bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 433: Mechanisms of resistance to BAY 2927088, the first reversible inhibitor targeting EGFR exon 20 insertion mutations in non-small cell lung cancer
Authors: Uzunbas Gizem Karsli , McVeigh Quinn , Gupta Akansha , Hoyt Stephanie , Cherniack Andrew , Siegel Franziska , Siegel Stephan , Meyerson Matthew , Greulich Heidi 
Published: June 2023

Abstract
Molecular therapies targeting EGFR-mutant non-small cell lung cancer (NSCLC) have dramatically improved prognosis for patients with the classical activating mutations, L858R and exon 19 deletion. Tumors harboring EGFR exon 20 insertions do not respond to inhibitors of classical activating mutations. Agents such as amivantamab and mobocertinib have been approved for treatment of lung cancer patients with exon 20 insertions, but agents with an improved selectivity profile versus wild-type EGFR are still needed. BAY 2927088, currently in phase I clinical trials, is a novel reversible inhibitor that targets EGFR exon 20 insertion mutations with decreased activity towards wild-type EGFR. Although most patients with advanced EGFR-mutant NSCLC eventually progress due to acquired resistance to EGFR inhibitors, the mechanisms of resistance to BAY 2927088 are currently unknown. Using two different methods of in vitro resistance generation, we identified mechanisms of intrinsic and acquired resistance to BAY 2927088 and other EGFR inhibitors. With the first method, involving initial incubation with a high concentration of inhibitor, we isolated drug-tolerant persister cells that underwent a transcriptional state transition resembling EMT. With the second method, involving gradual escalation of inhibitor concentrations, we identified NRAS hotspot mutations as a mechanism of resistance to BAY 2927088 and other EGFR inhibitors. As a parallel approach, we are developing a deep-scanning mutagenesis assay of the EGFR kinase domain to identify mutations that could cause resistance. Understanding these resistance mechanisms will help to identify second-line treatments for exon 20 insertion patients who develop resistance to EGFR inhibition.
Citation Format: Gizem Karsli Uzunbas, Quinn McVeigh, Akansha Gupta, Stephanie Hoyt, Andrew Cherniack, Franziska Siegel, Stephan Siegel, Matthew Meyerson, Heidi Greulich. Mechanisms of resistance to BAY 2927088, the first reversible inhibitor targeting EGFR exon 20 insertion mutations in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 433.
Abstract 4398: Validation of an updated algorithm to identify non-small cell lung cancer (NSCLC) patients in administrative claims databases
Authors: Patel Sandip Pravin , Wang Rongrong , Zhou Summera Qiheng , Sheinson Daniel , Johnson Ann , Lee Janet 
Published: June 2023

Abstract
Purpose: Administrative claims data using the ICD-9-CM or ICD-10-CM coding systems are not detailed enough to distinguish between lung cancer subtypes, which presents challenges for real-world research. This study updated and validated a previous treatment-based algorithm that uses claims data to identify NSCLC vs small-cell lung cancer (SCLC) (Turner RM, et al. Front Pharmacol 2017;8:883).
Methods: This study used Optum’s de-identified Market Clarity Data (2007-2021) which deterministically links medical and pharmacy claims with electronic health record (EHR) data from providers across the continuum of care. Included patients had lung cancer diagnosis and histology information available in the EHR, which is the gold standard for validation. Patients were required to have ≥3 months of continuous health plan enrollment before and after the diagnosis date. First, to replicate the Turner algorithm, patients were identified between Jun 2014 and Oct 2015 with any first-line NSCLC treatment and no SCLC treatment (Step 1). Next, the Turner algorithm was applied from Nov 2015 to Dec 2020 to evaluate if performance decreased given the approval of immunotherapies since 2015 (Step 2). Finally, the Turner algorithm was updated with NSCLC treatments approved since 2015 in concordance with the latest US treatment guidelines. Algorithm performance at each step was measured using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV).
Results: Sample sizes and performance statistics for each step are presented in the Table. From Step 1 to Step 2, specificity and PPV decreased while sensitivity and NPV increased. Algorithm performance improved slightly for all measures from Step 2 to Step 3.
Conclusions: This updated treatment-based algorithm improves validity and accuracy in identifying NSCLC patients in claims databases and supports its use in real-world research using claims databases when histology data is unavailable.
Step 1: Turner replication Step 2: Turner 2015-2020 Step 3: Updated Turner 2015-2020 Date range Jun 2014-Oct 2015 Nov 2015-Dec 2020 Nov 2015-Dec 2020 Sample size 406 2573 2744 Sensitivity 0.873 0.920 0.932 Specificity 0.933 0.865 0.923 PPV 0.987 0.976 0.988 NPV 0.560 0.640 0.673
Citation Format: Sandip Pravin Patel, Rongrong Wang, Summera Qiheng Zhou, Daniel Sheinson, Ann Johnson, Janet Lee. Validation of an updated algorithm to identify non-small cell lung cancer (NSCLC) patients in administrative claims databases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4398.
Abstract 4408: Provisional prognostic score for monomorphic epitheliotropic T-Cell lymphoma
Authors: Haddad Philip A. , Keerty Dinesh , Dadi Neelakanta 
Published: June 2023

Abstract
Background: Monomorphic Epitheliotropic Intestinal T-cell Lymphoma (MEITL) is a rare extranodal intestinal PTCL. It is an aggressive disease with an overall poor prognosis. However, the disease presents a diverse spectrum of survival outcomes. We conducted this study to develop a provisional MEITL prognostic score (MPS) for this rare disease.
Methods: We used our updated MEITL database, which contains retrospective data on 218 cases. Such data included demographics such as sex, age, and race. It also included disease presentation symptoms, duration of symptoms before diagnosis, site(s) of the disease, stage, blood counts, disease immune and molecular phenotype, types of treatment, quality of response, and survival outcomes. Out of the 218 cases, only 140 cases had complete survival and outcomes data, the sample chosen for this study. Cox proportional-hazards model and Log-rank tests were used to assess the influence of clinicopathologic factors on overall survival (OS). Due to the relatively small training cohort, we included factors that statistically impacted OS as well as factors that numerically trended that way.
Results: The median OS of the cohort was 11 months. The following dichotomous variables were identified as impactful prognostic factors in this cohort: Bone marrow involvement (9 vs. 14 months), Non-biclonal TCR status (10 vs. 17.5 months), CD56+ (10 vs. 26 months), Ki67&gt;70% (4 vs. 8 months), cMyc expression &gt;15% (7 vs. 12 months). A prognostic model was devised using these variables to identify different levels of risk. Each variable was assigned a score of 1 when present, except for cMyc, which was assigned 2 points for having the highest hazard ratio among all the variables. In this exploratory cohort, low risk was assigned a score of 0, intermediate risk a score of 1-2, and high risk a score of 3-6. This prognostic score system led to our cohort's most optimal risk discriminatory model, where low, intermediate, and high risk had a median OS of 26, 12, and 4 months, respectively (p=0.002).
Conclusion: This MPS is a promising new tool for risk-stratifying patients with MEITL. However, it still needs prospective validation.
Citation Format: Philip A. Haddad, Dinesh Keerty, Neelakanta Dadi. Provisional prognostic score for monomorphic epitheliotropic T-Cell lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4408.
Abstract 4454: Loss of CX3CL1 expression mediates immune evasion in STK11 mutated lung adenocarcinomas
Authors: Eksioglu Eria , Wright Gabriela M. , Percy Trent R. , Wright Kenneth L. , Cress W. Douglas 
Published: June 2023

Abstract
Immunotherapy has improved survival for many cancer patients, especially for immunogenic malignancies such as lung cancer. However, even in lung cancer, the response rate for anti-PD1 therapy (for example) does not exceed 20%. Thus, it is critical to identify mechanisms that block the response to immune checkpoint therapies. STK11 (also known as LKB1) is encoded by the serine threonine kinase 11 gene (STK11). Patients harboring tumors with STK11 mutations have reduced infiltrates of cytotoxic T-cells and clinical studies have shown that they respond poorly to anti-PD1 or anti-PDL-1 therapies regardless of PDL-1 status, which otherwise predicts benefit. Herein, we have used gene expression data from a cohort of 442 lung adenocarcinoma patients to identify CX3CL1 (fractalkine) as a gene silenced in STK11 mutant tumors with potential to be a key direct modulator of the immune system relevant to STK11 loss. To further explore this hypothesis, we have edited the STK11 gene in A549 cells back to wild type (STK11 corrected). As predicted, restoration of STK11 function resulted in modest expression of CX3CL1 as measured by Western blotting. Unexpectedly, exposure of STK11 corrected cells to human immune cells isolated from the blood of healthy donors resulted in a 5 to 10-fold increase in CX3CL1 suggesting interactive signaling between tumor and immune cells. Using transwell assays and STK11 corrected A549 cells we find that restoration of functional STK11 increases immune cell migration, adhesion and invasion in vitro. Finally, cytotoxicity assays demonstrate that STK11 corrected A549 cells are 3 to 5-fold more sensitive to immune cell killing. Taken together these results suggest the hypothesis that CX3CL1 loss mediates immune evasion in STK11 mutant lung adenocarcinomas. Future work will further explore the mechanisms underlying this pathway in preclinical models.
Citation Format: Eria Eksioglu, Gabriela M. Wright, Trent R. Percy, Kenneth L. Wright, W. Douglas Cress. Loss of CX3CL1 expression mediates immune evasion in STK11 mutated lung adenocarcinomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4454.
Abstract 4591: Mechanisms of tumor-mediated endothelial cell proliferation independent of VEGF
Authors: Sheng Kevin L. , Raj Jude , Wood Kris C. 
Published: June 2023

Abstract
A hallmark of cancer is dysregulated angiogenesis and blood vessel co-option, which are often driven by vascular endothelial growth factor (VEGF). Despite the key role of VEGF signaling in promoting endothelial cell (EC) proliferation, survival, and migration, the clinical use of VEGF inhibitors has modest success and faces many challenges. In particular, patients demonstrate variable initial responses to anti-VEGF therapy, and many of those who respond to treatment subsequently develop resistance. These challenges suggest that there may be VEGF-independent mechanisms driving EC proliferation in the tumor microenvironment. To study these mechanisms, we established an in vitro model using a dual-reporter system in a co-culture model of ECs and tumor cells. Specifically, we used an immortalized endothelial cell line (SVEC4-10) expressing GFP and Renilla luciferase and a mouse renal carcinoma cell line (RENCA) expressing Tomato and Firefly luciferase. This model allowed us to independently evaluate the growth rates and cell viabilities of both ECs and tumor cells in direct co-culture. Our preliminary data revealed that ECs exhibit increased growth rates when directly co-cultured with tumor cells. Interestingly, this EC proliferation is VEGF-independent and not impacted by VEGF-A knockout in tumor cells or with treatment of a pan-VEGFR small molecule inhibitor (axitinib). To further characterize if our phenotype was due to other tumor secreted factors, we used a transwell setup to eliminate direct contact between ECs and tumor cells and found that EC growth rates were substantially mitigated. These results revealed that tumor cells induced EC proliferation through a physical cell-to-cell interaction that is independent of VEGF. Further characterizing this unknown mechanism may inform therapeutic interventions to overcome the clinical challenges of anti-VEGF therapies for cancer. To expand our understanding of this VEGF-independent EC proliferation, we aim to characterize the cell surface proteome from tumor-conditioned ECs using cell surface mass spectrometry. We will validate hits from this study using our in vitro model and translate these findings to in vivo mouse models. We expect that our current and future research will reveal new insights into tumor co-option of the vascular system and identify novel targets for developing therapies to effectively treat cancer.
Citation Format: Kevin L. Sheng, Jude Raj, Kris C. Wood. Mechanisms of tumor-mediated endothelial cell proliferation independent of VEGF. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4591.
Abstract 4627: Immune profiling of immunotherapy and adjuvant chemotherapy pretreatment NSCLC tissues by CODEX
Authors: Monkman James , Moradi Afshin , O'Leary Connor , Wu Zhenqin , Hamel Steven , Mason David , Schneider Fabian , Mansfield James Robert , Meyer Aaron , O'Byrne Ken , Kulasinghe Arutha 
Published: June 2023

Abstract
Non-small cell lung cancer (NSCLC), including adenocarcinoma and squamous cell carcinoma subtypes, is a leading cause of cancer deaths worldwide. Treatment of NSCLC has advanced from chemotherapy modalities to the use of immunotherapy, namely immune checkpoint inhibitors (ICIs) which enhance the adaptive immune response against tumour cells. Thus, while the immune cell composition of tumours and its influence on treatment outcomes is poorly understood, it likely holds the key to effective, personalized treatment regimens.
Here we profiled an adjuvant chemotherapy (n=61) as well as a second line immunotherapy (n=42) NSCLC cohort by the Phenocycler CODEX technology (highplex spatial proteomics) to investigate the association between immune composition and patient outcome. We applied a panel of 38 markers to delineate naïve, memory, cytotoxic and hyperactivated T cell states, as well as B cells, Tregs and myeloid lineage innate immune cell types. Our study sought to understand the heterogeneity of tumour-immune composition across patients and investigate the spatial neighbourhoods and clusters that these cells inhabit within TMA cores. We used Phenoplex™ software for tissue segmentation (into classes for tumor, stroma, artifacts, blood vessels, etc.), cellular segmentation, and cellular phenotyping based on thresholds for each marker, and then performed spatial analyses (distances, interactions, neighborhoods) using SpatialMap1 to identify cellular motifs associated with clinical phenotypes.
Our study has identified spatial features associated with immune contexture linked to therapy outcome in both chemotherapy and immunotherapy modalities. Taken together, our study demonstrates the utility of spatial proteomics to identify cellular features associated with outcome to therapy in lung cancer.
1) Trevino A, Ivison G, Hamel S, Chiou A (2022). SpatialMap: Analysis of Spatial Biology Data. R package version 0.4.57.
Citation Format: James Monkman, Afshin Moradi, Connor O'Leary, Zhenqin Wu, Steven Hamel, David Mason, Fabian Schneider, James Robert Mansfield, Aaron Meyer, Ken O'Byrne, Arutha Kulasinghe. Immune profiling of immunotherapy and adjuvant chemotherapy pretreatment NSCLC tissues by CODEX. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4627.
Abstract 4742: Familial adenomatous polyposis epigenetic landscape as a precancer model of colorectal cancer
Authors: Lee Hayan , Krieger Gat , Clark Tyson , Zhu Yizhou , Khan Aziz , Hanson Casey R. , Horning Aaron , Esplin Edward D. , Badu Mohan , Paul Kristina , Chiu Roxanne , Bahmani Bahareh , Nevins Stephanie , Weimer Annika K. , Jaimovich Ariel , Curtis Christina , Greenleaf William , Ford James M. , Lipson Doron , Shipony Zohar , Snyder Michael P. 
Published: June 2023

Abstract
Aberrant shifts in DNA methylation have long been regarded as an early biomarker for cancer onset and progression. However, it is unclear when methylation aberrance starts and how it interacts with other epigenomic modifications. To address how epigenomic changes occur and interact during the transformation from normal healthy colon tissue to malignant colorectal cancer (CRC), we collected 51 samples from 15 familial adenomatous polyposis (FAP) and non-FAP colorectal cancer patients. We generated 30-70x of whole-genome enzymatic methylation sequencing (WGEM-seq) data via the novel Ultima Genomics ultra high-throughput sequencing platform. We observed hypermethylation and hypomethylation emerge early in the malignant transformation process in gene promoters and distal regulatory elements. We performed multifaceted analysis on methylation alterations with whole-genome sequencing (WGS), transposase accessibility (ATAC-seq), high-resolution chromatin accessibility (Tri-C), and gene expression (RNA-seq) data. Our multidimensional analysis demonstrates how collectively epigenomic alterations have affected gene expression throughout normal colon mucosa, benign and dysplasia polyps to adenocarcinoma. Epigenomic changes start as early as benign polyps, followed by other epigenomic shifts, including bivalent domains. Various epigenomic aberrances are associated with concomitant gene expression level changes. Our integrative analysis of multi-epigenomics data implicates collective and cumulative epigenomic instability in the early onset of colon carcinogenesis.
Citation Format: Hayan Lee, Gat Krieger, Tyson Clark, Yizhou Zhu, Aziz Khan, Casey R. Hanson, Aaron Horning, Edward D. Esplin, Mohan Badu, Kristina Paul, Roxanne Chiu, Bahareh Bahmani, Stephanie Nevins, Annika K. Weimer, Ariel Jaimovich, Christina Curtis, William Greenleaf, James M. Ford, Doron Lipson, Zohar Shipony, Michael P. Snyder. Familial adenomatous polyposis epigenetic landscape as a precancer model of colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4742.
Abstract 4745: Prostatic fluid-based cfDNA methylation profiling distinguish benign hyperplasia from prostate cancer
Authors: Dong Hang , Tang Haoran , Zhang Yue , Jia Shidong 
Published: June 2023

Abstract
Introduction: A challenge in the early diagnosis of prostate cancer (PC) is to distinguish between malignant tumor and benign prostatic hyperplasia (BPH) because of the similar symptoms. Methylation profiles provide a way for discriminating BPH from PC, which could prevent overdiagnosis and overtreatment. Applying methylation biomarkers to liquid biopsy specimens provides higher sensitivity to detect tumors.
Methods: Prostatic fluid samples were prospectively collected from 40 patients following digital rectal exam and isolated cell-free DNA to perform whole genome methylation sequencing using PredicineEPIC platform. Combing differentially methylated regions (DMR) with methylation signature identified from massive public data, a panel of methylation patterns was developed. The difference of methylation signal in profiled region were implemented by machine learning to robustly distinguish BPH from prostate cancer.
Results: We identified 324 biomarkers from prostatic fluid samples and collected 46 methylation biomarkers reported from previous research. Regions with extreme difference between benign prostatic hyperplasia and prostate cancer were identified as candidate biomarkers. A diagnostic model trained on these 55 biomarkers could distinguish BPH from PC in 10-fold cross-validation (AUC = 0.92). And this model could be applied for discriminating normal tissue from prostate tumor tissue with highly performance (AUC &gt; 0.95). Using this set of regions, we developed an NGS-based panel for detecting methylation alteration of cfDNA from prostate liquid, which inherited the ability of differentiation.
Conclusion: These methylation patterns could be developed as the novel biomarkers to support the development of prostatic fluid-based non-invasive diagnostic test and reduce unnecessary biopsies. This panel could be applied for differential diagnosis of benign hyperplasia and prostate cancer.
Citation Format: Hang Dong, Haoran Tang, Yue Zhang, Shidong Jia. Prostatic fluid-based cfDNA methylation profiling distinguish benign hyperplasia from prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4745.