Approximately 5% of advanced stage breast cancer (BC) will develop leptomeningeal disease (LMD), a rare form of metastasis in the meninges. The prognosis for LMD is dismal and current treatments are ineffective. Here, we found intrathecal (IT) delivery of MHC class II peptide-pulsed conventional Type 1 dendritic cells (cDC1s) could cure mice harbouring either HER2+ or triple negative breast cancer (TBNC) LMD. The data from our preclinical studies led to a Phase 1 clinical trial of cDC1s in HER2+ and TNBC LMD (NCT05809752; in progress).

METHODS

We created a “murine Ommaya” that mimics the clinically used Ommaya reservoir and allows for repeated IT injections of novel drugs at 3 – 7ml volume directly into the cerebral spinal fluid (CSF). A pipeline was developed for screening immunogenic MHC class II peptides from tumor-associated oncodrivers and using these targets we generated tumor-targeting cDC1 vaccine. We tested the efficacy of this therapy in murine BC-LMD by administering through the murine Ommaya.

RESULTS

We found cDC1 vaccine was highly effective against HER2+ LMD and TNBC-LMD; LMD mice that received IT cDC1s had reduced tumour burden and prolonged survival. Complete responses to treatment ranged between 30 - 70% in HER2+ LMD and TNBC-LMD and were CD4+ T cell and B cell dependent. Notably, some cured mice were protected against LMD reinoculation. Subsequent single cell RNA-sequencing analyses of pre- and post-treatment CSF revealed an adaptive change in the immune cellular landscape. We noted an elevation of Th1 proinflammatory cytokines such as IFN-g in the CSF. This was recapitulated in the CSF samples of patients enrolled in an on-going phase 1 trial, where early data showed IT cDC1 vaccine triggered a dramatic increase in the concentration of several proinflammatory Th1 cytokines.

CONCLUSIONS

IT cDC1 vaccine is effective against BC-LMD and prevents LMD recurrence. A future approach includes testing IT cDC1 platform in LMD from other cancers (e.g. melanoma etc.).
BSLM-10 MOLECULAR AND HISTOLOGICAL CHARACTERIZATION OF NSCLC PROGRESSION TO LEPTOMENINGEAL METASTASIS WITH COMORBID INTRAPARENCHYMAL DISEASE
Authors: Kandigian Savannah E , Chande Sampada , Dolezal Darin , Tang Tang , Wang Dejiang , Arnal-Estapé Anna , Cheok Stephanie K , McGuone Declan , Liu Yang , Goldberg Sarah B , Blondin Nicholas A , Chiang Veronica L , Nguyen Don X
Published: August 2024

Leptomeningeal disease (LMD) is a rare form of central nervous system (CNS) metastasis wherein tumor cells invade the cerebrospinal fluid (CSF) filled space that surrounds the brain and spinal cord. For patients with LMD, prognosis is extremely poor even with aggressive treatment. The mechanisms of progression to LMD and the adaptations tumor cells make to survive in this metabolically sparse microenvironment are poorly understood. As 60% of patients with LMD have concurrent or prior parenchymal metastases, our laboratory examined our established murine models of parenchymal metastases for signs of leptomeningeal infiltration. We identify two xenograft non-small cell lung cancer (NSCLC) models of intraparenchymal metastasis following intra-arterial injection that show progression to LMD in a subset of cases. In the H2030-BrM3 model, this occurs de novo, whereas the EGFR-mutant PC9-R2 model progresses to LMD only following onset of resistance to tyrosine kinase inhibitor treatment. Subsequent in vivo passaging of the H2030-BrM3 line through the cerebral lateral ventricles resulted in the H2030-LMD2 cell line, which has high affinity for leptomeningeal metastases and shows extensive perivascular invasion within the brain parenchyma. In vitro, the H2030-LMD2 line shows altered clustering behavior and increased survival when cultured in suspension. RNA-sequencing of this cell line across adherent and suspension culture conditions shows multiple biological processes upregulated in the LMD-tropic line, including chemotaxis, apical junction formation, and TGF-β signaling. Targetable pathways emerging from this analysis will be functionally investigated for their role in promoting progression to LMD, including through validation in the syngeneic KPN1-BrM line which has been selected for its CNS affinity and shows progression to LMD. Spatial sequencing and multiplexed immunofluorescence will furthermore investigate the tumor microenvironment in the perivascular niche and subarachnoid spaces. These findings will be clinically corroborated with molecular characterization of the CSF of patients with leptomeningeal metastases.
BSLM-11 ESTABLISHING AND VALIDATING IN VIVO MODELS FOR LEPTOMENINGEAL METASTASES IN BREAST CANCER: INSIGHTS AND THERAPEUTIC IMPLICATIONS
Authors: Kumar Dinesh , Silvestri Vanesa , Robinson Christina , Difilippantonio Simone , Steeg Patricia
Published: August 2024

Leptomeningeal metastases (LM), characterized by cancer cell growth in the linings of the brain and spinal cord, and the cerebrospinal fluid (CSF) compartment, have a dire prognosis represent 5-15% of central nervous system metastases. LM occur in all subclasses of breast cancer and are currently treated with intrathecal methotrexate or liposomal cytarabine or radiation therapy. Despite initial response to current treatments, median survival remains poor. Relatively little is known on the development of LM, due to the lack of adequate mouse models. This study aimed to develop and validate in vivo models of LM and to use them to credential potential therapies. Three breast cancer models were established using intracisternal injections of tumor cells covering the HER2+, ER+ lobular and triple negative breast cancer subtypes. The HER2+ model was produced from the JIMT-1-BR cell line that previously was enriched for metastasis to the brain parenchyma, reflecting clinical observations of concurrent parenchymal and LM spread. Multiple endpoints were implemented to assess disease progression: bioluminescence imaging, histopathology, MRI, tumor cells in CSF. Bulk RNA sequencing on all LM-tropic cell lines revealed significant alterations in cytokine-cytokine receptor interactions, calcium signaling pathways, cell adhesion molecules, and TNF signaling pathways across all models. Notably, several genes including PORCN, PGBD5, FAM43A and FHOD3 were differentially expressed and consistently alter across all models. Validation of these key genes is underway. For the JIMT-1-BR HER2+ model, efficacy studies compared standard therapy (trastuzumab + paclitaxel) with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd). T-DXd (10 mg/kg, iv q3w) demonstrated superior efficacy with extended survival and reduced extent of edema on MRI. This study established and validated three in vivo models of LM colonization. These models, incorporating diverse endpoints, and drug testing capabilities, offer a valuable platform for identifying novel therapeutic strategies to combat this aggressive form of breast cancer progression.
BMRK-04 EFFECT OF PRIMARY CANCER SITE AND EXTRACRANIAL PROGRESSION ON DEVELOPMENT OF BRAIN METASTASES IN PATIENTS TREATED WITH STEREOTACTIC BODY RADIOTHERAPY FOR OLIGOMETASTATIC SOLID TUMORS
Authors: Fan Kevin Yijun , Jerzak Katarzyna , Kumar Sudhir , Moravan Veronika , Said Badr Id , Das Sunit , Louie Alexander , Soliman Hany , Sahgal Arjun , Chen Hanbo
Published: August 2024

BACKGROUND

Patients with oligometastatic disease (OMD) may achieve long-term control with stereotactic body radiation therapy (SBRT). However, those who develop brain metastases (BrM) often have poor outcomes. We aimed to investigate variables associated with development of BrM in this population.

METHODS

Patients with ≤5 extracranial metastases from solid tumors treated with SBRT from 2008-2016 at Sunnybrook Odette Cancer Centre were included. We investigated the association between covariates and CIBrM (cumulative incidence of BrM) using Fine-Gray analysis with death as a competing risk, and progression-free survival (PFS) and overall survival (OS) using Cox regression. We investigated the association between widespread extracranial progression (≥5 sites) and CIBrM using a time-based conditional competing-risks analysis.

RESULTS

Among 404 patients, the most common primary sites were lung (32%), colorectal (26%), prostate (13%), breast (10%) and kidney (7%). Median follow-up was 49 months. Median PFS was 25 months and median OS was 70 months. 58 patients developed BrM, and 5-year CIBrM was 16%. The 5-year CIBrM was highest among patients with breast cancer (22%), lung cancer (15%) and kidney cancer (15%), and lowest among those with colorectal cancer (5%) and prostate cancer (0%). On multivariable analysis, primary site was associated with CIBrM (p<0.001), with colorectal cancer (HR 0.34) and prostate cancer (HR 0.00) associated with lower CIBrM compared to lung cancer. Time from primary diagnosis to OMD, number of extracranial metastases, location of metastases, and total planning target volume (PTV) were not associated with CIBrM. Development of widespread extracranial progression within 24 (HR 4.1, p=0.004), 36 (HR 3.7, p=0.013), 48 (HR 5.9 p=0.009) and 60 (HR 23, p=0.017) months of OMD diagnosis was independently associated with higher CIBrM.

CONCLUSIONS

Primary site and extracranial progression, but not baseline measures of OMD volume and distribution, are associated with development of BrM in patients with OMD treated with SBRT.
DSAI-01 TUMOR EVOLUTION OF BRAIN-SPECIFIC TROPISM IN METASTATIC RENAL CELL CARCINOMA
Authors: Elias Roy , Kamson David , Feinaj Ardit , Pallavajjala Aparna , Yerrapragada Anirudh , Dreschner Max , Patel Sunil , Fertig Elana , Markowski Mark , Yegnasubramanian Srinivasan , Matoso Andres , Baraban Ezra , Bettegowda Chetan , Ged Yasser , Singla Nirmish
Published: August 2024

BACKGROUND

Herein, we describe the molecular landscape of renal cell carcinoma (RCC) brain metastases (BrMs).

METHODS

Panel-based DNA (DNAseq) and whole-transcriptome sequencing (RNAseq) were used to assess BrM, non-BrM and matched primary renal tumors (PRT) from RCC patients who underwent resection.

RESULTS

95samples (BrM=54, nBrM=14, PRT=27) from 53patients were included (85% clear-cell histology). DNAseq of 85 samples (50pts) identified common mutations in VHL (18pts, 36%), TP53 (24%), PBRM1 (24%), SETD2 (24%), and BAP1 (8%). MTOR-pathway mutations were enriched, with 25pts (50%) having at least one mutation in PTEN (12pts, 24%), TSC1 (8%), TSC2 (10%), or MTOR (18%). Copy number analyses revealed frequent deletions in chr14q21(34pts, 68%) and chr9p21 (70%) and gains in chr20q13 (62%) and chr7p15 (62%). At the sample-level, PTEN mutations were more common in BrM (11pts, 22.9%) versus non-BrM (0) and PRT (12%, p=0.124), as were deletions in chr13q22 (BrM=26.5% [13pts], non-BrM=8.3%, PRT=4%; p=0.036) and gains in chr20q13 (BrM=61.2% [30pts], non-BrM=33.3%, PRT=32%; p=0.03). Chr9p21 deletions were enriched in BrM (32pts, 65.3%) and non-BrM (66.7%) relative to PRTs (28%, p=0.006). Other copy number alterations and somatic mutations had similar distribution across sites. Analysis of 86 samples (51pts) identified 806 genes expressed differentially between BrM and PRT (adjusted p<0.05), 399 between BrM and non-BrM (adj. p<0.05). Gene set enrichment analysis of MSigDB Hallmark gene sets revealed upregulation of MTORC1 signaling, glycolysis, and MYC targets in BrM comparted to PRT and non-BrM (adj. p<0.0001). Immune-related gene sets, e.g. interferon-alpha, interferon-gamma, TNF-alpha, were enriched in PRT relative to BrM (adj. p<0.0001), but not non-BrM (adj. p > 0.05). CIBERSORT cellular deconvolution analysis comparing BrM with PRT revealed increased proportions of M2 (p=0.0009), but decreased M1 macrophages (p=0.0003) and CD8+T-cells (p=0.0106).

CONCLUSIONS

RCC with BrM exhibit distinct MTOR-pathway enrichment and hyperactivation. The immunosuppressive milieu in BrM may be steroid-related. Further analyses are underway.
DSAI-04 AI-DRIVEN MR IMAGE FEATURES VERSUS RANO-BM CRITERIA IN DISTINGUISHING RECURRENT BRAIN METASTASES FROM RADIATION TREATMENT EFFECT: A COMPARATIVE, MULTI-INSTITUTIONAL STUDY
Authors: Um Hyemin , Ismail Marwa , Hill Virginia , Puri Sushant , Yu Jennifer , Lu Lan , Nayate Ameya , Rogers Lisa , Prasanna Prateek , Bardhan Mainak , Li Chengnan , Basree Mustafa , Baschnagel Andrew , McMillan Alan , Bhatia Ankush , Ahluwalia Manmeet , Veronesi Michael , Tiwari Pallavi
Published: August 2024

A significant challenge in brain metastases (BM) management is distinguishing radiation-induced treatment effect (TE) from tumor recurrence (TR). TE mimics the appearance of TR on follow-up MRI, making radiographic diagnosis unreliable. The standardized Response Assessment in Neuro-Oncology for brain metastases (RANO-BM) is suboptimal due to high inter-reader variability. We compared the performance of artificial intelligence (AI)-driven MRI features with that of RANO-BM criteria in differentiating TE from TR. We hypothesize AI-features from routine MRI can capture the pathophysiologic differences between TE and TR, occult on structural MRI and hence overlooked in standard-of-care evaluation. A total of 261 lesions with pathologically-confirmed diagnoses in 189 patients were retrospectively analyzed. 201 lesions (111 TR,90 TE) from Cleveland Clinic and University Hospitals, Cleveland were used for training a machine learning model. 60 lesions (33 TR,27 TE) from University of Wisconsin–Madison were used for model testing. MRI (Gd-T1w, T2w, FLAIR) were preprocessed, and lesions were expertly segmented into enhancing lesion, edema, and necrosis. 856 texture features were extracted from each sub-compartment, and a random forest classifier was employed for 3-fold cross-validation. Top-performing features and RANO-BM criteria were evaluated on the test set. Results show T1 features from edema were most discriminatory in differentiating TR from TE (training-AUC=0.86, test-accuracy=71.7%, test-sensitivity=78.8%). Using RANO-BM, 9 cases were excluded due to lack of longitudinal imaging to estimate lesion growth. Additionally, since no lesions decreased in sum of longest diameter, none were classified as partial response while the remaining 51 cases were classified as stable disease (n=14, (8 TR,6 TE)) or TR (n=37, accuracy=54.1%). Interestingly, 78.6% of the stable lesions were accurately classified using our AI-model as TE or TR, missing only 3 cases (2 TR,1 TE). Our results suggest AI-driven models on clinical MRI scans may reliably distinguish TR from TE, demonstrating potential utility in clinical practice.
DSAI-05 THE BRAIN TUMOR SEGMENTATION (BRATS-METS) CHALLENGE 2023: BRAIN METASTASIS SEGMENTATION ON PRE-TREATMENT MRI
Authors: Tahon Nourel hoda , Ashraf Nader , Moawad Ahmed , Janas Anastasia , Baid Ujjwal , Saluja Rachit , Velichko Yuri , Ramakrishnan Divya , Krantchev Kiril , Rudie Jeffrey , Bakas Spyridon , Aboian Mariam
Published: August 2024

PURPOSE

Clinical monitoring of metastatic disease to the brain using magnetic resonance imaging (MRI) can be laborious and time-consuming, particularly when multiple small metastases are involved and assessments are performed manually.

METHODS AND MATERIALS

The BraTS-METS 2023 dataset is acquired from varying MRI imaging quality across different vendors. The scans are pre-processed using different algorithms refined by a pool of annotators with different expertise. Two independent board-certified neuroradiologists finally reviewed the dataset. The datasets are divided into Training, validation, and testing. ASNR-MICCAI BraTS-METS 2023 challenge was evaluated based on Dice scores and Hausdorff distance for each lesion, including the whole tumor, enhancing tumor, and tumor core.

RESULTS

We received > 2500 multi-parametric MRIs from 12 different institutions, which underwent preprocessing to wipe out all PHI, reorient, and be consistent with all BraTS space and header. Initial raw data were pre-segmented with three different algorithms and fused together to get a consensus pre-segmentation file. A pool of 150 annotators (with different experience and training levels in radiology) and 50 board-certified attendees were recruited through ASNR mass calls for volunteer announcements, Segmentation workshops, and the ASNR annual meeting campaign. Studies are first assigned to annotators, reviewed by 1-2 board-certified neuroradiologists, and then reviewed by a single senior neuroradiologist for consistency and quality control final check. Finalized segmentation files underwent quantitative QC check to ensure harmonized imaging parameters, headers, and masks. Training and Validation datasets are made available to the public through the BraTS-METS 2023 website. The whole project is part of the TCIA/NCI moonshot program.

CONCLUSION

: The MICCAI-ASNR BraTS-METS Challenge is an important initiative for developing accurate segmentation algorithms to detect small brain metastasis. It includes multi-institutional and international datasets in order to develop a general model applied to all patients with brain metastasis.
DSAI-07 DATA-DRIVEN MODELING OF EMERGING TRENDS AND COLLABORATIVE NETWORKS ACROSS BRAIN METASTASES RESEARCH: THE PAST DECADE OF INNOVATION
Authors: Durrani Sulaman , Cote Ian , Carpintieri Sabrina , Martinez Joseph , Metzler Ashley , Graciolli Joacir , Shah Ashish , Oermann Eric , Komotar Ricardo , Ivan Michael , Benjamin Carolina , Sheehan Jason , Kondziolka Douglas , Tecle Najib El
Published: August 2024

With recent significant growth in brain metastases literature output, more comprehensive research is necessary to understand emerging trends and novel methods of diagnosis and treatment. We aimed to address this by providing a contemporary systematic global analysis of emerging brain metastases research in the last decade while visually depicting the international collaborative environment among its researchers. Data mining was performed on all brain metastases publications across the last decade indexed in Elsevier’s Scopus database. Our Scopus search revealed 6,362 publications from 1,184 sources from 2013-2022. Of those, 252 were identified as high-impact articles with an annual citation rate (CR) > 10. The compounded annual growth rate (CAGR) of brain metastases publications was 7.2% per year since 2013. There was an acceleration of scientific production, from 5.9% CAGR across 2013-2018 to 9.6% across 2019-2022. Authors per document increased from 7.2% to 8.5% while international co-authorships increased from 16.6% to 18.3% in the same periods, respectively. Recent trending topics were noted to be artificial intelligence, understanding the brain microenvironment, exosomes, novel mechanisms of diagnosis (such as circulating tumor cells), and targeted treatments. High-impact articles tended to revolve around specific therapies or biomarkers as opposed to general synopses. Clustering analysis revealed three separate pivotal collaborative communities centered around Brown PD/Sahgal A, Ahluwalia MS, and Wang Y, with Brown PD as most notable for high impact research. While the top institutional collaborative group centered around Mayo Clinic, the highest impact research centered around the Dana-Farber Cancer Institute. Sub-analyses revealed that studies involving multiple countries tended to have a higher impact. The median overall survival of brain metastases, by primary source, was illustrated across the last five decades. Overall, significant growth in scientific production is driven by the integration of novel technologies (such as artificial intelligence), interdisciplinary approaches, and collaboration across global communities.
IMUN-08 DURABLE RESPONSE TO IPILIMUMAB-NIVOLUMAB (IPI-NIVO) IN ANTI-PD1 REFRACTORY MERKEL CELL CARCINOMA WITH LEPTOMENINGEAL DISEASE PROGRESSION
Authors: Kennedy Lucy Boyce , Diaz Claudia Marcela , Cordova Christine , Dhawan Andrew , Balagamwala Ehsan , Koyfman Shlomo , You Jee Young , Chao Samuel , Suh John , Angelov Lilyana , Isaacs James , Ko Jennifer , Chan Timothy , Truong Thach-Giao
Published: August 2024

Leptomeningeal disease (LMD) is a rare complication of Merkel cell carcinoma (MCC), which has been described in limited case reports, none of which describe outcomes with IPI-NIVO. Here we describe a patient with PD-1 refractory MCC LMD with durable response to IPI-NIVO. A 69-year-old male diagnosed with stage IIIA MCC underwent left groin dissection and radiation. He developed recurrence in distant lymph nodes and started pembrolizumab (PEMBRO). Seven months after starting PEMBRO, he developed lower extremity weakness. Spine MRI showed LMD involving cauda equina. CSF testing detected tumor cells. Imaging did not show any recurrence aside from LMD. He received radiation to L1-S2 followed by IPI-NIVO. His LMD has remained clinically and radiographically stable 10 months after starting IPI-NIVO. Longitudinal circulating tumor DNA (ctDNA) monitoring demonstrated clearance both after starting PEMBRO and IPI-NIVO. ctDNA was detectable 5 weeks after starting PEMBRO and 5 months after starting IPI-NIVO and became undetectable 10 weeks after starting PEMBRO and again 8 months after starting IPI-NIVO. We prospectively collected peripheral blood at baseline prior to PEMBRO, when LMD developed, with cycle 3 IPI-NIVO, when he developed pneumonitis 4 months from cycle 1, and following CNS and systemic tumor clearance at 7 months from cycle 1 of IPI-NIVO with patient on maintenance NIVO alone. Peripheral flow cytometry, quantitative proteomics, and serum cytokines were used to characterize immune cell numbers and phenotypes in this exceptional responder. Kinetics of immune correlates, including CD33+HLADRlo, CD15+CD14-MDSC, CD57+ CD8+ T cells, showed distinctive changes during the clinical course. This case demonstrates unique response to IPI-NIVO with durable neurologic stability and confirmatory ctDNA clearance in a patient with PD-1 refractory MCC and less common CNS progression with documented LMD. Although the prognosis of MCC LMD is poor, this patient achieved an objective CNS response, and we reversed PD-1 resistance with IPI-NIVO.
MMOD-04 LASER INTERSTITIAL THERMAL THERAPY (LITT) AND IMMUNOTHERAPY SYNERGY FOR RECURRENT BRAIN CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Sharma Eshita , Sahin Oguz Kagan , Łajczak Paweł , Ahmed Aisha Rizwan , Silva Yasmin Picanço , Ayesha Ayesha , Chatterjee Anoushka , Raake Mohammed , Petry Iago Nathan Simon
Published: August 2024

BACKGROUND

The confluence of laser interstitial thermal therapy (LITT) with immunotherapeutic approaches represents a promising avenue for the management of recurrent brain metastases and glioblastoma. However, the potential synergy between these modalities prompts a thorough examination of their adverse effects. This meta-analysis seeks to evaluate the literature to elucidate the adverse effects associated with the combined use of LITT and immunotherapy in treating recurrent gliomas.

METHODS

Thorough systematic searches were performed on PubMed, Embase, and Web of Science databases using predefined search terms to identify pertinent studies. Inclusion criteria comprised case-control studies, cohort studies, and randomized controlled trials investigating the combined utilization of laser interstitial thermal therapy (LITT) with immunotherapy, among adult patients diagnosed with recurrent brain metastases and recurrent glioblastoma. Our analysis specifically targeted adverse events (AEs) as the primary outcome of interest.

RESULTS

Our systematic review included four studies, including one randomized controlled trial (RCT), one case-control study, and two prospective cohort studies, with a total of 162 patients. Utilizing a random effects model in STATA, we performed a single-arm analysis of adverse events experienced by 56 patients across 3 studies and reported the combination of LITT with immunotherapy for managing recurrent gliomas demonstrated no significant proportion of adverse effects (Proportion= 0.11, 95% CI= -0.02-0.25, P=0.09).

CONCLUSION

When evaluating adverse effects, the combined approach of LITT with immunotherapy in managing recurrent brain metastases and glioblastoma showed no notable significant percentage of patients incurring adverse events, thereby implying a potential comparable safety profile to conventional treatment modalities. However, further research is warranted to test differences in the incidence of adverse events from LITT with immunotherapy versus a control.
MMOD-05 THE IMPACT OF EGFR VARIANTS ON INTRACRANIAL PROGRESSION FREE SURVIVAL AND OVERALL SURVIVAL IN NSCLC PATIENTS WITH BRAIN METASTASES UNDERGOING STEREOTACTIC RADIOSURGERY
Authors: Burner Danielle , Leng Jim , Carpenter David , Chen Mark , Vaios Eugene , Alder Laura , Clarke Jeffrey , Green Michelle , Kelsey Christopher , Floyd Scott , Kirkpatrick John , Reitman Zachary , Mullikin Trey
Published: August 2024

Outcomes for patients with brain metastases (BM) from targetable epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) have been improved with tyrosine kinase inhibitors (TKIs). However, outcomes following stereotactic radiosurgery (SRS) for NSCLC BM patients with other pathogenic EGFR mutations and variants remain uncertain. We sought to characterize outcomes for NSCLC BM patients with pathogenic variants (PV) or variants of uncertain significance (VUS) in EGFR following SRS. We retrospectively identified 600 NSCLC BM patients who underwent an initial course of SRS during 2015- 2020. Demographic, clinical, genomic, and treatment characteristics were recorded. Intracranial progression-free survival (ICP-FS) and overall survival (OS) were estimated via the Kaplan Meier method. Median follow up was 9.6 months. 155 (25.8%) patients had actionable mutations, including in EGFR (112). Of those with EGFR mutations, next-generation sequencing (NGS) data was available for 65 patients. In patients with targetable EGFR mutations, 39 received pre-SRS and 69 received post-SRS treatment with a TKI, typically with a 1st/2nd generation TKI. Most patients (n=12/13) with EGFR VUS received (chemo)immunotherapy. OS was significantly better for patients with any EGFR mutation/variant compared to patients without a detected variant (median 21.1 mos vs 8.1 mos, p<0.0001), however, there was no difference in ICP-FS. Patients with EGFR VUS had improved OS and ICP-FS compared to EGFR PVs (median 56.3 mos vs 19 mos, p=0.022) and (median 53.1 mos vs 7.7 mos, p=0.041), respectively. While patients with EGFR mutation/variants demonstrated improvement in OS, ICP-FS was likely limited by use of early generation TKIs with SRS. Notably, there was compelling improvement in OS and ICP-FS associated with EGFR VUS, which is hypothesis generating and requires a larger cohort for further examination.
MMOD-11 RADIATION NECROSIS AFTER CONCOMITANT EGFR-TKI AND RADIATION: A CASE SERIES AND CONSIDERATION FOR FUTURE PATIENTS
Authors: Fritz Kelly , Malani Rachna
Published: August 2024

Optimal timing of radiation therapy (RT) for brain metastases (BM) and leptomeningeal disease (LMD) from novel targeted systemic therapy is largely unknown, as well as the long-term adverse effects of combination therapy. We describe the clinical course of two patients who developed radiation necrosis (RN) after RT and treatment with EGFR-TKIs. The first patient is a 79-year-old woman with EGFR L858R-mutated metastatic non-small cell lung cancer (NSCLC) who developed progressive BM after being on osimertinib therapy for 3 years. She received stereotactic radiosurgery (SRS) to 5 lesions. Osimertinib was held for 3 days surrounding SRS, and resumed at 80 mg/day. Four months post SRS, the patient developed progressive neurologic symptoms with neuroimaging consistent with RN. She was initiated on dexamethasone however after a 6 week taper, she experienced neurologic decline with repeat neuro-imaging demonstrating worsening RN. She started on therapy with bevacizumab with minimal clinical and radiographic benefit. The second a patient is a 63-year-old man with EGFR L858R-mutated NSCLC with BM. He received concurrent RT and osimertinib at diagnosis and continued osimertinib 80 mg/day for 2 years. Upon progression with LMD he was started on alectinib and received proton craniospinal irradiation. Seven months later he had neurologic decline with neuro-imaging most consistent with RN. He initiated bevacizumab and had clinical and radiographic improvement. The approval and use of novel targeted agents has outpaced the available data surrounding long term risks of combining these therapies with radiation, especially in those patients with BM and LMD. These cases illustrate the challenges of treating patients in the modern era and the need for a multimodal team approach to determine the risk and benefit of combination therapy. Addition of a clinical pharmacist to the decision can help provide expertise in the individual drug pharmacokinetics and dynamics for these complex cases.
MMOD-17 INTEGRATION OF MULTIMODAL ADVANCED MOLECULAR TESTING TO CLASSIFY METASTASES OF UNKNOWN PRIMARIES – A CASE OF A PATIENT WITH NO KNOWN MEDICAL HISTORY
Authors: Primdahl Ditte , Smith Heather , Jean Jeffrey , Duckett Drew , Vormittag-Nocito Erica , Nezami Behtash G , Jennings Lawrence J , Santana-Santos Lucas , Ahrendsen Jared , Castellani Rudolph J , Sukhanova Madina , Jamshidi Pouya
Published: August 2024

Metastases are the most common diagnosed brain tumors in adults. In up to 15% of brain metastases, the source of primary malignancy remains unknown despite a thorough workup. Here, we present a case of a 25-year-old male who presented with intracranial hemorrhage and a mass in the left occipital lobe. At the time, his past medical history was unknown to all care providers. He underwent emergent craniotomy for resection of the tumor. Multimodal advanced molecular diagnostic testing, including next-generation sequencing (NGS), chromosomal copy number analysis, and DNA methylation profiling using Northwestern Memorial Hospital’s Cancer of Unknown Primary (CUP) classifier were performed to classify the neoplasm and identify the primary source for his metastatic tumor. Histopathologic sections showed brain parenchyma with acute hemorrhage intermixed with small fragments of a primitive neoplasm. The immuno-profile of the tumor was suggestive of germ cell differentiation. The tumor harbored multiple molecular and cytogenetic alterations including amplification of CCND2 and 12p, gain of chromosomes X,1q, 7 and 8 and loss of chromosomes Y, 1p, 16 and 22. DNA methylation profiling did not match (i.e. score >0.9) with any tumor entity on the CUP classifier, however the tumor clustered closest to non-seminomatous testicular germ cell tumors on the t-distributed stochastic neighbor embedding (t-SNE) plot. This case highlights the value of utilizing multimodality advanced molecular testing when facing a diagnostically challenging case. While none of the molecular tests performed was independently diagnostically conclusive, in concert, they pointed to a definitive diagnosis. Upon diagnosis, imaging revealed a surgically absent left testicle and multiple lung metastases. Patient confirmed diagnosis of a testicular cancer few years prior to his current presentation. He is undergoing
NIRL-03 REGRESSION ANALYSIS OF NON-CATEGORICAL IMAGING PARAMETERS IN PATIENTS WITH BRAIN METASTASES
Authors: Paruchuri Venkata , Patel Dhaval , Hafeez-Baig M Ahmed
Published: August 2024

BACKGROUND

Estimating survival of patients who have brain metastases (BM) based on risk factors and properties of the metastasis would be useful in clinical practice. Imaging data routinely provides significant variables such as volumes of the tumor, surrounding necrosis, and associated edema. These values could be used to create models that could predict patient survival. Our work applied regression analysis to see how imaging parameters correlated to survival in BM patients.

METHODS

The open-access dataset Pretreat-MetsToBrain-Masks1,2 from the Yale Department of Radiology and Biomedical Imaging featuring 200 BM patients was accessed through the Cancer Imaging Archive. We utilized the Analysis TookPak in Microsoft Excel to perform regression analysis of all non-categorical variables with respect to survival. We performed multivariate regression between survival, edema volume, and necrosis volume. Patients with missing data were omitted from the regression analysis.

RESULTS

There is low correlation between survival and the individual parameters of necrosis ratio (R = 0.12), edema ratio (R = 0.06), necrosis volume (R = 0.02), edema volume (R = 0.06), enhancing tumor (ET) volume (R = 0.18), number of edema lesions (R = 0.10), number of necrotic lesions (R = 0.07), or number of ET lesions (R = 0.05). However, the relationship between enhancing tumor volume and survival does show significance (p = 0.01). The multivariate regression between survival, edema volume, and necrosis volume showed low correlation (0.05) and no statistical significance.

CONCLUSION

There is a significant need to estimate survival in BM patients. However, based on our analysis, we did not find utility in the assessed imaging parameters to estimate survival via a linear model. Still, ET volume was shown to have a significant relationship with survival, and a different model needs to be used to evaluate that relationship.
NIRL-07 DIAGNOSTIC AMBIGUITIES IN MRI CHANGES IN A PATIENT WITH BRAIN METASTASES AND RECURRENT STROKES
Authors: Prakash Neal , Chen Bihong , Fricke Jeremy , Babikian Razmig , Salgia Ravi
Published: August 2024

Brain magnetic resonance imaging (MRI) sequences, particularly gadolinium enhanced T1 images, diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) are used frequently in clinical practice. These modalities can help distinguish ischemia from brain metastasis, leptomeningeal disease, hypoxic injuries, and other brain lesions. We present a case of a patient with metastatic lung cancer to the brain with progressive hemiplegia, tumor progression, recurrent strokes, hypoxic brain injury and leptomeningeal disease. Sequential MRIs showed chronic DWI hyperintensity that corresponded to metastatic tumor, with superimposed acute DWI hyperintensities at different time intervals that corresponded to either ischemic events, hypoxic events, and/or tumor progression. We highlight the strengths and limitations of current MRI imaging modalities, particularly DWI, in distinguishing tumor progression from acute ischemic events in a patient with metastatic brain cancer. The correct diagnosis is crucial in guiding treatment strategies as the clinical course progresses, particularly in regard to selecting more aggressive anti-thrombotics versus changing cancer treatment, and defining goals of care.
NVTG-04 REAL-WORLD OUTCOMES WITH SACITUZUMAB GOVITECAN AMONG BREAST CANCER PATIENTS WITH CENTRAL NERVOUS SYSTEM (CNS) METASTASES
Authors: GRINDA Thomas , Morganti Stefania , Hsu Liangge , Kusmick Ross J , Aizer Ayal A , Giordano Antonio , Leone Jose P , Hughes Melissa , Tolaney Sara M , Lin Nancy U , Sammons Sarah L
Published: August 2024

Sacituzumab-govitecan (SG) demonstrated significant survival benefits over standard chemotherapy in pretreated triple-negative (TNBC) and hormone receptor-positive (HR+/HER2-) metastatic breast cancer (MBC) patients. Limited data on intracranial outcomes in MBC patients exist. We describe the real-world (RW) of intracranial efficacy and outcomes for SG in MBC patients with central nervous system metastases (CNS-mets).

METHOD

We retrospectively studied MBC patients with CNS-mets who began SG between 2018 and 2022, using an institutional MBC database. CNS involvement was subcategorized as active CNS-mets (new or progressive not yet treated with CNS-directed therapy) and leptomeningeal disease (LMD). An independent radiologist confirmed CNS response rates (rwCNS-RR) using RANO criteria. The Kaplan-Meier method estimated RW-CNS, bi-compartmental progression-free, and overall survival (rwCNS-PFS, rwBi-PFS, and OS).

RESULTS

33 women were included: 10 HR+/HER2- and 23 TNBC. 13/33 (39%) had active CNS-mets and 8/33 (24%) had LMD (2 HR+/HER2- and 6 TNBC). the median time from MBC diagnosis to SG initiation was 1.79 years (q1q3, 1.02-3.79), a median of 3 (q1q3, 2-6) prior lines received for MBC and 28/33 (84.8%) received prior brain radiotherapy. rwCNS-RR was 4/30 (13%; 1/9 HR+/HER2-; 3/21 TNBC). After a median follow-up of 20.70wks (95%CI 3.28-127.41) from SG initiation, median rwCNS-PFS, rwBi-PFS, and OS were 12.7 wks (95%CI 8.6–18.6), 11.3 wks (95%CI 8.3–17.6) and 29.1 wks (95%CI 13.6-43.3), respectively. Among patients with active CNS-mets, rwCNS-RR was 1/13 (8%). Among patients with LMD, rwCNS-RR was 1/7 (14.3%), and median OS was 15.8 wks (IC95% 7.4-47.6). The site of progression on SG was 1/33 (3%) CNS-only, 10/33 (30%) non-CNS only, 17/33 (52%) both, and 5/33 (15%) unknown because deceased.

CONCLUSION

In this RW analysis, SG was associated with modest clinical activity and intracranial response rates in heavily pretreated MBC patients with CNS metastases. Effective treatments demonstrated in prospective studies are needed for this patient.
NVTG-10 CLINICAL AND RADIOLOGICAL OUTCOMES OF ORBITAL METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY: A SINGLE INSTITUTION RETROSPECTIVE SERIES
Authors: Zamarud Aroosa , Hori Yusuke S , Kattaa Ahed H , Persad Amit R , Tayag Armine , Usttrzinsky Louisa , Emrich Sara Coleman , Soltys Scott G , Hancock Steven L , Park David J , Chang Steven D
Published: August 2024

INTRODUCTION

Orbital metastases (OM) are a rare complication of cancer that can result in visual impairment. Treatment options include surgery and radiotherapy, however, the optimal treatment for OM is unclear. The current evidence for stereotactic radiosurgery (SRS) is limited. We aim to report the efficacy and safety of SRS in patients with OM.

METHODS

The clinical and radiological outcomes of patients with OM treated with SRS between April 2006 and November 2023 were retrospectively reviewed. SRS was utilized to treat all the tumors. The post-treatment tumors were radiologically categorized to stable disease (SD), partial response (PS), and complete response per RECIST criteria.

RESULTS

We included 15 patients with 17 OM lesions in our study; 9 (60%) of whom were females, and their median age was 62 years (range: 21-82 years). The median overall survival was 6.5 months (range: 2-62 months). All these patients were treated with standalone CK SRS. The most common fractionation schedules were 24 Gy in 3 fractions (n=4). The median diameter of the lesions was 21 mm (range: 11-72 mm). The median volume treated was 2.6 cm3 (range: 0.3-78.8). At the last follow-up, 13 tumors (76.5%) showed SD, 2 tumors (11.8%) showed PR, 2 tumors (11.8%) showed CR, and no tumor (0%) showed PD. The lesions were followed for a median of 7 months (range: 2-62 months). The local control rates were 100% at 6-month and 12-month. No immediate or long-term radiation-induced necrosis was reported.

CONCLUSION

This is the largest series on OM treated with CK SRS with substantial follow-up data. Our study shows an excellent local tumor control with no immediate and long-term radiation induced necrosis.
OCTS-01 DOSE ESCALATION FOR PREOPERATIVE STEREOTACTIC RADIOSURGERY FOR PATIENTS WITH LARGE BRAIN METASTASES
Authors: Murphy Erin S , Yang Kailin , Suh John , Yu Jennifer , Stevens Glen , Angelov Lilyana , Vogelbaum Michael , Barnett Gene , Ahluwalia Manmeet , Neyman Gennady , Mohammadi Alireza , Chao Samuel
Published: August 2024

PURPOSE/OBJECTIVE(S)

We conducted a prospective phase I preoperative radiosurgery dose escalation trial for brain metastases greater than 2 cm. We report updated results with known prognostic variables.

MATERIALS/METHODS

Radiosurgery dose was escalated at 3 Gy increments for 3 cohorts based on maximum tumor diameter. Dose limiting toxicity (DLT) was defined as grade 3 or greater acute toxicity. Patients underwent surgical resection within 2 weeks and were followed with imaging and neurological evaluations every 3 months.

RESULTS

A total of 35 patients were enrolled. The most common histology was NSCLC (57.1%), followed by breast cancer (14.3%). Only 12 out of 35 patients had actionable mutations and received targeted therapy and/or immunotherapy. 13 (37%) underwent piecemeal resection. 7 (20%) were infratentorial. There were 3 DLTs: 2 in the >3-4 cm cohort and 1 in the >4-6 cm cohort. For >3-4 cm, the maximum tolerable dose (MTD) was 18 Gy (2nd dose level), and for >4-6 cm, 18 Gy (3rd dose level). Time to DLT occurred within 2 days to 2 months of surgery. With a median follow-up of 64.0 months, the 6- and 12-month local control rates were 85.9% and 76.6%, respectively. The 6- and 12-month distant brain control was 63.1% and 55.3%, respectively. Overall survival at 6 and 12 months was 82.9% and 59.0%. The rate of leptomeningeal disease (LMD) at 2 years was 0%.

CONCLUSION

Preoperative SRS with dose escalation followed by surgical resection for brain metastases greater than 2 cm in size demonstrates acceptable acute toxicity. The Phase II portion of the trial is accruing patients with tumor size >3-6 cm at 18Gy.
OCTS-02 ETOP 19-21 USZ-STRIKE: IMMUNOTHERAPY OR TARGETED THERAPY WITH OR WITHOUT STEREOTACTIC RADIOSURGERY FOR PATIENTS WITH BRAIN METASTASES FROM MELANOMA OR NON-SMALL CELL LUNG CANCER
Authors: Weller Michael , Rhun Emilie Le , Giacomo Anna Maria Di , Mayinger Michael , Roschitzki Heidi , Guckenberger Matthias , Ruepp Barbara , Dummer Reinhard , Dafni Urania , Maio Michele , Stahel Rolf
Published: August 2024

BACKGROUND

Brain metastases may affect 30% of patients with metastatic cancer and are a major cause for morbidity and mortality. Treatment approaches include neurosurgical interventions, various approaches of radiotherapy, notably radiosurgery, and systemic pharmacotherapy. Encouraging response rates and response duration have been observed in patients with melanoma and non-small cell lung cancer (NSCLC) and asymptomatic or oligo-symptomatic brain metastasis treated with novel systemic therapies including immune checkpoint inhibitors and targeted therapy, challenging the need for immediate radiosurgery and introducing a change into clinical practice not supported by data from controlled clinical trials.

METHODS

ETOP 19-21 USZ-STRIKE (NCT05522660) is a randomized phase III study conducted by the ETOP IBCSG Partners Foundation. Patients with brain metastases from melanoma or NSCLC are treated systemically with the most appropriate pharmacotherapy. Randomization determines whether they receive pharmacotherapy alone or in combination with radiosurgery. The primary endpoint is CNS-specific progression-free survival (PFS), locally assessed per iRANO criteria. Secondary endpoints include CNS-specific PFS per tumor cohort, objective CNS response rate, duration of CNS response, pattern of CNS-specific progression, extra-CNS progression, incidence of radionecrosis and pseudoprogression, overall survival, neurocognitive function, quality of life and functional independence, and toxicity. We assume that the addition of radiosurgery to systemic treatment increases median CNS specific PFS by 62% from a median of 4 and 8 months for melanoma and NSCLC, respectively, corresponding to a hazard ratio 0.62 for time to CNS failure. According to the log-rank test, at a one-sided significance level of 5%, 138 observed events yield 88% power, for a sample size of 190 patients. The trial is supported by philanthropic funds from the USZ foundation and conducted at 11 sites in four countries. Accrual is slower than predicted mostly because of equipoise and patient, caregiver and notably physician bias.
OCTS-03 A MULTICENTER, OPEN-LABEL, SINGLE-ARM, MULTICOHORT PHASE II CLINICAL TRIAL OF TRASTUZUMAB DERUXTECAN IN HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 (HER2)-POSITIVE AND HER2-LOW ADVANCED BREAST CANCER (ABC) WITH BRAIN METASTASES AND/OR LEPTOMENINGEAL CARCINOMATOSIS (LMC) – THE DEBBRAH STUDY
Authors: Vaz-Batista Marta , Pérez-García José Manuel , Cortez Patricia , Garrigós Laia , Ruiz-Borrego Manuel , de la Haba-Rodríguez Juan , de las Heras Begoña Bermejo , Servitja Sonia , Racca Fabricio , Fernández-Abad María , Blanch Salvador , Teurel Iris , Sáenz1 Jose Ángel Garcia , Ortega Adela Fernandez , Martrat Griselda , Shimizu Eileen , Alcalá-López Daniel , Pérez-Escuredo Jhudit , Braga Sofia , Llombart-Cussac Antonio , Cortes Javier
Published: August 2024

The DEBBRAH study (NCT04420598) evaluated the efficacy and safety of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate, in patients with HER2-positive and HER2-low ABC with brain metastases (BM) and/or LMC. Forty-one patients aged ≥18 years were enrolled in 5 cohorts: (1) HER2-positive ABC with non-progressing BM after radiotherapy and/or surgery (n=8); (2) HER2-positive or HER2-low ABC with asymptomatic untreated BM (n=10); (3) HER2-positive ABC with progressing BM after local treatment (n=9); (4) HER2-low ABC with progressing BM after local treatment (n=7); (5) HER2-positive or HER2-low ABC and pathologically confirmed LMC (n=7). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days until disease progression, unacceptable toxicity, or consent withdrawal. At the final analysis cut-off (4th April 2023), with a median follow-up of 15.2 months (range 2.1-30.1), three (7.3%) patients were still receiving T-DXd. In cohort 1, the 16-week progression-free survival rate was 87.5% (p<0.001), meeting the primary endpoint, with seven out of eight patients alive without progressive disease 16 weeks after initiating treatment, demonstrating intracranial and extracranial activity. Among cohorts 2, 3 and 4, intracranial overall response rates ranged from 50% to 70%. In cohort 5, the median overall survival rate was 13.3 months, meeting the primary endpoint. The most common hematologic treatment adverse events (TEAEs) (≥10%) were anemia (31.7%; 0% G≥3), neutropenia (24.4%; 9.8% G≥3) and thrombocytopenia (17.1%; 4.9% G≥3). Fatigue (60.9%; 4.9% G≥3) and nausea (52.2%; 2.4% G≥3) were the most common non-hematologic TEAEs. One (2.4%) patient died due to drug-related pneumonitis. In conclusion, T-DXd showed impressive activity and was consistent with the known safety profile in patients with HER2-positive and HER2-low ABC with a history of BMs and/or LMC. These results justify Destiny Breast 12 and reinforce the need to include this patient population in clinical trials evaluating HER2-targeted agents.