tbuckley/cabot-search huggingface dataset:
Abstract B074: Intrinsic subtypes in Ethiopian breast cancer patients: Implications for better care
Authors: Zelalem Desalegn Woldesonbet, Meron Yohannes, Martin Porsch, Kathrin Stückrath, Endale Anberber, Pablo Santos, Marcus Bauer, Adamu Addissie, Yonas Bekuretsion, Mathewos Assefa, Yasin Worku, Lesley Taylor, Tamrat Abebe, Eva J Kantelhardt, Martina Vetter
Journal: Clinical Cancer Research (2024)

Abstract Objective: The recent development of multi-gene assays for gene expression profiling has contributed significantly to the understanding of the clinically and biologically heterogeneous breast cancer (BC) disease. PAM50 is one of these assays used to stratify BC patients and individualize treatment. The present study was conducted to characterize PAM50-based intrinsic subtypes among Ethiopian BC patients. Patients and methods: Formalin-fixed paraffin- embedded tissues were collected from 334 BC patients who attended five different Ethiopian health facilities. All samples were assessed using the PAM50 algorithm for intrinsic subtyping. Results: The tumor samples were classified into PAM50 intrinsic subtypes as follows: 104 samples (31.1%) were luminal A, 91 samples (27.2%) were luminal B, 62 samples (18.6%) were HER2-enriched and 77 samples (23.1%) were basal-like. The intrinsic subtypes were found to be associated with clinical and histopathological parameters such as steroid hormone receptor status, HER2 status, Ki-67 proliferation index and tumor differentiation, but not with age, tumor size or histological type. An immunohistochemistry-based classification of tumors (IHC groups) was found to correlate with intrinsic subtypes. Conclusion: The distribution of the intrinsic subtypes confirms previous immunohistochemistry-based studies from Ethiopia showing potentially endocrine-sensitive tumors in more than half of the patients. Health workers in primary or secondary-level health care facilities can be trained to offer endocrine therapy to improve breast cancer care. Additionally, the findings indicate that PAM50-based classification offers a robust method for the molecular classification of tumors in the Ethiopian context. Citation Format: Zelalem Desalegn Woldesonbet, Meron Yohannes, Martin Porsch, Kathrin Stückrath, Endale Anberber, Pablo Santos, Marcus Bauer, Adamu Addissie, Yonas Bekuretsion, Mathewos Assefa, Yasin Worku, Lesley Taylor, Tamrat Abebe, Eva J Kantelhardt, Martina Vetter. Intrinsic subtypes in Ethiopian breast cancer patients: Implications for better care [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B074.
Abstract IA004: Early cancer dissemination: Circulating tumor cells in ductal carcinoma in situ patients
Authors: Sunitha Nagrath, Neha Nagpal, Brittany Rupp, Yan Hong, Fariba Behbod, Max Wicha
Journal: Clinical Cancer Research (2024)

Abstract Raised awareness about the importance of early breast cancer diagnostics has led to an increased detection rate of ductal carcinoma in situ (DCIS) through mammographic screening. DCIS, often termed as 'Stage 0' carcinoma, is characterized by neoplastic cells confined within the basement membrane. Despite the significant treatment efforts for most DCIS patients, the 20-year breast cancer mortality rate post-diagnosis, with or without treatment, remains at 3.3%. To deepen the understanding of breast cancer oncogenesis, recent studies have highlighted the clonal diversity within the DCIS tumor microenvironment and the presence of disseminated tumor cells in DCIS patients. Nonetheless, significant gaps persist in identifying diagnostic characteristics that predict which DCIS patients are more likely to experience progression or recurrence. Ultimately, this project aims to enhance DCIS patient stratification through the high-throughput isolation and analysis of circulating biomarkers. In this study, we establish a novel workflow that addresses the limitations of traditional tissue-based diagnostics by transitioning to liquid biopsies. This research not only builds upon emerging evidence of early breast cancer cell dissemination during carcinogenesis but also explores the utility of circulating tumor cells (CTCs) as biomarkers in DCIS. The use of the labyrinth, a high-throughput inertial microfluidic device, has shown success in isolating CTCs based on their larger size relative to white blood cells. Unlike antigen- based isolation methods, inertial microfluidic devices can capture heterogeneous CTCs with varying surface proteins. Leveraging this technology, we successfully isolated and identified CTCs in DCIS patients. Furthermore, single-cell RNA sequencing of the isolated DCIS CTCs allowed us to identify prognostically significant signatures. Overall, our study presents a workflow capable of identifying characteristics associated with a greater risk of progression, thus contributing valuable insights into the stratification and management of DCIS patients. Citation Format: Sunitha Nagrath, Neha Nagpal, Brittany Rupp, Yan Hong, Fariba Behbod, Max Wicha. Early cancer dissemination: Circulating tumor cells in ductal carcinoma in situ patients [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr IA004.
Abstract IA017: ctDNA based detection of MRD in colon cancer: Towards clinical implementation
Authors: Jeanne Tie
Journal: Clinical Cancer Research (2024)

Abstract Patient selection for adjuvant treatment remains a challenge with our current clinicopathologic criteria. While adjuvant chemotherapy has been shown to improve relapse risk and survival in stage III colon cancer and perhaps less so in stage II disease, the absolute benefit remains modest, risking the over-treatment of many patients and potential under-treatment of some. Additionally, beyond fluoropyrimidine and oxaliplatin, no new adjuvant therapy has been shown to improve survival over the past 2 decades, especially for MMR proficient tumors. The ability of ctDNA to detect minimal residual disease offers a paradigm shift to the conventional tissue- based risk assessment. Post-op ctDNA detection has been shown to be one of the strongest independent prognostic markers in curatively resected colorectal cancer. Alongside technological advancement, multiple randomized trials are investigating different applications of ctDNA MRD analysis in the clinic, from adjuvant treatment de-escalation in patients with ctDNA-negative result, treatment escalation in ctDNA-positive result to the role of ctDNA as a surveillance tool. Understanding the strengths and limitations of this test will help inform future trial design and optimize clinical implementation. Citation Format: Jeanne Tie. ctDNA based detection of MRD in colon cancer: Towards clinical implementation [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr IA017.
Abstract IA025: A DNA methylation atlas of normal human cell types
Authors: Tommy Kaplan
Journal: Clinical Cancer Research (2024)

Abstract DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies. Citation Format: Tommy Kaplan. A DNA methylation atlas of normal human cell types [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr IA025.
Abstract B068: Inferring enhancer activity from cell-free DNA fragmentation patterns
Authors: Alexis Yang
Journal: Clinical Cancer Research (2024)

Abstract We present a framework for inferring enhancer activity from cell-free DNA (cfDNA) fragmentation patterns, offering a novel feature set for cfDNA analysis that reflects gene regulation. Enhancers are promoter-distal regulatory elements that regulate gene expression programs that define cell types and cellular states. Despite advances in inferring gene regulation in cancer using liquid biopsy, it remains challenging to identify signals of enhancer activity from cell-free DNA (cfDNA). Active enhancers are characterized by transcription of short enhancer RNAs (eRNAs). Recent studies demonstrated that cfDNA from promoters of transcribed genes demonstrates high variation in DNA fragment length, or “fragmentation entropy”. We tested whether eRNA transcription can be inferred based on cfDNA fragmentation entropy. We quantified “enhancer fragmentation entropy” (EFE) to profile enhancer activity in plasma by measuring Shannon entropy of cfDNA fragments around enhancer transcription start sites (TSS). Using PRO-cap data from lymphoblastoid cell lines, we analyzed EFE signals at 70,000 transcribed enhancers and observed distinct patterns between active (expressed) and inactive enhancers in cfDNA from healthy individuals. cfDNA from patients with prostate cancer showed elevated EFE at enhancers activated in prostate cancer. EFE at these sites correlated with circulating tumor DNA (ctDNA) levels in a published cfDNA dataset of 41 prostate cancer plasma samples. Lower-dimensional projections of the entropy signals across 300 “modules” of co-regulated enhancers revealed tighter clustering of samples within the same cancer type, suggesting that these entropy patterns capture cell-type specific enhancer activity. Our findings suggest that enhancer fragmentation entropy captures cell-type specific signals and, when measured at cancer-specific enhancers in cfDNA, could serve as a promising biomarker for cancer detection and monitoring. Ongoing work is focused on validating these findings in larger cohorts and applying EFE to cancer monitoring and clinical subtyping. Citation Format: Alexis Yang. Inferring enhancer activity from cell-free DNA fragmentation patterns [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B068.
Abstract B067: Dynamic chromatin landscapes of colorectal cancer development and cell-free DNA fragmentation
Authors: Nicholas A. Vulpescu, Zachariah H. Foda, Pieter H.A. Wisse, Christopher Cherry, Jaime E. Medina, Vilmos Adleff, Remond J.A. Fijneman, Robert B. Scharpf, Gerrit A. Meijer, Beatriz Carvalho, Victor E. Velculescu
Journal: Clinical Cancer Research (2024)

Abstract This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR016) of the Conference Program/Proceedings. Citation Format: Nicholas A. Vulpescu, Zachariah H. Foda, Pieter H.A. Wisse, Christopher Cherry, Jaime E. Medina, Vilmos Adleff, Remond J.A. Fijneman, Robert B. Scharpf, Gerrit A. Meijer, Beatriz Carvalho, Victor E. Velculescu. Dynamic chromatin landscapes of colorectal cancer development and cell-free DNA fragmentation [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B067.
Abstract B047: Monitoring treatment response and toxicity in BRAF V600-mutant metastatic melanoma with circulating cell-free DNA
Authors: Sidharth S Jain, A. Patrick IV McDeed, Megan E McNamara, Amber R Alley, Dori S Rosenstrauch, Harry Sun, Natalie Thompson, John M Kirkwood, Geoffrey T Gibney, Michael B Atkins, Anton Wellstein
Journal: Clinical Cancer Research (2024)

Abstract Background: The DREAMseq trial (EA6134, NCT02224781) was a national multi-center randomized phase III trial coordinated by ECOG-ACRIN that found that immune checkpoint inhibitor (IO) treatment achieves improved survival outcomes compared to targeted therapy (TT) in patients with BRAF V600-mutant metastatic melanoma. Still, approximately 40% of patients do not respond to IO, and existing biomarkers fail to distinguish this subset of patients who do not benefit from IO therapy. Additionally, as many as 80% of patients may experience immune- related adverse events (irAEs), which range from mild dermatological symptoms to life- threatening myocarditis. Here, we explore the use of the methylation status of cell-free DNA (cfDNA) in serially collected blood samples to measure response and toxicity in the context of IO- and TT-treated metastatic melanoma. Methods: Serial serum samples were collected from patients with BRAF V600-mutant metastatic melanoma treated with ipilimumab/nivolumab (IO) or dabrafenib/trametinib (TT). Circulating cfDNA was isolated from serially collected serum samples, enriched for regions of interest by hybridization capture and sequenced using enzymatic methyl-seq. Cell-type deconvolution was performed to determine the abundance of cell type- specific methylation patterns of cfDNA molecules in patient serum at different time points of treatment. The BRAF V600 mutation abundance in total cfDNA was also assessed. Results: We identified melanocyte lineage-specific DNA methylation regions and demonstrate that the methylation status of these regions remains conserved in malignant melanoma. We characterized the changes in abundance of the melanocyte-lineage cfDNA over the course of treatment and show that these changes distinguish responders from non-responders to either IO or TT. Furthermore, we track the abundance of cell type-specific DNA from normal tissues to identify markers indicative of adverse effects or disease progression. Conclusions: We established melanocyte-lineage methylation markers and evaluated the use of cell-type specific DNA methylation to monitor treatment effects of immune checkpoint or BRAF/MEK inhibitors in metastatic melanoma using serially collected blood samples. Citation Format: Sidharth S Jain, A. Patrick IV McDeed, Megan E McNamara, Amber R Alley, Dori S Rosenstrauch, Harry Sun, Natalie Thompson, John M Kirkwood, Geoffrey T Gibney, Michael B Atkins, Anton Wellstein. Monitoring treatment response and toxicity in BRAF V600-mutant metastatic melanoma with circulating cell-free DNA [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B047.
Abstract A069: Effect of different voided urine sample storage time and temperature, and preservatives, on analysis with the multiplex bead-based Oncuria® bladder cancer immunoassay
Authors: Sunao Tanaka, Kaoru Murakami, Toru Sakatani, Riko Lee, Wayne Hogrefe, Fernando Siguencia, Steven M Smith, Charles J Rosser, Hideki Furuya
Journal: Clinical Cancer Research (2024)

Abstract Urinalysis accuracy requires reliable sample stability that is dependent on the chosen collection and storage conditions. If urine sample storage at room temperature (20°C) does not affect sample quality, this may reduce laboratory handling time and expense. This study evaluated whether different voided urine sample collection and storage parameters affected subsequent biomarker analysis by the multiplex Oncuria® bladder cancer immunoassay. The Oncuria® immunoassay simultaneously quantifies 10 protein analytes in urine to generate a bladder cancer diagnostic signature. Samples were stored at varied temperatures (20°C, 4°C, -80°C) for up to 1 month. The effects of adding two commercial urine sample stabilizers and antibiotics (trimethoprim) were also assessed. Subsequently, multiple potential biospecimen stabilizers were added to urine samples and evaluated with Oncuria® in hopes of allowing the urine sample to remain at room temperature for extended periods of time. First, it was demonstrated that voided urine samples stored at room temperate without such stabilizers had different levels of the 10 analytes associated with the Oncuria® test compared to voided urine samples stored at 4°C. Next, we evaluated the effects of commercially available biospecimen stabilizers. Despite the addition of these stabilizers, the levels of the 10 analytes were altered when the samples were stored at room temperature for prolonged periods of time. Therefore, we could not identify a suitable biospecimen stabilizer that would not require sample refrigeration. In conclusion, to minimize sample degradation/alteration after collection, voided urine samples should be refrigerated until analyzed with Oncuria® as the refrigeration is advantageous for the storage and the transport of these urine samples. Citation Format: Sunao Tanaka, Kaoru Murakami, Toru Sakatani, Riko Lee, Wayne Hogrefe, Fernando Siguencia, Steven M Smith, Charles J Rosser, Hideki Furuya. Effect of different voided urine sample storage time and temperature, and preservatives, on analysis with the multiplex bead-based Oncuria® bladder cancer immunoassay [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A069.
Abstract B029: Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction
Authors: Xinxing Li, Tao Liu, Antonella Bacchiocchi, Mengxing Li, Wen Cheng, Tobias Wittkop, Fernando Mendez, Yingyu Wang, Paul Tang, George Yeung, Qianqian Yao, Marcus Bosenberg, Mario Sznol, Qin Yan, Malek Faham, Li Weng, Ruth Halaban, Hai Jin, Zhiqian Hu
Journal: Clinical Cancer Research (2024)

Abstract While whole genome sequencing (WGS) of cell-free DNA (cfDNA) holds enormous promise for detection of molecularresidual disease (MRD), its performance is limited by WGS error rate. Here we introduce AccuScan, an efficient cfDNA WGS technology that enables genome-wide error correction at single read level, achieving an error rate of 4.2 × 10-7, which is about two orders of magnitude lower than a read-centric de-noising method. Application of AccuScan to MRD demonstrated analytical sensitivity down to 10-6 circulating tumor allele fraction at 99% sample level specificity. AccuScan showed 90% landmark sensitivity (within 6 weeks after surgery) and 100% specificity for predicting relapse in colorectal cancer. It also showed 67% sensitivity and 100% specificity with esophageal cancer using samples collected within one week after surgery. When AccuScan was applied to monitor immunotherapy in melanoma patients, the circulating tumor DNA (ctDNA) levels and dynamic profiles were consistent with clinical outcomes. Overall, AccuScan provides a highly accurate WGS solution for MRD detection, empowering ctDNA detection at parts per million rangewithout requiring high sample input or personalized reagents. Citation Format: Xinxing Li, Tao Liu, Antonella Bacchiocchi, Mengxing Li, Wen Cheng, Tobias Wittkop, Fernando Mendez, Yingyu Wang, Paul Tang, George Yeung, Qianqian Yao, Marcus Bosenberg, Mario Sznol, Qin Yan, Malek Faham, Li Weng, Ruth Halaban, Hai Jin, Zhiqian Hu. Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B029.
Abstract B061: Assessing saliva for cancer biomarker discovery: A liquid biopsy approach
Authors: Srinivas V Koduru, Mark Kidd, Abdel B Halim
Journal: Clinical Cancer Research (2024)

Abstract Introduction: Liquid biopsy has been gaining traction as a replacement for invasive tumor biopsies in oncology. Several blood-based in vitro diagnostics have been approved by the FDA and other regulatory agencies, and efforts are being made to validate urine, saliva, and buccal swabs as alternative matrices. The primary aim of this study was to investigate the relative mRNA expression in paired blood and saliva samples from cancer patients and healthy individuals. Methods: We collected matched saliva and blood samples from 35 subjects, comprising 26 patients with prostate, breast, colon, lung, melanoma, and pancreatic cancers, and 9 healthy individuals. Samples were collected using Wren's proprietary stabilization buffer kit, and total RNA extracted by TRIzol-based Qiagen reagents. RNA sequencing (RNA-Seq) was performed on a Novaseq 6000 platform, and data was analyzed using high-performance computing (HPC) with PartekFlow software, employing the BWA aligner (hg38). We focused on comparing gene expression in cancers (as a group) compared to controls. Results: The total number of genes detected in saliva was 3,985, compared to 14,459 genes detected in blood samples. A substantial overlap was observed, with more than 92.8% of saliva-detected genes also found in blood. We also examined housekeeping gene detection in both matrices. In this set of 1,003 housekeeping genes, 30% (n=305) were expressed in both saliva and blood. When we narrowed the scope to only include the 1,154 cancer-related genes as listed by the OncoKB database, 88.3% were detected in saliva and/or blood, with 37.1% of these genes (n=429) were expressed in both saliva and blood. Lastly, we examined a set of 241 cancer-associated biomarkers utilized in RT-PCR-based diagnostic blood assays clinically validated by our laboratory. This subset analysis revealed that 23.2% of these biomarkers were expressed in both saliva and blood. Conclusion: Our data indicate that the majority of mRNA detected in saliva was also detected in blood, with differential expression observed in cancer patients compared to normal controls. Given the relatively high limit of detection (low sensitivity) using RNA-Seq technology compared to PCR and the relatively small number of subjects, the data may suggest that saliva could function as a surrogate biomarker matrix for blood. Citation Format: Srinivas V Koduru, Mark Kidd, Abdel B Halim. Assessing saliva for cancer biomarker discovery: A liquid biopsy approach [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B061.