Jeremy Rudnick

Loss of PTEN is not associated with poor survival in newly diagnosed glioblastoma patients of the temozolomide era.

Introduction Pre-temozolomide studies demonstrated that loss of the tumor suppressor gene PTEN held independent prognostic significance in GBM patients. We investigated whether loss of PTEN predicted shorter survival in the temozolomide era. The role of PTEN in the PI3K/Akt pathway is also reviewed. Methods Patients with histologically proven newly diagnosed GBM were identified from a retrospective database between 2007 and 2010. Cox proportional hazards analysis was used to calculate the independent effects of PTEN expression, age, extent of resection, Karnofsky performance scale (KPS), and treatment on overall survival. Results Sixty-five percent of patients were men with median age of 63 years, and 70% had KPS≥80. Most patients (81%) received standard treatment (temozolomide with concurrent radiation). A total of 72 (47%) patients had retained PTEN expression. Median overall survival (OS) was 19.1 months (95% CI: 15.0–22.5). Median survival of 20.0 months (95% CI: 15.0–25.5) and 18.2 months (95% CI: 13.0–25.7) was observed in PTEN retained and PTEN loss patients, respectively (p = .71). PTEN loss patients were also found to have amplifications of EGFR gene more frequently than patients with retained PTEN (70.8% vs. 47.8%, p = .01). Multivariate analysis showed that older age (HR 1.64, CI: 1.02–2.63, p = .04), low KPS (HR 3.57, CI: 2.20–5.79, p<.0001), and lack of standard treatment (HR 3.98, CI: 2.38–6.65, p<.0001) yielded worse survival. PTEN loss was not prognostic of overall survival (HR 1.31, CI: 0.85–2.03, p = .22). Conclusions Loss of expression of PTEN does not confer poor overall survival in the temozolomide era. These findings imply a complex and non-linear molecular relationship between PTEN, its regulators and effectors in the tumorigenesis of glioblastoma. Additionally, there is evidence that temozolomide may be more effective in eradicating GBM cancer cells with PTEN loss and hence, level the outcomes between the PTEN retained and loss groups.

Clinical Practice Experience With NovoTTF-100A™ System for Glioblastoma: The Patient Registry Dataset (PRiDe)

Recurrent glioblastoma multiforme (GBM) is a highly aggressive cancer with poor prognosis, and an overall survival of 6 to 7 months with optimal therapies. The NovoTTF-100A™ System is a novel antimitotic cancer therapy recently approved for the treatment of recurrent GBM, based on phase III (EF-11) trial results. The Patient Registry Dataset (PRiDe) is a post-marketing registry of all recurrent GBM patients who received NovoTTF Therapy in a real-world, clinical practice setting in the United States between 2011 and 2013. Data were collected from all adult patients with recurrent GBM who began commercial NovoTTF Therapy in the United States between October 2011 and November 2013. All patients provided written consent before treatment was started. Overall survival (OS) curves were constructed for PRiDe using the Kaplan-Meier method. Median OS in PRiDe was compared for patients stratified by average daily compliance (≥75% v<75% per day) and other prognostic variables. Adverse events were also evaluated. Data from 457 recurrent GBM patients who received NovoTTF Therapy in 91 US cancer centers were analyzed. More patients in PRiDe than the EF-11 trial received NovoTTF Therapy for first recurrence (33% v 9%) and had received prior bevacizumab therapy (55.1% v 19%). Median OS was significantly longer with NovoTTF Therapy in clinical practice (PRiDe data set) than in the EF-11 trial (9.6 v 6.6 months; HR, 0.66; 95% CI, 0.05 to 0.86, P = .0003). One- and 2-year OS rates were more than double for NovoTTF Therapy patients in PRiDe than in the EF-11 trial (1-year: 44% v 20%; 2-year: 30% v 9%). First and second versus third and subsequent recurrences, high Karnofsky performance status (KPS), and no prior bevacizumab use were favorable prognostic factors. No unexpected adverse events were detected in PRiDe. As in the EF-11 trial, the most frequent adverse events were mild to moderate skin reactions associated with application of the NovoTTF Therapy transducer arrays. Results from PRiDe, together with those previously reported in the EF-11 trial, indicate that NovoTTF Therapy offers clinical benefit to patients with recurrent GBM. NovoTTF Therapy has high patient tolerability and favorable safety profile in the real-world, clinical practice setting.

Retrospective analysis of the tolerability and activity of lacosamide in patients with brain tumors: clinical article.

OBJECT The object of this study was to determine the tolerability and activity of lacosamide in patients with brain tumors. METHODS The authors reviewed the medical records at 5 US academic medical centers with tertiary brain tumor programs, seeking all patients in whom a primary brain tumor had been diagnosed and who were taking lacosamide. RESULTS The authors identified 70 patients with primary brain tumors and reviewed seizure frequency and toxicities. The majority of the patients had gliomas (96%). Fifty-five (78%) had partial seizures only, and 12 (17%) had generalized seizures. Most of the patients (74%) were started on lacosamide because of recurrent seizures. Forty-six patients (66%) reported a decrease in seizure frequency, and 21 patients (30%) reported stable seizures. Most of the patients (54 [77%]) placed on lacosamide did not report any toxicities. CONCLUSIONS This retrospective analysis demonstrated that lacosamide was both well tolerated and active as an add-on antiepileptic drug (AED) in patients with brain tumors. Lacosamides novel mechanism of action will allow for concurrent use with other AEDs, as documented by its activity across many different types of AEDs used in this patient population. Larger prospective studies are warranted.

Multi-platform molecular profiling of a large cohort of glioblastomas reveals potential therapeutic strategies.

Glioblastomas (GBM) are the most aggressive and prevalent form of gliomas with abysmal prognosis and limited treatment options. We analyzed clinically relevant molecular aberrations suggestive of response to therapies in 1035 GBM tumors. Our analysis revealed mutations in 39 genes of 48 tested. IHC revealed expression of PD-L1 in 19% and PD-1 in 46%. MGMT-methylation was seen in 43%, EGFRvIII in 19% and 1p19q co-deletion in 2%. TP53 mutation was associated with concurrent mutations, while IDH1 mutation was associated with MGMT-methylation and TP53 mutation and was mutually exclusive of EGFRvIII mutation. Distinct biomarker profiles were seen in GBM compared with WHO grade III astrocytoma, suggesting different biology and potentially different treatment approaches. Analysis of 17 metachronous paired tumors showed frequent biomarker changes, including MGMT-methylation and EGFR aberrations, indicating the need for a re-biopsy for tumor profiling to direct subsequent therapy. MGMT-methylation, PR and TOPO1 appeared as significant prognostic markers in sub-cohorts of GBM defined by age. The current study represents the largest biomarker study on clinical GBM tumors using multiple technologies to detect gene mutation, amplification, protein expression and promoter methylation. These data will inform planning for future personalized biomarker-based clinical trials and identifying effective treatments based on tumor biomarkers.

Profiles of brain metastases: Prioritization of therapeutic targets: Profiling brain metastases

We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next‐generation sequencing with a targeted 47‐gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

Adult Brainstem Glioblastoma Multiforme: Long-term Survivor

Adult, malignant brainstem gliomas are rare entities that often cause treatment conundrums due to the difficulty of surgical resection and, therefore, the absence of pathological diagnosis. This leads to a reliance on radiological imaging for diagnosis, which can often be unreliable. These shortcomings have made the treatment of brainstem gliomas challenging with unpredictable outcomes. The mainstay of treatment consists of chemotherapy and radiation; however, recurrence is inevitable. Predicting outcomes has been the major difficulty in treating these patients as adult malignant brainstem gliomas Grade II have a median survival between five to seven years while Grades III and IV are between 10-17 months (with some studies showing significantly longer survival in Grade III). Here, we present the case of a patient with the pathologic diagnosis of a right brachium pontis glioblastoma who had a remarkable survival of 73 months, whereas the expected median survival for these patients is 10-17 months.

Abstract 2692: Nanoconjugates for inhibition of laminin-411-integrin β1-Dll4-Notch1 pathway to treat glioblastoma multiforme

Glioblastoma multiforme (GBM) is an aggressive tumor with 14.6 months median survival rate. We have previously shown that laminin-411, a vascular basement membrane (BM) protein is a marker of tumor blood vessels that correlates with aggressiveness of GBMs. The laminin-411 pathway involving its β1 chain-containing integrin receptors, and ligand Dll4 for cancer stem cell (CSC) Notch1 was studied in mouse xenograft models to better understand glial tumor growth and new vasculature system development. To confirm the importance of laminin-411 expression for GBM progression and outcome prediction, sections from formalin-fixed paraffin embedded human brain tumors were studied. Immunohistochemical analysis of 107 GBM samples has revealed 87% cases with overexpression of laminin-411, whereas it was only 34% for high-grade (III) and 10.6% for low-grade (I/II) gliomas. The median survival for patients with GBM overexpressing laminin-411 was 10 months, compared to 20.2 months for those expressing “normal” laminin-421. The median recurrence rate was 5.6 and 9.3 months respectively. Morphometric analysis of CSC Notch1, nestin, CD133, and c-myc was correlated with laminin-411 overexpression in patients with high-grade gliomas. Nanobioconjugate PolycefinTM was synthesized to block BM laminin-411 in mice bearing intracranial human U87MG-derived GBM. Two antisense oligonucleotides against laminin-411 α4 and β1 chains were covalently attached on polymalic acid nanoplatform. The nanodrug, PolycefinTM, was able to cross blood brain tumor barrier and delivered drugs into cancer cells (Ding et al. 2010, 2013) using pH-dependent endosome releasing unit Leu-Leu-Leu. Evidence of cross talk was observed between BM, CSCs and tumor proliferation when mice were treated with PolycefinTM. It is shown that blocking synthesis of laminin-411 leads to significally lower tumor expression of integrin β1 chain, Notch ligand Dll4, and Notch1. The CSC markers nestin, CD133, and c-myc that are known indicators of glial tumor progression also showed quantitative reduction by morphometric analysis in tumors of mice treated with anti-laminin-411 Polycefin compared to PBS-treated animals. The data point to the importance of laminin-411-integrin β1-Dll4-Notch1 pathway in GBM development and to the ability of Polycefin to negatively impact CSC as a possible mechamism of GBM inhibition. The results provide new insights in glioma microenvironment and tumor endothelial and parenchymal cell signaling suggesting a novel approach for future therapeutics to target CSCs in vivo through inhibition of laminin-411 to treat highly infiltrating GBMs. Citation Format: Pallavi R. Gangalum, Alexander V. Ljubimov, Alexandra Chesnokova, Bindu Konda, Hui Ding, Jose Portilla-Arias, Adam Mamelak, Serguei Bannykh, Surasak Phuphanich, Jeremy Rudnick, Jethro Hu, Keith L. Black, Julia Y. Ljubimova. Nanoconjugates for inhibition of laminin-411-integrin β1-Dll4-Notch1 pathway to treat glioblastoma multiforme. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2692. doi:10.1158/1538-7445.AM2014-2692

415OALTERNATING ELECTRIC FIELDS THERAPY FOR RECURRENT GLIOBLASTOMA - NOVOTTF-100A SYSTEM: UPDATED OUTCOMES AND TOXICITY BASED ON THE ANALYSIS OF PATIENT REGISTRY DATA

ABSTRACT Aim: To present updated outcomes and toxicity data from patients with recurrent glioblastoma treated with the commercially available NovoTTF-100A System using patient registry database. Methods: The NovoTTF-100A device has been available by prescription at 126 oncology centers in the United States since November 2011. We retrospectively analyzed the outcomes and toxicity data from patients who were prescribed the device from November 2011 to November 2013 as treatment for recurrent glioblastoma. Overall survival (OS) was calculated based on social security death registry data. It was defined as the time from the treatment start until the date of death or last known date patient was alive. We analyzed performance status, compliance records, treatment history and adverse effects for all subjects. Results: There were 148 female and 309 male patients (n = 457) who were treated with NovoTTF-100A System. The median age was 55 years (range 18 to 86). Median Karnofsky Performance Status (KPS) was 80 (range 10-100) and 33% of patients were at their first recurrence when therapy was initiated. Over half of the patients (n = 252) received bevacizumab prior to NovoTTF- 100A therapy. The median OS was 9.6 (95% [CI] 8.0 to 13.7) months and the median treatment duration was 4.1 (95% [CI] 3.5 to 4.8) months. The average patient compliance with the use of the device was 70%. OS was positively correlated with higher compliance (= > 75%) and KPS (70-100), and negatively correlated with recurrence number and prior use of bevacizumab. Debulking surgery prior to the introduction of NovoTTF-100A therapy did not influence OS. The most common device-related adverse events included skin reactions (24.3%), neurological disorders (10.4%), heat sensation (8.9%), electric sensation (7.7%) and headache (5.7%). Conclusions: Treatment with NovoTTF-100A System, as prescribed in the neuro-oncology clinical practice to patients with recurrent glioblastoma offers favorable outcomes when compared to historical data. Patient compliance with the prescribed use of the system is high and positively correlates with improved survival. Bevacizumab naive patients benefit more while patients with poor KPS and multiple prior recurrences benefit less from this treatment. NovoTTF-100A System is well tolerated and has no new unexpected toxicities since its introduction to clinical practice. Disclosure: M.M. Mrugala: On Advisory Board of Novocure. PI on the clinical trial sponsored by Novocure; H.H. Engelhard: I have participated in Novocures Advisory Boards; N. Butowski: I participated in Novocures Advisory Board; D.D. Tran: I have received honorarium from Novocure for advisory board and speaker bureau; Y. Kew: I have participated in Novocures Advisory Boards; R. Cavaliere: I have been a consultant for Novocure; J. Villano: Member of a speakers bureau and served on an advisory board for Novocure. D. Bota: Novocure Advisory Board; S. Kesari: I have received funding for advisory board meetings and clinical trials sponsored by Novocure; J. Rudnick: I have been a consultant for Novocure; A. Sumrall: I have been a Faculty Speaker and participated in an Advisory Board for Novocure; J.J. Zhu: Novocure Advisory Board; E.T. Wong: I received research funding from Novocure.