Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-576
A. Murad, J. C. Rocha
Background: Analysis of genomic alterations in advanced malignant disease is quickly becoming the standard of care in oncology. Biopsies are risky, often costly and may not capture genetic changes that can emerge over time or in response to therapy. In contrast, GUARDANT360, a blood-based liquid biopsy (LB) approach that analyzes circulating tumor DNA (ctDNA), offers a simple and comprehensive tool for real-time tumor NGS (next generation sequencing) genetic profiling in advanced refractory cancer patients. Methods: We studied the performance of GUARDANT360 in several advanced solid cancers already refractory to conventional therapy. GUARDANT360 is a single-molecule next-generation digital sequencing assay with ability to detect somatic mutations, gene fusions and copy number variations with exquisite sensitivity. The assay covers sequences across a total of 74 actionable genes covering approximately 80 kbps and it also detects MSI (microsatellite instability). Thus, therapeutic decisions were made on the basis of ctDNA actionable alterations detected. A total of 90 plasma samples (2 for each patient) of 45 patients with advanced solid tumors and refractory to convencional therapy were studied. Results: The overall detection rate of somatic pathogenic variants potentially actionable (PVPA) in ctDNA approached 64% (29 patients) for all indications (the range of detectable ctDNA mutations was 0.03%-57%). The total number of PVPA in all 29 patients was 50 as follows. CRC( Colorectal Cancer): 12 (27%) tested, in 10 we found 23 PVPA: KRAS - 4, MSI-H -1, ATM - 2, FGFR1(amp)- 1, PIK3CA - 3, BRCA1 - 1, BRCA2 - 2, APC - 4, PTEN - 1, MTOR - 1, NF1 - 1, BRAF - 1, MAP2K1 - 1. Pancreatic cancer: 7 (16%) tested, in 3 we found 4 PVPA: STK11 - 1, AKT1 - 1, APC - 1, FGFR1 amp- 1. NSCLC(Non-Small Cell Lung Adenocarcinoma): 6(14%) tested, in 4 we found 4 PVPA: ALK-EML4 fusion - 1, ERBB2 (G776 Delins VC) - 1, ATM -2. Ovarian cancer: 3(7%) tested, in 3 we found 3 PVPA: BRCA1 - 1, PIK3CA - 2. Breast cancer: 4(9%) tested, in 3 we found 7 PVPA: ESR1 - 2, PIK3CA -1, FGFR1 amp -2, ERBB2 amp -1, CCND1 - 1. Head and Neck cancers: 2(4.5%) tested, in 1 we found 3 PVPA: PTEN - 1, PIK3CA - 1, FGFR1 amp - 1. CUP (carcinoma of unknown primary): 2 (4.5%) tested, in 2 we found 2 PVPA: CDK6 - 1, FGFR1 amp - 1. Renal cancer: 1 tested, in 1 we found 2 PVPA: NF1 - 1, JAK2 -1. Prostate cancer: 1 (2%) tested, in 1 we found 1 PVPA: AR. NET (neuroendocrine tumor): 1 (2%) tested, in 1 we found 1 PVPA: ATM. We also tested 1(1%) gallbladder, 1(1%) GIST, 1(1%) endometrial 1(1%) duodenal, 1(1%) SCLC (Small Cell Lung Cancer) and 1(1%) sarcoma and no PVPA were found. Conclusion: Our results suggest that GUARDANT360 LB is a highly feasible, comprehensive and sensitive LB technology and should be used for a routine laboratory detection of the important genomic variations to determine the targeted therapy in patients with varied advanced solid tumors with with clear benefits compared to tissue diagn
{"title":"Abstract 576: A single institution experience with Guardant360 liquid biopsy for therapeutic decision in advanced solid tumors","authors":"A. Murad, J. C. Rocha","doi":"10.1158/1538-7445.AM2021-576","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-576","url":null,"abstract":"Background: Analysis of genomic alterations in advanced malignant disease is quickly becoming the standard of care in oncology. Biopsies are risky, often costly and may not capture genetic changes that can emerge over time or in response to therapy. In contrast, GUARDANT360, a blood-based liquid biopsy (LB) approach that analyzes circulating tumor DNA (ctDNA), offers a simple and comprehensive tool for real-time tumor NGS (next generation sequencing) genetic profiling in advanced refractory cancer patients. Methods: We studied the performance of GUARDANT360 in several advanced solid cancers already refractory to conventional therapy. GUARDANT360 is a single-molecule next-generation digital sequencing assay with ability to detect somatic mutations, gene fusions and copy number variations with exquisite sensitivity. The assay covers sequences across a total of 74 actionable genes covering approximately 80 kbps and it also detects MSI (microsatellite instability). Thus, therapeutic decisions were made on the basis of ctDNA actionable alterations detected. A total of 90 plasma samples (2 for each patient) of 45 patients with advanced solid tumors and refractory to convencional therapy were studied. Results: The overall detection rate of somatic pathogenic variants potentially actionable (PVPA) in ctDNA approached 64% (29 patients) for all indications (the range of detectable ctDNA mutations was 0.03%-57%). The total number of PVPA in all 29 patients was 50 as follows. CRC( Colorectal Cancer): 12 (27%) tested, in 10 we found 23 PVPA: KRAS - 4, MSI-H -1, ATM - 2, FGFR1(amp)- 1, PIK3CA - 3, BRCA1 - 1, BRCA2 - 2, APC - 4, PTEN - 1, MTOR - 1, NF1 - 1, BRAF - 1, MAP2K1 - 1. Pancreatic cancer: 7 (16%) tested, in 3 we found 4 PVPA: STK11 - 1, AKT1 - 1, APC - 1, FGFR1 amp- 1. NSCLC(Non-Small Cell Lung Adenocarcinoma): 6(14%) tested, in 4 we found 4 PVPA: ALK-EML4 fusion - 1, ERBB2 (G776 Delins VC) - 1, ATM -2. Ovarian cancer: 3(7%) tested, in 3 we found 3 PVPA: BRCA1 - 1, PIK3CA - 2. Breast cancer: 4(9%) tested, in 3 we found 7 PVPA: ESR1 - 2, PIK3CA -1, FGFR1 amp -2, ERBB2 amp -1, CCND1 - 1. Head and Neck cancers: 2(4.5%) tested, in 1 we found 3 PVPA: PTEN - 1, PIK3CA - 1, FGFR1 amp - 1. CUP (carcinoma of unknown primary): 2 (4.5%) tested, in 2 we found 2 PVPA: CDK6 - 1, FGFR1 amp - 1. Renal cancer: 1 tested, in 1 we found 2 PVPA: NF1 - 1, JAK2 -1. Prostate cancer: 1 (2%) tested, in 1 we found 1 PVPA: AR. NET (neuroendocrine tumor): 1 (2%) tested, in 1 we found 1 PVPA: ATM. We also tested 1(1%) gallbladder, 1(1%) GIST, 1(1%) endometrial 1(1%) duodenal, 1(1%) SCLC (Small Cell Lung Cancer) and 1(1%) sarcoma and no PVPA were found. Conclusion: Our results suggest that GUARDANT360 LB is a highly feasible, comprehensive and sensitive LB technology and should be used for a routine laboratory detection of the important genomic variations to determine the targeted therapy in patients with varied advanced solid tumors with with clear benefits compared to tissue diagn","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86710908","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.AM2021-403
Linlin Zhang, Fuyu Gong, F. Meng, Xin Wang, D. Zhong
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 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, including 12278 (55.4%) male and 9865 (44.6%) female with a median age of 63. There are 9560 patients has the EGFR mutation, and the frequency of EGFR mutation is 43.2%. Among the EGFR mutation patients, 1602 patients have been collected tumor tissue, and the PD-L1 expression have been tested by FDA-approved SP263 and 22C3 antibodies. Among all the EGFR mutation cases assessed PD-L1 expression (n=1602), 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: Linlin Zhang, Fuyu Gong, Fanlu Meng, Xin Wang, DianSheng Zhong. The landscape of PD-L1 expression in lung cancer harboring 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 403.
{"title":"Abstract 403: The landscape of PD-L1 expression in lung cancer harboring EGFR mutations","authors":"Linlin Zhang, Fuyu Gong, F. Meng, Xin Wang, D. Zhong","doi":"10.1158/1538-7445.AM2021-403","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-403","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 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, including 12278 (55.4%) male and 9865 (44.6%) female with a median age of 63. There are 9560 patients has the EGFR mutation, and the frequency of EGFR mutation is 43.2%. Among the EGFR mutation patients, 1602 patients have been collected tumor tissue, and the PD-L1 expression have been tested by FDA-approved SP263 and 22C3 antibodies. Among all the EGFR mutation cases assessed PD-L1 expression (n=1602), 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: Linlin Zhang, Fuyu Gong, Fanlu Meng, Xin Wang, DianSheng Zhong. The landscape of PD-L1 expression in lung cancer harboring 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 403.","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86648198","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.AM2021-358
N. Menssouri, L. Poiraudeau, C. Helissey, L. Bigot, J. Sabio, T. Ibrahim, C. Nicotra, M. Ngocamus, L. Tselikas, T. Baère, E. Rouleau, L. Lacroix, Anne Chaucherau, L. Friboulet, R. Flippot, G. Baciarello, L. Albiges, E. Colomba, P. Lavaud, S. Michiels, A. Maillard, A. Italiano, F. Barlesi, J. Soria, J. Scoazec, C. Massard, B. Besse, F. André, K. Fizazi, D. Gautheret, Y. Loriot
Background: The androgen receptor axis inhibitors (ARi) (e.g, enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown. Methods: In a prospective trial MATCH-R (NCT02517892), 55 mCRPC patients underwent whole exome sequencing (WES) (n=45) and RNA-sequencing (RNA-seq) (n=52) of metastatic biopsies before starting ARi. Also, 16 mCRPC patients underwent biopsy at time of resistance (WES=14, RNA-seq = 14). The objectives were to identify genomic alterations associated with resistance to ARi as well as to describe clonal evolution. Primary resistance was determined at 4 months of treatment using composite criteria for progression that included serum prostate specific antigen measurements, bone scan, CT imaging and symptom assessments. Acquired resistance was defined by occurrence of progressive disease after initial response or stable disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher9s exact tests. Results: At 4 months, 22/55 patients in the cohort had disease progression (primary resistance). No genomic alterations from WES analysis were significantly associated with primary resistance. Analysis of sequential biopsies suggests that mCRPC follows mainly a parallel evolution model and involve DNA-repair related mutational processes. At time of acquired resistance to ARi, most tumors acquired new drivers affecting AR pathway (e.g, AR, NCOR1/2) or lineage switching (e.g, RB1, PTEN, TP53). Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis to identify pathways whose activity state correlated with resistance. AR gene alterations and AR expression were similar between responding and non-responding patients. Transcriptional analysis demonstrated that multiple specific gene sets — including those linked to low AR transcriptional activity, stemness program, RB loss and homologous repair deficiency — were activated in both primary and acquired resistance. Conclusion: Resistance to AR axis inhibitors results from multiple transcriptional programs already activated in pre-treatment samples. Clonal evolution analysis along with RNA-seq data indicate the role of genomic instability and lineage switching in driving acquired resistance Citation Format: Naoual Menssouri, Loic Poiraudeau, Carole Helissey, Ludovic Bigot, Jonathan Sabio, Tony Ibrahim, Claudio Nicotra, Maud Ngocamus, Lambros Tselikas, Thierry De Baere, Etienne Rouleau, Ludovic Lacroix, Anne Chaucherau, Luc Friboulet, Ronan Flippot, Giulia Baciarello, Laurence Albiges, Emeline Colomba, Pernelle Lavaud, Stefan Michiels, Aline Maillard, Antoine Italiano, Fabrice Barlesi, Jean-Charles Soria, Jean-Yves Scoazec, christophe Massard, Benjamin Besse, Fabrice Andre, Karim Fizazi, Dani
背景:雄激素受体轴抑制剂(ARi)(例如，恩杂鲁胺，醋酸阿比特龙)在转移性去势抵抗性前列腺癌(mCRPC)患者的日常治疗中使用。然而，并非所有患者都有反应，原发和获得性耐药的机制在很大程度上仍然未知。方法:在一项前瞻性试验MATCH-R (NCT02517892)中，55名mCRPC患者在开始ARi前接受了转移性活检的全外显子组测序(WES) (n=45)和rna测序(RNA-seq) (n=52)。此外，16例mCRPC患者在耐药时进行了活检(WES=14, RNA-seq =14)。目的是确定与ARi抗性相关的基因组改变以及描述克隆进化。在治疗4个月时，使用包括血清前列腺特异性抗原测量、骨扫描、CT成像和症状评估在内的进展综合标准确定原发性耐药性。获得性耐药的定义是初始反应后病情进展或病情稳定。基因组和转录组改变与原发耐药的关联使用Wilcoxon和fisher9精确试验确定。结果:在4个月时，队列中有22/55例患者出现疾病进展(原发性耐药)。WES分析的基因组改变与原发耐药无显著相关性。序列活检分析表明，mCRPC主要遵循平行进化模型，并涉及dna修复相关的突变过程。在ARi获得性耐药时，大多数肿瘤获得了影响AR通路(如AR、NCOR1/2)或谱系转换(如RB1、PTEN、TP53)的新驱动因子。利用计算方法，我们测量了AR的转录功能，并进行了基因集富集分析，以确定其活性状态与抗性相关的途径。AR基因改变和AR表达在有反应和无反应患者之间相似。转录分析表明，多个特定基因集(包括与低AR转录活性、干性程序、RB丢失和同源修复缺陷相关的基因集)在原发性和获得性抗性中都被激活。结论:对AR轴抑制剂的耐药源于预处理样品中已经激活的多个转录程序。克隆进化分析和RNA-seq数据表明，基因组不稳定性和谱系转换在驱动获得性抗性中的作用。Naoual Menssouri, Loic Poiraudeau, Carole Helissey, Ludovic Bigot, Jonathan Sabio, Tony Ibrahim, Claudio Nicotra, Maud Ngocamus, Lambros Tselikas, Thierry De Baere, Etienne Rouleau, Ludovic Lacroix, Anne Chaucherau, Luc Friboulet, Ronan Flippot, Giulia Baciarello, Laurence Albiges, Emeline Colomba, Pernelle Lavaud, Stefan Maillard, Antoine Italiano, Fabrice Barlesi, Jean-Charles Soria, Jean-Yves Scoazec, christophe Massard, Benjamin Besse, Fabrice Andre, Karim Fizazi，Daniel Gautheret, Yohann Loriot。一项对前列腺癌转移的前瞻性研究发现了雄激素受体活性低、与雄激素受体轴抑制剂耐药相关的干细胞程序，并揭示了克隆进化的机制[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358期。
{"title":"Abstract 358: A prospective study of prostate cancer metastases identifies an androgen receptor activity-low, stemness program associated with resistance to androgen receptor axis inhibitors and unveils mechanisms of clonal evolution","authors":"N. Menssouri, L. Poiraudeau, C. Helissey, L. Bigot, J. Sabio, T. Ibrahim, C. Nicotra, M. Ngocamus, L. Tselikas, T. Baère, E. Rouleau, L. Lacroix, Anne Chaucherau, L. Friboulet, R. Flippot, G. Baciarello, L. Albiges, E. Colomba, P. Lavaud, S. Michiels, A. Maillard, A. Italiano, F. Barlesi, J. Soria, J. Scoazec, C. Massard, B. Besse, F. André, K. Fizazi, D. Gautheret, Y. Loriot","doi":"10.1158/1538-7445.AM2021-358","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-358","url":null,"abstract":"Background: The androgen receptor axis inhibitors (ARi) (e.g, enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown. Methods: In a prospective trial MATCH-R (NCT02517892), 55 mCRPC patients underwent whole exome sequencing (WES) (n=45) and RNA-sequencing (RNA-seq) (n=52) of metastatic biopsies before starting ARi. Also, 16 mCRPC patients underwent biopsy at time of resistance (WES=14, RNA-seq = 14). The objectives were to identify genomic alterations associated with resistance to ARi as well as to describe clonal evolution. Primary resistance was determined at 4 months of treatment using composite criteria for progression that included serum prostate specific antigen measurements, bone scan, CT imaging and symptom assessments. Acquired resistance was defined by occurrence of progressive disease after initial response or stable disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher9s exact tests. Results: At 4 months, 22/55 patients in the cohort had disease progression (primary resistance). No genomic alterations from WES analysis were significantly associated with primary resistance. Analysis of sequential biopsies suggests that mCRPC follows mainly a parallel evolution model and involve DNA-repair related mutational processes. At time of acquired resistance to ARi, most tumors acquired new drivers affecting AR pathway (e.g, AR, NCOR1/2) or lineage switching (e.g, RB1, PTEN, TP53). Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis to identify pathways whose activity state correlated with resistance. AR gene alterations and AR expression were similar between responding and non-responding patients. Transcriptional analysis demonstrated that multiple specific gene sets — including those linked to low AR transcriptional activity, stemness program, RB loss and homologous repair deficiency — were activated in both primary and acquired resistance. Conclusion: Resistance to AR axis inhibitors results from multiple transcriptional programs already activated in pre-treatment samples. Clonal evolution analysis along with RNA-seq data indicate the role of genomic instability and lineage switching in driving acquired resistance Citation Format: Naoual Menssouri, Loic Poiraudeau, Carole Helissey, Ludovic Bigot, Jonathan Sabio, Tony Ibrahim, Claudio Nicotra, Maud Ngocamus, Lambros Tselikas, Thierry De Baere, Etienne Rouleau, Ludovic Lacroix, Anne Chaucherau, Luc Friboulet, Ronan Flippot, Giulia Baciarello, Laurence Albiges, Emeline Colomba, Pernelle Lavaud, Stefan Michiels, Aline Maillard, Antoine Italiano, Fabrice Barlesi, Jean-Charles Soria, Jean-Yves Scoazec, christophe Massard, Benjamin Besse, Fabrice Andre, Karim Fizazi, Dani","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87325857","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-LB034
E. Torlakovic, S. R. Sompuram, K. Vani, S. Bogen
BACKGROUND. The challenges in accurate patient stratification for immune checkpoint inhibitors have been compounded by the fact that the FDA-cleared PD-L1 IHC tests are analytic ‘black boxes9. Relatively basic analytic parameters such as lower limit of detection and analytic dynamic range are unknown to both developers of assays as well as end users. The recent development of standardized PD-L1 immunohistochemistry (IHC) reference materials enables quantitative test characterizations that were not previously possible. METHODS. We surveyed 41 PD-L1 testing laboratories in North America and Europe, quantitatively defining each of the PD-L1 tests9 analytic performance in terms of lower limit of detection and dynamic range. All four commercial PD-L1 kits were assessed by multiple laboratories. A variety of laboratory-developed tests (LDTs) we also assessed. The reference materials incorporated defined concentrations of PD-L1 peptide (intracellular domain) or recombinant extracellular domain protein, traceable to NIST Standard Reference Material 1934. Each laboratory received a slide with 10 separate PD-L1 calibrator concentrations: 2,200 - 600,000 molecules of PD-L1 extracellular domain or 34,000 - 2,200,000 molecules of PD-L1 intracellular domain. The calibrator concentrations ranged from those that are below the lower limit of detection to others that yield maximal staining. RESULTS. The data obtained with the four PD-L1 kits (VENTANA PD-L1 (SP263) Assay, VENTANA PD-L1 (SP142) Assay, DAKO PD-L1 IHC 28-8 pharmDx and DAKO PD-L1 IHC 22C3 pharmDx assays) revealed that the lower limits of detection (PD-L1 molecules per cell equivalent) are approximately: 50,000 - 180,000 (SP263), 800,000 - 1,200,000 (SP142), 220,000 - 360,000 (28-8), and 200,000 - 400,000 (22C3). The dynamic ranges for all of these tests are generally narrow, spanning less than a log concentration of PD-L1. The SP263 and SP142 assays showed no overlap of their analytic response curves. This means that a maximal stain intensity with SP263 kit can be associated with zero staining with the SP142 kit. Consequently, it is not possible to compensate for the variability in analytic sensitivity between these two tests by adjusting the percent positive cell cutoff. The 28-8 was more sensitive than, but statistically indistinguishable from the 22C3 assay. Laboratory-developed tests (LDTs) using these and other primary antibodies have their own unique analytic performance characteristics. CONCLUSIONS. The PD-L1 reference materials enable precise definitions of analytic test performance and linking them with clinical management thresholds. Therefore, this tool finds its most important implementation at the stage of development of new IHC predictive biomarkers in clinical trials as well as at the stage of methodology transfer to clinical IHC laboratories. Furthermore, our results also help define more precisely the possibility for assay interchangeability and to what degree the assays may be harmoni
{"title":"Abstract LB034: Analysis of PD-L1 IHC tests using NIST SRM 1934-traceable reference materials: A new paradigm for development of predictive IHC biomarkers","authors":"E. Torlakovic, S. R. Sompuram, K. Vani, S. Bogen","doi":"10.1158/1538-7445.AM2021-LB034","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB034","url":null,"abstract":"BACKGROUND. The challenges in accurate patient stratification for immune checkpoint inhibitors have been compounded by the fact that the FDA-cleared PD-L1 IHC tests are analytic ‘black boxes9. Relatively basic analytic parameters such as lower limit of detection and analytic dynamic range are unknown to both developers of assays as well as end users. The recent development of standardized PD-L1 immunohistochemistry (IHC) reference materials enables quantitative test characterizations that were not previously possible. METHODS. We surveyed 41 PD-L1 testing laboratories in North America and Europe, quantitatively defining each of the PD-L1 tests9 analytic performance in terms of lower limit of detection and dynamic range. All four commercial PD-L1 kits were assessed by multiple laboratories. A variety of laboratory-developed tests (LDTs) we also assessed. The reference materials incorporated defined concentrations of PD-L1 peptide (intracellular domain) or recombinant extracellular domain protein, traceable to NIST Standard Reference Material 1934. Each laboratory received a slide with 10 separate PD-L1 calibrator concentrations: 2,200 - 600,000 molecules of PD-L1 extracellular domain or 34,000 - 2,200,000 molecules of PD-L1 intracellular domain. The calibrator concentrations ranged from those that are below the lower limit of detection to others that yield maximal staining. RESULTS. The data obtained with the four PD-L1 kits (VENTANA PD-L1 (SP263) Assay, VENTANA PD-L1 (SP142) Assay, DAKO PD-L1 IHC 28-8 pharmDx and DAKO PD-L1 IHC 22C3 pharmDx assays) revealed that the lower limits of detection (PD-L1 molecules per cell equivalent) are approximately: 50,000 - 180,000 (SP263), 800,000 - 1,200,000 (SP142), 220,000 - 360,000 (28-8), and 200,000 - 400,000 (22C3). The dynamic ranges for all of these tests are generally narrow, spanning less than a log concentration of PD-L1. The SP263 and SP142 assays showed no overlap of their analytic response curves. This means that a maximal stain intensity with SP263 kit can be associated with zero staining with the SP142 kit. Consequently, it is not possible to compensate for the variability in analytic sensitivity between these two tests by adjusting the percent positive cell cutoff. The 28-8 was more sensitive than, but statistically indistinguishable from the 22C3 assay. Laboratory-developed tests (LDTs) using these and other primary antibodies have their own unique analytic performance characteristics. CONCLUSIONS. The PD-L1 reference materials enable precise definitions of analytic test performance and linking them with clinical management thresholds. Therefore, this tool finds its most important implementation at the stage of development of new IHC predictive biomarkers in clinical trials as well as at the stage of methodology transfer to clinical IHC laboratories. Furthermore, our results also help define more precisely the possibility for assay interchangeability and to what degree the assays may be harmoni","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88668431","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.AM2021-430
L. Baezconde-Garbanati, C. Aristizabal, S. Suther, F. Webb, M. Stern
{"title":"Abstract 430: Perceptions among African Americans of prostate cancer and clinical trials: A focus group study","authors":"L. Baezconde-Garbanati, C. Aristizabal, S. Suther, F. Webb, M. Stern","doi":"10.1158/1538-7445.AM2021-430","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-430","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79179268","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.AM2021-392
Amber M. Johnson, P. Ng, Michael Kahle, J. Castillo, Bianca E. Amador, Vijaykumar Holla, Thuy Vu, Le Huang, Fei Su, Sun-Hee Kim, Jia Zeng, Abu Shufean, Tara Conway, K. Shaw, T. Yap, J. Rodón, F. Meric-Bernstam
Purpose: There is increasing recognition that variants within an actionable gene may differ in their functional impact and therapeutic implications. The Precision Oncology Decision Support (PODS) team at MD Anderson Cancer Center (MDA) curates a knowledgebase of cancer-associated genomic alterations for their functional impact and therapeutic actionability. However, a substantial number of variants are not characterized within the published literature. In the MDA-PODS classification scheme, these variants are classified as “potentially” actionable, as opposed to “unknown”, if evidence exists that other variants within the same region are oncogenic. To determine the value of this tiered actionability approach, we assessed if a variant with a “potentially” assertion is more likely to have an experimentally validated oncogenic effect within a functional genomics platform (Ng et al., Cancer Cell, 2018). Procedures: Alterations researched within the published literature and found to be of unknown significance were submitted to the functional genomics platform. These variants were tested within two cell line models (Ba/F3 and MCF10A) to assess growth factor-independent survival. Results were returned to PODS indicating whether the variant conferred a change in cell viability compared with the wildtype gene. PODS then compared the functional effect of the variant with the predetermined actionability assertion. Results: During 2015-2019, PODS received functional genomics results for 485 alterations spanning 38 genes. 115 (24%) of the alterations increased survival and were thus actionable, while 364 (75%) had no effect or suppressed cell viability. Six alterations had conflicting effects in the two cell line models and were not further considered. Of the 479 variants (in 38 genes), 208 variants (43%) in 20 genes were classified as “potentially” actionable prior to functional genomics, while 254 variants (53%) in 35 genes were classified as “unknown”. 17 (4%) were classified as Yes/No for actionability based on other criteria, such as drug response. 78 (38%) of the 208 “potentially” actionable variants were found to be oncogenic in the functional genomics platform as opposed to only 29 (11%) of the 254 variants classified as “unknown” for actionability (p Conclusions: These data display the value of providing a tiered, variant-level actionability scheme that includes a “potentially” actionable assertion, as it is associated with a greater likelihood of being functionally validated. Although genomically-matched therapy is most compelling for patients with known actionable variants and functional testing adds value, tiered actionability predictions can inform therapeutic decisions. Citation Format: Amber Johnson, Patrick Kwok-Shing Ng, Michael Kahle, Julia Castillo, Bianca Amador, Vijaykumar Holla, Thuy Vu, Le Huang, Fei Su, Sunhee Kim, Jia Zeng, Md Abu Shufean, Tara Conway, Kenna R. Shaw, Timothy A. Yap, Jordi Rodon, Funda Meric-Bernstam. Patient-specific,
目的:越来越多的人认识到，一个可操作基因的变异可能在其功能影响和治疗意义上有所不同。MD安德森癌症中心(MDA)的精确肿瘤学决策支持(PODS)团队为癌症相关基因组改变的功能影响和治疗可操作性策划了一个知识库。然而，大量的变体并没有在已发表的文献中被描述。在MDA-PODS分类方案中，如果有证据表明同一区域内的其他变异是致癌的，则这些变异被归类为“潜在的”可操作的，而不是“未知的”。为了确定这种分层可操作性方法的价值，我们在功能基因组学平台上评估了具有“潜在”断言的变体是否更有可能具有实验验证的致癌效应(Ng等人，Cancer Cell, 2018)。程序:在已发表的文献中研究发现的未知意义的改变提交到功能基因组学平台。这些变异在两种细胞系模型(Ba/F3和MCF10A)中进行了测试，以评估不依赖生长因子的生存。结果返回给pod，表明与野生型基因相比，该变体是否赋予细胞活力变化。然后，PODS将变体的功能效果与预先确定的可操作性断言进行比较。结果:2015-2019年期间，PODS获得了38个基因的485个改变的功能基因组学结果。115例(24%)的改变增加了存活，因此是可操作的，而364例(75%)没有影响或抑制细胞活力。六种改变在两种细胞系模型中有相互冲突的影响，没有进一步考虑。在479个变异(38个基因)中，20个基因中的208个变异(43%)在功能基因组学之前被归类为“潜在”可操作，而35个基因中的254个变异(53%)被归类为“未知”。17例(4%)根据其他标准(如药物反应)可操作性被分类为“是”/“否”。在功能基因组学平台上，208个“潜在”可操作的变异中有78个(38%)被发现是致癌的，而254个变异中只有29个(11%)被归类为可操作性“未知”(p)。结论:这些数据显示了提供分层的变异水平可操作方案的价值，该方案包括一个“潜在”可操作的断言，因为它与功能验证的可能性更大。虽然基因组匹配治疗对于已知可操作变异的患者最具吸引力，功能测试增加了价值，但分层可操作性预测可以为治疗决策提供信息。引文格式:Amber Johnson, Patrick kwook - shing Ng, Michael Kahle, Julia Castillo, Bianca Amador, Vijaykumar Holla, Thuy Vu, Le Huang, Fei Su, Sunhee Kim, Jia Zeng, Md Abu Shufean, Tara Conway, Kenna R. Shaw, Timothy A. Yap, Jordi Rodon, Funda Meric-Bernstam。在生长生存测定中，患者特异性、分层、变异水平的可操作性与功能效应相关[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392期。
{"title":"Abstract 392: Patient-specific, tiered, variant-level actionability correlates with functional effect in growth survival assay","authors":"Amber M. Johnson, P. Ng, Michael Kahle, J. Castillo, Bianca E. Amador, Vijaykumar Holla, Thuy Vu, Le Huang, Fei Su, Sun-Hee Kim, Jia Zeng, Abu Shufean, Tara Conway, K. Shaw, T. Yap, J. Rodón, F. Meric-Bernstam","doi":"10.1158/1538-7445.AM2021-392","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-392","url":null,"abstract":"Purpose: There is increasing recognition that variants within an actionable gene may differ in their functional impact and therapeutic implications. The Precision Oncology Decision Support (PODS) team at MD Anderson Cancer Center (MDA) curates a knowledgebase of cancer-associated genomic alterations for their functional impact and therapeutic actionability. However, a substantial number of variants are not characterized within the published literature. In the MDA-PODS classification scheme, these variants are classified as “potentially” actionable, as opposed to “unknown”, if evidence exists that other variants within the same region are oncogenic. To determine the value of this tiered actionability approach, we assessed if a variant with a “potentially” assertion is more likely to have an experimentally validated oncogenic effect within a functional genomics platform (Ng et al., Cancer Cell, 2018). Procedures: Alterations researched within the published literature and found to be of unknown significance were submitted to the functional genomics platform. These variants were tested within two cell line models (Ba/F3 and MCF10A) to assess growth factor-independent survival. Results were returned to PODS indicating whether the variant conferred a change in cell viability compared with the wildtype gene. PODS then compared the functional effect of the variant with the predetermined actionability assertion. Results: During 2015-2019, PODS received functional genomics results for 485 alterations spanning 38 genes. 115 (24%) of the alterations increased survival and were thus actionable, while 364 (75%) had no effect or suppressed cell viability. Six alterations had conflicting effects in the two cell line models and were not further considered. Of the 479 variants (in 38 genes), 208 variants (43%) in 20 genes were classified as “potentially” actionable prior to functional genomics, while 254 variants (53%) in 35 genes were classified as “unknown”. 17 (4%) were classified as Yes/No for actionability based on other criteria, such as drug response. 78 (38%) of the 208 “potentially” actionable variants were found to be oncogenic in the functional genomics platform as opposed to only 29 (11%) of the 254 variants classified as “unknown” for actionability (p Conclusions: These data display the value of providing a tiered, variant-level actionability scheme that includes a “potentially” actionable assertion, as it is associated with a greater likelihood of being functionally validated. Although genomically-matched therapy is most compelling for patients with known actionable variants and functional testing adds value, tiered actionability predictions can inform therapeutic decisions. Citation Format: Amber Johnson, Patrick Kwok-Shing Ng, Michael Kahle, Julia Castillo, Bianca Amador, Vijaykumar Holla, Thuy Vu, Le Huang, Fei Su, Sunhee Kim, Jia Zeng, Md Abu Shufean, Tara Conway, Kenna R. Shaw, Timothy A. Yap, Jordi Rodon, Funda Meric-Bernstam. Patient-specific,","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":"76430207","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.AM2021-516
N. Miheecheva, Y. Lyu, Akshaya Ramachandran, Danil Stupichev, A. Bagaev, E. Postovalova, K. Nomie, F. Frenkel, N. Fowler, I. AtaullakhanovRavshan, J. Hsieh
{"title":"Abstract 516: AI-driven multifaceted predictive biomarkers of response to tyrosine kinase inhibition and immune checkpoint blockade in clear cell renal cell carcinoma","authors":"N. Miheecheva, Y. Lyu, Akshaya Ramachandran, Danil Stupichev, A. Bagaev, E. Postovalova, K. Nomie, F. Frenkel, N. Fowler, I. AtaullakhanovRavshan, J. Hsieh","doi":"10.1158/1538-7445.AM2021-516","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-516","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"62 5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77317290","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.AM2021-666
Jihao Zhou, Min Zuo, P. Ke, Q. Shen, Lifeng Li, Yaping Xu, Lina Hu, Guoqiang Li, Chun Feng, Xuan Gao, Y. Guan, X. Xia, Xinyou Zhang, Yuhua Huang
{"title":"Abstract 666: PIM1 and CD79b mutation status impact outcome in primary central nervous system DLBCL after high-dose methotrexate-based chemoimmunotherapy","authors":"Jihao Zhou, Min Zuo, P. Ke, Q. Shen, Lifeng Li, Yaping Xu, Lina Hu, Guoqiang Li, Chun Feng, Xuan Gao, Y. Guan, X. Xia, Xinyou Zhang, Yuhua Huang","doi":"10.1158/1538-7445.AM2021-666","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-666","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"32 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91438741","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.AM2021-595
T. Tayoun, V. Faugeroux, M. Oulhen, E. Pailler, O. Deas, L. Mezquita, Laura Brullé-Soumaré, S. Cairo, J. Scoazec, V. Marty, A. Aberlenc, M. Ngo-Camus, C. Nicotra, D. Planchard, P. Kannouche, B. Besse, J. Judde, P. Pawlikowska, F. Farace
{"title":"Abstract 595: Patterns and dynamics of genome instability drive metastatic activity in non-small cell lung cancer (NSCLC) circulating tumor cell (CTC)-derived xenograft (CDX) models","authors":"T. Tayoun, V. Faugeroux, M. Oulhen, E. Pailler, O. Deas, L. Mezquita, Laura Brullé-Soumaré, S. Cairo, J. Scoazec, V. Marty, A. Aberlenc, M. Ngo-Camus, C. Nicotra, D. Planchard, P. Kannouche, B. Besse, J. Judde, P. Pawlikowska, F. Farace","doi":"10.1158/1538-7445.AM2021-595","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-595","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"56 3-4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91492911","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.AM2021-459
E. Dorado, M. L. Doria, A. Nagelkerke, J. McKenzie, Stefania Maneta-Stavrakaki, C. Ion, T. Whittaker, J. Nicholson, M. Stevens, R. Coombes, Z. Takáts
{"title":"Abstract 459: Lipidomic analysis of extracellular vesicles and its potential for the identification of body fluid-based biomarkers for breast cancer diagnosis","authors":"E. Dorado, M. L. Doria, A. Nagelkerke, J. McKenzie, Stefania Maneta-Stavrakaki, C. Ion, T. Whittaker, J. Nicholson, M. Stevens, R. Coombes, Z. Takáts","doi":"10.1158/1538-7445.AM2021-459","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-459","url":null,"abstract":"","PeriodicalId":10518,"journal":{"name":"Clinical Research (Excluding Clinical Trials)","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91368237","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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