Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-LB057
N. Coleman, Charles Abbot, N. Somaiah, S. Piha-Paul, S. Pant, J. Rodón, S. G. Call, S. Boyle, F. Meric-Bernstam, F. Janku
Background: The discovery of oncogenic mutations as potential targets for cancer therapy has revolutionized the treatment of GIST and other cancers. However, adaptive resistance ultimately develops in nearly all patients, which emphasizes the need for a more detailed understanding of the underlying molecular profile. Methods: Using the Personalis ImmunoID NeXT Platform® (Personalis, Inc.; Menlo Park, CA), an augmented exome/transcriptome platform and analysis pipeline, we performed whole exome sequencing (WES) and whole transcriptome total RNA sequencing (RNA-Seq) of paired baseline tumor and normal tissue. NeXT Liquid Biopsy™ (Personalis, Inc.) was used for WES of plasma-derived ctDNA from serially collected samples collected at baseline, after 1 month and at progression to experimental systemic therapies in 15 patients with advanced/metastatic GIST. Results: WES of tumor tissue samples from all 15 patients confirmed underlying KIT mutation in all patients. There was large heterogeneity of other molecular alterations, which included therapeutically relevant molecular alterations, such as microsatellite instability-high (MSI-high) in 1 sample. RNA-Seq of tumor tissue revealed recurrent overexpression of GALR2, NY-ESO-1 and other genes involved in cancer progression, angiogenesis and anticancer immunity. Patients with response to systemic therapies demonstrated lower levels of cytolytic activity measured by CYT score in tumor tissue compared to patients without response (P=0.04). KIT mutations were detected in serially collected ctDNA samples from 12 (80%) of 15 patients. Quantity of KIT and other mutant ctDNA dynamically tracked the clonal evolution and clinical course during systemic therapy. Conclusions: Comprehensive genomic profiling (WES and RNA-Seq) of tumor tissue and WES of serially collected ctDNA is feasible and detects underlying druggable KIT mutations and other molecular alterations. Citation Format: Niamh Coleman, Charles Abbot, Neeta Somaiah, Sarina Piha-Paul, Shubham Pant, Jordi Rodon, S. Greg Call, Sean Boyle, Funda Meric-Bernstam, Filip Janku. Whole exome sequencing of tumor tissue and circulating tumor DNA ingastrointestinal stromal tumors (GIST) [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 LB057.
背景:致癌突变作为癌症治疗的潜在靶点的发现已经彻底改变了GIST和其他癌症的治疗。然而，几乎所有患者最终都会出现适应性耐药，这强调了对潜在分子谱更详细了解的必要性。方法:使用Personalis ImmunoID NeXT Platform®(Personalis, Inc.;Menlo Park, CA)，一个增强的外显子组/转录组平台和分析管道，我们对配对基线肿瘤和正常组织进行了全外显子组测序(WES)和全转录组总RNA测序(RNA- seq)。NeXT Liquid Biopsy™(Personalis, Inc.)用于对15例晚期/转移性GIST患者在基线、1个月后和进行实验性全身治疗时连续收集的样本进行血浆来源ctDNA的WES检测。结果:所有15例患者肿瘤组织样本的WES均证实所有患者存在潜在的KIT突变。其他分子改变存在很大的异质性，其中包括治疗相关的分子改变，例如1个样本中的微卫星不稳定性高(MSI-high)。肿瘤组织RNA-Seq显示GALR2、NY-ESO-1等参与肿瘤进展、血管生成和抗癌免疫的基因反复过表达。与无反应的患者相比，对全身治疗有反应的患者肿瘤组织中CYT评分显示出较低的细胞溶解活性水平(P=0.04)。从15例患者中连续收集的12例(80%)的ctDNA样本中检测到KIT突变。在全身治疗期间，KIT和其他突变ctDNA的数量动态跟踪克隆进化和临床过程。结论:肿瘤组织的全面基因组图谱(WES和RNA-Seq)和连续采集的ctDNA的WES是可行的，可以检测潜在的可药物KIT突变和其他分子改变。引文格式:Niamh Coleman, Charles Abbot, Neeta Somaiah, Sarina Piha-Paul, Shubham Pant, Jordi Rodon, S. Greg Call, Sean Boyle, Funda Meric-Bernstam, philip Janku。胃肠道间质瘤(GIST)肿瘤组织和循环肿瘤DNA的全外显子组测序[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):摘要nr LB057。
{"title":"Abstract LB057: Whole exome sequencing of tumor tissue and circulating tumor DNA ingastrointestinal stromal tumors (GIST)","authors":"N. Coleman, Charles Abbot, N. Somaiah, S. Piha-Paul, S. Pant, J. Rodón, S. G. Call, S. Boyle, F. Meric-Bernstam, F. Janku","doi":"10.1158/1538-7445.AM2021-LB057","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB057","url":null,"abstract":"Background: The discovery of oncogenic mutations as potential targets for cancer therapy has revolutionized the treatment of GIST and other cancers. However, adaptive resistance ultimately develops in nearly all patients, which emphasizes the need for a more detailed understanding of the underlying molecular profile. Methods: Using the Personalis ImmunoID NeXT Platform® (Personalis, Inc.; Menlo Park, CA), an augmented exome/transcriptome platform and analysis pipeline, we performed whole exome sequencing (WES) and whole transcriptome total RNA sequencing (RNA-Seq) of paired baseline tumor and normal tissue. NeXT Liquid Biopsy™ (Personalis, Inc.) was used for WES of plasma-derived ctDNA from serially collected samples collected at baseline, after 1 month and at progression to experimental systemic therapies in 15 patients with advanced/metastatic GIST. Results: WES of tumor tissue samples from all 15 patients confirmed underlying KIT mutation in all patients. There was large heterogeneity of other molecular alterations, which included therapeutically relevant molecular alterations, such as microsatellite instability-high (MSI-high) in 1 sample. RNA-Seq of tumor tissue revealed recurrent overexpression of GALR2, NY-ESO-1 and other genes involved in cancer progression, angiogenesis and anticancer immunity. Patients with response to systemic therapies demonstrated lower levels of cytolytic activity measured by CYT score in tumor tissue compared to patients without response (P=0.04). KIT mutations were detected in serially collected ctDNA samples from 12 (80%) of 15 patients. Quantity of KIT and other mutant ctDNA dynamically tracked the clonal evolution and clinical course during systemic therapy. Conclusions: Comprehensive genomic profiling (WES and RNA-Seq) of tumor tissue and WES of serially collected ctDNA is feasible and detects underlying druggable KIT mutations and other molecular alterations. Citation Format: Niamh Coleman, Charles Abbot, Neeta Somaiah, Sarina Piha-Paul, Shubham Pant, Jordi Rodon, S. Greg Call, Sean Boyle, Funda Meric-Bernstam, Filip Janku. Whole exome sequencing of tumor tissue and circulating tumor DNA ingastrointestinal stromal tumors (GIST) [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 LB057.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"246 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76982439","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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-581
Min-Kyeong Kim, Dongeun Lee, Yun-Hee Kim, Sang Jae Park, S. Woo, S. Kong
Circulating tumor DNA (ctDNA) has been evaluated as potential biomarkers for prognosis in pancreatic adenocarcinoma(PDAC) including our previous study, which proved KRAS mutation as a prognostic marker through the quantitative analysis. Then we investigated in a larger samples to validate the results of previous studies. Total of 213 PDAC patients has been enrolled in this study and the median age was 66 years old and 120 males (56.1%). Plasma was separated by established centrifugation method and ctDNA was extracted from 2.0 mL plasma using a QIAamp Circulating Nucleic Acid Kit (Qiagen Cat# 61504, Hilden, Germany) or a Chemagic cfDNA 2K kit (PerkinElmer, Waltham, Massachusetts, U.S.). Extracted ctDNA was quantified using the Qubit dsDNA HS Assay Kit (Thermo Fisher Scientific, USA). The detection of KRAS mutation was performed using QX200 Droplet Digital PCR System (Biorad, USA) by KRAS screening multiplex droplet digital PCR kit which covers seven common mutation sites (Biorad, USA) and compared with that in 93 matched formalin-fixed paraffin-embedded (FFPE) tissues. Mutant concentration and fractional abundance were analyzed by QuantaSoft software (Biorad, USA). The KRAS mutation rates in tissue and ctDNA were 98.9% and 82.8%, respectively, and the concordance rate between them was 78 of 93 samples (83.9%). Univariable analyses demonstrated that KRAS fraction (Hazard ratio (HR), 1.59; 95% CI, 1.02-2.49; P = 0.040) were significant factors for PFS, whereas KRAS mutation concentration (HR, 1.69; 95% CI, 1.03-2.77; P = 0.038) and KRAS fraction (HR, 1.88; 95% CI, 1.17-3.02; P = 0.010) for OS. This study proved the usefulness of the KRAS mutation of ctDNA as a prognostic marker in PDAC. (This study was supported by National cancer center, Korea, Grant no. 1910192) Citation Format: Min Kyeong Kim, Dong-Eun Lee, Yun Hee Kim, Sang Jae Park, Sang Myung Woo, Sun-Young Kong. Prognostic implication of circulating tumor-derived KRAS mutation in pancreatic ductal adenocarcinoma [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 581.
{"title":"Abstract 581: Prognostic implication of circulating tumor-derived KRAS mutation in pancreatic ductal adenocarcinoma","authors":"Min-Kyeong Kim, Dongeun Lee, Yun-Hee Kim, Sang Jae Park, S. Woo, S. Kong","doi":"10.1158/1538-7445.AM2021-581","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-581","url":null,"abstract":"Circulating tumor DNA (ctDNA) has been evaluated as potential biomarkers for prognosis in pancreatic adenocarcinoma(PDAC) including our previous study, which proved KRAS mutation as a prognostic marker through the quantitative analysis. Then we investigated in a larger samples to validate the results of previous studies. Total of 213 PDAC patients has been enrolled in this study and the median age was 66 years old and 120 males (56.1%). Plasma was separated by established centrifugation method and ctDNA was extracted from 2.0 mL plasma using a QIAamp Circulating Nucleic Acid Kit (Qiagen Cat# 61504, Hilden, Germany) or a Chemagic cfDNA 2K kit (PerkinElmer, Waltham, Massachusetts, U.S.). Extracted ctDNA was quantified using the Qubit dsDNA HS Assay Kit (Thermo Fisher Scientific, USA). The detection of KRAS mutation was performed using QX200 Droplet Digital PCR System (Biorad, USA) by KRAS screening multiplex droplet digital PCR kit which covers seven common mutation sites (Biorad, USA) and compared with that in 93 matched formalin-fixed paraffin-embedded (FFPE) tissues. Mutant concentration and fractional abundance were analyzed by QuantaSoft software (Biorad, USA). The KRAS mutation rates in tissue and ctDNA were 98.9% and 82.8%, respectively, and the concordance rate between them was 78 of 93 samples (83.9%). Univariable analyses demonstrated that KRAS fraction (Hazard ratio (HR), 1.59; 95% CI, 1.02-2.49; P = 0.040) were significant factors for PFS, whereas KRAS mutation concentration (HR, 1.69; 95% CI, 1.03-2.77; P = 0.038) and KRAS fraction (HR, 1.88; 95% CI, 1.17-3.02; P = 0.010) for OS. This study proved the usefulness of the KRAS mutation of ctDNA as a prognostic marker in PDAC. (This study was supported by National cancer center, Korea, Grant no. 1910192) Citation Format: Min Kyeong Kim, Dong-Eun Lee, Yun Hee Kim, Sang Jae Park, Sang Myung Woo, Sun-Young Kong. Prognostic implication of circulating tumor-derived KRAS mutation in pancreatic ductal adenocarcinoma [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 581.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77058594","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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-LB062
D. Davar, A. Dzutsev, J. McCulloch, R. Rodrigues, Joe-Marc Chauvin, Robert M. Morrison, R. DeBlasio, Carmine Menna, Quanquan Ding, Ornella Pagliano, Bochra Zidi, Shuowen Zhang, J. Badger, Marie Vetizou, A. Cole, M. R. Fernandes, Stephanie Prescott, R. G. Costa, A. Balaji, A. Morgun, I. Vujkovic-Cvijin, Hong Wang, Amir A. Borhani, M. Schwartz, Howard M. Dubner, Scarlett J. Ernst, Amy Rose, Y. Najjar, Y. Belkaid, J. Kirkwood, G. Trinchieri, H. Zarour
{"title":"Abstract LB062: Efficacy of Responder-derived Fecal Microbiota Transplant (R-FMT) and Pembrolizumab in Anti-PD-1 Refractory Patients with Advanced Melanoma","authors":"D. Davar, A. Dzutsev, J. McCulloch, R. Rodrigues, Joe-Marc Chauvin, Robert M. Morrison, R. DeBlasio, Carmine Menna, Quanquan Ding, Ornella Pagliano, Bochra Zidi, Shuowen Zhang, J. Badger, Marie Vetizou, A. Cole, M. R. Fernandes, Stephanie Prescott, R. G. Costa, A. Balaji, A. Morgun, I. Vujkovic-Cvijin, Hong Wang, Amir A. Borhani, M. Schwartz, Howard M. Dubner, Scarlett J. Ernst, Amy Rose, Y. Najjar, Y. Belkaid, J. Kirkwood, G. Trinchieri, H. Zarour","doi":"10.1158/1538-7445.AM2021-LB062","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB062","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76416590","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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-559
W. Cho, W. Hsiao, K. Tan, J. Li, Shu-Jen Chen
Introduction: Advanced lung cancer is a highly lethal disease worldwide. Recently, immune checkpoint inhibitors (ICIs) have made a significant breakthrough in the management of advanced lung cancer. Even though only a proportion of patients respond to ICI, the duration of such responders due to immunological memory is remarkable and is longer than other agents in refractory disease. Circulating tumor DNA (ctDNA) exhibits the potential in identifying genomic alterations and monitoring ICI treatment in advanced lung cancer patients. Identification of these genomic alterations may help to triage patients who will achieve better clinical benefit with minimal toxicity in therapies with ICIs. Materials and Methods: ctDNA mutational changes were monitored in the longitudinal blood samples (n = 39) of seven stage IV lung adenocarcinoma patients between baseline and after ICI therapy (complete monitoring until disease progression or the end of follow-up). The mutation spectrum in these patients was detected by a next-generation sequencing panel consisting of 50 cancer-related genes. Results: Among the seven patients, 15 variants were identified. All patients harbored at least one mutation, with an average of 2.1 mutations per patient. The most frequently mutated genes were TP53 (42.9%) and EGFR (42.9%). Baseline measurement showed eight mutations (EGFR E746V, L747P, A763_Y764insFQEA; TP53 R158C, A159S; ATM V2439G; ERBB2 Y772_A755dup; KRAS Q61H) in five patients. Seven mutations (TP53 I254fs, I255del, A276P, R280S; EGFR I740_K745dup; FGFR2 G261fs; STK11 D162fs) were observed in four patients following ICI therapy, suggesting that these alterations might be acquired during treatment. Most importantly, all patients harbored at least one clinically targetable gene mutation, including ATM, EGFR, ERBB2, STK11, and KRAS. Among these genes, the oncogenic mutations of EGFR and ERBB2 are FDA-recognized biomarkers predictive of response to specific targeted drugs in non-small cell lung cancer. Conclusion: This study demonstrates that ctDNA monitoring is a useful method for molecular genotyping of advanced lung cancer patients. Genomic profiling of liquid biopsy may help to identify gene signatures for biomarkers predictive of response to treatment. The gene mutations identified in the individual patient of this study may help access the clinical benefit of therapy with ICIs or other drugs. The identification of druggable genes may potentially help to develop more effective treatment strategies. Considering the small percentage of patients receiving ICI therapy, this is a small-scale pilot study and a larger study is warranted. Citation Format: William C. Cho, Wen Hsiao, Kien Thiam Tan, Jacky Y. Li, Shu-Jen Chen. Next-generation sequencing of circulating tumor DNA in advanced lung cancer patients treated with the immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. P
晚期肺癌是世界范围内的一种高致死率疾病。近年来，免疫检查点抑制剂(ICIs)在晚期肺癌的治疗方面取得了重大突破。尽管只有一部分患者对ICI有反应，但由于免疫记忆，这种反应持续的时间是显著的，并且在难治性疾病中比其他药物更长。循环肿瘤DNA (ctDNA)在晚期肺癌患者中显示出识别基因组改变和监测ICI治疗的潜力。鉴定这些基因组改变可能有助于对患者进行分诊，这些患者将在ICIs治疗中获得更好的临床效益和最小的毒性。材料和方法:监测7例IV期肺腺癌患者在基线和ICI治疗后(完成监测直至疾病进展或随访结束)的纵向血液样本(n = 39)中的ctDNA突变变化。这些患者的突变谱通过由50个癌症相关基因组成的下一代测序小组进行检测。结果:在7例患者中，鉴定出15种变异。所有患者都携带至少一个突变，平均每个患者有2.1个突变。最常见的突变基因是TP53(42.9%)和EGFR(42.9%)。基线测量显示8个突变(EGFR E746V, L747P, A763_Y764insFQEA;Tp53 r158c, a159s;ATM V2439G;ERBB2 Y772_A755dup;KRAS Q61H)。7个突变(TP53 I254fs、I255del、A276P、R280S;表皮生长因子受体I740_K745dup;FGFR2 G261fs;在4例接受ICI治疗的患者中观察到STK11 D162fs)，提示这些改变可能是在治疗期间获得的。最重要的是，所有患者都携带至少一种临床靶向基因突变，包括ATM、EGFR、ERBB2、STK11和KRAS。在这些基因中，EGFR和ERBB2的致癌突变是fda认可的预测非小细胞肺癌对特异性靶向药物反应的生物标志物。结论:ctDNA监测是晚期肺癌患者分子基因分型的有效方法。液体活检的基因组分析可能有助于识别预测治疗反应的生物标志物的基因特征。在本研究的个体患者中发现的基因突变可能有助于获得使用ICIs或其他药物治疗的临床益处。鉴定可用药基因可能有助于开发更有效的治疗策略。考虑到接受ICI治疗的患者比例很小，这是一项小规模的试点研究，需要进行更大规模的研究。引用格式:William C. Cho, hsiwen, Kien Thiam Tan, Jacky Y. Li, Shu-Jen Chen。免疫检查点抑制剂治疗晚期肺癌患者循环肿瘤DNA的新一代测序[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志，2021;81(13 -增刊):559。
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-558
Xuejing Chen, Kun Li, Zichen Liu, F. Gai, G. Zhu, Shun Lu, N. Che
Background Pleural effusion from patients with advanced non-small cell lung cancer has been proved valuable for molecular analysis, especially when the tissue sample not available. However, simultaneous detection of multiple driver gene alterations especially the fusions is still challenging. Methods In this study, 77 patients with advanced NSCLC and pleural effusion were enrolled, 49 of whom had matched tumor tissues. Supernatants, cell sediments, and FFPE cell blocks were prepared from pleural effusion samples for detection of driver alterations by a PCR-based 9-gene mutation detection kit. Results In addition to mutations in EGFR, KRAS and HER2 detected in genomic DNA from cell sediments, FFPE cell blocks, and in cfDNA from supernatants, and fusions in ALK detected in RNA from cell sediments and FFPE cell blocks, fusions in ALK were also successfully detected in cfRNA from supernatants. Compared with matched tumor tissue, the supernatant showed the highest overall sensitivity (81.3%), with 81.5% for SNV/Indels by cfDNA and 80% for fusions by cfRNA, followed by FFPE cell blocks (71.0%) and the cell sediments (66.7%). Within the group of treatment-naive patients or malignant cells observed in the cell sediments, supernatant showed higher overall sensitivity (89.5%, 92.3%) with both 100% for fusions. Based on the results, an optimized driver gene mutations detection procedure of pleural effusion is proposed. With the proposed procedure, an overall sensitivity 85.3% was achieved, with 82.1% for SNV/Indels and 100% for fusions. Conclusions CfDNA and cfRNA derived from pleural effusion supernatant (PES) have been successfully tested with a PCR-based multi-gene detection kit. An optimized procedure could maximize clinical value of testing pleural effusion samples and has good potential for routine clinical application. Citation Format: Xuejing Chen, Kun Li, Zichen Liu, Fei Gai, Guanshan Zhu, Shun Lu, Nanying Che. Muti-gene ARMS PCR using both cfDNA and cfRNAin the supernatant of pleural effusion achieves rapid and accuracy driver gene mutations detection [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 558.
{"title":"Abstract 558: Muti-gene ARMS PCR using both cfDNA and cfRNAin the supernatant of pleural effusion achieves rapid and accuracy driver gene mutations detection","authors":"Xuejing Chen, Kun Li, Zichen Liu, F. Gai, G. Zhu, Shun Lu, N. Che","doi":"10.1158/1538-7445.AM2021-558","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-558","url":null,"abstract":"Background Pleural effusion from patients with advanced non-small cell lung cancer has been proved valuable for molecular analysis, especially when the tissue sample not available. However, simultaneous detection of multiple driver gene alterations especially the fusions is still challenging. Methods In this study, 77 patients with advanced NSCLC and pleural effusion were enrolled, 49 of whom had matched tumor tissues. Supernatants, cell sediments, and FFPE cell blocks were prepared from pleural effusion samples for detection of driver alterations by a PCR-based 9-gene mutation detection kit. Results In addition to mutations in EGFR, KRAS and HER2 detected in genomic DNA from cell sediments, FFPE cell blocks, and in cfDNA from supernatants, and fusions in ALK detected in RNA from cell sediments and FFPE cell blocks, fusions in ALK were also successfully detected in cfRNA from supernatants. Compared with matched tumor tissue, the supernatant showed the highest overall sensitivity (81.3%), with 81.5% for SNV/Indels by cfDNA and 80% for fusions by cfRNA, followed by FFPE cell blocks (71.0%) and the cell sediments (66.7%). Within the group of treatment-naive patients or malignant cells observed in the cell sediments, supernatant showed higher overall sensitivity (89.5%, 92.3%) with both 100% for fusions. Based on the results, an optimized driver gene mutations detection procedure of pleural effusion is proposed. With the proposed procedure, an overall sensitivity 85.3% was achieved, with 82.1% for SNV/Indels and 100% for fusions. Conclusions CfDNA and cfRNA derived from pleural effusion supernatant (PES) have been successfully tested with a PCR-based multi-gene detection kit. An optimized procedure could maximize clinical value of testing pleural effusion samples and has good potential for routine clinical application. Citation Format: Xuejing Chen, Kun Li, Zichen Liu, Fei Gai, Guanshan Zhu, Shun Lu, Nanying Che. Muti-gene ARMS PCR using both cfDNA and cfRNAin the supernatant of pleural effusion achieves rapid and accuracy driver gene mutations detection [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 558.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"130 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76754187","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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-LB030
Ki Hyun Kim, R. Patel, Yong Gu Lee, Soohwan Kim, Jihoon Choi, Sung-min Kim, G. Kim, Jong-Ho Lee, Hyun-Jong Lee, Ji-Ho Park, Guewha Lee, Lei Cui, M. Yoon, Ki-Hyun Kim, Soohyun Kim, I. Hwang, Youngha Lee, Bong-Kook Ko, Jong-Seo Lee, J. Chung, M. Ruella
{"title":"Abstract LB030: A novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19","authors":"Ki Hyun Kim, R. Patel, Yong Gu Lee, Soohwan Kim, Jihoon Choi, Sung-min Kim, G. Kim, Jong-Ho Lee, Hyun-Jong Lee, Ji-Ho Park, Guewha Lee, Lei Cui, M. Yoon, Ki-Hyun Kim, Soohyun Kim, I. Hwang, Youngha Lee, Bong-Kook Ko, Jong-Seo Lee, J. Chung, M. Ruella","doi":"10.1158/1538-7445.AM2021-LB030","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB030","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"163 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76833181","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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-589
A. Raghavakaimal, M. Cristofanilli, Cha-Mei Tang, R. Alpaugh, Kirby P. Gardener, S. Chumsri, D. Adams
{"title":"Abstract 589: CCR5 upregulation in two subtypes of tumor associated circulating cells predict worse prognosis in metastatic breast cancer","authors":"A. Raghavakaimal, M. Cristofanilli, Cha-Mei Tang, R. Alpaugh, Kirby P. Gardener, S. Chumsri, D. Adams","doi":"10.1158/1538-7445.AM2021-589","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-589","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74415468","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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-351
Yuta Myojin, T. Kodama, H. Hikita, R. Sakamori, T. Takehara
Background: Several tyrosine kinase inhibitors (TKIs) have been developed for hepatocellular carcinoma (HCC). However, their efficacy is limited partly due to the diversity of its genetic drivers. In this study, we sought for HCC oncogenes involved in susceptibility of TKIs and aimed to develop their serum biomarkers. Methods: We created a novel HCC mouse model in which tumor diversity of genetic drivers was recapitulated by transposon-based intrahepatic delivery of a pooled barcode-tagged 10-oncogene cDNA library. Tumor-bearing mice were then treated with lenvatinib (LEN), or sorafenib (SOR), or vehicle until moribund. The relative abundance of each oncogene cDNA in each tumor was quantified by a high-throughput barcode sequence. In vitro LEN susceptibility was assessed in 9 human HCC cell lines and LEN-resistant Hep3B cells (LEN-R) established by its long-term exposure. Tumor-derived secreted proteins were screened via cellular proteomic and secretomic analyses of Huh7 and Hep3B cells. Serum and tumor levels of identified proteins were examined in 62 HCC patients who underwent hepatectomy. Efficacy of biomarker candidates was assessed using pre-treated serum of 96 HCC patients who underwent TKI therapy. Results: Mice developed multiple genetically heterogeneous liver tumors as early as 2 weeks after delivery of the pooled library. Upon TKI administration, their sequencing analysis showed that LEN selectively eliminated FGF19-expressing tumors, whereas SOR did MET- and NRAS-expressing tumors. Among 9 HCC cell lines, HuH7 and Hep3B cells showed the highest FGF19 levels and LEN susceptibility. FGF19 inhibition eliminated their susceptibility. LEN-R cells showed reduction of FGF19 levels and got resensitized to LEN by FGF19 replenishment. Thus, FGF19-driven HCC is susceptible to LEN. Proteomics identified 6 secreted proteins downregulated by FGF19 inhibition in Hep3B cells. Among them, ST6GAL1 was the most positively correlated with FGF19 in HCC cell lines and in mouse and human HCC tissues. FGF19 knockdown in Hep3B cells decreased phosphorylation of STAT3, whereas FGF19 overexpression increased its phosphorylation with ST6GAL1 upreguation. Silencing of STAT3 signal by inhibitor or siRNA significantly decreased ST6GAL1 expression. In surgically-resected HCC patients, serum ST6GAL1 levels were positively correlated with tumor site FGF19 expression and were markers for disease progression. In TKI-treated HCC patients with high baseline serum ST6GAL1 levels, LEN therapy showed significantly longer survival than SOR. Conclusion: ST6GAL1 is a tumor-derived secreted protein downstream of FGF19 and may be a useful serum biomarker for identification of patients with FGF19-driven HCC who may benefit from LEN therapy. Citation Format: Yuta Myojin, Takahiro Kodama, Hayato Hikita, Ryotaro Sakamori, Tetsuo Takehara. Serum ST6GAL1 is a novel biomarker for predicting efficacy of tyrosine kinase inhibitors in hepatocellular carcinoma by detecting FGF19 expressing
{"title":"Abstract 351: Serum ST6GAL1 is a novel biomarker for predicting efficacy of tyrosine kinase inhibitors in hepatocellular carcinoma by detecting FGF19 expressing tumor","authors":"Yuta Myojin, T. Kodama, H. Hikita, R. Sakamori, T. Takehara","doi":"10.1158/1538-7445.AM2021-351","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-351","url":null,"abstract":"Background: Several tyrosine kinase inhibitors (TKIs) have been developed for hepatocellular carcinoma (HCC). However, their efficacy is limited partly due to the diversity of its genetic drivers. In this study, we sought for HCC oncogenes involved in susceptibility of TKIs and aimed to develop their serum biomarkers. Methods: We created a novel HCC mouse model in which tumor diversity of genetic drivers was recapitulated by transposon-based intrahepatic delivery of a pooled barcode-tagged 10-oncogene cDNA library. Tumor-bearing mice were then treated with lenvatinib (LEN), or sorafenib (SOR), or vehicle until moribund. The relative abundance of each oncogene cDNA in each tumor was quantified by a high-throughput barcode sequence. In vitro LEN susceptibility was assessed in 9 human HCC cell lines and LEN-resistant Hep3B cells (LEN-R) established by its long-term exposure. Tumor-derived secreted proteins were screened via cellular proteomic and secretomic analyses of Huh7 and Hep3B cells. Serum and tumor levels of identified proteins were examined in 62 HCC patients who underwent hepatectomy. Efficacy of biomarker candidates was assessed using pre-treated serum of 96 HCC patients who underwent TKI therapy. Results: Mice developed multiple genetically heterogeneous liver tumors as early as 2 weeks after delivery of the pooled library. Upon TKI administration, their sequencing analysis showed that LEN selectively eliminated FGF19-expressing tumors, whereas SOR did MET- and NRAS-expressing tumors. Among 9 HCC cell lines, HuH7 and Hep3B cells showed the highest FGF19 levels and LEN susceptibility. FGF19 inhibition eliminated their susceptibility. LEN-R cells showed reduction of FGF19 levels and got resensitized to LEN by FGF19 replenishment. Thus, FGF19-driven HCC is susceptible to LEN. Proteomics identified 6 secreted proteins downregulated by FGF19 inhibition in Hep3B cells. Among them, ST6GAL1 was the most positively correlated with FGF19 in HCC cell lines and in mouse and human HCC tissues. FGF19 knockdown in Hep3B cells decreased phosphorylation of STAT3, whereas FGF19 overexpression increased its phosphorylation with ST6GAL1 upreguation. Silencing of STAT3 signal by inhibitor or siRNA significantly decreased ST6GAL1 expression. In surgically-resected HCC patients, serum ST6GAL1 levels were positively correlated with tumor site FGF19 expression and were markers for disease progression. In TKI-treated HCC patients with high baseline serum ST6GAL1 levels, LEN therapy showed significantly longer survival than SOR. Conclusion: ST6GAL1 is a tumor-derived secreted protein downstream of FGF19 and may be a useful serum biomarker for identification of patients with FGF19-driven HCC who may benefit from LEN therapy. Citation Format: Yuta Myojin, Takahiro Kodama, Hayato Hikita, Ryotaro Sakamori, Tetsuo Takehara. Serum ST6GAL1 is a novel biomarker for predicting efficacy of tyrosine kinase inhibitors in hepatocellular carcinoma by detecting FGF19 expressing ","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":"76223727","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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-331
M. Cristea, B. Chmielowski, D. Oh, R. Funke, D. Bota, M. Abedi
{"title":"Abstract 331: Characterization of neoepitope (neoE)-specific T cells from peripheral blood for adoptive neoTCR-T cell therapy for patients with breast cancer (bc) or ovarian cancer (oc)","authors":"M. Cristea, B. Chmielowski, D. Oh, R. Funke, D. Bota, M. Abedi","doi":"10.1158/1538-7445.AM2021-331","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-331","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"92 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76274263","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}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-651
Y. Wada, M. Shimada, A. Goel
{"title":"Abstract 651: A novel gene signature that predicts recurrence following hepatectomy in patients with colorectal liver metastasis","authors":"Y. Wada, M. Shimada, A. Goel","doi":"10.1158/1538-7445.AM2021-651","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-651","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"125 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76426155","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}
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