bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3594: DEK overexpression in breast epithelial tissue creates a pro-oncogenic environment
Authors: Johnstone Megan , Cheek Jon , Vinnedge Lisa M. Privette 
Published: August 2018

Abstract
Dense epithelial breast tissue, as detected by mammography, is correlated with a four- to six-fold increased risk for developing breast cancer (BC). It is currently not possible to distinguish dense breast tissue from that which will develop into cancer. Therefore, the need to identify novel markers will improve breast cancer screening and reduce expensive overdiagnosis and overtreatment. Previous research has failed to define reliable diagnostic biomarkers that specify dense breast tissue from that which has the possibility to transform into malignant tissue. DEK, a chromatin binding and DNA repair protein, is upregulated in the majority of solid cancers including breast cancer. Previous publications from our lab demonstrate, in vitro, that DEK overexpression promotes proliferation, increased motility, and epithelial polarization in part through canonical WNT/β-catenin signaling. In vivo experiments with a DEK knockout murine model display a mitigated tumor development response as compared to wild-type mice. Given that DEK is highly expressed in over 60% of BC, we generated a conditional mammary epithelial specific doxycycline-regulated Dek overexpressing (DEK OE) murine model. We find that DEK OE leads to dense epithelial breast tissue, largely due to lobuloalveolar hyperplasia. Longitudinal findings demonstrate that DEK OE results in transformation of mammary epithelial tissue with microtumor development. DEK OE tissue sections display increased transcription of Wnt genes, with upregulation of downstream WNT signaling targets such as AXIN and β-catenin. Conversely, longitudinal repression of DEK OE with doxycycline displays normal tissue morphology and organization. Our data suggest that DEK OE stimulates hyperplasia of mammary epithelium, due to increased proliferation, similar to dense breast tissue as detected by mammography, and may increase risk for spontaneous transformation and BC development later in life.
Citation Format: Megan Johnstone, Jon Cheek, Lisa M. Privette Vinnedge. DEK overexpression in breast epithelial tissue creates a pro-oncogenic environment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3594.
Abstract 3602: Validation and implementation of next-generation sequencing in liquid biopsies by a novel NGS platform: Focus on non-small cell lung cancer
Authors: Bisgin Atil , Sonmezler Ozge , Boga Ibrahim 
Published: August 2018

Abstract
Introduction: Liquid biopsy as a novel and non-invasive test for the surveillance of cancer is rapidly growing, by next-generation sequencing (NGS) technologies with multi-gene panels.
Objective: The aim of this study was to describe the validation and implementation of a cell free tumor DNA (cfDNA) from the patients with non-small cell lung cancer (NSCLC), to sequence for 19 genes and copy number variation analyses for 5 genes via a novel NGS platform; GeneReader NGS System.
Materials and Methods: We performed the complete NGS workflow with modifications, and sequenced the cfDNA extracted from 100 NSCLC patients. The multi-gene panel includes 19 lung cancer related genes (AKT1, ALK, BRAF, DDR, ERBB2, ESR1, KIT, KRAS, MAP2K1, NRAS, NTRK, PDGFRA, PIK3CA, PTEN and ROS) to sequence and additional copy number variations of 5 genes (RICTOR, EGFR, MET, FGFR1 and ERBB2) that all were selected to represent the most actionable genes for the clinical oncology and molecular diagnostics. The sequencing was performed using a novel NGS platform (GeneReader NGS System, Qiagen).
Results: The validation process and the implementation of genetic testing from the cfDNA by this novel NGS system have been utilized for the clinical use. After quality assessment, the data from this NGS system was bioinformatically processed and a tertiary analysis was performed using QCI-Analyze and QCI-Interpret bioinformatics tools. The data was then reviewed on alterations and those reported in different mutation databases. The clinically relevant alterations were identified and reported due to the testing indications. Overall, actionable variants in EGFR, ALK, KRAS, PIK3CA, MET, FGFR1 and ERBB2 genes were detected and reported in 62 % of all NSCLC patients while the majority were in EGFR.
Conclusions: For each of the 100 samples tested thus far, at least one variant was detected showing the high sensitivity and specificity of both the multi-gene panel and this novel NGS platform. Our evaluation yielded good results for the actionable multi-gene panel selected and provides a comprehensive NGS analysis and workflow for this new platform.
Citation Format: Atil Bisgin, Ozge Sonmezler, Ibrahim Boga. Validation and implementation of next-generation sequencing in liquid biopsies by a novel NGS platform: Focus on non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3602.
Abstract 3623: The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation
Authors: Veitonmäki Niina , Thagesson Mia , Werchau Doreen , Hägerbrand Karin , Smedenfors Kristine , Månsson-Kvarnhammar Anne , Rosén Anna , Johansson Maria , Furebring Christina , Norlén Per , Ellmark Peter 
Published: August 2018

Abstract
ATOR-1015 is a CTLA-4 x OX40 bispecific immune activating antibody developed for tumor-directed immunotherapy. ATOR-1015 binds both targets simultaneously, promoting cell-cell interactions expected to enhance the immuno-stimulating effect of the compound. The mode of action of ATOR-1015 is thought to be a combination of regulatory T cell (Treg) depletion and effector T cell activation. It can be seen as a next generation CTLA-4 antibody with tumor-directed activity and augmented Treg depletion. The ability to induce ADCC of human Treg was investigated using an FcγR expressing reporter assay demonstrating superior effect of ATOR-1015 compared to the monospecific antibody counterparts. Further, ATOR-1015 has been shown to induce activation of T cells in the presence of CTLA-4 expressing cells, ability that is not observed when combining the monoclonal counterparts. Syngeneic tumor models in vivo using human transgenic mice cross-reacting with both targets demonstrate that ATOR-1015 reduces tumor growth and prolongs survival. Further, ATOR-1015 treatment demonstrates superior increase in the intratumoral CD8+ T cell/Treg ratio compared to the monospecific counterparts, without affecting systemic T cells. This tumor directed immune activation is demonstrated to be due to the tumor localization abilities of ATOR-1015. In conclusion, ATOR-1015 is a next generation CTLA-4 antibody with tumor directed activity with augmented T-reg depletion. It is currently in GLP manufacturing of clinical material and will start clinical trials in the second half of 2018.
Citation Format: Niina Veitonmäki, Mia Thagesson, Doreen Werchau, Karin Hägerbrand, Kristine Smedenfors, Anne Månsson-Kvarnhammar, Anna Rosén, Maria Johansson, Christina Furebring, Per Norlén, Peter Ellmark. The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3623.
Abstract 3634: PET/CT imaging prediction of response to checkpoint blockade in advanced non-small cell lung cancer patients
Authors: Mu Wei , Qi Jin , Lu Hong , Schabath Mathew , Balagurunathan Yoganand , Tunali Ilke , Pilon-Thomas Shari , Gillies Robert J. 
Published: August 2018

Abstract
Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors PD-1 and PD-L1 has emerged as a one of the most successful treatment approaches in advanced Non-small Cell Lung Cancer (NSCLC) patients. However, given its adverse effects, high cost and only approximately 20% response rate, accurate response predication is import to identify patients most likely to respond. In previous work, we and others have shown that tumor acidosis, generated from high rates of glucose metabolism, was a potent inhibitor of anti-tumor immunity and that neutralization of acid improved response to checkpoint blockade. In this study, we investigated the value of pre-therapy PET/CT images on response prediction to test the hypothesis that the most metabolically active tumors would have the poorest response to checkpoint blockade. 64 patients were retrospectively curated with pathology verified NSCLC and who did not receive intervening treatments between the PET/CT imaging and initiation of anti-PD1 therapy. Responders (long-term and ongoing responders, n=22) and non-responders (non-responders and transient responders, n=42) were classified according to RECIST criteria. These patients were randomly divided into two groups (n=32 each) for training and testing, respectively. From their images, we constructed 5 different fusion images comprised of PET and CT data. We then extracted 455 quantitative features from these fusion images, as well as the original PET/CT images. We then generated an additional 975 fusion features calculated from the above 455 features, as well as some clinical features (location, age, sex, and histologic type). From these, the most informative features were selected with Receiver Operating Characteristic Curve (ROC) analysis, and these were analyzed with a combined 2-layer cascade support vector machine (cSVM) classification model to relate the features to prediction of objective response. From this we determined that the most informative features were fusion features. With the cSVM, the training set achieved accuracy and area under the ROC curve (AUROC) for classifying response of 100% and 1.00, respectively. Using this model on the test set achieved accuracy and AUROC of 89.66% and 0.86, respectively. We conclude from that PET/CT fusion images may be useful prior to initiation of therapy to predict response to checkpoint blockade in advanced non-small cell lung cancer patients.
Citation Format: Wei Mu, Jin Qi, Hong Lu, Mathew Schabath, Yoganand Balagurunathan, Ilke Tunali, Shari Pilon-Thomas, Robert J. Gillies. PET/CT imaging prediction of response to checkpoint blockade in advanced non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3634.
Abstract 3636: The immune checkpoint, HVEM, is associated with PDL1 expression in lung cancer cell lines
Authors: Ren Shengxiang , Amar Nadav , YU Hui , Rivard Christopher , Ellison Kim , Rozeboom Leslie , Hirsch Fred R. 
Published: August 2018

Abstract
Background: Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (BTLA) or activation of immune activity (LIGHT). This study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in cell lines and patient tumor tissue.Methods: A TMA of 53 characterized NSCLC, 48 SCLC cell lines and 35 malignant tumors were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was Dako Link48 autostainer using a polyclonal antibody from R&D Systems(AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 22C3 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used.Results: IHC HVEM staining was optimized and demonstrated membranous staining with little or no cytoplasmic or nuclear staining. HVEM expression in the NSCLC and SCLC cell lines and malignant tumor TMA revealed a positive H-score more than 1 was 45.3%, 58.3% and 82.9% respectively. In comparison, PDL1 TPS expression of more than 1% was in 59.2%, 16.67% and 45.71% in NSCLC, SCLC cell lines and malignant tumor respectively. A significant correlation of HVEM with PDL1 expression was found in the NSCLC cell lines (r=0.518, p&lt;0.001), while there was no significant association of HVEM with PDL1 expression in the small cell line cohort (r=0.059, p=0.688). Conclusion: HVEM expression was found to be higher in SCLC cell lines as compared to NSCLC cell lines and substantially greater in the general malignant tumor tissues. HVEM expression is associated with PD-L1 expression in NSCLC cell lines but not in SCLC cell lines. This data suggests a potential benefit of combined PD-L1 and HVEM blockade in patients with NSCLC to improve the efficacy of immune-therapy.
Table 1. HVEM Expression in the studyH score01-100101-200201-300NSCLC Cell lines(n=53)29 (54.72%)23 (43.4%)1 (1.8%)0SCLC Cell lines(n=48)20 (41.67%)26 (54.17%)2 (4.17%)0Malignant TMA n=356 (17.14%)16 (45.71%)9 (25.71%)4 (11.43%)
Citation Format: Shengxiang Ren, Nadav Amar, Hui YU, Christopher Rivard, Kim Ellison, Leslie Rozeboom, Fred R. Hirsch. The immune checkpoint, HVEM, is associated with PDL1 expression in lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3636.
Abstract 3644: Blood tumor mutational burden (bTMB) from circulating tumor DNA (ctDNA) as a biomarker for both mutational status and tumor burden in non-small cell lung cancer (NSCLC)
Authors: Davis Andrew A. , Galvez Carlos , Pan Alan , Mohindra Nisha , Villaflor Victoria , Chae Young Kwang 
Published: August 2018

Abstract
Background:
Tissue tumor mutational burden (tTMB) has emerged as a viable biomarker for response to immune checkpoint blockade (ICB) in multiple histologies including NSCLC. Blood TMB (bTMB) is a novel summative measure of ctDNA genomic alterations in the peripheral blood. Few studies have examined the clinical utility and correlation of bTMB with tumor burden and survival.
Methods:
We identified 53 patients, retrospectively, who had paired blood (Guardant Health) and tissue (Foundation Medicine) next-generation sequencing testing. bTMB was determined by taking the number of reported mutations over the sequencing length of ctDNA. bTMB was calculated for research purposes and has not been approved for clinical use. From the cohort, 36 patients had baseline CT scans with measurable scores by RECIST version 1.1. Survival analyses by quartile were performed for the subset of patients (N=18 PFS, N=19 OS) treated with ICB.
Results:
bTMB was significantly correlated with baseline RECIST tumor burden estimations (p=0.010, Pearson Correlation, r=0.42, Table 1). There was a trend toward mutant allele frequency (MAF) of the highest clone in blood correlating with RECIST score (p=0.061). No significant correlation was found when comparing blood and tissue TMB scores in paired patients (p=0.70). In the subset of patients treated with ICB, higher bTMB was significantly associated with shorter PFS (HR 1.81 [1.03-3.18], p=0.038) and OS (HR 2.23 [1.09-4.58], p=0.029).
Conclusions:
This study demonstrated the feasibility and clinical utility of bTMB. Our findings may indicate that bTMB reflects tumor shedding into the blood as a surrogate for tumor burden and heterogeneity given the correlation with RECIST scores. In survival analyses, higher bTMB predicted shorter survival, which also reflects bTMB as a biomarker for tumor burden. Prospective studies are necessary to study bTMB in larger cohorts of patients treated with ICB.
Correlation CoefficientPRECIST-Blood TMB r = 0.424P = 0.010RECIST-Tissue TMB r = 0.238P = 0.198RECIST-MAFr = 0.316P = 0.061MAF-Blood TMB r = 0.182P = 0.289MAF-Tissue TMB r = 0.336P = 0.065Tissue TMB-Blood TMB r = 0.073P = 0.695
Citation Format: Andrew A. Davis, Carlos Galvez, Alan Pan, Nisha Mohindra, Victoria Villaflor, Young Kwang Chae. Blood tumor mutational burden (bTMB) from circulating tumor DNA (ctDNA) as a biomarker for both mutational status and tumor burden in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3644.
Abstract 3665: Longitudinal monitoring of prostate cancer evolution by plasma genome sequencing
Authors: Ramesh Naveen , Sei Emi , Gao Ruli , Tsai Pei Ching , Logothetis Christopher , Zurita Amado J. , Navin Nicholas E. 
Published: August 2018

Abstract
Castration-resistant prostate cancer (CRPC) is associated with poor survival and frequent metastasis to the bone. Disease progression and evolution of therapy resistance have been challenging to study, in part due to the difficulty in collecting invasive core biopsy samples longitudinally over time. While liquid biopsy methods hold great potential for longitudinal monitoring, they are currently limited to targeted measurements of single genes, or small cancer gene panels. To address this challenge, we developed an unbiased whole-genome sequencing method called PEGASUS (Plasma Exome and Genome Analysis by Size-Selection and Unbiased Sequencing) that enables the detection of copy number aberrations and exome mutations from circulating-tumor DNA (ctDNA). We applied PEGASUS to 15 CRPC patients, which identified common driver mutations and copy number aberrations in plasma DNA including AR, MYC, RB1 and PTEN. We compared matched ctDNA and metastatic tumor samples in 8 CRPC patients, which showed a high correlation (r=0.79) of copy number profiles and moderate concordance of exome mutations (~56%), but also revealed a number of ctDNA and metastasis-specific mutations. We further applied PEGASUS to analyze longitudinal samples from 10 prostate cancer patients that were treated with chemotherapy or androgen inhibition to delineate clonal evolution in response to therapy. Clonal subpopulations and dynamics were inferred from mutation frequencies, revealing both chemoresistant and chemosensitive clones. These data showed that while a subset of point mutations were under positive and negative selection; most copy number aberrations remained stable and did not change in response to therapy. Our data show the technical feasibility of performing whole-genome and exome profiling of plasma DNA and pave the way for future clinical applications in biomarker discovery and informing clinical treatment decisions in prostate cancer patients.
Citation Format: Naveen Ramesh, Emi Sei, Ruli Gao, Pei Ching Tsai, Christopher Logothetis, Amado J. Zurita, Nicholas E. Navin. Longitudinal monitoring of prostate cancer evolution by plasma genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3665.
Abstract 3666: Diagnostic application of novel ACE technology: Treatment response monitoring via quantification of cell-free DNA (cfDNA) in plasma from late-stage cancer patients
Authors: Kovelman Robert , Hinestrosa Juan Pablo , Ye Delia , Desmond Patrick , Nguyen Michelle , Turner Robert , Searson David , Uswatta Suren , Madsen James , Bodkin David , Bazhenova Lyudmila , Bahador Afshin , Krishnan Rajaram 
Published: August 2018

Abstract
We have developed a novel microfluidic technology that makes use of Alternating Current Electrokinetics (ACE) to isolate macromolecules such as high-molecular-weight DNA and protein complexes as well as nanoparticles, including cell-derived exosomes. As one of the first applications of this novel technology, we have developed procedures and assays for the isolation and quantification of cell-free DNA (cfDNA) in plasma. We show that this methodology allows for the rapid, robust, and highly quantitative assay of cfDNA in undiluted plasma. Analytical studies indicate that these ACE assays are sensitive, have a very broad dynamic range, and allow for highly effective calibration strategies, thereby enabling comparison of results over time and between laboratories. Importantly, we show correspondence between the results of ACE assays and those that employ traditional technologies such as PCR. We have applied this technology to the quantification of cfDNA in plasma from cancer patients, with an initial focus on stage III and IV non-small cell lung cancer (NSCLC). With a goal of enabling less invasive, more frequent, and lower-cost treatment response monitoring in cancer patients, we have conducted clinical studies showing that the results generated from ACE assays provide informative and useful findings related to disease progression and therapeutic alternatives. We are conducting laboratory and clinical studies oriented toward the development of this technology for in vitro diagnostic use.
Citation Format: Robert Kovelman, Juan Pablo Hinestrosa, Delia Ye, Patrick Desmond, Michelle Nguyen, Robert Turner, David Searson, Suren Uswatta, James Madsen, David Bodkin, Lyudmila Bazhenova, Afshin Bahador, Rajaram Krishnan. Diagnostic application of novel ACE technology: Treatment response monitoring via quantification of cell-free DNA (cfDNA) in plasma from late-stage cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3666.