bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex-specific mortality trends in adolescents and young adults with cancer from 2007 to 2016.
Authors: Close Allison , Seynnaeve Brittani , Miller Kimberly , Rapkin Louis
Published: May 2019

1570

Background: Adolescents and young adults (AYA) aged 15-39 years make up approximately 70,000 new oncology cases in the USA. Historically, mortality from cancer has smaller incremental improvements in AYA patients when compared to children and older adults, and not much is known about current sex-specific trends. We assessed overall and sex specific AYA mortality for the last 10 years (2007-2016). Methods: Trends in age-adjusted mortality rates per 100,000 (1972-2016) were obtained from the CDC’s National Center for Health Statistics (NCHS). Average annual percent changes (AAPCs) in relative survival were analyzed using NCI’s JPSurv webtool and mortality AAPCs were quantified using Joinpoint regression analysis. Results: Overall declines in mortality are similar in AYA men and women from 1972-2016, with 54% and 51% decline, respectively. In the most recent 10 years of data (2007 to 2016), combined sex AYA mortality AAPC’s declined by about 0.8% per year, slightly slower than declines in children <15 years (1.3% per year) and adults ages >40 years (1.5% per year). Among AYA males there have been 10 year AAPC mortality declines in leukemia (-1.8%), Hodgkin lymphoma (HL) (-5.1%), Non-Hodgkin lymphoma (NHL) (-4.1%) and melanoma of the skin (-3.4%). For AYA females, 10 year AAPC mortality declines occurred in leukemia (-1.9%), ovarian (-1.5%), HL (-10%), NHL (-4.9%) and melanoma (-2.8%). These declines have been offset by stable or increasing mortality rates for several common AYA cancers, including colorectal cancer (CRC) (1.1%) and bone and joint cancer (0.6%) in AYA males. AYA females have experienced mortality increases for CRC (0.6%), bone and joint cancer (0.5%) and uterine corpus cancer (2.8%). Conclusions: In general, mortality rates for both AYA men and women have declined over the past 10 years due to decreased mortality in hematologic malignancies and melanoma. Despite overall improvement, tumor categories in both AYA males and female such as CRC, bone and joint cancer, and uterine corpus cancers show increasing mortality. These diseases require specific investigations by both pediatric and adult researchers.
Genomic profiling of pulmonary lymphoepithelioma-like carcinoma (PLELC).
Authors: Zhou Chengzhi , Xie Zhanhong , Qin Yinyin , Liu Laiyu , Zhang Hua , Feng Weineng , Xie Xiaohong , Lin Xinqing , Zhang Jiexia , Ouyang Ming , Gu Yingying , Li Bing , Han-Zhang Han , Liu Jing , Mai Suiyi , Chen Shuyin , Zhang Lu
Published: May 2019

1572

Background: PLELC, a rare and distinct type of primary lung cancer, is characterized by Epstein-Barr virus (EBV) infection. Histologically, it resembles undifferentiated nasopharyngeal carcinomas (NPC). Only a few hundred cases have been reported since its discovery. Due to the extreme rareness, its genomic landscape remains elusive. Methods: Tissue samples of 27 PLELC patients (13 males and 14 females) with various stages (Ib to IV) were subjected to targeted sequencing using a panel consisting of 520 cancer-related genes, spanning 1.6Mb of human genome. Results: Collectively, we identified 184 somatic mutations spanning 109 genes, including 107 SNVs, 12 insertions or deletions (INDELs) and 65 copy-number amplifications (CNAs). Approximately, 50% of patients had CNAs. One patient had no mutation detected from this panel. Except for 2 patients, 1 with HER2 amplification and another with KRAS mutation, no other classic NSCLC driver genes were detected. The most frequently mutated genes were CCND1, TP53, DAXX and NF kBIA, occurring in 30%, 26%, 22% and 22% of patients, respectively. Interestingly, 78% (21/27) patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in epigenetics-related genes. Pathway analysis also revealed an enrichment of genes participating in chromatin remodeling and organization. Next, we compared the genomic profile of PLELC with lung adenocarcinoma and EBV positive NPC. The frequency of TP53 mutations was significantly higher in lung adenocarcinoma (68% vs 26%, p = 0.021). Comparing to NPC, PLELC had significantly more mutations in epigenetic regulators. TMB analysis revealed a median TMB of 1.6/Mb, significantly lowered than lung adenocarcinomas (p < 0.01). We also assessed PD-L1expression and revealed that 67% had an overexpression of PD-L1. Interestingly, TP53-mutant patients were more likely to associated low PD-L1 expression (p < 0.01). Conclusions: In this study, we elucidated a distinct genomic landscape associated with PLELC with no classic NSCLC driver mutation but an enrichment of mutations in epigenetic regulators. The observation of high expression of PD-L1 and lack of canonical druggable driver mutation raises the potential of immunocheckpoint blockade therapy for PLELC.
Characterization of genomic alterations in Chinese LCNEC and SCLC via comprehensive genomic profiling.
Authors: Wu Lin , Cao Liming , Chen Likun , Zhu Bo , HU Xiaohua , Gen Lin , Lin Yingcheng , Zhang Sheng , Huang Cheng , Peng Wenying , Jiang Meilin , Mao Xinru , Zhang Tengfei , Ye Junyi , Zhang Lu
Published: May 2019

1575

Background: LCNEC and SCLC are aggressive neuroendocrine carcinomas with overlap in clinical, histopathologic, morphologic and genomic features. Differential molecular features between the two subtypes have not been well elucidated, contributing the uncertainty for optimal clinical strategy for each subtype. Here we interrogated the genomic characteristics in LCNEC as compared to SCLC along with their histologically related subtypes: carcinoids and atypical carcinoids via comprehensive genomic profiling. Methods: FFPE samples from 31 LCNECs, 35 SCLCs, 14 carcinoids and 22 atypical carcinoids were sequenced in a CLIA-certified sequencing laboratory using 520-cancer-related gene panel, with an average sequencing depth of 1385×. Results: Comparative mutational analysis revealed that both LCNEC and SCLC sub-cohorts displayed higher rate of TP53 alterations than that of carcinoid (p < 0.001, p < 0.001). SCLC patients harbored more RB1 and PIK3CA mutations than LCNECs (p < 0.001, p = 0.014) and carcinoids (p < 0.001, p = 0.018). In addition, mutation frequencies of LRP1B, FAT1, PRKDC, NOTCH1, SPTA1, EPHA3 and KEAP1 in SCLC were significantly higher than that in carcinoid. Mutations in TP53 and RB1 occurred concurrently in 83% (29/35) SCLC patients, whereas in only 32.3% (10/31) LCNECs. We further investigated the distribution of mutations across KEGG pathways and found that mutation frequencies in both HIF-1 and Notch signaling pathways were lower in LCNEC than SCLC (p = 0.032, p = 0.025). Copy number variation (CNV) analysis revealed that LCNEC and SCLC had comparable CNVs which were significantly higher than carcinoid (p < 0.001, p < 0.001) and atypical carcinoid (p = 0.010, p = 0.028). TMB analysis also revealed a comparable TMB status of LCNEC (12.7/Mb) and SCLC (11.9/Mb), and relatively lower TMB in both carcinoid (2.4/Mb, p < 0.001, p < 0.001) and atypical carcinoid (5.6/Mb, p = 0.003, p = 0.009) than LCNEC and SCLC. Conclusions: We demonstrated the differential genomic characteristics in the four subtypes of neuroendocrine carcinomas. Compared with SCLC, LCNEC has lower mutation frequencies in RB1, PIK3CA, as well as HIF-1 and Notch signaling pathways. In addition, LCNEC and SCLC had comparable CNV and TMB status, which significantly higher than that of carcinoids and atypical carcinoid.
Tumor sequencing with germline genetic testing: Identification of patients with hereditary cancer and precision treatment eligibility.
Authors: Michalski Scott T. , Pineda Alvarez Daniel Esteban , Russell Meaghan , Yang Shan , Sonpavde Guru , Esplin Edward D.
Published: May 2019

1580

Background: Cancer is a fundamentally genetic disease, as such, somatic and germline mutation analysis is used in the comprehensive assessment of patients with cancer. Studies report that approximately 10% of patient’s tumors have clinically significant variants known to predispose to hereditary cancer, with medical implications for both patients and family members. We retrospectively reviewed a series of patients where providers suspected a somatic variant also existed in the germline and followed up with clinical germline genetic testing. We report the rate of concordance between germline and somatic results and their clinical impact. Methods: Our study used de-identified data from 1043 consecutive patients who underwent somatic genetic testing followed by germline testing with NGS-based hereditary cancer gene panels. Results: Somatic results most frequently prompting germline testing included variants in BRCA2 (290), BRCA1 (174), TP53 (158), ATM (70), MLH1 (65), APC (65), PMS2 (61), MSH6 (58), PTEN (54) and CDH1 (42). In 364/1043 cases (35%) the variant was detected as likely pathogenic or pathogenic (LP/P) in the germline. Genes confirmed as germline variants in 60-100% of cases included: FANCA, AXIN2, RAD50, MUTYH, BLM, PALB2, CHEK2, FANCD2, MITF, SDHB. Variants in: FH, BRCA2, RET, ATM, SDHA, BRIP1, MSH2, BRCA1, BAP1, EGFR and RAD51D confirmed in the germline in 25-60%. Variants were rarely germline for TP53 (3%), APC (3%), PTEN (2%) and none in CDKN2A, NF1 and STK11. In 24 (2%) cases a LP/P germline variant was detected but not reported in the tumor. Conclusions: Approximately ⅓ of patients suspected to have hereditary risk after tumor testing had LP/P germline variants. Notably, some genes had a high probability of variants occurring in the germline, while others were primarily seen in tumors. Interestingly, 6% of the germline variants were not included on the somatic report due to technical and gene content differences in either assays or due to differences of clinical classification between somatic and germline testing. Adding germline results to somatic testing may inform options for precision treatment, prevention, or early detection of, secondary malignancies and guide genetic counseling of family members.
Comprehensive germline multigene panel testing changes clinical care for patients with breast cancer: Untapped clinical utility and PARP inhibitor trial eligibility.
Authors: Beitsch Peter D. , Whitworth Pat W. , Hughes Kevin S. , Patel Rakesh , Baron Paul , Rosen Barry , Grady Ian , Holmes Dennis , Simmons Rache M. , Smith Linda Ann , Compagnoni Gia , Coomer Cynara L. , Brown Eric Allen , Barbosa Karen , Clark Patricia , Gold Linsey P. , Riley Lee B. , Esplin Edward D. , Yang Shan , Nussbaum Robert L.
Published: May 2019

1583

Background: HBOC testing guidelines were established to identify patients with clinically actionable variants and limit economic burden. We report the impact of germline results on health outcome based on clinical decision making and treatment interventions, regardless of guidelines, in a multi-center registry. Methods: 20 community-based and academic participated in an IRB approved registry. Patients with breast cancer were tested with an 80-gene panel; clinical information was collected. Results: Data on 912 patients has been analyzed to date. 50.5% met NCCN criteria; 49.5% did not. Pathogenic/likely pathogenic (P/LP) germline mutations were found in 8.65% of patients. Of all patients with P/LP findings, 85% had variants in cancer-risk genes with established management recommendations and 80% had germline variants conferring eligibility for clinical trials and precision medicine-based cancer treatments, such as PARP inhibitors. For 62% of patients with P/LP germline mutations, clinicians reported results impacted patients’ health outcome. And for 69%, results impacted the health outcome of patients’ relatives. There was no significant association between BRCAPRO scores and patients having a P/LP finding, whether in BRCA1/2 alone (p = 0.42) or for any cancer gene (p = 0.57). Physician reported impact on patient outcome associated significantly with the presence of P/LP germline findings (p < 0.00001). There was no significant difference in the clinician reported clinical utility of variants of uncertain significance (VUS) compared to negative results (p = 0.467). Conclusions: Comprehensive panel testing of breast cancer patients impacts physician assessed patient outcomes and informs changes in surgical treatment strategy, medical therapies and proactive screening. The data suggest that BRCAPRO calculators are poor predictors of germline presence of P/LP findings. Physicians in this study demonstrate the ability to discern the clinically actionable value of P/LP mutations from non-actionable VUS. Multigene panels impact breast cancer patient care by identifying precision medicine treatment interventions, and guiding long-term medical management and preventive surveillance for patients and family members.
Randomized phase IIb clinical trial of continuation or non-continuation with six cycles of temozolomide after the first six cycles of standard first-line treatment in patients with glioblastoma: A Spanish research group in neuro-oncology (GEINO) trial.
Authors: Balana Carmen , Mesia Barroso Carlos , Berron Sonia Del Barco , Pineda Losada Estela , Muñoz-Langa José , Estival Anna , De las Peñas Ramon , Fuster Jose , Gil Gil Miguel J. , Navarro L Miguel , Alonso Miriam , Herrero Ana , Vaz Salgado María Ángeles , Peralta Sergi , Olier Clara , Pérez-Segura Pedro , Covela Rúa Marta , Carrato Cristina , Sanz Carolina , Sepulveda-Sanchez Juan Manuel
Published: May 2019

2001

Background: The GEINO-14-01 trial (NCT02209948) investigated the role of extending temozolomide (TMZ) for 6 cycles after the standard 6 cycles to improve 6m-PFS, SLP and OS in newly diagnosed glioblastoma (GBM) patients (p). Methods: Between 08/2014 and 11/2018, 166 p were screened and 159 randomized to extend (80p) or not (79p) TMZ treatment for 6 cycles after proving stable disease in the MRI performed before inclusion. Centralized review of histology and determination of MGMT status, if not previously available, were performed before randomizing patients. Two criteria of stratification were used: MGMT status and presence/absence of residual disease on the basal MRI (defined as a residual enhancement larger than 1cm in one). The primary endpoint was differences in 6mPFS, secondary endpoints were differences in PFS, OS, toxicity, between arms and per stratification factors. Results: Median age was 60.3 (range 29-83), 97p (61%) were methylated, basal MRI showed residual disease in 57p (35.8%). After a median follow up of 14.0 months, with 121 p(76.1%) already progressed and 81p (50.9%) already dead, median PFS is presented. Median (m) PFS is 8.0 months (95%CI: 5.7-10.2). There is no difference in mPFS between arms (adjusted HR = 0.98, 95% CI: 0.82-1.18, P = 0.907). Methylated tumors had longer mPFS (HR=0.57, 95% CI: 0.39-0.83, P=0.004) irrespectively to the study treatment. Conclusions: There is not apparent benefit of continuing TMZ treatment for more than 6 cycles. Data will be actualized for the congress.Supported by a Grant of the ISCIII: PI13/01751. Clinical trial information: NCT02209948.
A phase I study of convection-enhanced delivery of 124I-8H9 radio-labeled monoclonal antibody in children with diffuse intrinsic pontine glioma: An update with dose-response assessment.
Authors: Souweidane Mark M. , Kramer Kim , Pandit-Taskar Neeta , Zhou Zhiping , Zanzonico Pat , Donzelli Maria , Lyashchenko Serge K. , Haque Sofia , Thakur Sunitha B , Cheung Nai-Kong V. , Larson Steven M. , Dunkel Ira J.
Published: May 2019

2008

Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for efficiently distributing therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard phase I dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion of radiation therapy. Seven dose levels of a single injection of 124I-8H9 (Omburtamab) (range 0.25 to 4.0 mCi) were studied. Results: 37 children were treated with 34 evaluable for primary and secondary endpoints. The median age at enrollment was 6.8 years old (range 3.2 - 17.9). There was no dose limiting toxicity (DLT). Among adverse events that were at least possibly related to the treatment, there were no grade 4 or 5 events, and only 4 reversible grade 3 events in 4 patients (2 hemiparesis, 1 skin infection and 1 anxiety). Estimations of distribution volumes based on T2-weighted imaging were dose dependent and ranged from 1.5 to 20.8 cm3, and for dose level 7, 10.5 - 19.0 cm3. The mean volume of distribution/volume of infusion ratio (Vd/Vi) was 3.4 ±1.1, and for dose level 7, 3.5 ± 1.0. The mean lesion absorbed dose was 33.3 ± 25.9 Gy, and for dose level 7, 50.1 ± 22.9 Gy. The mean ratio of lesion-to-whole body absorbed dose was 910. The mean volume of distribution/tumor volume ratio on dose level 7 was 82.5%, but the mean tumor overlap was 40.5%. No death occurred as a result of the treatment. Median survival was 15.3 months (n = 29, 95% CI 12.7 - 17.4). Median follow-up time of the 5 surviving patients is 27.2 months (range 11.5 - 72.4). Overall survival rate at 12 months was 64.7% (22/34, 4 alive), and overall survival rate at 24 months 14.7% (5/34, 3 alive). Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. An infusion volume of 4,000 mcl appears to be a reasonable single dose for a target distribution volume but enhanced tumor coverage is likely needed. There seems to be a survival benefit using this therapeutic strategy and outcomes might be dependent on dosimetry and distribution patterns. Clinical trial information: NCT01502917.
Circulating tumor DNA analysis (ctDNA) for genomic testing in NSCLC patients with isolated CNS progression.
Authors: Aldea Mihaela , Mezquita Laura , Hendriks Lizza , Auclin Edouard , Remon Jordi , Planchard David , Jovelet Cecile , Benitez Jose Carlos , Gazzah Anas , Lavaud Pernelle , Naltet Charles , Lacroix Ludovic , Morris Clive D. , Green Emma , Howarth Karen , Nicotra Claudio , Besse Benjamin
Published: May 2019

2015

Background: Genomic DNA profiles are mandatory in advanced, treatment naive non-small cell lung cancer (NSCLC) patients (pts) and strongly recommended at progression (PD) on personalized treatment. In pts with PD limited to central nervous system (CNS), tissue biopsy is difficult and the performance of ctDNA is unknown. Methods: Clinical, molecular, imaging data of NSCLC pts included in 2 prospective studies from 01.2016 to 11.2018 at Gustave Roussy were collected. Inclusion criteria were: stage IV disease and any known tissue genomic alteration (GA) EGFR, ALK, BRAF, KRAS, HER2, ROS1, MET, PIK3CA, TP53. Plasma ctDNA collected at baseline/PD were analyzed by next-generation sequencing (NGS-InVisionFirst™-Lung) in 3 groups: pts with isolated CNS (iCNS), extra-CNS only (noCNS) or both combined (cCNS) disease. iCNS was defined as any PD to CNS, while stable/absent extra-CNS metastases (mts). ctDNA was considered positive if ≥1 GA was found. ctDNA in cerebrospinal fluid (CSF) were also collected. Results: Out of 245 pts with ≥1 ctDNA: 56 had iCNS (66 samples), 97 noCNS (127 samples) and 92 cCNS (107 samples). In this cohort, 60% were female, median age 60 years, 47% smokers; 92% had adenocarcinoma. The median number of mts sites was 3 in noCNS/cCNS groups. Proportions of tissue GA at baseline were (iCNS vs noCNS/cCNS): EGFR (50% vs 44%), ALK (30% vs 11%), BRAF (4% vs 12%), KRAS (5% vs 15%), HER2 (2% vs 5%), ROS1 (5% vs 4%). Tyrosine kinase inhibitors were used in 73% iCNS vs 61% noCNS/cCNS. Local brain treatments were performed in 43% (n = 24) vs 32% (n = 29) and leptomeningeal mts (LM) detected in 34% (n = 19) vs 8% (n = 9), in iCNS and cCNS, respectively. CtDNA was positive (+) in 52% in iCNS vs 84% in noCNS and 92% in cCNS (p < 0.0001). In iCNS, there was a non-significantly higher proportion of + ctDNA in pts with LM vs only brain disease (59 vs 48%, P = 0.44). 12/56 pts of iCNS group had serial ctDNA, being collected also at time of cCNS. In 25% of cases, a negative ctDNA at time of iCNS shifted to + at time of cCNS. In 12 iCNS pts, ctDNA was + in 6 (50%) plasma and in 10 (83%) paired CSF (p = 0.193). Conclusions: Detection of GA by plasma ctDNA is lower in NSCLC pts with isolated CNS PD. Alternative strategies (as CSF analysis) should be explored.
Longitudinal analysis of quality of life following treatment with asunercept plus reirradiation versus reirradiation in progressive glioblastoma patients.
Authors: Wick Wolfgang , Krendyukov Andriy , Junge Klaus , Höger Thomas , Kunz Claudia , Fricke Harald
Published: May 2019

2022

Background: Palliation of symptoms and the maintenance of quality of life (QoL) are important goals in cancer treatment.1,2 Beyond progression free survival (PFS) and overall survival (OS), health related QoL was one of the secondary endpoints in the asunercept plus irradiation Phase II trial (NCT01071837) in recurrent glioblastoma.3 Current analysis presents time to deterioration (TtD) of QoL using data from this study. Methods: Data from patients (pts) with a baseline and ≥1 post-baseline QoL assessment were included in this analysis. TtD was defined as the time from randomization to the first deterioration in the EORTC QLQ-C15, PAL EORTC QLQ-BN20 and Medical Research Council (MRC)-Neurological status. Deterioration was defined as a decrease of ≥10 points from baseline in the QLQ-C15 PAL overall QoL and functioning scales, an increase of ≥10 points from baseline in the QLQ-C15 PAL fatigue scale and the QLQ-BN20 total sum of score, and a rating of “Worse” in the MRC-Neurological status. Pts without a deterioration were censored at the last QoL assessment. Kaplan-Meier estimates were used to describe TtD and both treatment groups compared using the logrank test. The relationship between progression of disease (PD) and QoL deterioration has been investigated. Results: Compared to reirradiation alone, treatment with asunercept + reirradiation was associated with significant improvement of TtD (P≤0.01; Table). PD was a key driver for QoL deterioration and the median TtD was comparable with PFS in favour of the asunercept treatment arm. Conclusions: Treatment with asunercept plus irradiation significantly prolongs TtD and maintains QoL, versus reirradiation alone in progressive glioblastoma patients. Clinical trial information: NCT01071837. References: 1. NCCN. Central Nervous System Cancers. Version 2018.2; 2. Stupp R et al. Ann Oncol 2014;25(S3):iii93-iii101; 3. Wick et al. Clin Cancer Res 2014;20:6304–13.[Table: see text]
Study of tumor infiltrating immune CELLS and vasculature in human gliomas: Differences in IDH1/2 mutant versus IDH1/2WT tumors.
Authors: Martin Soberón Maria Cruz , Sepulveda Sanchez Juan Manuel Manuel , Gargini Ricardo , Segura Berta , Gutierrez Jacquelin , Ruano Yolanda , Cantero Diana , Hernandez-Lain Aurelio , Sanchez-Gomez Pilar , Perez-Núñez Angel , Jimenez Roldan Luis , Marín Patricia , Castellano Daniel E. , De Velasco Guillermo , Cejalvo Teresa
Published: May 2019

2030

Background: Gliomas harboring mutations in IDH1/2 show a higher overall survival time than “wild type” (wt) tumors. Although the clinical aspects are well described, little is known about the underlying mechanisms by which these mutations generate such a difference in the clinical course. Our group has recently described that IDH1/2 mutations induce a distinct vascular phenotype in the tumors, with less blood-brain barrier (BBB) leakage than the IDH1/2 wt gliomas (In Press, DOI:10.1101/541326). Methods: Prospective study analyzing a cohort of 20 patients with primary gliomas resected in one institution. Samples were obtained in the first surgery and 12 IDHmut and 8 IDHwt gliomas were included. Immune infiltration was analysed by flow cytometry and vasculature by inmunohistochemistry. For molecular biology studies, western blots were performed with Mini-PROTEAN system. Proteins were visible by enhanced chemoluminescence. Results: We show that the immune component also differentiates these two pathologies. There is significantly less immune infiltration in IDH1/2 mutant gliomas. Within the CD45 subset, IDH1/2 mutant gliomas have a reduced proportion of T lymphocytes with a different T cell exhaustion profile and an increased proportion of CD11b+ cells in comparison to IDH1/2 wt cases. Myeloid compartment distribution is also different in these two types of tumors, showing an augmented proportion of the M2 (CD206+) and the neutrophil subsets in IDH1/2 wt gliomas. Moreover, a higher proportion of CD45 PDL1+ was present in the IDH1/2 wt tumors samples. The analysis of the vasculature showed an increase density and the lumen size of the vessels of the IDH1/2 wt compared to the IDH1/2 mutant gliomas which correlate with changes in the immune profile. The biochemical analysis showed that there is an increment in EGFR and PDGFR activity in the IDH wt gliomas that is related with more vascular aberrations and higher CD45 infiltrate. This suggests that EGFR and PDGFR are the key regulators of the tumor microenvironment. Conclusions: To understand the matching between the immune infiltration and vasculogenesis is relevant for interpreting data coming from the clinical trials with checkpoints inhibitors. At the time abstract submission survival analysis is not yet available due to the short time of follow-up but in May 2019, the number of expected events for analysis will be reached.
MDNA55: A locally administered IL4 guided toxin as a targeted treatment for recurrent glioblastoma.
Authors: Randazzo Dina , Achrol Achal , Aghi Manish K. , Bexon Martin , Brem Steven , Brenner Andrew Jacob , Butowski Nicholas A. , Chandhasin Chandtip , Chowdhary Sajeel A. , Coello Melissa , Floyd John , Kesari Santosh , Merchant Fahar , Merchant Nina , Vogelbaum Michael A. , Vrionis Frank D , Zabek Miroslaw , Sampson John H.
Published: May 2019

2039

Background: IL4 receptor (IL4R) is frequently and intensely expressed on a variety of human cancers and is associated with poor survival outcomes. Determining the role of the IL4R biomarker in glioblastoma (GBM) will be important for treatment with targeted therapies such as the IL4 fusion toxin MDNA55. Methods: A classification for IL4Rα expression in GBM tissues by H-Score was developed using a validated immunohistochemistry-based approach. MDNA55-05 is an open-label study of MDNA55 administered intratumorally via convection enhanced delivery in recurrent GBM. Levels of IL4Rα expression were assessed retrospectively in 24 subjects in the clinical trial and were correlated with GBM history, imaging responses and survival outcomes following treatment with MDNA55 to explore clinical validation. Results: Range, linearity, specificity and sensitivity testing using a rabbit polyclonal antibody to IL4Rα were performed using normal cortex (negative control) and a panel of normal human tissues and GBM cases from tissue banks. A total of 41 GBM samples were screened and grouped by reactivity thresholds: H-Scores ≥50 were observed in 95% of cases (39/41), H-Scores ≥200 were observed in 51% of cases (21/41), and H-Scores ≥250 were observed in 24% of cases (10/41). GBM tissues obtained at initial diagnosis from subjects enrolled in the trial show that moderate/high IL4R expression (H-Score > 75) was associated with shorter time to first relapse when compared to subjects with low IL4R expression (H-Score ≤ 75) (10.3 mos vs. 16.7 mos, respectively) after upfront standard-of-care treatment, consistent with published findings that IL4R expression is associated with more aggressive disease. Remarkable decreases in tumor size seen in some subjects following MDNA55 treatment were associated only with moderate/high IL4R expression and survival rate at 12 months in this group was also improved (OS12 = 55%) compared to subjects with low IL4R expression (OS12 = 30%). Conclusions: Treatment options for patients with recurrent GBM are very limited and positive outcomes remain rare. Targeting therapies such as MDNA55 by IL4R status may improve patient outcomes and help guide patient selection strategies for future clinical studies. Clinical trial information: NCT02858895.
Interim results of a phase I/IIa trial of a therapeutic CMV vaccine against recurrent glioblastoma (GBM).
Authors: Lassman Andrew B. , Reardon David A. , Lee Eudocia Quant , Iwamoto Fabio Massaiti , Diaz-Mitoma Francisco , Anderson David E , Wen Patrick Y.
Published: May 2019

2048

Background: Cytomegalovirus (CMV) antigens have been reported in over 90% of GBM tumors. CD4+and CD8+T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. Methods: We have initiated a phase I/IIa clinical trial for patients with recurrent GBM using gB/pp65 enveloped virus-like particles (eVLPs) formulated with GM-CSF and administered intradermally. Subjects are vaccinated monthly until tumor progression, with immunomonitoring performed 2 weeks after each vaccination and MRI exams every 6 weeks. In phase I, eligible patients were age 18-70 with Karnofsky Performance Status at least 70, normal end-organ function, on stable or decreasing corticosteroids of at most 4mg dexamethasone (or equivalent), with recurrent GBM following any standard initial therapy and any number of recurrences. The primary endpoint was safety/tolerability and secondarily to assess immunogenicity. Three vaccine doses (0.4µg, 2µg, and 10µg pp65) were evaluated with 6 subjects in each cohort and DSMB safety review of the first 3 subjects in each cohort prior to enrolling additional subjects. Results: The DSMB identified no DLTs or safety concerns with any of the doses. Grade 2, 3 or 4 AEs occurred in 66%, 22% and 11% of participants, respectively, but were not related to vaccine administration. Twelve men and 6 women were enrolled with a median age 54 (range 39-66). Prior therapies included radiotherapy, temozolomide, and nivolumab. Immunological analyses demonstrate robust boosting of CMV-specific antibody titers and T cell responses against both gB and pp65 antigens in some but not all subjects, across all dose cohorts. Boosting of IFN-gsecreting T cells (measured by ELISPOT) exceeded the assay threshold for several subjects. Stable disease by MRI of 3 months or greater has been observed in 2 subjects in the high dose cohort and 1 subject in the low dose cohort and may correlate with vaccine response. Conclusions: The phase IIa extension phase of the trial planned to begin in Q2 2019 is designed to explore efficacy in an additional 10 subjects that will receive the optimal vaccine dose and includes the additional requirements of unifocal, measurable enhancing tumor 1-3 cm across at first recurrence and no prior immunotherapy. Clinical trial information: NCT03382977.
Evaluation of controlled IL-12 as monotherapy in subjects with recurrent GBM.
Authors: Lukas Rimas Vincas , Chiocca E. Antonio , Kurz Sylvia Christine , Yu John , Landolfi Joseph C. , Rao Ganesh , Barrett John A. , Buck Jill Y. , Demars Nathan , Smith Amy , Miao John , Zhou Qiang (John) , Gelb Arnold Bruce , Cooper Laurence
Published: May 2019

2053

Background: Interleukin-12 (IL-12), a master regulator of the immune system, results in anti-tumor responses in preclinical models, but safe use requires tightly controlled production. It was conditionally produced in Ph1 “main” study (NCT02026271) in subjects with recurrent glioblastoma (rGBM) using a replication-incompetent adenovirus modified to express IL-12 under transcriptional control of the proprietary RheoSwitch Therapeutic System (Ad-RTS-hIL-12, Ad) regulated by dose of veledimex (V). Monotherapy resulted in sustained intra-tumor influx of activated cytotoxic T cells, consistent with immune-mediated anti-tumor effect, improving overall survival (OS). This correlated with increased circulating CD8+/FoxP3+ T-cell ratio (“cytoindex”), an emerging biomarker of OS. While widely used with neurosurgery, dexamethasone (dex) blunts response to immunotherapies, nevertheless median mOS of subjects who received 20mg V of 12.7 mo (n=15) at 13.1 mo follow-up. However, subanalysis (n=6) showed low-dose dex (total ≤20 mg) during V dosing improved mOS (17.8 mo). We report a 36 subject substudy in rGBM with limited dex, total rGBM treated (n=70+). Methods: Ongoing Phase 1 substudy (NCT03679754) assesses safety and tolerability of local, inducible IL-12 by single intratumoral injection of Ad (2 x 1011 viral particles) + V (20 mg PO QD x15 doses Days 0-14) in subjects not receiving dex 4 wks prior to Ad. Results: As of 03Jan19, the majority of new subjects received low-dose dex (total ≤20mg Days 0-14). The initial impact of dex on mOS will be reported. As in the main study, Ad+V 20 mg respectively increased (median) serum IL-12 and downstream IFN-g from Days 0-3: 0.8 to 8.8 pg/mL and 0 to 8.6 pg/mL. Between Days 0-14, there was net increase in cytoindex (from 20 to 46). The safety profile was similar to the main study with the main adverse reaction (AR) being mild to moderate cytokine release syndrome (CRS) characterized by flu-like symptoms. No grade 4 CRS was noted; all ARs were manageable and reversable upon holding V. Conclusions: Local, controlled IL-12 production using the Ad + V platform in subjects with rGBM safely activates the immune system and when dex is limited, appears to further improve mOS, which warrants continued investigation. Clinical trial information: NCT03679754.
Analysis of the EF-14 phase III trial reveals that tumor treating fields alter progression patterns in glioblastoma.
Authors: Jeyapalan Suriya A. , Toms Steven A , Hottinger Andreas Felix , Kleinberg Lawrence , Pollom Erqi , Soltys Scott G. , Glas Martin
Published: May 2019

2055

Background: The EF-14 [NCT00916409] trial showed that addition of alternating electric fields (Tumor Treating Fields, TTFields) to Temozolomide (TMZ) resulted in improved survival in newly diagnosed Glioblastoma (GBM) patients with supratentorial tumors treated compared to TMZ alone. TTFields delivery is planned to optimize dose at the tumor bed, leading to the hypothesis that TTFields treated patients are more likely to exhibit distal progressions, including progression to the infratentorial brain where TTFields dose is minimal when targeting the supratentorium. Here we present analysis of the EF-14 trial testing this hypothesis. Methods: Patients on treatment for more than two months who had an MRI that exhibited progression were included in the study (treatment: N=280/466, control: N=122/229). Regions of enhancing tumor, necrosis and resection were contoured on T1 contrast MRIs acquired at baseline and at the date of first progression. New lesions at progression were classified as distal if they appeared outside of a Proximal Boundary Zone (PBZ) of 20 mm surrounding the lesions identified in the baseline MRI. The rate of occurrence of distal progressions in the TTFields-treated arm was compared to the rate observed in the control arm. Patients with (distal) infratentorial progression were identified. Results: Distal progressions were more common in the treatment arm (49/280 (18%) vs. 10/122 (8%) P<0.02; chi-squared). Infratentorial progression were observed in 4% (10 patients) of the treatment arm vs. 0 patients in the control (P<0.002 t-test). Distal lesions at progression were more distant from the original lesion in the TTFields treated arm (58.57 + 28.12 mm vs 46.61 + 20.48 mm, P<0.02; Wilcoxon rank sum test. The relative tumor growth rates in TTFields treated patients were significantly slower than those observed in the control arm (0.036+ 0.126 ml/day vs. 0.036+ 0.183 ml/day P<0.03; t-test). Conclusions: This analysis indicates that adding TTFields to TMZ could impact GBM growth patterns. The results suggest that TTFields increases local control of tumor growth, emphasizing the need for adaptive treatment after progression to control progressing disease. Clinical trial information: NCT00916409.
Detection of targetable somatic alterations in glioblastoma (GBM) and clinical impact.
Authors: Fusco Michael , Macaulay Robert J , Forsyth Peter A. J. , Walko Christine Marie
Published: May 2019

2058

Background: In GBM, molecular markers are utilized to establish an integrated diagnosis as described in the WHO 2016 guidelines and identify patients (pts) with molecular targets amenable to therapeutic intervention. Herein we review our experience at Moffitt Cancer Center. Methods: A retrospective chart review between 4/1/2013 and 11/1/2018 was performed to collect demographic, clinical, disease, treatment and outcome variables on 163 unique pts with GBM whose tumors underwent comprehensive genomic profiling by FoundationOne or CDx testing. Genomic data was analyzed for recurrent alterations and tumor mutational burden (TMB). Results: Median age was 58 years (range 19 to 85). 13% were IDH1 or 2-mutated. Among the 141 IDH-wild type (wt) pts, TERT promoter mutations occurred in 83% and CDKN2A/B co-deletion in 65%. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was seen in 33%. A median of 5 clinically relevant alterations were identified per tumor sample (range, 2 to 34) and a median of 2 mutations (range, 0 to 6) were found to be actionable after review by our molecular tumor board. The most commonly actionable alterations were found in EGFR, BRAF and genes associated with homologous recombination deficiency (HRD) (see table). Four pts were treated with EGFR-targeted therapy, one pt with an HRD alteration received a PARP inhibitor (progression free survival [PFS] of 34 weeks), and two pts with BRAF V600E received dabrafenib/trametinib combination therapy (treatment ongoing at 14 weeks and 38 months, respectively). Median TMB (n = 118) was 4 (range, 0 to 371 Muts/Mb). One pt who received 44 months of temozolomide exposure had a hypermutated tumor (371 Muts/Mb) and was treated on trial with pembrolizumab, but progressed after 2 months. Conclusions: Though limited in patients with GBM, clinically actionable alterations are found in a small subset and can translate into meaningful clinical benefit. [Table: see text]
A phase I study of MGMT-P140K transfected hematopoetic progenitor cells (HPC) combined with TMZ/O6BG dose escalation for newly diagnosed, MGMT unmethylated glioblastoma: Tolerance and evidence of survival benefit.
Authors: Sloan Andrew E. , Roger Lisa , Murphy Chris , Reese Jane , Lazarus Hillard M. , Dropulic Boro , Gerson Stanton L.
Published: May 2019

2062

Background: GBM is the most common malignant brain tumor with a median survival of 15 months despite surgery and radio-chemotherapy. The most important mechanism of TMZ resistance is the O6-methylguanine-DNA methyltransferase (MGMT) gene which repairs temozolamide-induced DNA methylation. The MGMT inhibitor O6-benzylguanine (BG) demonstrated efficacy in depleting MGMT and maximizing tumor response in early phase clinical trials. However, MGMT expression is also low in hematopoietic cells, so this approach led to unacceptable bone marrow toxicity and thus has been abandoned. We hypothesized that chemoprotection of hematopoietic HPC with an MGMT mutant (MGMT-P140K) characterized by normal methyltransferase activity, coupled with low affinity for BG would maximize anti-tumor response while enabling patients to tolerate TMZ & BG dose escalation with minimal toxicity. A phase I trial was performed to test this hypothesis. Methods: 10 adults with newly diagnosed MGMT unmethylated, IDH-1 WT, GBM underwent standard surgery and radiation, followed by transplantation with autologous CD34+ HPC engineered to express MGMT-P140K using a lentiviral vector. We tested tolerance and efficacy of three different paradigms for conditioning bone marrow and re-infusion of HPC. To assess chemo-protection, patients’ blood counts and transgene marking were monitored during and after treatment, as was toxicity, response, and progression-free and overall survival. Results: Treatment was moderately toxic with 3/10 patients suffering grade 3-4 hematologic toxicity; no high grade non-hematologic toxicity was observed . Viral transduction rates ranged from 3-75% and were clearly improved in Arm III utilizing BCNU conditioning and intra-patient dose escalation of TMZ/O6GB. In patients tolerating 3 cycles or more, P140K-MGMT gene markings in peripheral blood and bone marrow cells increased 3-26-fold with only mild (Grade 2-3) mylosuppression consistent with chemo-protection as hypothesized. Median PFS and OS was 22 and 31 months respectfully, and three patients in Arm III are healthy and progression free at 36-39 months. OS exceeded RPA predicted survival by 3.3-fold suggesting clinical benefit. Viral insertion site analysis demonstrate lack of clonal dominance. Conclusions: P140K-MGMT transfected HPC enables TMZ/ BG dose escalation with acceptable toxicity and increased survival in a small cohort of selected patients. A phase II study is ongoing. Clinical trial information: NCT01269424.
Prospective phase II trial in patients with first relapse of high-grade astrocytoma using TVB-2640 in combination with bevacizumab versus bevacizumab alone.
Authors: Konkel Brandon , Caflisch Laura D , Diaz Duque Adolfo Enrique , Michalek Joel , Liu Qianqian , Brenner Andrew Jacob
Published: May 2019

2064

Background: Recurrent glioblastoma (rGBM) following chemoradiation is associated with a poor prognosis. While bevacizumab is the most common salvage therapy, responses remain brief and without an associated survival benefit. Resistance may involve overexpression of Fatty Acid Synthase (FASN). Our institution is conducting a phase 2 study of bevacizumab with FASN inhibitor TVB-2640 in patients with GBM in first relapse. Methods: This is a prospective, phase 2 study of bevacizumab with TVB-2640 in patients with GBM in first relapse. Primary end point is progression free survival (PFS). Inclusion criteria are: age ≥ 18, ECOG 0 to 2, GBM progression following standard combined modality treatment. Randomization into two arms for the first 28 days is included for exploratory biochemical analysis: patients in arm 1 receive bevacizumab every 2 weeks in combination with TVB-2640; those in arm 2 receive bevacizumab alone every 2 weeks. MR-Spectroscopy (MRS) and serum sampling for exosome analysis are obtained on patients at day 1 and 28 of first cycle. Starting on cycle 2 day 1, all patients converge to a single arm and continue to receive bevacizumab in combination with TVB-2640. Results: We have enrolled 24 patients to date; 23 have started treatment. Of those 23 patients, 10 have died, 4 have progressed but are still alive, 2 withdrew, and 7 are still active on trial. The PFS6 is and OS9 are both currently 50%, which compares favorably with historical controls. There have been no reports of grade 4 or 5 treatment-related AEs (of note, 2 deaths were thought definitely unrelated to treatment, including 1 case of intracerebral hemorrhage, and 1 case of sepsis). There have been two cases of grade 3 hand-foot syndrome thought definitely related to treatment. Updated results will include PFS, response, and biomarker analysis (exosome, MRS). Conclusions: The combination of TVB2640 with bevacizumab appears be well tolerated. PFS6 and OS9 are both currently 50%. The study has completed accrual with final data expected later in 2019. Clinical trial information: NCT03032484.
Insight into the brain metastasis journey: Initial survey results from patients and caregivers.
Authors: Willmarth Nicole , Elder Scott , Fine Avery , Ahluwalia Manmeet Singh , Barnholtz-Sloan Jill , Brastianos Priscilla Kaliopi , Brat Daniel , Mehta Minesh P. , Page Robin , DeVitto Ralph , Robins Debbie
Published: May 2019

2069

Background: Brain metastases (BM) are the most common central nervous system tumors in the US. Though the exact incidence is unknown, BM are estimated to occur in up to 10-20% of all cancers. Despite the high frequency, there is little systematic knowledge about how BM are typically diagnosed and treated. The American Brain Tumor Association (ABTA) seeks to understand the BM journey: symptoms, diagnosis, treatment, and end of life, through a survey of BM patients and caregivers. Methods: Two surveys were developed by the ABTA with vendor, PSB Research, after careful literature review. The surveys were reviewed by a panel of clinicians who treat BM patients. Online survey research was conducted between 8/13-9/16/18, with one survey for adults with BM (N = 237) and another for caregivers (N = 211). Respondents came from PSB’s panels and ABTA collaborators: LUNGevity, Melanoma Research Foundation and the Kidney Cancer Association. Results: Ninety percent of patients, and a similar number of caregivers, were surprised by the diagnosis, with only 20% of patients knowing about BM before diagnosis. Most caregivers were the adult child of a patient. The impact of the diagnosis was primarily emotional. Top concerns after diagnosis, for both patients and caregivers, were likelihood of treatment success and impact on quality of life. Although a majority of patients were happy with the quality of information given, they stated a need to receive a greater quantity of information about treatment success and options. Only 30% of patients were referred to a patient advocacy organization. When referred, information on treatment success rates and options was most sought. Conclusions: Direct patient and caregiver feedback provides valuable insight towards understanding the BM journey and resources needed to support patients and caregivers. A subsequent survey among oncologists and other clinicians, planned for spring of 2019, will add to these findings.
A phase II trial of bevacizumab in patients with recurrent solid tumor brain metastases who have failed whole brain radiation therapy (WBRT).
Authors: Kumthekar Priya , Dixit Karan , Grimm Sean Aaron , Lukas Rimas Vincas , Schwartz Margaret A. , Rademaker Alfred , Sharp Laura , Nelson Valerie , Raizer Jeffrey J.
Published: May 2019

2070

Background: Brain metastases (BM) are the most common intracranial malignancy with overall a poor prognosis estimated at approximately 4 months from time of initial diagnosis for treated patients, and even lower after failing WBRT after which treatment options have been limited and outcomes poor. Methods: This is an open label phase 2 study where patients who have previously failed WBRT received bevacizumab at a dose of 10 mg/kg intravenously every two weeks until CNS disease progression with one cycle being defined as 4 weeks. The primary endpoint was objective radiographic tumor response as defined by modified Response Assessment in Neuro-oncology (RANO) criteria. Secondary endpoints included progression free survival (PFS) at 6 months, time to progression, time to response, duration of response, overall survival (OS), quality of life (QOL) as measured by the FACT-G and FACT-Br and safety. Results: A total of 27 patients were consented and registered to study of which 24 were evaluable for ORR (3 came off study prior to first follow up MRI brain). Medianage was 53 (range 27-73), median number of cycles was 5.5 (range 1-20) with a median follow up of 8.7 months (range 2.4-47.9mo). Of the 24evaluable patients, there were 6 Partial response, 16 stable disease and 2progressive disease. The 6 month PFS: 46% (95% CI: 25% - 67%) and median PFS was 5.3 months. Median OS was 9.5 months (95% confidence interval 6.3m – 15.0m). For the patients who completed sequential QOL assessments, there was no significant decline in QOL but there was a nonsignificant improvement in the FACT-Br scores. Overall, treatment was well tolerated with 3grade 3 adverse events seen: hypertension (n = 3), headache (n = 1) and thrombotic event (n = 1). Conclusions: For this WBRT failure BM population, we were able to show a 25% disease response to bevacizumab therapy along with good drug tolerability and no noted central nervous system bleeding. Improved survival as compared to historical controls was seen 9.5 m. Of the 24 evaluable patients, 81% (22/24) experienced clinical benefit defined as stable disease or better. Bevacizumab therapy could be a viable option for solid tumor BM patients who experience progression following WBRT, however a larger trial is required to confirm this data. Clinical trial information: NCT01898130.