Publications by authors named "Stephen J Bagley"

39 Publications

Immune Checkpoint Inhibitor Uptake in Real-World Patients With Malignant Pleural Mesothelioma.

JTO Clin Res Rep 2021 Jun 18;2(6):100188. Epub 2021 May 18.

Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Introduction: Since the July 2017 National Comprehensive Cancer Network (NCCN) malignant pleural mesothelioma (MPM) guideline revision recommended second-line immune checkpoint inhibitors (ICIs), studies have suggested a greater response to ICI among patients with nonepithelioid MPM. Nevertheless, little is known regarding adoption of ICI in routine practice and if uptake differs by histologic subtype. Our objectives were to evaluate the real-world uptake of second-line ICI among patients with MPM and to reveal its association with histologic subtype.

Methods: This was a multicenter, retrospective cohort study of real-world patients with MPM receiving at least two lines of systemic therapy between 2011 and 2019. We found the uptake of second-line ICI over time and evaluated the association between histologic subtype and ICI use, adjusting for relevant patient demographic and clinical factors.

Results: Among the 426 patients with MPM in our cohort, 310 had epithelioid and 116 nonepithelioid histologic subtype. The median age was 73 years (interquartile range: 67-78). Overall, 144 patients (33.8%) received second-line ICI and 282 (66.2%) traditional chemotherapy. ICI uptake began in early 2015 before the NCCN guideline revision and increased rapidly to 2019. After the 2017 NCCN guideline revision, patients with nonepithelioid MPM histologic subtypes had more than 3 times the odds of receiving second-line ICI (OR = 3.26; 95% confidence interval: 1.41-7.54).

Conclusions: Among real-world patients with MPM, second-line ICI uptake began over two years before the 2017 NCCN guideline recommendations and was associated with nonepithelioid histologic subtype after contemporary studies suggested increased clinical benefit in this population, reflecting prompt integration of scientific discovery into clinical practice.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474474PMC
June 2021

Designing Clinical Trials for Combination Immunotherapy: A Framework for Glioblastoma.

Clin Cancer Res 2021 Sep 24. Epub 2021 Sep 24.

Duke University Medical Center, Duke University

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both pre-clinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2681DOI Listing
September 2021

Glioblastoma Clinical Trials: Current Landscape and Opportunities for Improvement.

Clin Cancer Res 2021 Sep 24. Epub 2021 Sep 24.

Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on ClinicalTrials.gov as "recruiting" or "not yet recruiting" as of February 2021.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2750DOI Listing
September 2021

Serious Illness Communication Practices in Glioblastoma: An Institutional Perspective.

J Palliat Med 2021 Aug 23:1-9. Epub 2021 Aug 23.

Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Early, high-quality advance care planning discussions are essential for supporting goal-concordant care among glioblastoma (GBM) patients. Using mixed methods, we sought to characterize current serious illness (SI) communication practices at our institution. The electronic medical records of 240 deceased GBM patients cared for at the Abramson Cancer Center in Philadelphia, PA between 2017 and 2019 were systematically reviewed for documented SI conversations about four domains: prognosis, goals, end-of-life planning, and code status. Patient outcomes and SI conversation characteristics were analyzed using descriptive statistics. Standardized interviews about GBM care were held with five clinicians. Interview transcripts were analyzed using grounded-theory coding to identify emergent themes. Nearly all patients (96%) had at least one documented SI conversation (median: 4, interquartile range [IQR] 2-7), mostly outpatient with medical oncology physicians. Median timing of first SI conversation was 360 days before death. SI conversations were not significantly associated with patient outcomes, including inpatient death and hospice enrollment. Seven themes emerged from clinician interviews: balancing hope and reality, anticipatory guidance, neglect of the "big picture," need for earlier conversations, care coordination, the role of clinical expertise, and communication training. SI conversations were documented early and often in our sample, but their quality was difficult to assess. Contrary to our quantitative findings, interviewees reported that SI conversations were late, infrequent, inadequate, and fragmented across specialties, failing to explore critical issues such as prognosis and functional decline.
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http://dx.doi.org/10.1089/jpm.2021.0121DOI Listing
August 2021

TP53 Mutation and Extraneural Metastasis of Glioblastoma: Insights From an Institutional Experience and Comprehensive Literature Review.

Am J Surg Pathol 2021 11;45(11):1516-1526

Departments of Pathology and Laboratory Medicine.

Extraneural metastases of glioblastoma (GBM), although rare, are becoming an increasingly recognized occurrence. Currently, the biological mechanism underlying this rare occurrence is not understood. To explore the potential genomic drivers of extraneural metastasis in GBM, we present the molecular features of 4 extraneural metastatic GBMs, along with a comprehensive review and analysis of previously reported cases that had available molecular characterization. In addition to our 4 cases, 42 patients from 35 publications are reviewed. To compare the molecular profiles between GBM cases with extraneural metastasis and the general GBM population, genomic data from GBM samples in The Cancer Genome Atlas (TCGA) database were also analyzed. We found that 64.5% (20/31) of the cases with extraneural metastasis that were tested for TP53 changes had at least 1 TP53 pathogenic variant detected in either 1 or both primary and metastatic tumors. In contrast, TP53 mutation was significantly less frequent in the unselected GBM from TCGA (22.6%, 56/248) (P=0.000). In addition, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was more common in unselected TCGA GBM cases (48.6%, 170/350) than in cases with extraneural metastasis (31.8%, 7/22), although not statistically significant. Although isocitrate dehydrogenase (IDH) mutation is a rare occurrence in high-grade astrocytomas, IDH-mutant grade 4 astrocytomas are at least as likely to metastasize as IDH wild-type GBMs; 3 metastatic cases definitively harbored an IDH1 (p.R132H) mutation in our analysis. Our findings not only provide potential biomarkers for earlier screening of extraneural metastasis, but could also suggest clues to understanding biological mechanisms underlying GBM metastasis, and for the development of therapeutic modalities.
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http://dx.doi.org/10.1097/PAS.0000000000001762DOI Listing
November 2021

Withdrawn as duplicate: Commentary: "Zooming in" on Glioblastoma: Understanding Tumor Heterogeneity and its Clinical Implications in the Era of Single-Cell Ribonucleic Acid Sequencing.

Neurosurgery 2021 09;89(4):E237-E238

University of Pennsylvania, Philadelphia, Pennsylvania, USA.

This article has been withdrawn due to an error that caused the article to be duplicated. The definitive version of this article is published under DOI 10.1093/neuros/nyab288.
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http://dx.doi.org/10.1093/neuros/nyab280DOI Listing
September 2021

Quantification of tumor microenvironment acidity in glioblastoma using principal component analysis of dynamic susceptibility contrast enhanced MR imaging.

Sci Rep 2021 07 22;11(1):15011. Epub 2021 Jul 22.

Department of Radiology, Perelman School of Medicine, Hospital of University of Pennsylvania, University of Pennsylvania, Philadelphia, PA, USA.

Glioblastoma (GBM) has high metabolic demands, which can lead to acidification of the tumor microenvironment. We hypothesize that a machine learning model built on temporal principal component analysis (PCA) of dynamic susceptibility contrast-enhanced (DSC) perfusion MRI can be used to estimate tumor acidity in GBM, as estimated by pH-sensitive amine chemical exchange saturation transfer echo-planar imaging (CEST-EPI). We analyzed 78 MRI scans in 32 treatment naïve and post-treatment GBM patients. All patients were imaged with DSC-MRI, and pH-weighting that was quantified from CEST-EPI estimation of the magnetization transfer ratio asymmetry (MTR) at 3 ppm. Enhancing tumor (ET), non-enhancing core (NC), and peritumoral T2 hyperintensity (namely, edema, ED) were used to extract principal components (PCs) and to build support vector machines regression (SVR) models to predict MTR values using PCs. Our predicted map correlated with MTR values with Spearman's r equal to 0.66, 0.47, 0.67, 0.71, in NC, ET, ED, and overall, respectively (p < 0.006). The results of this study demonstrates that PCA analysis of DSC imaging data can provide information about tumor pH in GBM patients, with the strongest association within the peritumoral regions.
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http://dx.doi.org/10.1038/s41598-021-94560-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298590PMC
July 2021

Understanding the global impact of primary brain tumors: The untapped potential of population-based cancer registries.

Neuro Oncol 2021 10;23(10):1625-1626

Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

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http://dx.doi.org/10.1093/neuonc/noab165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485434PMC
October 2021

Systematic review of combinations of targeted or immunotherapy in advanced solid tumors.

J Immunother Cancer 2021 07;9(7)

Duke Cancer Institute, Duke University, Durham, North Carolina, USA

With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.
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http://dx.doi.org/10.1136/jitc-2021-002459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256733PMC
July 2021

Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40.

Nat Commun 2021 06 8;12(1):3424. Epub 2021 Jun 8.

Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA.

Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mϕs. Combination of IL-6 inhibition with CD40 stimulation reverses Mϕ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models, particularly inducing complete regression of GL261 tumors after checkpoint blockade. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting opportunities for GBM and other solid tumors.
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http://dx.doi.org/10.1038/s41467-021-23832-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187342PMC
June 2021

Association of plasma cell-free DNA with survival in patients with IDH wild-type glioblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab011. Epub 2021 Jan 16.

Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Background: We aimed to determine whether plasma cell-free DNA (cfDNA) concentration is associated with survival in patients with isocitrate dehydrogenase () wild-type glioblastoma (GBM).

Methods: Pre-operative and post-chemoradiotherapy blood samples were prospectively collected from patients with newly diagnosed wild-type GBM. Patients underwent surgical resection or biopsy and received adjuvant radiotherapy with concomitant temozolomide. Cell-free DNA (cfDNA) was isolated from plasma and quantified using SYBR Green-based q polymerase chain reaction (qPCR).

Results: Sixty-two patients were enrolled and categorized into high vs. low cfDNA groups relative to the pre-operative median value (25.2 ng/mL, range 5.7-153.0 ng/mL). High pre-operative cfDNA concentration was associated with inferior PFS (median progression-free survival (PFS), 3.4 vs. 7.7 months; log-rank = .004; hazard ratio [HR], 2.19; 95% CI, 1.26-3.81) and overall survival (OS) (median OS, 8.0 vs. 13.9 months; log-rank = .01; HR, 2.43; 95% CI, 1.19-4.95). After adjusting for risk factors, including O-methylguanine-DNA methyltransferase () promoter methylation status, pre-operative cfDNA remained independently associated with PFS (HR, 2.70; 95% CI, 1.50-4.83; .001) and OS (HR, 2.65; 95% CI, 1.25-5.59; = .01). Post-hoc analysis of change in cfDNA post-chemoradiotherapy compared to pre-surgery ( = 24) showed increasing cfDNA concentration was associated with worse PFS (median, 2.7 vs. 6.0 months; log-rank = .003; HR, 4.92; 95% CI, 1.53-15.84) and OS (median, 3.9 vs. 19.4 months; log-rank < .001; HR, 7.77; 95% CI, 2.17-27.76).

Conclusions: cfDNA concentration is a promising prognostic biomarker for patients with wild-type GBM. Plasma cfDNA can be obtained noninvasively and may enable more accurate estimates of survival and effective clinical trial stratification.
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http://dx.doi.org/10.1093/noajnl/vdab011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883768PMC
January 2021

Plasma cfDNA in Glioblastoma-Response.

Clin Cancer Res 2020 05;26(9):2276

Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1158/1078-0432.CCR-20-0285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291816PMC
May 2020

Immunotherapy and Response Assessment in Malignant Glioma: Neuro-oncology Perspective.

Top Magn Reson Imaging 2020 Apr;29(2):95-102

Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.

Glioblastoma (GBM) is the deadliest form of brain cancer and recurs uniformly. Despite aggressive treatment with maximal safe surgical resection, adjuvant radiation with temozolomide chemotherapy, and alternating electrical field therapy, median survival for newly diagnosed GBM remains <2 years. Novel therapies are desperately needed. Immunotherapy, which has led to significant improvement in patient outcomes across many tumor types, is currently being studied in a large number of GBM clinical trials. One of the biggest challenges in immunotherapy trials in GBM has been accurate response assessment using currently available imaging modalities, including magnetic resonance imaging. In this review, we will discuss the rationale for immunotherapy for GBM, immunotherapeutic modalities currently under clinical evaluation in GBM, and the challenges and recent advances in imaging response assessment in GBM immunotherapy.
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http://dx.doi.org/10.1097/RMR.0000000000000233DOI Listing
April 2020

F-Fluciclovine PET to distinguish treatment-related effects from disease progression in recurrent glioblastoma: PET fusion with MRI guides neurosurgical sampling.

Neurooncol Pract 2020 Mar 8;7(2):152-157. Epub 2019 Dec 8.

Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia.

Differentiation of true tumor progression from treatment-related effects remains a major unmet need in caring for patients with glioblastoma. Here, we report how the intraoperative combination of MRI withF-fluciclovine PET guided surgical sampling in 2 patients with recurrent glioblastoma.F-Fluciclovine PET is FDA approved for use in prostate cancer and carries an orphan drug designation in glioma. To investigate its utility in recurrent glioblastoma, we fused PET and MRI images using 2 different surgical navigation systems and performed targeted stereotactic biopsies from the areas of high ("hot") and low ("cold") radiotracer uptake. Concordant histopathologic and imaging findings suggest that a combinedF-fluciclovine PET-MRI-guided approach can guide neurosurgical resection of viable recurrent glioblastoma in the background of treatment-related effects, which can otherwise look similar on MRI.
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http://dx.doi.org/10.1093/nop/npz068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081387PMC
March 2020

Cancer Imaging Phenomics via CaPTk: Multi-Institutional Prediction of Progression-Free Survival and Pattern of Recurrence in Glioblastoma.

JCO Clin Cancer Inform 2020 03;4:234-244

Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Purpose: To construct a multi-institutional radiomic model that supports upfront prediction of progression-free survival (PFS) and recurrence pattern (RP) in patients diagnosed with glioblastoma multiforme (GBM) at the time of initial diagnosis.

Patients And Methods: We retrospectively identified data for patients with newly diagnosed GBM from two institutions (institution 1, n = 65; institution 2, n = 15) who underwent gross total resection followed by standard adjuvant chemoradiation therapy, with pathologically confirmed recurrence, sufficient follow-up magnetic resonance imaging (MRI) scans to reliably determine PFS, and available presurgical multiparametric MRI (MP-MRI). The advanced software suite Cancer Imaging Phenomics Toolkit (CaPTk) was leveraged to analyze standard clinical brain MP-MRI scans. A rich set of imaging features was extracted from the MP-MRI scans acquired before the initial resection and was integrated into two distinct imaging signatures for predicting mean shorter or longer PFS and near or distant RP. The predictive signatures for PFS and RP were evaluated on the basis of different classification schemes: single-institutional analysis, multi-institutional analysis with random partitioning of the data into discovery and replication cohorts, and multi-institutional assessment with data from institution 1 as the discovery cohort and data from institution 2 as the replication cohort.

Results: These predictors achieved cross-validated classification performance (ie, area under the receiver operating characteristic curve) of 0.88 (single-institution analysis) and 0.82 to 0.83 (multi-institution analysis) for prediction of PFS and 0.88 (single-institution analysis) and 0.56 to 0.71 (multi-institution analysis) for prediction of RP.

Conclusion: Imaging signatures of presurgical MP-MRI scans reveal relatively high predictability of time and location of GBM recurrence, subject to the patients receiving standard first-line chemoradiation therapy. Through its graphical user interface, CaPTk offers easy accessibility to advanced computational algorithms for deriving imaging signatures predictive of clinical outcome and could similarly be used for a variety of radiomic and radiogenomic analyses.
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http://dx.doi.org/10.1200/CCI.19.00121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113126PMC
March 2020

Imaging and histopathologic correlates of plasma cell-free DNA concentration and circulating tumor DNA in adult patients with newly diagnosed glioblastoma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa016. Epub 2020 Feb 27.

Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Plasma cell-free DNA (cfDNA) concentration is lower in glioblastoma (GBM) compared to other solid tumors, which can lead to low circulating tumor DNA (ctDNA) detection. In this study, we investigated the relationship between multimodality magnetic resonance imaging (MRI) and histopathologic features with plasma cfDNA concentration and ctDNA detection in patients with treatment-naive GBM.

Methods: We analyzed plasma cfDNA concentration, MRI scans, and tumor histopathology from 42 adult patients with newly diagnosed GBM. Linear regression analysis was used to examine the relationship of plasma cfDNA concentration before surgery to imaging and histopathologic characteristics. In a subset of patients, imaging and histopathologic metrics were also compared between patients with and without a detected tumor somatic mutation.

Results: Tumor volume with elevated (>1.5 times contralateral white matter) rate transfer constant ( , a surrogate of blood-brain barrier [BBB] permeability) was independently associated with plasma cfDNA concentration ( = .001). Histopathologic characteristics independently associated with plasma cfDNA concentration included CD68+ macrophage density ( = .01) and size of tumor vessels ( = .01). Patients with higher (grade ≥3) perivascular CD68+ macrophage density had lower volume transfer constant ( , = .01) compared to those with lower perivascular CD68+ macrophage density. Detection of at least 1 somatic mutation in plasma cfDNA was associated with significantly lower perivascular CD68+ macrophages ( = .01).

Conclusions: Metrics of BBB disruption and quantity and distribution of tumor-associated macrophages are associated with plasma cfDNA concentration and ctDNA detection in GBM patients. These findings represent an important step in understanding the factors that determine plasma cfDNA concentration and ctDNA detection.
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http://dx.doi.org/10.1093/noajnl/vdaa016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045782PMC
February 2020

Histopathology-validated machine learning radiographic biomarker for noninvasive discrimination between true progression and pseudo-progression in glioblastoma.

Cancer 2020 06 4;126(11):2625-2636. Epub 2020 Mar 4.

Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Imaging of glioblastoma patients after maximal safe resection and chemoradiation commonly demonstrates new enhancements that raise concerns about tumor progression. However, in 30% to 50% of patients, these enhancements primarily represent the effects of treatment, or pseudo-progression (PsP). We hypothesize that quantitative machine learning analysis of clinically acquired multiparametric magnetic resonance imaging (mpMRI) can identify subvisual imaging characteristics to provide robust, noninvasive imaging signatures that can distinguish true progression (TP) from PsP.

Methods: We evaluated independent discovery (n = 40) and replication (n = 23) cohorts of glioblastoma patients who underwent second resection due to progressive radiographic changes suspicious for recurrence. Deep learning and conventional feature extraction methods were used to extract quantitative characteristics from the mpMRI scans. Multivariate analysis of these features revealed radiophenotypic signatures distinguishing among TP, PsP, and mixed response that compared with similar categories blindly defined by board-certified neuropathologists. Additionally, interinstitutional validation was performed on 20 new patients.

Results: Patients who demonstrate TP on neuropathology are significantly different (P < .0001) from those with PsP, showing imaging features reflecting higher angiogenesis, higher cellularity, and lower water concentration. The accuracy of the proposed signature in leave-one-out cross-validation was 87% for predicting PsP (area under the curve [AUC], 0.92) and 84% for predicting TP (AUC, 0.83), whereas in the discovery/replication cohort, the accuracy was 87% for predicting PsP (AUC, 0.84) and 78% for TP (AUC, 0.80). The accuracy in the interinstitutional cohort was 75% (AUC, 0.80).

Conclusion: Quantitative mpMRI analysis via machine learning reveals distinctive noninvasive signatures of TP versus PsP after treatment of glioblastoma. Integration of the proposed method into clinical studies can be performed using the freely available Cancer Imaging Phenomics Toolkit.
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http://dx.doi.org/10.1002/cncr.32790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893811PMC
June 2020

EGFRvIII upregulates DNA mismatch repair resulting in increased temozolomide sensitivity of MGMT promoter methylated glioblastoma.

Oncogene 2020 04 17;39(15):3041-3055. Epub 2020 Feb 17.

Laboratory of Radiobiology & Experimental Radiation Oncology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The oncogene epidermal growth factor receptor variant III (EGFRvIII) is frequently expressed in glioblastomas (GBM) but its impact on therapy response is still under controversial debate. Here we wanted to test if EGFRvIII influences the sensitivity towards the alkylating agent temozolomide (TMZ). Therefore, we retrospectively analyzed the survival of 336 GBM patients, demonstrating that under standard treatment, which includes TMZ, EGFRvIII expression is associated with prolonged survival, but only in patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated tumors. Using isogenic GBM cell lines with endogenous EGFRvIII expression we could demonstrate that EGFRvIII increases TMZ sensitivity and results in enhanced numbers of DNA double-strand breaks and a pronounced S/G2-phase arrest after TMZ treatment. We observed a higher expression of DNA mismatch repair (MMR) proteins in EGFRvIII+ cells and patient tumor samples, which was most pronounced for MSH2 and MSH6. EGFRvIII-specific knockdown reduced MMR protein expression thereby increasing TMZ resistance. Subsequent functional kinome profiling revealed an increased activation of p38- and ERK1/2-dependent signaling in EGFRvIII expressing cells, which regulates MMR protein expression downstream of EGFRvIII. In summary, our results demonstrate that the oncoprotein EGFRvIII sensitizes a fraction of GBM to current standard of care treatment through the upregulation of DNA MMR.
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http://dx.doi.org/10.1038/s41388-020-1208-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142016PMC
April 2020

Optimizing eligibility criteria and clinical trial conduct to enhance clinical trial participation for primary brain tumor patients.

Neuro Oncol 2020 05;22(5):601-612

Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Building on an initiative to enhance clinical trial participation involving the Society for Neuro-Oncology, the Response Assessment in Neuro-Oncology Working Group, patient advocacy groups, clinical trial cooperative groups, and other partners, we evaluate the impact of eligibility criteria and trial conduct on neuro-oncology clinical trial participation. Clinical trials often carry forward eligibility criteria from prior studies that may be overly restrictive and unnecessary and needlessly limit patient accrual. Inclusion and exclusion criteria should be evaluated based on the goals and design of the study and whether they impact patient safety and/or treatment efficacy. In addition, we evaluate clinical trial conduct as a barrier to accrual and discuss strategies to minimize such barriers for neuro-oncology trials.
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http://dx.doi.org/10.1093/neuonc/noaa015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229255PMC
May 2020

Clinical activity of the tyrosine kinase inhibitor osimertinib in -mutant glioblastoma.

CNS Oncol 2019 11 15;8(3):CNS43. Epub 2019 Nov 15.

Division of Hematology & Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. The gene is among the most commonly deranged genes in GBM and thus an important therapeutic target. We report the case of a young female with heavily pretreated -mutated GBM, for whom we initiated osimertinib, an oral, third-generation tyrosine kinase inhibitor that irreversibly inhibits EGFR and has significant brain penetration. We then review some of the main challenges in targeting EGFR, including lack of central nervous system penetration with most tyrosine kinase inhibitors, molecular heterogeneity of GBM and the need for enhanced specificity for the mutations relevant in GBM.
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http://dx.doi.org/10.2217/cns-2019-0014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880297PMC
November 2019

Clinical Utility of Plasma Cell-Free DNA in Adult Patients with Newly Diagnosed Glioblastoma: A Pilot Prospective Study.

Clin Cancer Res 2020 01 30;26(2):397-407. Epub 2019 Oct 30.

Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Purpose: The clinical utility of plasma cell-free DNA (cfDNA) has not been assessed prospectively in patients with glioblastoma (GBM). We aimed to determine the prognostic impact of plasma cfDNA in GBM, as well as its role as a surrogate of tumor burden and substrate for next-generation sequencing (NGS).

Experimental Design: We conducted a prospective cohort study of 42 patients with newly diagnosed GBM. Plasma cfDNA was quantified at baseline prior to initial tumor resection and longitudinally during chemoradiotherapy. Plasma cfDNA was assessed for its association with progression-free survival (PFS) and overall survival (OS), correlated with radiographic tumor burden, and subjected to a targeted NGS panel.

Results: Prior to initial surgery, GBM patients had higher plasma cfDNA concentration than age-matched healthy controls (mean 13.4 vs. 6.7 ng/mL, < 0.001). Plasma cfDNA concentration was correlated with radiographic tumor burden on patients' first post-radiation magnetic resonance imaging scan (ρ = 0.77, = 0.003) and tended to rise prior to or concurrently with radiographic tumor progression. Preoperative plasma cfDNA concentration above the mean (>13.4 ng/mL) was associated with inferior PFS (median 4.9 vs. 9.5 months, = 0.038). Detection of ≥1 somatic mutation in plasma cfDNA occurred in 55% of patients and was associated with nonstatistically significant decreases in PFS (median 6.0 vs. 8.7 months, = 0.093) and OS (median 5.5 vs. 9.2 months, = 0.053).

Conclusions: Plasma cfDNA may be an effective prognostic tool and surrogate of tumor burden in newly diagnosed GBM. Detection of somatic alterations in plasma is feasible when samples are obtained prior to initial surgical resection.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980766PMC
January 2020

Clinical investigation of CAR T cells for solid tumors: Lessons learned and future directions.

Pharmacol Ther 2020 01 16;205:107419. Epub 2019 Oct 16.

Glioblastoma Translational Center of Excellence, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA 19104, United States; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States.

Chimeric antigen receptor (CAR) T cells are a form of autologous immunotherapy that has changed the therapeutic landscape of hematologic malignancies. CAR T cell therapy involves collection of a patient's T cells by apheresis, ex vivo genetic modification of the T cells to encode a synthetic receptor that binds a specific tumor antigen, and infusion of the T cells back into the patient. With the unprecedented success of CAR T cells in leukemia and lymphoma, a growing number of preclinical studies and clinical trials have focused on translating this treatment to solid tumors. In non-hematologic malignancies, however, response rates have been much less favorable. Some of the most significant challenges for CAR T cell immunotherapy in solid cancers include a paucity of unique tumor target antigens, limited CAR T cell trafficking to tumor sites, tumor heterogeneity and antigen loss, and the severely immunosuppressive tumor microenvironment. This review article provides an update on completed and ongoing clinical trials of CAR T cells for solid tumors, as well as an overview of strategies to improve CAR T cell efficacy in non-hematologic malignancies.
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http://dx.doi.org/10.1016/j.pharmthera.2019.107419DOI Listing
January 2020

Top Ten Tips Palliative Care Clinicians Should Know When Caring for Patients with Brain Cancer.

J Palliat Med 2020 03 15;23(3):415-421. Epub 2019 Oct 15.

Department of Medicine and the Palliative and Advanced Illness Research Center, University of Pennsylvania, Philadelphia, Pennsylvania.

The diagnosis of an aggressive, primary brain tumor is life altering for those affected and too often portends a poor prognosis. Despite decades of research, neither a cure nor even a therapy that reliably and dramatically prolongs survival has been found. Fortunately, there are a number of treatments that may prolong the life of select brain tumor patients although the symptom burden can sometimes be high. This article brings together neuro-oncologists, neurologists, and palliative care (PC) physicians to help shine a light on these diseases, their genetics, treatment options, and the symptoms likely to be encountered both from the underlying illness and its treatment. We hope to increase the understanding that PC teams have around these illnesses to improve care for patients and families.
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http://dx.doi.org/10.1089/jpm.2019.0507DOI Listing
March 2020

Negative prognostic impact of epidermal growth factor receptor copy number gain in young adults with isocitrate dehydrogenase wild-type glioblastoma.

J Neurooncol 2019 Nov 21;145(2):321-328. Epub 2019 Sep 21.

Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, 10th Floor, South Pavilion, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.

Purpose: Young adults with isocitrate-dehydrogenase wild-type (IDH-WT) glioblastoma (GBM) represent a rare, understudied population compared to pediatric high-grade glioma, IDH-mutant GBM, or IDH-WT GBM in older patients. We aimed to explore the prognostic impact of epidermal growth factor receptor copy number gain (EGFR CN gain), one of the most common genetic alterations in IDH-WT glioma, in young adults with IDH-WT GBM.

Methods: We performed a retrospective cohort study of patients 18-45 years old with newly diagnosed, IDH-WT GBM whose tumors underwent next-generation sequencing at our institution between 2014 and 2018. The impact of EGFR CN gain on time to tumor progression (TTP) and overall survival (OS) was assessed. A validation cohort of patients 18-45 years old with IDH-WT GBM was analyzed from The Cancer Genome Atlas (TCGA).

Results: Ten of 28 patients (36%) from our institution had EGFR CN gain, which was associated with shorter TTP (median 6.5 vs. 11.9 months; p = 0.06) and OS (median 16.3 vs. 23.5 months; p = 0.047). The negative prognostic impact of EGFR CN gain on OS persisted in a multivariate model (HR 6.40, 95% CI 1.3-31.0, p = 0.02). In the TCGA cohort (N = 43), EGFR CN gain was associated with shorter TTP and worse OS, although these did not reach statistical significance (TTP, median 11.5 vs. 14.4 months, p = 0.18; OS, median 23.6 vs. 27.8 months; p = 0.18).

Conclusions: EGFR CN gain may be associated with inferior outcomes in young adults with newly diagnosed, IDH-WT GBM, suggesting a potential role for targeting EGFR in this population.
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http://dx.doi.org/10.1007/s11060-019-03298-6DOI Listing
November 2019

Arterial Spin Labeling and Dynamic Susceptibility Contrast-enhanced MR Imaging for evaluation of arteriovenous shunting and tumor hypoxia in glioblastoma.

Sci Rep 2019 06 19;9(1):8747. Epub 2019 Jun 19.

Department of Radiology, Hospital of University of Pennsylvania, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. Significant challenges in the care of patients with GBM include marked vascular heterogeneity and arteriovenous (AV) shunting, which results in tumor hypoxia and inadequate delivery of systemic treatments to reach tumor cells. In this study, we investigated the utility of different MR perfusion techniques to detect and quantify arteriovenous (AV) shunting and tumor hypoxia in patients with GBM. Macrovascular shunting was present in 33% of subjects, with the degree of shunting ranging from (37-60%) using arterial spin labeling perfusion. Among the dynamic susceptibility contrast-enhanced perfusion curve features, there were a strong negative correlation between hypoxia score, DSC perfusion curve recovery slope (r = -0.72, P = 0.018) and angle (r = -0.73, P = 0.015). The results of this study support the possibility of using arterial spin labeling and pattern analysis of dynamic susceptibility contrast-enhanced MR Imaging for evaluation of arteriovenous shunting and tumor hypoxia in glioblastoma.
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http://dx.doi.org/10.1038/s41598-019-45312-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584644PMC
June 2019

Comparative Effectiveness of Carboplatin/Pemetrexed With Versus Without Bevacizumab for Advanced Nonsquamous Non-Small Cell Lung Cancer.

J Natl Compr Canc Netw 2019 05;17(5):469-477

Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, and.

Background: Despite recent advances in targeted therapy and immunotherapy for advanced non-small cell lung cancer (NSCLC), carboplatin/pemetrexed/bevacizumab remains a commonly used first-line regimen. However, it is unknown whether the addition of bevacizumab to carboplatin/pemetrexed improves overall survival (OS).

Materials And Methods: Using nationally representative curated electronic health record data from Flatiron Health, we performed a retrospective cohort study of patients diagnosed with advanced nonsquamous NSCLC who received ≥1 cycle of carboplatin/pemetrexed ± bevacizumab as initial systemic therapy for stage IV or metastatic/recurrent disease. The OS impact of adding bevacizumab to carboplatin/pemetrexed was assessed using a Cox proportional hazards model to adjust for age, sex, race, original tumor stage, time between diagnosis of metastatic disease and start of chemotherapy, and performance status. In a secondary analysis of patients at a single academic institution, we also adjusted for the presence of brain metastases, hemoptysis, and anticoagulation.

Results: A total of 4,724 patients were included, of which 2,759 patients (58%) received carboplatin/pemetrexed and 1,965 (42%) received carboplatin/pemetrexed/bevacizumab. Median OS was 12.1 months (95% CI, 11.2-12.9 months) in the carboplatin/pemetrexed/bevacizumab group compared with 8.6 months (95% CI, 8.1-9.1 months) in the carboplatin/pemetrexed group (P<.001). Bevacizumab use remained associated with improved OS in a multivariate model (hazard ratio, 0.80; 95% CI, 0.75-0.86; P<.001). In the secondary, institutional analysis (N=539), the effect of bevacizumab was unchanged (hazard ratio, 0.75; 95% CI, 0.59-0.96; P=.02).

Conclusions: In this large, real-world dataset, the addition of bevacizumab to first-line carboplatin/pemetrexed for metastatic nonsquamous NSCLC was associated with improved OS.
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http://dx.doi.org/10.6004/jnccn.2018.7102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661525PMC
May 2019

Histopathologic quantification of viable tumor versus treatment effect in surgically resected recurrent glioblastoma.

J Neurooncol 2019 Jan 16;141(2):421-429. Epub 2018 Nov 16.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: The prognostic impact of the histopathologic features of recurrent glioblastoma surgical specimens is unknown. We sought to determine whether key histopathologic characteristics in glioblastoma tumors resected after chemoradiotherapy are associated with overall survival (OS).

Methods: The following characteristics were quantified in recurrent glioblastoma specimens at our institution: extent of viable tumor (accounting for % of specimen comprised of tumor and tumor cellularity), mitoses per 10 high-power fields (0, 1-10, > 10), Ki-67 proliferative index (0-100%), hyalinization (0-6; none to extensive), rarefaction (0-6), hemosiderin (0-6), and % of specimen comprised of geographic necrosis (0-100%; converted to 0-6 scale). Variables associated with OS in univariate analysis, as well as age, eastern cooperative oncology group performance status (ECOG PS), extent of repeat resection, time from initial diagnosis to repeat surgery, and O-methylguanine-DNA methyltransferase promoter methylation, were included in a multivariable Cox proportional hazards model.

Results: 37 specimens were assessed. In a multivariate model, high Ki-67 proliferative index was the only histopathologic characteristic associated with worse OS following repeat surgery for glioblastoma (hazard ratio (HR) 1.3, 95% CI 1.1-1.5, p = 0.003). Shorter time interval from initial diagnosis to repeat surgery (HR 1.11, 95% CI 1.02-1.21, p = 0.016) and ECOG PS ≥ 2 (HR 4.19, 95% CI 1.72-10.21, p = 0.002) were also independently associated with inferior OS.

Conclusion: In patients with glioblastoma undergoing repeat resection following chemoradiotherapy, high Ki-67 index in the recurrent specimen, short time to recurrence, and poor PS are independently associated with worse OS. Histopathologic quantification of viable tumor versus therapy-related changes has limited prognostic influence.
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http://dx.doi.org/10.1007/s11060-018-03050-6DOI Listing
January 2019

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma.

J Neurooncol 2019 Jan 23;141(1):95-102. Epub 2018 Oct 23.

Division of Hematology/Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Introduction: We sought to determine which therapeutically targetable immune checkpoints, costimulatory signals, and other tumor microenvironment (TME) factors are independently associated with immune cytolytic activity (CYT), a gene expression signature of activated effector T cells, in human glioblastoma (GBM).

Methods: GlioVis was accessed for RNA-seq data from The Cancer Genome Atlas (TCGA). For subjects with treatment-naïve, primary GBM, we quantified mRNA expression of 28 therapeutically targetable TME factors. CYT (geometric mean of GZMA and PRF1 expression) was calculated for each tumor. Multiple linear regression was performed to determine the relationship between the dependent variable (CYT) and mRNA expression of each of the 28 factors. Variables associated with CYT in multivariate analysis were subsequently evaluated for this association in an independent cohort of newly diagnosed GBMs from the Chinese Glioma Cooperative Group (CGCG).

Results: 109 TCGA tumors were analyzed. The final multiple linear regression model included the following variables, each positively associated with CYT except VEGF-A (negative association): CSF-1 (p = 0.003), CD137 (p = 0.042), VEGF-A (p < 0.001), CTLA4 (p = 0.028), CD40 (p = 0.023), GITR (p = 0.020), IL6 (p = 0.02), and OX40 (p < 0.001). In CGCG (n = 52), each of these variables remained significantly associated with CYT in univariate analysis except for VEGF-A. In multivariate analysis, only CTLA4 and CD40 remained statistically significant.

Conclusions: Using multivariate modeling of RNA-seq gene expression data, we identified therapeutically targetable TME factors that are independently associated with intratumoral cytolytic T-cell activity in human GBM. As a myriad of systemic immunotherapies are now available for investigation, our results could inform rational combinations for evaluation in GBM.
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http://dx.doi.org/10.1007/s11060-018-03010-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342649PMC
January 2019

Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development.

Cancer Cell 2018 07;34(1):163-177.e7

Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFR). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFR mutants, corroborated in mice bearing intracranial tumors expressing EGFR and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFR tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFR mutation in glioblastoma, postulating EGFR as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies.
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http://dx.doi.org/10.1016/j.ccell.2018.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424337PMC
July 2018
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