Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-360
E. Dikoglu, Xu Naizhen, Luke P O'Connor, Peter A. Pinto, M. Merino
Background: Understanding the relationship between tumor genomics and the immune response in cancer has gotten more attention with the advance of immunotherapy. Microsatellite instability (MSI) is a molecular marker that provides prognostic and predictive information in many types of tumors including prostate cancer (PC). In PC, MSI-H and dMMR have been reported anywhere from 1% in primary tumors to up to 12% in metastasis. Reliable testing strategies for MSI/MMR status are critical for clinical management of patients with PC. MSI detection methods include PCR based molecular tests, NGS-based MSI detection or immunohistochemical staining (IHC). We observe technical difficulties in our daily practice with current molecular diagnostic tests. Design: We examined MMR protein expression (MSH2, MSH6, MLH1, PMS2) and PD-L1 by IHC in 30 PC. Results: Among 30 PC tested, 1 tumor (3%) was completely negative for MLH1 and PMS2 and 1 tumor (3%) revealed loss of PMS2 by IHC even though gene panel did not reveal any mutation in PMS2. The PD-L1 IHC was 44% positive, but the single MMR negative biopsy was PD-L1 negative. PD-L1 expression in PC samples did not show correlation with defective MMR expression. Conclusion: In our study, controversial results were obtained. Based on our experience; even though many exons of MMR genes are covered with these panels, there are some exons do not get enough coverage to be analyzed. This low coverage problem creates false negative results. There are also pseudogene pairs of these genes, especially PMS2. For some specific regions, even though there is enough coverage it is impossible to know if the pathogenic variant is on the PMS2 or the pseudogene without additional test. This result suffers from false positive results without a confirmatory test. It is also known that 5% to 11% of MSI-H cases demonstrate intact MMR staining and localization (proficient MMR, pMMR) due to retained antigenicity and nonfunctional protein. So far, in regular practice we use MMR analyzing strategies which set up for colon cancer where the tumor is uniform. PC is more complex; most of the time more than one clone is involving.We believe MSI detection for PC requires improvement the technics of detection, robust set up of testing strategy with high sensitivity and specificity, analyzing strategy and training of pathologists. Due to technical difficulties of the detection, we believe that the prevalence of MSI-high/dMMR PC might be higher than reported in the literature so far. Citation Format: Esra Dikoglu, Xu Naizhen, Luke P. O9Connor, Peter Pinto, Maria J. Merino. The dilemma of the current diagnostic tests for MSI in prostate 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 360.
背景:随着免疫治疗技术的发展,肿瘤基因组学与肿瘤免疫反应之间的关系越来越受到人们的关注。微卫星不稳定性(Microsatellite instability, MSI)是一种分子标志物,可为包括前列腺癌(PC)在内的多种肿瘤提供预后和预测信息。在PC中,MSI-H和dMMR在原发肿瘤中的发生率为1%,在转移瘤中的发生率高达12%。可靠的MSI/MMR状态检测策略对于PC患者的临床管理至关重要。MSI检测方法包括基于PCR的分子检测、基于ngs的MSI检测或免疫组织化学染色(IHC)。我们观察到目前分子诊断测试在日常实践中的技术困难。设计:我们通过免疫组化检测了30例PC中MMR蛋白(MSH2、MSH6、MLH1、PMS2)和PD-L1的表达。结果:在30例PC检测中,1例肿瘤(3%)MLH1和PMS2完全阴性,1例肿瘤(3%)IHC显示PMS2缺失,尽管基因板未显示PMS2突变。PD-L1 IHC为44%阳性,但单例MMR阴性活检为PD-L1阴性。PC样品中PD-L1表达与MMR缺陷表达无相关性。结论:在我们的研究中,得到了有争议的结果。根据我们的经验;尽管MMR基因的许多外显子被这些面板覆盖,但仍有一些外显子没有得到足够的覆盖,无法进行分析。这种低覆盖率问题会产生假阴性结果。这些基因也有假基因对,尤其是PMS2。对于某些特定区域,即使有足够的覆盖范围,如果不进行额外的检测,也不可能知道致病变异是在PMS2上还是在假基因上。这个结果是假阳性结果,没有确认测试。由于保留了抗原性和无功能蛋白,5%至11%的MSI-H病例显示完整的MMR染色和定位(熟练的MMR, pMMR)。到目前为止,在常规实践中,我们使用MMR分析策略,这是为肿瘤均匀的结肠癌设置的。PC更复杂;大多数情况下涉及不止一个克隆。我们认为,PC的MSI检测需要改进检测技术,健全建立高灵敏度和特异性的检测策略,分析策略和病理学家的培训。由于检测的技术困难,我们认为MSI-high/dMMR PC的患病率可能比目前文献报道的要高。引文格式:Esra Dikoglu, Xu Naizhen, Luke P. O9Connor, Peter Pinto, Maria J. Merino。当前前列腺癌MSI诊断试验的困境[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):摘要第360期。
{"title":"Abstract 360: The dilemma of the current diagnostic tests for MSI in prostate cancer","authors":"E. Dikoglu, Xu Naizhen, Luke P O'Connor, Peter A. Pinto, M. Merino","doi":"10.1158/1538-7445.AM2021-360","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-360","url":null,"abstract":"Background: Understanding the relationship between tumor genomics and the immune response in cancer has gotten more attention with the advance of immunotherapy. Microsatellite instability (MSI) is a molecular marker that provides prognostic and predictive information in many types of tumors including prostate cancer (PC). In PC, MSI-H and dMMR have been reported anywhere from 1% in primary tumors to up to 12% in metastasis. Reliable testing strategies for MSI/MMR status are critical for clinical management of patients with PC. MSI detection methods include PCR based molecular tests, NGS-based MSI detection or immunohistochemical staining (IHC). We observe technical difficulties in our daily practice with current molecular diagnostic tests. Design: We examined MMR protein expression (MSH2, MSH6, MLH1, PMS2) and PD-L1 by IHC in 30 PC. Results: Among 30 PC tested, 1 tumor (3%) was completely negative for MLH1 and PMS2 and 1 tumor (3%) revealed loss of PMS2 by IHC even though gene panel did not reveal any mutation in PMS2. The PD-L1 IHC was 44% positive, but the single MMR negative biopsy was PD-L1 negative. PD-L1 expression in PC samples did not show correlation with defective MMR expression. Conclusion: In our study, controversial results were obtained. Based on our experience; even though many exons of MMR genes are covered with these panels, there are some exons do not get enough coverage to be analyzed. This low coverage problem creates false negative results. There are also pseudogene pairs of these genes, especially PMS2. For some specific regions, even though there is enough coverage it is impossible to know if the pathogenic variant is on the PMS2 or the pseudogene without additional test. This result suffers from false positive results without a confirmatory test. It is also known that 5% to 11% of MSI-H cases demonstrate intact MMR staining and localization (proficient MMR, pMMR) due to retained antigenicity and nonfunctional protein. So far, in regular practice we use MMR analyzing strategies which set up for colon cancer where the tumor is uniform. PC is more complex; most of the time more than one clone is involving.We believe MSI detection for PC requires improvement the technics of detection, robust set up of testing strategy with high sensitivity and specificity, analyzing strategy and training of pathologists. Due to technical difficulties of the detection, we believe that the prevalence of MSI-high/dMMR PC might be higher than reported in the literature so far. Citation Format: Esra Dikoglu, Xu Naizhen, Luke P. O9Connor, Peter Pinto, Maria J. Merino. The dilemma of the current diagnostic tests for MSI in prostate 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 360.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81603107","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.AM2021-568
L. Gardner, D. Rothwell, C. Dive, Kostas Kostarelos, Marilena Hadjidemetriou
Despite the tremendous potential of liquid biopsies to revolutionise cancer care, there has been limited success translating blood-circulating proteomic and genomic biomarkers into the clinic. This is fundamentally due to the extremely low concentration of tumour-derived biomolecules in blood circulation, particularly at an early disease stage, which makes the discovery phase of the biomarker pipeline extremely challenging. Nanotechnology offers a promising solution, with a nanoparticle-biomolecule enrichment tool recently developed to enrich low-abundant, low molecular weight proteins in the blood of ovarian cancer patients.[1] Proteomic analysis followed by immunoassay-based validation of selected proteins demonstrated the potential of the nanoparticle-platform proposed to discover novel biomarkers with greater specificity and sensitivity than the clinically used biomarkers. In addition, we recently confirmed the presence of cell-free DNA (cfDNA) captured onto the surface lipid nanoparticles incubated ex vivo with human plasma.[2] A significantly higher abundance of cfDNA was detected in the nanoparticle-enriched plasma samples of late-stage ovarian cancer patients compared to age-matched female controls. Proteomic analysis of the same samples also revealed tumour-specific elevations in histone proteins, which are commonly found in circulation complexed with cfDNA. These findings have highlighted the opportunity for the development of a nano-proteogenomics platform able to simultaneously purify both proteins and cell-free nucleic acids from human plasma, an important step in the discovery of novel multi-omic biomarker panels. Utilising the above patented nanotechnology, we have compared proteomic and genomic profiles derived from nanoparticle-biomolecule samples of cancer patients with age- and sex-matched controls to uncover new potential blood-based biomarkers in a proof-of-principle study. In brief, ex-vivo plasma samples were incubated with lipid-based nanoparticles and purified using a two-step size-based purification protocol. The purified samples were then analysed by label-free proteomics (LC-MS/MS) and next-generation sequencing to uncover both proteomic and genomic tumour-specific signatures, including differentially abundant proteins, genomic copy number alterations and tumour-specific mutations. This work highlights the potential of our nanotechnology-based enrichment platform to enhance the discovery of cancer-specific proteogenomic biomarker panels, a vital step in developing sensitive and specific liquid biopsies for the early detection of cancer. References: [1] M. Hadjidemetriou, L. Papafilippou, R. D. Unwin, J. Rogan, A. Clamp, K. Kostarelos, Nano Today 2020, 34, 100901. [2] L. Gardner, J. Warrington, J. Rogan, D. G. Rothwell, G. Brady, C. Dive, K. Kostarelos, M. Hadjidemetriou, Nanoscale Horizons 2020, 5, 1476. Citation Format: Lois Gardner, Dominic G. Rothwell, Caroline Dive, Kostas Kostarelos, Marilena Hadjidemetriou. Nanon
{"title":"Abstract 568: Nanonets for multiomics blood analysis and cancer biomarker discovery","authors":"L. Gardner, D. Rothwell, C. Dive, Kostas Kostarelos, Marilena Hadjidemetriou","doi":"10.1158/1538-7445.AM2021-568","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-568","url":null,"abstract":"Despite the tremendous potential of liquid biopsies to revolutionise cancer care, there has been limited success translating blood-circulating proteomic and genomic biomarkers into the clinic. This is fundamentally due to the extremely low concentration of tumour-derived biomolecules in blood circulation, particularly at an early disease stage, which makes the discovery phase of the biomarker pipeline extremely challenging. Nanotechnology offers a promising solution, with a nanoparticle-biomolecule enrichment tool recently developed to enrich low-abundant, low molecular weight proteins in the blood of ovarian cancer patients.[1] Proteomic analysis followed by immunoassay-based validation of selected proteins demonstrated the potential of the nanoparticle-platform proposed to discover novel biomarkers with greater specificity and sensitivity than the clinically used biomarkers. In addition, we recently confirmed the presence of cell-free DNA (cfDNA) captured onto the surface lipid nanoparticles incubated ex vivo with human plasma.[2] A significantly higher abundance of cfDNA was detected in the nanoparticle-enriched plasma samples of late-stage ovarian cancer patients compared to age-matched female controls. Proteomic analysis of the same samples also revealed tumour-specific elevations in histone proteins, which are commonly found in circulation complexed with cfDNA. These findings have highlighted the opportunity for the development of a nano-proteogenomics platform able to simultaneously purify both proteins and cell-free nucleic acids from human plasma, an important step in the discovery of novel multi-omic biomarker panels. Utilising the above patented nanotechnology, we have compared proteomic and genomic profiles derived from nanoparticle-biomolecule samples of cancer patients with age- and sex-matched controls to uncover new potential blood-based biomarkers in a proof-of-principle study. In brief, ex-vivo plasma samples were incubated with lipid-based nanoparticles and purified using a two-step size-based purification protocol. The purified samples were then analysed by label-free proteomics (LC-MS/MS) and next-generation sequencing to uncover both proteomic and genomic tumour-specific signatures, including differentially abundant proteins, genomic copy number alterations and tumour-specific mutations. This work highlights the potential of our nanotechnology-based enrichment platform to enhance the discovery of cancer-specific proteogenomic biomarker panels, a vital step in developing sensitive and specific liquid biopsies for the early detection of cancer. References: [1] M. Hadjidemetriou, L. Papafilippou, R. D. Unwin, J. Rogan, A. Clamp, K. Kostarelos, Nano Today 2020, 34, 100901. [2] L. Gardner, J. Warrington, J. Rogan, D. G. Rothwell, G. Brady, C. Dive, K. Kostarelos, M. Hadjidemetriou, Nanoscale Horizons 2020, 5, 1476. Citation Format: Lois Gardner, Dominic G. Rothwell, Caroline Dive, Kostas Kostarelos, Marilena Hadjidemetriou. Nanon","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84249986","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.AM2021-603
M. Tanemura, Kenta Furukawa, M. Mikamori, Y. Matsuura, Kenichi Matsumoto, T. Asaoka, Y. Urata
{"title":"Abstract 603: Viable circulating tumor cells predict occult metastatic disease and prognosis, and aberrant expression of PD-L1 on viable CTC in pancreatic cancer","authors":"M. Tanemura, Kenta Furukawa, M. Mikamori, Y. Matsuura, Kenichi Matsumoto, T. Asaoka, Y. Urata","doi":"10.1158/1538-7445.AM2021-603","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-603","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84488659","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-LB040
Chia‐Chi Lin, P. Zucali, B. Carthon, T. Bauer, M. Tucci, A. Italiano, R. Iacovelli, W. Su, C. Massard, Monsoor Saleh, G. Daniele, A. Greystoke, M. Gutierrez, S. Pant, Ying-Chun Shen, M. Perrino, R. Meng, G. Abbadessa, Helen Lee, Yingwen Dong, M. Chiron, Rui Wang, Laure Loumagne, J. Bono
Background: CD38 is implicated in noncanonical adenosine synthesis and its overexpression on tumor cells has been implicated in T-cell exhaustion and resistance to immune checkpoint blockade. Preclinical data suggest that concurrent treatment of anti-CD38 and anti-PD-1/PD-L1 antibodies substantially reduce primary tumor growth via suppressing acquired resistance to immune checkpoint blockade, and thus enhancing anti-PD-1/PD-L1 efficacy. Methods: This Phase 1/2 study (NCT03367819) enrolled pts with metastatic castration-resistant prostate cancer (mCRPC) or advanced non-small cell lung cancer (NSCLC). The primary objectives of Phase 1 were safety and tolerability of Isa (anti-CD38 monoclonal antibody) + Cemi (anti-PD-1 monoclonal antibody) in pts with mCRPC (naive to anti-PD-1/PD-L1 therapy) or NSCLC (progressed on anti-PD-1/PD-L1-containing therapy). Phase 2 used a Simon9s 2-stage design with response rate (RR) as the primary endpoint. An interim analysis was planned after the first 24 (mCRPC) and 20 (NSCLC) pts receiving Isa+Cemi were enrolled in Phase 2. Tolerability, immunogenicity, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed, including CD38, PD-L1, tumor-infiltrating lymphocytes in the tumor microenvironment (TME), and peripheral immune cell phenotyping. Results: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. All pts experienced ≥1 treatment-emergent adverse event. Grade ≥3 events occurred in 13 (54.2%) mCRPC pts and 12 (60.0%) NSCLC pts. Based on PCWG3 criteria, assessment of best overall response (BOR) with Isa+Cemi in mCRPC revealed no complete responses (CR), 1 unconfirmed partial response (PR) (4.2%), and 5 (20.8%) pts with stable disease (SD). Per RECIST 1.1, NSCLC pts receiving Isa+Cemi achieved no CR or PR, and 13 (65%) achieved SD. Isa+Cemi resulted in ~40% reduction in CD38+ tumor-infiltrating immune cells in post-therapy biopsies. The combination triggered a significant increase in peripheral activated and cytolytic T cells, but decreased NK cells. In addition, low baseline CD38 levels on tumor cells were observed in NSCLC pts who progressed on prior checkpoint inhibitor treatment. No significant modulation of Tregs or PD-L1 in the TME or CD38 expression on tumor cells was observed. Conclusions: The present study suggests that CD38 and PD-1 modulation by Isa+Cemi has a manageable safety profile, reduces CD38+ immune cells in the TME, and activates peripheral T cells; however, this was not associated with significant antitumor activity in these small cohorts of mCRPC and NSCLC pts. Citation Format: Chia-Chi Lin, Paolo Zucali, Bradley Carthon, Todd M. Bauer, Marcello Tucci, Antoine Italiano, Roberto Iacovelli, Wu-Chou Su, Christophe Massard, Monsoor Saleh, Gennaro Daniele, Alastair Greystoke, Martin Gutierrez, Shubham Pant, Ying-Chun Shen, Matteo Perrino, Robin Meng, Giovanni Abbadessa, Helen Lee, Yingwen Dong, Marielle Chiron, Rui Wang, Laure Loumagne, Johann de Bono, Johann
{"title":"Abstract LB040: Targeting CD38 and PD-1 with isatuximab (Isa) plus cemiplimab (Cemi) in patients (pts) with advanced malignancies: Results from a Phase 1/2 open-label, multicenter study","authors":"Chia‐Chi Lin, P. Zucali, B. Carthon, T. Bauer, M. Tucci, A. Italiano, R. Iacovelli, W. Su, C. Massard, Monsoor Saleh, G. Daniele, A. Greystoke, M. Gutierrez, S. Pant, Ying-Chun Shen, M. Perrino, R. Meng, G. Abbadessa, Helen Lee, Yingwen Dong, M. Chiron, Rui Wang, Laure Loumagne, J. Bono","doi":"10.1158/1538-7445.AM2021-LB040","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB040","url":null,"abstract":"Background: CD38 is implicated in noncanonical adenosine synthesis and its overexpression on tumor cells has been implicated in T-cell exhaustion and resistance to immune checkpoint blockade. Preclinical data suggest that concurrent treatment of anti-CD38 and anti-PD-1/PD-L1 antibodies substantially reduce primary tumor growth via suppressing acquired resistance to immune checkpoint blockade, and thus enhancing anti-PD-1/PD-L1 efficacy. Methods: This Phase 1/2 study (NCT03367819) enrolled pts with metastatic castration-resistant prostate cancer (mCRPC) or advanced non-small cell lung cancer (NSCLC). The primary objectives of Phase 1 were safety and tolerability of Isa (anti-CD38 monoclonal antibody) + Cemi (anti-PD-1 monoclonal antibody) in pts with mCRPC (naive to anti-PD-1/PD-L1 therapy) or NSCLC (progressed on anti-PD-1/PD-L1-containing therapy). Phase 2 used a Simon9s 2-stage design with response rate (RR) as the primary endpoint. An interim analysis was planned after the first 24 (mCRPC) and 20 (NSCLC) pts receiving Isa+Cemi were enrolled in Phase 2. Tolerability, immunogenicity, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed, including CD38, PD-L1, tumor-infiltrating lymphocytes in the tumor microenvironment (TME), and peripheral immune cell phenotyping. Results: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. All pts experienced ≥1 treatment-emergent adverse event. Grade ≥3 events occurred in 13 (54.2%) mCRPC pts and 12 (60.0%) NSCLC pts. Based on PCWG3 criteria, assessment of best overall response (BOR) with Isa+Cemi in mCRPC revealed no complete responses (CR), 1 unconfirmed partial response (PR) (4.2%), and 5 (20.8%) pts with stable disease (SD). Per RECIST 1.1, NSCLC pts receiving Isa+Cemi achieved no CR or PR, and 13 (65%) achieved SD. Isa+Cemi resulted in ~40% reduction in CD38+ tumor-infiltrating immune cells in post-therapy biopsies. The combination triggered a significant increase in peripheral activated and cytolytic T cells, but decreased NK cells. In addition, low baseline CD38 levels on tumor cells were observed in NSCLC pts who progressed on prior checkpoint inhibitor treatment. No significant modulation of Tregs or PD-L1 in the TME or CD38 expression on tumor cells was observed. Conclusions: The present study suggests that CD38 and PD-1 modulation by Isa+Cemi has a manageable safety profile, reduces CD38+ immune cells in the TME, and activates peripheral T cells; however, this was not associated with significant antitumor activity in these small cohorts of mCRPC and NSCLC pts. Citation Format: Chia-Chi Lin, Paolo Zucali, Bradley Carthon, Todd M. Bauer, Marcello Tucci, Antoine Italiano, Roberto Iacovelli, Wu-Chou Su, Christophe Massard, Monsoor Saleh, Gennaro Daniele, Alastair Greystoke, Martin Gutierrez, Shubham Pant, Ying-Chun Shen, Matteo Perrino, Robin Meng, Giovanni Abbadessa, Helen Lee, Yingwen Dong, Marielle Chiron, Rui Wang, Laure Loumagne, Johann de Bono, Johann","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85989250","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.AM2021-447
J. Lopategui, Bonnie L. Balzer, Yizhou Wang, C. Santiskulvong, Carissa A. Hyunh, Chun Yat Ong, M. Araña, M. Gayhart, F. Amersi, A. Silberman
Uterine leiomyosarcoma (LMS) is a highly aggressive but rare malignancy with a dismal prognosis. In nearly all cases, LMS is unsuspected prior to resection for a presumed leiomyoma. The risk of occult uterine LMS is reported to be 0.2% (1 in 500) in the largest cohort study of women undergoing surgery for presumed fibroid disease. The major problem is that there is no reliable preoperative method to distinguish LMS from a leiomyoma (LM) or STUMP (smooth muscle tumor of uncertain malignant potential), and the patient9s prognosis for LMS is even poorer if the tumor is transected, which occurs in procedures performed for LM. Effective therapy for LMS is lacking and most patients eventually succumb to the disease. Thus, there is a considerable need for a reliable preoperative test to triage patients into the proper surgical procedure for LMS. TP53 alterations are reportedly associated with uterine LMS in about 40% of cases. We screened plasma for TP53 variants in patients with pathologically confirmed LMS. We evaluated TP53 circulating tumor DNA (ctDNA) by deep next-generation sequencing in a cohort of 7 patients with LMS, 1 patient with STUMP, and 3 patients with LM. Clinical data were reviewed to assess disease burden. LMS patients9 tumor burden ranged from no evidence to extensive metastatic disease. DNA extraction was performed using the QIAamp DNA Micro Kit, QIAamp DNA FFPE Tissue Kit, or QIAamp MinElute ccfDNA Mini Kit. DNA quality was assessed using the TapeStation Genomic DNA kit. NGS libraries targeting the entire exonic region of the p53 gene were prepared using the QIASeq Targeted DNA Custom Panel. Sequencing was performed on the MiSeq system using 150bp paired end sequencing with a minimum read depth of 2x0.5M reads for plasma and 2x1M reads for formalin-fixed paraffin embedded and fresh-frozen tissue samples. Raw sequencing data were demultiplexed by bcl2fastq to generate the FASTQ files. Then raw sequencing reads were aligned to the human reference genome GRCh38 by BWA-MEM 0.7.9a-r786. SmCounter2 was used for p53 variants calling and variants quality control. We discovered TP53 ctDNA variants in 5 of 7 (71.4%) LMS cases including p.E258V, p.R248Q, P.R337C, p.E221*, p.R174_R175delinsWC, but not in the control cases of LM or STUMP. In the 5 plasma samples with TP53 mutated LMS, the patients had extensive metastatic disease and in the 2 TP53 wild-type LMS and STUMP cases, the patients had no evidence of disease. To our knowledge, this is the first pilot study to demonstrate the comparative use of TP53 ctDNA in patients with LMS, LM, and STUMP. Further study of these rare LMS is needed to determine the preoperative utility of NGS TP53 ctDNA mutational status as a useful molecular biomarker to help guide surgery and avoid unwarranted manipulation and pelvic contamination of undetected LMS. Supported by the Gottlieb, Buss and Snyder Endowments in Surgical Oncology Citation Format: Jean R. Lopategui, Bonnie Balzer, Yizhou Wang, Chintda Santisk
子宫平滑肌肉瘤(LMS)是一种高度侵袭性但罕见的恶性肿瘤,预后不佳。在几乎所有的病例中,在切除平滑肌瘤之前,LMS是不被怀疑的。据报道,在一项最大的队列研究中,隐性子宫LMS的风险为0.2%(1 / 500)。主要的问题是,术前没有可靠的方法来区分LMS与平滑肌瘤(LM)或STUMP(恶性潜能不确定的平滑肌肿瘤),如果在LM手术中发生肿瘤横切,LMS患者的预后更差。LMS缺乏有效的治疗方法,大多数患者最终死于这种疾病。因此,有相当大的需要一个可靠的术前检查,以分类患者进入适当的手术程序LMS。据报道,约40%的子宫LMS病例与TP53改变有关。我们在病理证实的LMS患者中筛查血浆TP53变异。我们对7例LMS患者、1例STUMP患者和3例LM患者的TP53循环肿瘤DNA (ctDNA)进行了深度下一代测序。回顾临床资料以评估疾病负担。LMS患者的肿瘤负荷范围从无证据到广泛的转移性疾病。采用QIAamp DNA Micro Kit、QIAamp DNA FFPE Tissue Kit或QIAamp MinElute ccfDNA Mini Kit进行DNA提取。使用TapeStation基因组DNA试剂盒评估DNA质量。使用QIASeq Targeted DNA Custom Panel制备针对p53基因整个外显子区域的NGS文库。在MiSeq系统上进行测序,采用150bp配对末端测序,血浆样品最小读取深度为2x0.5M,福尔马林固定石蜡包埋和新鲜冷冻组织样品最小读取深度为2x1M。原始测序数据通过bcl2fastq解复用生成FASTQ文件。然后用BWA-MEM 0.7.9a-r786将原始测序reads与人类参考基因组GRCh38进行比对。SmCounter2用于p53变异体的调用和变异体的质量控制。我们在7例LMS病例中发现了5例(71.4%)TP53 ctDNA变异,包括p.E258V、p.R248Q、P.R337C、p.E221*、p.R174_R175delinsWC,但在LM或STUMP的对照病例中没有发现TP53 ctDNA变异。在5例TP53突变LMS的血浆样本中,患者有广泛的转移性疾病,在2例TP53野生型LMS和STUMP病例中,患者无疾病证据。据我们所知,这是第一个证明TP53 ctDNA在LMS、LM和STUMP患者中比较使用的初步研究。需要对这些罕见的LMS进行进一步的研究,以确定NGS TP53 ctDNA突变状态作为一种有用的分子生物标志物,帮助指导手术,避免对未检测到的LMS进行不必要的操作和盆腔污染。引用格式:Jean R. Lopategui, Bonnie Balzer, yzhou Wang, Chintda Santiskulvong, Carissa A. Hyunh, Chun Yat Ong, Manuel Arana, Matthew Gayhart, Farin Amersi, Allan W. Silberman。循环TP53肿瘤DNA作为子宫平滑肌肉瘤术前鉴别的潜在生物标志物[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):447。
{"title":"Abstract 447: Circulating TP53 tumor DNA as a potential biomarker for pre-operative identification of uterine leiomyosarcoma","authors":"J. Lopategui, Bonnie L. Balzer, Yizhou Wang, C. Santiskulvong, Carissa A. Hyunh, Chun Yat Ong, M. Araña, M. Gayhart, F. Amersi, A. Silberman","doi":"10.1158/1538-7445.AM2021-447","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-447","url":null,"abstract":"Uterine leiomyosarcoma (LMS) is a highly aggressive but rare malignancy with a dismal prognosis. In nearly all cases, LMS is unsuspected prior to resection for a presumed leiomyoma. The risk of occult uterine LMS is reported to be 0.2% (1 in 500) in the largest cohort study of women undergoing surgery for presumed fibroid disease. The major problem is that there is no reliable preoperative method to distinguish LMS from a leiomyoma (LM) or STUMP (smooth muscle tumor of uncertain malignant potential), and the patient9s prognosis for LMS is even poorer if the tumor is transected, which occurs in procedures performed for LM. Effective therapy for LMS is lacking and most patients eventually succumb to the disease. Thus, there is a considerable need for a reliable preoperative test to triage patients into the proper surgical procedure for LMS. TP53 alterations are reportedly associated with uterine LMS in about 40% of cases. We screened plasma for TP53 variants in patients with pathologically confirmed LMS. We evaluated TP53 circulating tumor DNA (ctDNA) by deep next-generation sequencing in a cohort of 7 patients with LMS, 1 patient with STUMP, and 3 patients with LM. Clinical data were reviewed to assess disease burden. LMS patients9 tumor burden ranged from no evidence to extensive metastatic disease. DNA extraction was performed using the QIAamp DNA Micro Kit, QIAamp DNA FFPE Tissue Kit, or QIAamp MinElute ccfDNA Mini Kit. DNA quality was assessed using the TapeStation Genomic DNA kit. NGS libraries targeting the entire exonic region of the p53 gene were prepared using the QIASeq Targeted DNA Custom Panel. Sequencing was performed on the MiSeq system using 150bp paired end sequencing with a minimum read depth of 2x0.5M reads for plasma and 2x1M reads for formalin-fixed paraffin embedded and fresh-frozen tissue samples. Raw sequencing data were demultiplexed by bcl2fastq to generate the FASTQ files. Then raw sequencing reads were aligned to the human reference genome GRCh38 by BWA-MEM 0.7.9a-r786. SmCounter2 was used for p53 variants calling and variants quality control. We discovered TP53 ctDNA variants in 5 of 7 (71.4%) LMS cases including p.E258V, p.R248Q, P.R337C, p.E221*, p.R174_R175delinsWC, but not in the control cases of LM or STUMP. In the 5 plasma samples with TP53 mutated LMS, the patients had extensive metastatic disease and in the 2 TP53 wild-type LMS and STUMP cases, the patients had no evidence of disease. To our knowledge, this is the first pilot study to demonstrate the comparative use of TP53 ctDNA in patients with LMS, LM, and STUMP. Further study of these rare LMS is needed to determine the preoperative utility of NGS TP53 ctDNA mutational status as a useful molecular biomarker to help guide surgery and avoid unwarranted manipulation and pelvic contamination of undetected LMS. Supported by the Gottlieb, Buss and Snyder Endowments in Surgical Oncology Citation Format: Jean R. Lopategui, Bonnie Balzer, Yizhou Wang, Chintda Santisk","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80928997","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.AM2021-382
Jian-Guo Zhou, Hu Ma, U. Gaipl, B. Frey, M. Hecht, R. Fietkau
Background: Numerus studies already proved C-reactive protein (CRP) in pre-treat is a predictive biomarkers to for cancer patients treated with anti-PD(L)-1 antibodies. However, there aren9t any study has evaluated CRP levels longitudinally in patients with immune checkpoint inhibitors (ICIs). This study provides a comprehensive investigation of CRP levels as well as its longitudinal trajectories as a dynamic predictor of treatment response and survival outcome in metastatic cancer patients undergoing immunotherapy with anti PD-1 or anti PD-L1 agents. Methods: A total number of 104 patients were prospectively enrolled. First, multivariate survival analysis for clinical factors, which including cancer types, line of treatment, PD-L1 expression, brain metastases (BM), etc. Then, used multivariate joint modelling of longitudinal and time to event data to establish the relationship between longitudinal CRP and the overall survival (OS). Results: 92/102 patients with more than 2 times CRP results in all of treatment timepoints. Longitudinal CRP levels combine with clinical factors emerged as independent predictors of worse OS (HR of jointed model= 1.82, 95% CI: 1.45-2.32, p Conclusion: Our study highlights longitudinal CRP serves as potential personalized dynamic predictions for immunotherapeutic benefit of metastatic cancer patients. Keywords: metastatic cancers, immune checkpoint inhibitors, C-reactive protein, dynamic predictor Trial registration: Prospectively registered in ClinicalTrials.gov (NCT03453892) on January 24, 2018. Citation Format: Jian-Guo Zhou, Hu Ma, Udo Gaipl, Benjamin Frey, Markus Hecht, Rainer Fietkau. Longitudinal C-reactive protein (CRP) as an individualized dynamic predictor for metastatic cancer patients treated with immune checkpoint inhibitors: Findings from the prospective ST-ICI cohort [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 382.
背景:大量研究已经证明,c反应蛋白(CRP)在治疗前是一种预测性生物标志物,可用于抗pd (L)-1抗体治疗的癌症患者。然而,目前还没有任何研究对免疫检查点抑制剂(ICIs)患者的CRP水平进行纵向评估。这项研究提供了一项全面的研究,CRP水平及其纵向轨迹作为转移性癌症患者接受抗PD-1或抗PD-L1免疫治疗的治疗反应和生存结果的动态预测因子。方法:共纳入104例患者。首先,临床因素的多因素生存分析,包括肿瘤类型、治疗方式、PD-L1表达、脑转移(BM)等。然后,采用纵向和时间到事件数据的多变量联合建模,建立纵向CRP与总生存期(OS)的关系。结果:92/102例CRP≥2次的患者在所有治疗时间点均有结果。纵向CRP水平与临床因素联合成为预后不良的独立预测因素(关节模型的HR = 1.82, 95% CI: 1.45-2.32, p)。结论:我们的研究强调纵向CRP可作为转移性癌症患者免疫治疗获益的潜在个性化动态预测。试验注册:于2018年1月24日在ClinicalTrials.gov (NCT03453892)前瞻性注册。引用格式:周建国,胡玛,Udo Gaipl, Benjamin Frey, Markus Hecht, Rainer Fietkau。纵向c反应蛋白(CRP)作为接受免疫检查点抑制剂治疗的转移性癌症患者的个体化动态预测因子:来自前瞻性ST-ICI队列的研究结果[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):摘要第382期。
{"title":"Abstract 382: Longitudinal C-reactive protein (CRP) as an individualized dynamic predictor for metastatic cancer patients treated with immune checkpoint inhibitors: Findings from the prospective ST-ICI cohort","authors":"Jian-Guo Zhou, Hu Ma, U. Gaipl, B. Frey, M. Hecht, R. Fietkau","doi":"10.1158/1538-7445.AM2021-382","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-382","url":null,"abstract":"Background: Numerus studies already proved C-reactive protein (CRP) in pre-treat is a predictive biomarkers to for cancer patients treated with anti-PD(L)-1 antibodies. However, there aren9t any study has evaluated CRP levels longitudinally in patients with immune checkpoint inhibitors (ICIs). This study provides a comprehensive investigation of CRP levels as well as its longitudinal trajectories as a dynamic predictor of treatment response and survival outcome in metastatic cancer patients undergoing immunotherapy with anti PD-1 or anti PD-L1 agents. Methods: A total number of 104 patients were prospectively enrolled. First, multivariate survival analysis for clinical factors, which including cancer types, line of treatment, PD-L1 expression, brain metastases (BM), etc. Then, used multivariate joint modelling of longitudinal and time to event data to establish the relationship between longitudinal CRP and the overall survival (OS). Results: 92/102 patients with more than 2 times CRP results in all of treatment timepoints. Longitudinal CRP levels combine with clinical factors emerged as independent predictors of worse OS (HR of jointed model= 1.82, 95% CI: 1.45-2.32, p Conclusion: Our study highlights longitudinal CRP serves as potential personalized dynamic predictions for immunotherapeutic benefit of metastatic cancer patients. Keywords: metastatic cancers, immune checkpoint inhibitors, C-reactive protein, dynamic predictor Trial registration: Prospectively registered in ClinicalTrials.gov (NCT03453892) on January 24, 2018. Citation Format: Jian-Guo Zhou, Hu Ma, Udo Gaipl, Benjamin Frey, Markus Hecht, Rainer Fietkau. Longitudinal C-reactive protein (CRP) as an individualized dynamic predictor for metastatic cancer patients treated with immune checkpoint inhibitors: Findings from the prospective ST-ICI cohort [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 382.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84160275","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.AM2021-676
E. Nystuen, A. Bates, K. O'Leary, S. Emma, Elizabeth G. Sumiec, L. Schuler, Z. Morris
{"title":"Abstract 676: Fulvestrant and radiation modify the tumor immune microenvironment in ER+ metastatic breast cancer and cooperate to enhance response to anti-PDL1 checkpoint blockade","authors":"E. Nystuen, A. Bates, K. O'Leary, S. Emma, Elizabeth G. Sumiec, L. Schuler, Z. Morris","doi":"10.1158/1538-7445.AM2021-676","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-676","url":null,"abstract":"","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":"78257397","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.AM2021-556
Charles J. Vaske, Christopher J. Troll, Camille Schwartz, Colin Naughton, A. Ali, A. Raza, Varsha Rao, Kelly Harkins-Kincaid, R. Green
DNA sequencing library preparation is a crucial step for next-generation sequencing of cell free DNA of plasma for cancer diagnostics. We present SRSLY, a robust single-stranded DNA library preparation method, that generates libraries with unique molecule identifiers (UMIs), with advantages over traditional double-stranded DNA preparations. Using 5 ng of plasma-derived cfDNA from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and gastrointestinal cancer cases, we prepared both SRSLY and double-stranded DNA (dsDNA) sequencing libraries with UMIs. The libraries were enriched using a Twist Biosciences custom hybridization probe set for an 800 kilobase cancer mutation panel. We sequenced to a panel depth of 1000x to 2000x, after correcting UMI sequences and removing duplicate reads. With comparable fold enrichment and on-target percentages, we observe complexities of 11-21 million unique molecules with SRSLY. This is approximately four times higher than dsDNA complexity of 2.8-4.9 million unique molecules. Using duplicate reads from the same unique molecule, we perform error correction on template read bases and are able to call low-variant allele frequency mutations. In particular, we show an increase in KRAS p.G12D variant allele fraction during progression from MDS to AML. SRSLY shows increased recovery of small fragments over dsDNA preparations and retains the native lengths and termini of all fragments. Apart from improved library complexity, we show that MDS and AML samples can be distinguished from healthy samples by their disrupted genomic profile of short to long fragments, which has been previously demonstrated in solid tumors but not for MDS or AML. Citation Format: Charles J. Vaske, Chris Troll, Camille Schwartz, Colin Naughton, Abdullah Mahmood Ali, Azra Raza, Varsha Rao, Kelly Harkins-Kincaid, Richard Edward Green. Highly complex DNA sequencing library preparation for cfDNA enrichment panels using a single-stranded approach [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 556.
DNA测序文库的制备是下一代血浆游离DNA测序用于癌症诊断的关键步骤。我们提出了SRSLY,一种强大的单链DNA文库制备方法,它产生具有独特分子标识符(UMIs)的文库,比传统的双链DNA制备具有优势。利用5 ng来自急性髓性白血病(AML)、骨髓增生异常综合征(MDS)和胃肠道癌症病例的血浆来源cfDNA,我们用UMIs制备了SRSLY和双链DNA (dsDNA)测序文库。这些文库使用Twist Biosciences定制的杂交探针进行富集,用于800千碱基的癌症突变面板。在校正UMI序列并去除重复读取后,我们对面板深度进行了1000x至2000x的测序。在可比较的倍丰度和靶率下,我们观察到SRSLY具有1100 - 2100万个独特分子的复杂性。这比dsDNA的280 - 490万个独特分子的复杂性大约高出4倍。使用来自同一独特分子的重复读取,我们对模板读取碱基进行错误校正,并能够调用低变异等位基因频率突变。特别是,我们发现KRAS p.G12D变异等位基因在MDS到AML的过程中增加。SRSLY显示,与dsDNA制剂相比,小片段的恢复增加,并保留了所有片段的天然长度和末端。除了提高文库的复杂性外,我们还发现MDS和AML样本可以通过其短片段到长片段的基因组图谱被破坏来与健康样本区分开来,这在实体肿瘤中已经被证明,但在MDS或AML中没有被证明。引文格式:Charles J. Vaske, Chris Troll, Camille Schwartz, Colin Naughton, Abdullah Mahmood Ali, Azra Raza, Varsha Rao, Kelly Harkins-Kincaid, Richard Edward Green。利用单链方法制备cfDNA富集板的高度复杂DNA测序文库[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):556。
{"title":"Abstract 556: Highly complex DNA sequencing library preparation for cfDNA enrichment panels using a single-stranded approach","authors":"Charles J. Vaske, Christopher J. Troll, Camille Schwartz, Colin Naughton, A. Ali, A. Raza, Varsha Rao, Kelly Harkins-Kincaid, R. Green","doi":"10.1158/1538-7445.AM2021-556","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-556","url":null,"abstract":"DNA sequencing library preparation is a crucial step for next-generation sequencing of cell free DNA of plasma for cancer diagnostics. We present SRSLY, a robust single-stranded DNA library preparation method, that generates libraries with unique molecule identifiers (UMIs), with advantages over traditional double-stranded DNA preparations. Using 5 ng of plasma-derived cfDNA from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and gastrointestinal cancer cases, we prepared both SRSLY and double-stranded DNA (dsDNA) sequencing libraries with UMIs. The libraries were enriched using a Twist Biosciences custom hybridization probe set for an 800 kilobase cancer mutation panel. We sequenced to a panel depth of 1000x to 2000x, after correcting UMI sequences and removing duplicate reads. With comparable fold enrichment and on-target percentages, we observe complexities of 11-21 million unique molecules with SRSLY. This is approximately four times higher than dsDNA complexity of 2.8-4.9 million unique molecules. Using duplicate reads from the same unique molecule, we perform error correction on template read bases and are able to call low-variant allele frequency mutations. In particular, we show an increase in KRAS p.G12D variant allele fraction during progression from MDS to AML. SRSLY shows increased recovery of small fragments over dsDNA preparations and retains the native lengths and termini of all fragments. Apart from improved library complexity, we show that MDS and AML samples can be distinguished from healthy samples by their disrupted genomic profile of short to long fragments, which has been previously demonstrated in solid tumors but not for MDS or AML. Citation Format: Charles J. Vaske, Chris Troll, Camille Schwartz, Colin Naughton, Abdullah Mahmood Ali, Azra Raza, Varsha Rao, Kelly Harkins-Kincaid, Richard Edward Green. Highly complex DNA sequencing library preparation for cfDNA enrichment panels using a single-stranded approach [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 556.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80332934","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.AM2021-692
A. Morello, Justine Durand, Margaux Seite, V. Thepenier, G. Teppaz, E. Wilhelm, Arianne Desselle, C. Mary, N. Poirier
{"title":"Abstract 692: Optimized antagonist anti-PD-1/IL-7 bispecific antibody to sustain exhausted T cell function and to disarm Treg suppressive activity","authors":"A. Morello, Justine Durand, Margaux Seite, V. Thepenier, G. Teppaz, E. Wilhelm, Arianne Desselle, C. Mary, N. Poirier","doi":"10.1158/1538-7445.AM2021-692","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-692","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"192 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76968112","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.AM2021-617
Hyojin Kim, Eun Sun Kim, Song Kook Lee, Jeong Hoon Lee, K. Paeng, C. Ock, D. Suh, Kidong Kim, J. No, Yong‐Beom Kim
{"title":"Abstract 617: Artificial intelligence-powered tissue analysis reveals distinct tumor-infiltrating lymphocyte profile as a potential biomarker of molecular subtypes in endometrial cancer","authors":"Hyojin Kim, Eun Sun Kim, Song Kook Lee, Jeong Hoon Lee, K. Paeng, C. Ock, D. Suh, Kidong Kim, J. No, Yong‐Beom Kim","doi":"10.1158/1538-7445.AM2021-617","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-617","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"64 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81451015","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}