Clinical Research (Excluding Clinical Trials)最新文献

{"title":"Abstract 588: Mesenchymal markers: The new avenue for circulating tumor cells detection","authors":"Mariacristina Ciccioli, Natalia Bravo-Santano, Amy Davis, Jolie Lewis, R. Malcolm, A. Pailhes-Jimenez","doi":"10.1158/1538-7445.AM2021-588","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-588","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75522630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 611: Colibactin mutation signatures are associated with a distinct colorectal cancer clinicopathologic phenotype","authors":"M. Lumish, A. Luthra, S. Asawa, F. Cambuli, M. Donoghue, Hyung Jun Woo, A. Cercek, R. Yaeger, J. Shia, F. Sánchez-Vega, K. Ganesh","doi":"10.1158/1538-7445.AM2021-611","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-611","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75891275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 685: A social epigenomic investigation of racial disparity in pulmonary impairment among aging survivors of childhood cancer","authors":"N. Song, Jin-ah Sim, Q. Dong, Yinan Zheng, L. Hou, Zhenghong Li, Chia-Wei Hsu, H. Pan, H. Mulder, J. Easton, Emily Walker, G. Neale, Carmen L. Wilson, K. Ness, K. Krull, D. Srivastava, Y. Yasui, Jinghui Zhang, M. Hudson, L. Robison, I. Huang, Zhaoming Wang","doi":"10.1158/1538-7445.AM2021-685","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-685","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73169396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 338: Peripheral blood monocyte count prediction for anti-HER2 combination therapy: Outcomes in HER2-positive metastatic breast cancer patients","authors":"Amer Radwi, R. K. Albeladi, Shahrazad Abdulsalam Alzahrani, R. Alahmadi, Haneen Abdulrahman Aljohani, Dalia Ahmed","doi":"10.1158/1538-7445.AM2021-338","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-338","url":null,"abstract":"Background: Breast cancer is the commonest cancer in Saudi Arabia and worldwide. Nineteen percent of breast cancers are HER2-positive. Both trastuzumab and pertuzumab inhibit cancer cell proliferation by blocking HER2 activation and HER2-mediated downstream signals. They also induce extracellular antibody-dependent cell-mediated cytotoxicity (ADCC), exerted by immune cells expressing surface CD16 Fcγ receptors (FcγRs), such as NK cells subset of human blood monocytes. Inside tissue, monocytes differentiate to macrophages and potentiate anti-cancer innate immunity. Increased macrophages9 infiltration in the tumor tissue was associated with enhanced efficacy of trastuzumab antitumor efficacy in mouse xenograft tumor models. In Metastatic HER2-positive breast cancer, increased M1 polarized macrophages improved survival and were independent prognostic predictors. Herceptin significantly increased peripheral blood monocyte (PBMC) cytotoxicity against HER-2 positive cancer cells. This study aims to determine the impact of peripheral blood monocyte (PBMC) count on response rate (RR) and progression-free survival (PFS) in metastatic HER2-positive breast cancer patients treated with trastuzumab and pertuzumab. Method: A retrospective chart review at Princess Norah Oncology Center (PNOC) that included histopathology-proven metastatic HER2-positive breast cancer patients receiving first-line anti-HER2 systemic therapy from January 2008 to May 2018. Younger patients ( Results: Of 307 identified cases, 81 were analyzed. The median age was 62 years, 73% were postmenopausal, and 70% had grade 3 tumors. All had visceral metastases, treated with chemotherapy, along with an anti-HER2 agent. We found improved RR with high PBMC before the second cycle (P = 0.025) and increased PFS for high PBMC before the third cycle (P = 0.048). Conclusion(s): Peripheral blood monocyte count before cycle 2 and 3 might predict a favorable outcome of chemotherapy anti-HER2 combination in metastatic HER2-positive breast cancer. Citation Format: Amer Naeem Radwi, Reyadh Khalid Albeladi, Shahrazad Abdulsalam Alzahrani, Raghad Abdulrahman Alahmadi, Haneen Abdulrahman Aljohani, Dalia Ismaiel Ahmed. Peripheral blood monocyte count prediction for anti-HER2 combination therapy: Outcomes in HER2-positive metastatic breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 338.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74385275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB010: SMMART Program: A multi-omics tumor board with a focus on breast cancer","authors":"B. Kong, Brett E. Johnson, Jamie M. Keck, S. Mitri, Patrick Leyshock, J. Stommel, Kiara Siex, Marlana Klinger, C. Zheng, Rochelle Williams-Belizaire, S. McWeeney, Jeremy Goecks, A. Kolodzie, A. Guimaraes, G. Thomas, C. Corless, Zahi I. Mitri, J. Gray, G. Mills, R. Bergan","doi":"10.1158/1538-7445.AM2021-LB010","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB010","url":null,"abstract":"Many of the current approaches to personalized medicine rely on sequencing DNA to identify actionable mutations. However, growing evidence suggests that a multi-omic approach to more broadly assess biology is needed to improve patient outcomes. We have implemented a workflow for tissue acquisition, multi-omic clinical testing, and correlated computational biology analysis, within the Serial Measurements of Molecular and Architectural Responses to Therapy (SMMART) Program (Mitri et al, J Transl Med 2018). We report biopsy metrics, CLIA analytics utilized, the operation of a multi-omics tumor board, and clinical outcomes in metastatic breast cancer patients. A detailed clinical history of each patient was obtained, including demographics, tumor type, treatment and response to prior therapies, imaging, and blood tumor biomarkers. A comprehensive set of clinical assays was performed on newly obtained tumor biopsies, including immunohistochemistry (ER, PR, HER2, AR, BCL-2, and PD-L1), a targeted next-generation sequencing panel covering 225 genes (GeneTrails® Comprehensive Solid Tumor Panel), whole exome sequencing (Tempus xE), whole transcriptomic sequencing (Illumina TruSeq RNA exome), and a multiplex protein analysis of 22 key cancer proteins and phosphoproteins on the Nanostring platform (NanoString Vantage 3D™ Solid Tumor Panel). The integrated clinical and analytical information was made available to the multidisciplinary SMMART Clinical Tumor Board that provided treatment recommendations; the final treatment plan was at the discretion of the treating physician. Between 1/1/2017-1/1/2020, 53 breast cancer patients were consented. Seven screen-failed due to a lack of sites amenable to biopsy and 8 were actively co-consented to other clinical trials. The remaining 38 patients are included in this preliminary report. A total of 63 biopsies were collected from lymph node, liver, bone, soft tissue, lung, skin, breast, and brain. Serial biopsies (≥2) were obtained for 15 patients. Analytics were generated in 93.7% of biopsies. Tumor boards were held for 15 patients (17 total sessions). The experience and information gathered thus far have yielded the following unique cases: (1) single patient analysis of omics, imaging, and response over 42 months, (2) identification of an ERBB3 mutation with downstream pathway activation that responded to HER2-targeted therapy, and (3) clinically significant variation in hormonal and HER2 receptor status over time. We will provide an analysis across the 38 patients of treatment outcomes, analytics information content, biological changes observed through serial biopsies, and tumor board interventions. We demonstrate the feasibility of implementing a deep, real-time analytics platform for metastatic breast cancer patients that can provide new insight into therapeutic opportunities. The observed clinical responses support further use and investigation of this approach. Citation Format: Ben L. Kong, Brett E. Johnson, Jam","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74637875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 349: Association of DNA damage response capacity with neoadjuvant chemoradiation response in locally advanced rectal cancer","authors":"E. Demidova, Randy Lesh, V. Avkshtol, M. Einarson, E. Golemis, S. Arora, J. Meyer","doi":"10.1158/1538-7445.AM2021-349","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-349","url":null,"abstract":"Background: Locally advanced rectal cancer (RC) cases are ~60% of newly diagnosed RCs, with neoadjuvant chemoradiation therapy (nCRT) followed by surgery as the standard of care. While nCRT is highly toxic, it is also beneficial. Recent prospective trials reported that up to 59% locally advanced RC cases exhibit complete clinical response, suggesting these patients as ideal candidates for organ preservation. However, currently there is no biomarker to predict who will or will not benefit from nCRT. The goal of this study was to establish a predictive biomarker for benefit from nCRT, based on the hypothesis that inherent DNA damage response (DDR) capacity contributes to nCRT response in RC. Methods: To gain insight into inherent DDR capacity, we profiled primary peripheral blood lymphocytes (pPBLs) from RC patients by quantitative immunofluorescence, Luminex-multianalyte assay, and pPBL DNA whole exome sequencing (WES). RC patients analyzed were segregated by neoadjuvant rectal (NAR) score: NAR 14, poor responders (PoRs), n=21; 1 Results: pPBLs from CRs showed significantly elevated γH2AX foci (a hallmark of double strand breaks) vs. PoRs (P 0.082 as a cutpoint, we could include 90% patients with a CR. Finally, WES analysis of pPBL DNA from 15 CRs and 15 PoRs revealed that CRs were enriched in predicted-pathogenic variants in base excision repair genes vs. PoRs (p Conclusion and future work: Overall, our data suggests inherent DDR capacity testing may predict the magnitude of benefit from nCRT and assist in patient selection for treatment. Validation in a larger RC patient population is needed to confirm these findings. Biological studies testing the impact of the identified variants in base excision repair on inherent DDR capacity are warranted. Citation Format: Elena V. Demidova, Randy W. Lesh, Vladimir Avkshtol, Margret B. Einarson, Erica A. Golemis, Sanjeevani Arora, Joshua E. Meyer. Association of DNA damage response capacity with neoadjuvant chemoradiation response in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 349.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73413006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract LB033: Longitudinal ctDNA changes in patients with long-term response to palbociclib combination therapy for advanced breast cancer: A preliminary analysis from the real-world POLARIS study","authors":"J. Blum, A. Bardia, S. Wilks, S. McCune, C. Dul, J. Migas, D. W. Spell, Zhe Zhang, Yuan Liu, Yao Wang, D. Tripathy","doi":"10.1158/1538-7445.AM2021-LB033","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB033","url":null,"abstract":"Background POLARIS is an ongoing, prospective, real-world (RW) study of palbociclib (PAL) in patients (pts) with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC). A biomarker goal of this study was to evaluate serial changes in circulating tumor DNA (ctDNA) dynamics among pts with long-term clinical response to PAL plus endocrine therapy (ie, received ≥18 cycles). Methods The data set included pts who received PAL combination therapy, gave consent for blood collection to obtain ctDNA, and had long-term clinical response. The Guardant360 Next-Generation Sequencing platform, which analyzed approximately 73 genes, was used to sequence ctDNA for somatic single-nucleotide variants, including copy number variants. Longitudinal ctDNA changes (at baseline and various time points) and the RW clinical response to PAL are described. Results As of December 17, 2020, 35 pts of 1280 enrolled received ≥18 cycles of PAL combination therapy, with blood samples collected over a minimum of a 24-month period. Pts received PAL plus an aromatase inhibitor (n=16) or fulvestrant (n=19). Median age was 64 years. Thirty pts (85.7%) were white, 29 (82.9%) were postmenopausal, 31 (88.6%) had an Eastern Cooperative Oncology Group score of 0 or 1, 12 (34.3%) had visceral disease, 9 (25.7%) had de novo disease, and 24 (68.6%) had recurrent disease. Six pts (17.1%) had a RW best overall response (BOR) of complete response (CR), 9 (25.7%) had partial response (PR), and 20 (57.1%) had stable disease (SD). Two pts had disease progression resulting in change of therapy at cycles 25 and 38, respectively. Biomarker samples were collected from a median (range) total number of 9 (3-12) visits. The median (range) number of somatic variants detected was 4 (0-11) and included the most prevalent somatic mutations (eg, PIK3CA, TP53, BRCA1/2, FGFR2, GATA3). No ctDNA mutations were detected in 6 pts (17%) post baseline up to 24 months. Among 15 pts who achieved CR/PR, 12 (80%) either had no detectable or sustained very low ctDNA burden or had corresponding ctDNA decrease. Among 16 pts who remained with SD, 12 (75%) either had no detectable or sustained very low ctDNA burden or had ctDNA decrease. Among 8 pts whose disease progressed, 5 (63%) had an increasing trend in ctDNA mutation frequency. Conclusions This study is among the first to provide serial blood-based tumor genotyping data from routine clinical practice. Interim data indicate that even pts with ongoing detectable ctDNA have a BOR of CR, PR, or SD with PAL for HR+/HER2- ABC, suggesting certain mutations might not be drivers of PAL resistance. Dynamic changes of ctDNA mutations may be predictive for treatment response, and may have clinical utility in disease surveillance monitoring. Additional longitudinal data will be presented. Pfizer; NCT03280303 Citation Format: Joanne L. Blum, Aditya Bardia, Sharon Wilks, Steven L. McCune, Carrie L. Dul, John J. Migas, Derrick","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73839627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 583: Analysis of solid pediatric tumor methylomes reveals a shared cancer recurrence signature in cell-free DNA","authors":"D. Buckley, B. Tew, G. Gooden, T. Triche, B. Salhia","doi":"10.1158/1538-7445.AM2021-583","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-583","url":null,"abstract":"Cancer is the second most common cause of death in children aged 1-14 years in the United States, with approximately 11,000 new cases and 1200 deaths annually. Due in part to the rarity and diversity of childhood tumors, a non-invasive diagnostic to identify patients at high risk of recurrence does not exist for patients with pediatric solid cancer. Cell-free (cf)DNA is rapidly becoming the standard for non-invasive screening, diagnosis, treatment and monitoring of human tumors. In particular, cfDNA methylation detection has proven to be a robust platform for “liquid biopsies,” with several important advantages over simple somatic variant detection. Here we present a cfDNA methylation signature derived from a pan-methylome analysis of recurrent pediatric tumors. The methylomes spanned 34 tumor tissue samples, 13 patient-matched adjacent normal, and 16 patient-matched plasma samples from 27 individuals, representing 11 different pediatric tumor types, including 10 neuroblastomas, 4 osteosarcomas and 2 hepatoblastomas. In addition, 13 adjacent normal samples and 15 normal plasma samples were used as DNA methylation controls. These samples were obtained from the Pediatric Oncology Experimental Investigators9 Consortium (POETIC) under informed consent. DNA methylation was analyzed for all samples by whole genome bisulfite sequencing (WGBS). Using consensus DNA methylation calling, we identified a set of 402 differentially methylated regions (DMR) in genomic DNA from tissue, with substantial enrichment of hypomethylated DMRs across a majority of samples. CpGs that were commonly hypomethylated were combined into consensus ‘hotspots.9 In order to discriminate between tumor/normal samples in tissue, we applied supervised machine learning to train a classifier on these 402 features. Mean methylation across these 402 CpG hotspots was significantly (p Citation Format: David N. Buckley, Ben Tew, Gerald Gooden, Timothy Triche, Bodour Salhia. Analysis of solid pediatric tumor methylomes reveals a shared cancer recurrence signature in cell-free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 583.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85424437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 454: The landscape of PD-L1 expression in lung cancer harboring driver oncogene mutations except EGFR mutations","authors":"Ningbo Liu, Fuyu Gong","doi":"10.1158/1538-7445.AM2021-454","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-454","url":null,"abstract":"Background: Results from previous studies indicated that lung cancer patients harboring EGFR sensitizing mutations may receive unfavorable outcomes from immunotherapy. The present study aims to investigate the landscape of PD-L1 expression in lung cancer harboring driver oncogene mutations except EGFR mutations. Methods: Tissue samples were subjected to NGS in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab for driver oncogene mutations and PD-L1 expression. Results: A total of 22143 lung cancer patients were selected, there are 2120 patients have the driver oncogene mutation, including 1115 (5.04%) ALK positive cases,498 (2.25%) MET positive cases,239(1.08%) RET positive cases,182(0.82%) BRAF positive cases, 72 (0.33%) ROS1 positive cases and 14 (0.03%) NTRK positive cases. Among all the driver oncogene mutation patients, 481 patients have been collected tumor tissue, and the PD-L1 expression have been tested by FDA-approved 22C3 antibodies. Among all the driver oncogene mutation cases assessed PD-L1 expression (n=481), low PD-L1 expression levels ( Conclusion: Our study supported that NSCLC patients harboring sensitizing oncogenic mutations may potentially benefit from anti-PD-1/L1 especially for those with positive indicators of immunotherapy with strong positive PD-L1 expression. Citation Format: Ningbo Liu, Fuyu Gong. The landscape of PD-L1 expression in lung cancer harboring driver oncogene mutations except EGFR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 454.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82138511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract 456: Liquid biopsy for patient stratification and monitoring of dacomitinib clinical trial in patients with EGFR amplified recurrent glioblastoma","authors":"A. Yekula, R. Kitchen, S. Chakrabortty, B. Carter, J. Skog, L. Balaj","doi":"10.1158/1538-7445.AM2021-456","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-456","url":null,"abstract":"Introduction Liquid biopsy for the detection and monitoring of brain tumors is of significant clinical interest. This ability to non-invasively profile tumors, opens new avenues for diagnosis, patient stratification to novel therapies, as well as monitoring. Here, we provide evidence of extracellular vesicle EV RNA-based diagnosis, patient stratification, and assessment of response to therapy in the setting of a clinical trial evaluating the efficacy of dacomitinib, EGFR tyrosine kinase inhibitor in patients with recurrent, EGFR amplified GBM in a multi-armed, multi-institutional clinical trial (NCT01112527). Methods We performed RNASeq on long RNA extracted from the serum samples, pre-treatment and 1-month post-treatment. Results Firstly, our novel RNASeq workflow on EV derived long RNA allowed the detection of thousands of protein coding genes, lincRNAs and antisense RNAs enabling the study of a wider repertoire of potential RNA based biomarkers of GBM. Secondly, we observed a differential expression profile is serum EV RNA of GBM patients and healthy controls. Combining our findings with TCGA data and literature screening, we generated a 25 gene signature representative of critical pathways in several hallmarks of cancer including gliogenesis, epithelial to mesenchymal transition, invasion, regulation of stemness, apoptosis and cell cycle regulation, immune regulation and metabolic remodeling. Thirdly, we observed a differential expression profile is serum EV RNA of responders compared to non-responders in pre-treatment serum. Specifically, the EV mRNAs ZNF35 and LAMTOR2 distinguish responders from non-responders (p-adjusted = 2.6E-8 and 2.4E-6, respectively) allowing potential patient stratification. Finally, we also observed a differential expression profile is serum EV RNA of responders compared to non-responders in post-treatment serum. EV mRNA DNMT3A is significantly enriched (p-adjusted = 1.8E-4) in post-treatment serum of responders compared to non-responders to dacomitinib allowing potential monitoring of response to therapy. Conclusion This study is unique because it represents the first longitudinal profiling of the EV RNA in a cohort of genomically selected GBM patients. These findings are a tantalizing step toward liquid biopsy-based biomarkers for the detection of GBM, as well as patient stratification and monitoring. Citation Format: Anudeep Yekula, Robert R. Kitchen, Sudipto K. Chakrabortty, Bob S. Carter, Johan Skog, Leonora Balaj. Liquid biopsy for patient stratification and monitoring of dacomitinib clinical trial in patients with EGFR amplified recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 456.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"103 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79467203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}