bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5015: Genomic profiling of colorectal cancer - insights from liquid biopsy comparisons between U.S. and China cohorts
Authors: Tang Haoran , Jia Cancan , Xie Feng , Zhang Yue , Dong Xiaoxi , Huang Yong , Jia Shidong 
Published: March 2024

Abstract
Background: Molecular characteristics play a pivotal role in cancer diagnosis, treatment selection, and disease monitoring across various tumor types. While previous research has elucidated the molecular classification of colorectal cancer using tissue NGS, limited investigation has explored the molecular profile of colorectal cancer through liquid biopsy, especially across diverse human races. This study presents a comprehensive genomic profiling analysis of colorectal cancer patients, using a globally harmonized liquid biopsy assay to compare patient cohorts from both the U.S. and China.
Methods: The prospective study is part of Predicine’s Phoenix Program, a global molecular biomarker screening initiative across multiple solid tumors. At present, the study has enrolled 57 patients in the U.S. and 62 patients in China, all presenting with advanced colorectal cancer. A 10ml blood sample was collected from each patient and tested using PredicineCARE, an NGS-based liquid biopsy assay, to profile somatic mutations, copy number variations, and gene fusions among these patients.
Results: The assay, validated in both the U.S. and China using the same reference materials, achieved a LOD of 0.25% mutation allele frequency, with a positive predictive value exceeding 99%. Subsequently, the assay was applied to profile molecular aberrations in colorectal patients in both the U.S. and China. Among U.S. patients, the most commonly altered genes were APC (60%), KRAS (56%), TP53 (54%), MYC (25%), PIK3CA (16%), and EGFR (14%). In Chinese patients, the predominant altered genes were TP53 (48%), APC (42%), KRAS (32%), GNAS (21%), EGFR (16%), and PIK3CA (11%). The prevalence of GNAS variations was significantly higher in China than in the U.S. (p &lt; 0.05), while the prevalence of APC (p &lt; 0.05), KRAS (p &lt; 0.01), and MYC (p &lt; 0.001) variations was significantly higher in the U.S. than in China.
Conclusions: This study reveals the extensive mutational landscape in advanced colorectal cancer patients through liquid biopsy. Distinct prevalence patterns in certain genes between the U.S. and China cohorts offer novel biomarkers for clinical diagnosis and provide insights for targeted therapy mechanism studies.
Citation Format: Haoran Tang, Cancan Jia, Feng Xie, Yue Zhang, Xiaoxi Dong, Yong Huang, Shidong Jia. Genomic profiling of colorectal cancer - insights from liquid biopsy comparisons between U.S. and China cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5015.
Abstract 5034: Analytic validation of an ultra-sensitive tumor-informed circulating tumor DNA assay based on whole genome sequencing
Authors: Northcott Josette , Bartha Gabor , Harris Jason , Ma Shuyuan , Hong Manqing , Zhang Qi , Chen Richard , Lyle John 
Published: March 2024

Abstract
Monitoring of circulating tumor DNA (ctDNA) levels has demonstrated utility in the detection of residual and recurrent disease after tumor resection, and as a prognostic indicator of patient outcome following initial therapy, in a wide range of cancers. Here we describe the analytic validation of the NeXT Personal® assay, an ultra-sensitive, quantitative, tumor-informed ctDNA assay for use in patients diagnosed with solid tumors. NeXT Personal utilizes whole genome sequencing (WGS) of tumor and normal samples and advanced noise suppression to accurately identify somatic variants and generate a patient-specific diagnostic panel based on up to ~1,800 single nucleotide variants. This personalized panel is used to test for the presence of ctDNA in the patient’s blood samples. The NeXT Personal validation was performed using 123 matched tumor, normal and plasma clinical sample sets representing 9 cancer types. The assay achieved 100% specificity on donor normal plasma samples with an in silico approach giving us a confidence interval of 99.87% to 100%. The analytical range measurements were performed using two paired tumor and normal cell lines, one of which is a commercially available MRD control. The detection threshold for the analytical range measurement was 1.68 parts per million (PPM) with a limit of detection at 95% (LOD95) of 3.52 PPM. Furthermore, NeXT Personal showed linearity over a range of 0.8 PPM to 300,000 PPM (Pearson correlation coefficient= 0.9998) with a limit of quant (LOQ) of 10 PPM. The assay also demonstrated strong performance across varying cfDNA input amounts from 2 ng to 30 ng. These studies demonstrate that NeXT Personal is an ultra-sensitive, highly specific, quantitative and robust assay, giving it the potential to detect residual disease and recurrence earlier than less sensitive assays.
Citation Format: Josette Northcott, Gabor Bartha, Jason Harris, Shuyuan Ma, Manqing Hong, Qi Zhang, Richard Chen, John Lyle. Analytic validation of an ultra-sensitive tumor-informed circulating tumor DNA assay based on whole genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5034.
Abstract 5067: Exploring the genomic landscape of de novo neuroendocrine prostate cancer: Insights for innovative therapies from spatial gene expression analysis
Authors: Watanabe Ryuta , Miura Noriyoshi , Kurata Mie , Kitazawa Riko , Kikugawa Tadahiko , Saika Takashi 
Published: March 2024

Abstract
Introduction & Objectives Neuroendocrine prostate cancer (NEPC) accounts for less than 1% of all prostate cancers but has a worse prognosis than androgen receptor-positive prostate adenocarcinoma (ARPC). Rare cases exist where both de novo NEPC and ARPC are found in the same tissue sample. Our study examines one such unique case: a 78-year-old male treated at Ehime University Hospital who was diagnosed with both ARPC and adjacent de novo metastatic NEPC. This case provides an excellent opportunity for studying gene expression in these two types of prostate cancer. Materials & Methods We used Visium CytAssist Spatial Gene Expression technology from 10x Genomics to analyze formalin-fixed, paraffin-embedded (FFPE) tissue samples from this unique patient. Results We observed elevated expression levels of specific neuroendocrine markers like PEG10, DLL3, NCAM1, SYP, and CHGA in de novo NEPC regions. In contrast, androgen receptor markers such as KLK3, ACPP, TMPRSS2, and NKX3.1 were more prevalent in ARPC areas. Furthermore, genes like Chek1, BRCA1/2, TOP2A, and FANCA were also elevated in NEPC, suggesting that PARP and TOP2 inhibitors could be effective. Expression levels of Rbfox3 and SFRTM2 were lower in NEPC areas, implying possible roles in epithelial-mesenchymal transition (EMT) and Wnt signaling pathways. Additionally, fibrotic markers like HGF, HMOX1, ELN, and GREM1 were upregulated, suggesting that de novo NEPC tumors might be 'immune cold,' thus requiring treatments to boost the effectiveness of immune checkpoint inhibitors. Conclusion The data from additional cases could open the door for new treatment options for NEPC and improve survival rates for castration-resistant prostate cancer patients. Our research serves as a pioneering application of Visium CytAssist on FFPE samples and is the first to examine gene expression in both ARPC and de novo NEPC. A subset of these findings was published in the International Journal of Molecular Science (IJMS) in May 2023.
Citation Format: Ryuta Watanabe, Noriyoshi Miura, Mie Kurata, Riko Kitazawa, Tadahiko Kikugawa, Takashi Saika. Exploring the genomic landscape of de novo neuroendocrine prostate cancer: Insights for innovative therapies from spatial gene expression analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5067.
Abstract 5073: Advancing precision oncology: Insights from pan-cancer proteogenomic signatures
Authors: Li Yize , Terekhanova Nadezhda V. , Wendl Michael C. , Chen Feng , Ding Li 
Published: March 2024

Abstract
Somatic mutations in cancer genomes arise from diverse mutational processes, leaving distinct mutational signatures. However, the proteogenomic implications of these signatures and their connections to environmental influences and immune interactions remain largely unexplored. In this study, we comprehensively investigated these signatures from a broader proteogenomic perspective to further discern their genetic, proteomic, phosphoproteomic, and environmental ramifications. The harmonized dataset of 1064 samples across ten cancer types from the Clinical Proteomics Tumor Analysis Consortium (CPTAC) pan-cancer resource was utilized for this investigation. Beyond genetic alterations and mutational signatures, we harnessed high-throughput multi-omics data to detect critical changes and infer expression signatures associated with the transitions to seven tumor-linked phenotypes: aging, Apolipoprotein B mRNA Editing Catalytic Polypeptide (APOBEC), Homologous Recombination Deficiency (HRD), Microsatellite Instability (MSI), Polymerase Epsilon (POLE), smoking, and ultraviolet (UV) light exposure at the pan-cancer level. We prioritized the top differentially expressed markers uniquely found at the protein and phosphoprotein levels and developed a quantitative score predicting each phenotype status, such as MSI. Respectively, we pinpointed potential candidates as actionable therapeutic targets by linking the identified markers to druggable databases. This offers additional cues to optimize therapeutic options for patients. Specifically, directing attention to genes up-regulated in HRD tumors treated with PARP1 inhibitors shows potential promise in overcoming resistance. Moreover, we explored environmental exposure-related tumor proteogenomic signatures and their association with immune infiltration levels and phenotypes. Notably, smoking strongly influenced the tumor microenvironment (TME) and prognosis in lung cancer. In summary, our identification of expression signatures facilitates phenotype prediction and unveils their molecular mechanisms. We anticipate clinical utility in classifying samples using proteogenomics, particularly in cases where a solely genomic assessment is inconclusive.
Citation Format: Yize Li, Nadezhda V. Terekhanova, Michael C. Wendl, Feng Chen, Li Ding. Advancing precision oncology: Insights from pan-cancer proteogenomic signatures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5073.
Abstract 5092: Development of a priming approach to enhance antigen-directed therapies in hematological malignancies and solid tumors
Authors: Vanderlaag Kathryn E. , Dhar Anukriti , Volkman Molly , Werner Erik , Nguyen Transon , Ali Kamran 
Published: March 2024

Abstract
Clinical success of antigen-directed therapies in cancer has been limited by heterogeneous antigen expression and a narrow therapeutic window. In many patients, failure of antigen-directed therapies such as CAR T-cell therapies, antibody-drug conjugates (ADC) or radioligand therapies (RLT) has less to do with a lack of potency or specificity of the agent and more to do with variable and suboptimal antigen expression in the patient. We are developing combination therapies that introduce a priming agent designed to optimize antigen expression in the patient and improve the therapeutic window of existing antigen-directed therapies. Our high-throughput platform utilizes machine learning and automation to scale functional combinatorial screening for small molecule priming agents using cell lines and patient samples. Using this platform, we are identifying priming therapies for CD123, CD33, CD22, and CD19 in hematological malignancies including acute myeloid leukemia (AML), and HER2, HER3, and TROP2 in solid tumors including breast cancer.For our CD123 program, we have identified priming agents that selectively upregulate CD123 expression ≥2-fold on AML cells without increasing expression on normal myeloid progenitor cells, which also express CD123. AML cells treated with a CD123 priming agent in combination with a CD123 ADC showed greater tumor-cell killing compared to the ADC alone. In comparison, normal myeloid progenitor cells from healthy bone marrow treated with the same CD123 priming-ADC combination treatment did not show an increase in ADC-mediated cell killing. From our mechanistic studies, we have identified a somatic mutation associated with CD123 upregulation that may lead to selective upregulation on cancer cells and not on normal cells. Additionally, this marker can be used for patient selection. We have also observed CD123 upregulation in vivo using mouse models of AML and are currently conducting additional in vivo proof of concept studies to demonstrate that CD123 priming therapy enhances efficacy.There are two distinct advantages of a priming approach paired with an antigen-directed therapy, which include: (1) improving the durability of patient responses and (2) expanding the patient population. Our priming combination approach has the potential to overcome antigen heterogeneity and thereby improve the clinical success of antigen-directed therapies.
Citation Format: Kathryn E. Vanderlaag, Anukriti Dhar, Molly Volkman, Erik Werner, Transon Nguyen, Kamran Ali. Development of a priming approach to enhance antigen-directed therapies in hematological malignancies and solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5092.
Abstract 5093: Analysis of protein expression in head and neck cancers as therapeutic targets for antibody drug conjugates
Authors: Moyers Justin Tyler , Smith Seth L. , Mora Miranda M. , Pestana Roberto Carmagnani 
Published: March 2024

Abstract
Introduction: Antibody Drug Conjugates (ADCs) represent a new category of therapeutic molecular targeting for solid tumors. To date 6 ADCs have been approved in solid tumors against 5 targets (HER2/ERBB2, Folate alpha, Tissue Factor, Nectin-4, and Trop-2). Thus far, no ADCs have been approved for head and neck cancers.
Methods: We queried protein expression data from a publically available consortium of datasets (TNMPlot.com) containing protein expression data from over 56,000 tumor and normal samples from GEO, GTex, TCGA, and TARGET databases. Genes examined for protein targets, included those with ADC targets of both presently approved and investigational drugs from clinical trials.The level of overexpression was determined as the percent of tumors over the 75th percentile of expression in normal tissue.
Results: Protein expression data were available for 99 HNSCC samples. Among targets with ADCs available, increased protein expression was seen in HNSCC for 0% of ERBB2 (n=0/99), 38% of FOLR1 (n=38/99), 0% of TACSTD2 (n=0/99), and 42% of F2 (n=42/99) genes.Among gene targets with investigational ADCs, increased protein expression was seen in HNSCC for 35% of of AXL (n=35/99), 13% of B7H3/CD27 (n=12/99), 50% of EGFR (n=50/99), 63% of VTCN1 (n=63/99), 10% of MSLN (n=10/99), 77% of CDH3 (n=76/99), and 39% of PDGFRA (n=39/99).
Conclusion: Increased protein expression for approved ADC targets were infrequent in HNSCC. However, increased protein expression is seen for several ADCs under clinical investigation supporting the potential therapeutic approaches for investigational ADC targets.
Citation Format: Justin Tyler Moyers, Seth L. Smith, Miranda M. Mora, Roberto Carmagnani Pestana. Analysis of protein expression in head and neck cancers as therapeutic targets for antibody drug conjugates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5093.
Abstract 5109: Novel acylfulvene LP184 shows single agent and combinatorial efficacy with PARP inhibitors in atypical teratoid rhabdoid tumors
Authors: Tindall Abigail , Kwon Hyuk J. , Musa Istabraq , Findlay Tyler , Lee Su Chan , Eberhart Charles , Raabe Eric 
Published: March 2024

Abstract
Atypical Teratoid Rhabdoid Tumor (AT/RT) is an aggressive form of pediatric brain cancer that spreads quickly and leads to survival rates of less than 40%. Current treatments are insufficient at reducing this poor prognosis. A hallmark feature of ATRT is a SMARCB1 mutation. Illudins are a class of cytotoxic compounds with activity against pediatric solid tumors, including AT/RT. LP-184 is a novel synthetic illudin with improved brain penetration and activity against adult high-grade glioma orthotopic xenografts. We tested LP-184 against a battery of AT/RT cell lines including BT37, CHLA06, CHLA05, and CHLA266. LP-184 decreases viability at nanomolar concentrations with IC50s ranging from 9.91nM - 23.92nM. LP-184 decreased proliferation as measured by immunofluorescence and confirmed by western blots (BT37 p=0.0001, CHLA06 =0.0001, CHLA05=0.033). LP-184 also induced apoptosis as demonstrated in immunofluorescent images and western blots (BT37 p=0.0001, CHLA06 =0.0001, CHLA05=0.0015, CHLA266 p=0.002). Furthermore, LP-184 shows strong synergy with the PARP inhibitor Rucaparib, suggesting that inhibition of DNA repair potentiates LP-184 activity. LP-184 reduces viable cell count by as much as 50% and combination with Rucaparib further decreases viability by 75% (BT37=0.0001, CHLA06=0.0002, CHLA05=0.0077). The dual therapy also demonstrates cytostatic and cytotoxic effects as confirmed by immunofluorescence and western blots (BT37 BrdU = 0.0004, BT37 CC3 = 0.0002, CHLA06 BrdU = 0.0033, CHLA06 CC3 = 0.0117 compared to control). Further studies in vivo are being conducted to test single agent and combination therapies of LP-184 and Rucaparib in ATRT, as our data indicates that the two could provide a compelling treatment option for patients with this poor prognosis brain tumor.
Citation Format: Abigail Tindall, Hyuk J. Kwon, Istabraq Musa, Tyler Findlay, Su Chan Lee, Charles Eberhart, Eric Raabe. Novel acylfulvene LP184 shows single agent and combinatorial efficacy with PARP inhibitors in atypical teratoid rhabdoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5109.
Abstract 5146: Clinical significance of inter-assay discrepancy in PD-L1 expression evaluation for the efficacy of pembrolizumab in advanced NSCLC patients with high PD-L1 expression
Authors: Miyakoshi Jun , Kashima Jumpei , Shirasawa Masayuki , Torasawa Masahiro , Matsumoto Yuji , Masuda Ken , Shinno Yuki , Okuma Yusuke , Yoshida Tatsuya , Goto Yasushi , Horinouchi Hidehito , Shiraishi Kouya , Kohno Takashi , Yamamoto Noboru , Yatabe Yasushi , Ohe Yuichiro 
Published: March 2024

Abstract
Introduction: The expression of programmed cell death ligand-1 (PD-L1) is a predictive biomarker for the efficacy of pembrolizumab in advanced non-small cell lung cancer (NSCLC). While several assays have been approved for evaluating PD-L1 expression status, the inter-assay discordances are observed. The clinical significance of these discrepancies is still unclear.
Methods: We retrospectively reviewed treatment-naïve NSCLC patients with available PD-L1 expression status by both 22C3 and SP142 assays. Among these patients, efficacy analysis was performed in those with PD-L1 tumor proportion score (TPS) ≥ 50% (22C3) who received the first-line pembrolizumab monotherapy. Additionally, we conducted RNA-sequence analysis in the patients with TPS ≥ 50% to investigate the distinct immune profiles with the inter-assay discordance.
Results: A total of 611 patients were evaluated for PD-L1 expression status by both assays. Of 198 patients with TPS ≥ 50%, 91 (46%) had TC score ≤ 1 (SP142, i.e., inter-assay discrepancy). In 52 patients who received the first-line pembrolizumab monotherapy, the efficacy in patients with the inter-assay discrepancy was significantly lower than those without the discrepancy (shown in Table). While there was no difference in tumor microenvironments such as the tumor-infiltrating lymphocytes, the transcriptome analysis revealed significantly more CD274 splicing variants with aberrant 3’-terminal sequences in tumors with the inter-assay discrepancy than those without discrepancy, leading to the suppressed PD-1/PD-L1 pathway in those with the discrepancy.
Conclusion: The inter-assay discrepancy in the PD-L1 expression status on tumor cells between the 22C3 and SP142 assays, reflecting an imbalance of the CD274 splicing variants, could be a primary-resistance mechanism to the pembrolizumab monotherapy in highly PD-L1-expressing NSCLCs.
PD-L1(22C3) Discrepancy Pts. ORR(%) p value Median PFS(months) 95%CI p value TPS ≥ 50% yes 17 18 &lt; 0.001 3.2 0.8–5.5 &lt; 0.001 no 35 83 8.3 5.7–24.2
Citation Format: Jun Miyakoshi, Jumpei Kashima, Masayuki Shirasawa, Masahiro Torasawa, Yuji Matsumoto, Ken Masuda, Yuki Shinno, Yusuke Okuma, Tatsuya Yoshida, Yasushi Goto, Hidehito Horinouchi, Kouya Shiraishi, Takashi Kohno, Noboru Yamamoto, Yasushi Yatabe, Yuichiro Ohe. Clinical significance of inter-assay discrepancy in PD-L1 expression evaluation for the efficacy of pembrolizumab in advanced NSCLC patients with high PD-L1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5146.