Correlation of circulating tumor DNA (ctDNA) assessment with tissue-based comprehensive genomic profiling (CGP) in metastatic urothelial cancer (mUC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 453-453 ◽  
Author(s):  
Bradley Alexander McGregor ◽  
Jon Chung ◽  
Paulo Gustavo Bergerot ◽  
Brady Forcier ◽  
Petros Grivas ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Circulating Tumor Dna ◽  
Attractive Alternative ◽  
Clinical Test ◽  
Data Sets ◽  
Genomic Profiling ◽  
Illumina Hiseq ◽  
Metastatic Urothelial Cancer ◽  
Comprehensive Genomic Profiling ◽  
Clinical Annotation

453 Background: Emerging data suggest a role for targeted therapy in patients (pts) with mUC whose tumors contain actionable genomic alterations (GA). Liquid biopsy of ctDNA from blood provides an attractive alternative for CGP in pts in whom tissue-based testing is not feasible. Methods: Hybrid capture-based genomic profiling was performed using FoundationACT assay in a CLIA-certified, CAP-accredited, NY State-approved laboratory. Cell free DNA was extracted from plasma using 20 ml whole blood and underwent CGP of 62 genes. Sequencing was performed to a median unique coverage of 6756× using the Illumina HiSeq 2500/4000 platform. Barcode-based error correction enabled analysis of GA at low allele frequency (AF), including base substitutions and short in/dels (AF≥0.1% for both), rearrangements, and copy number amplification. For several pts, non-temporally matched tissue-based CGP data was available. Comparisons to other CGP datasets of UC ctDNA and tissue were performed. Results: 66 pts with median age 68 (range 29-86) underwent ctDNA assessment as clinical test. There was evidence for ctDNA in 56 pts (85%), and ≥1 GA was noted in 48 pts (73%). The estimated median ctDNA fraction in plasma was 1.9%. In cases with detectable ctDNA, the most frequently altered genes were TP53 (68%), TERT-promoter (38%), PIK3CA (13%), FGFR3 (13%), KRAS (11%), NF1 (6%), ERBB2 (6%). Observed GA frequencies were comparable to prior studies of ctDNA and tissue. Both tissue and ctDNA-based CGP data with clinical correlation was available for several pts. A pt with FGFR3 GA in baseline tumor tissue had disappearance of FGFR3 GA and detection of new TP53 GA in ctDNA after targeted treatment with FGFR3 inhibitor. In a pt with ERBB2 and TP53 GAs in baseline tumor tissue, ctDNA at time of resistance to cisplatin-based therapy showed persistence of ERBB2 and TP53 GAs and new NF1 GA. Conclusions: Most pts with mUC had detectable ctDNA, and frequencies were comparable to prior data sets Detection of potentially targetable GA support further clinical utility assessment. Concordance between tissue and ctDNA in temporally matched samples with clinical annotation warrants further investigation.

Circulating tumor DNA-based genomic profiling of small bowel adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3523-3523
Author(s):  
Pat Gulhati ◽  
Karan Pandya ◽  
Hiba I. Dada ◽  
Christopher R. Cogle ◽  
Jason S. Starr ◽  
...  
Keyword(s):  
Small Bowel ◽  
Large Scale ◽  
Clinical Decision Making ◽  
Circulating Tumor Dna ◽  
Therapeutic Resistance ◽  
Molecular Entity ◽  
Small Bowel Adenocarcinoma ◽  
Genomic Profiling ◽  
Comprehensive Genomic Profiling ◽  
Tumor Dna

3523 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy, with lower incidence, later stage at diagnosis, and worse overall survival compared to other intestinal cancers, such as colorectal cancer (CRC). Since the majority of small bowel tumors are not accessible to endoscopic biopsy, comprehensive genomic profiling using circulating tumor DNA (ctDNA) may enable non-invasive detection of targetable genomic alterations (GA) in SBA patients. In this study, we characterize the ctDNA GA landscape in SBA. Methods: Analysis of 299 ctDNA samples prospectively collected from 265 SBA patients between 2017 to 2020 was performed using a 73 gene next generation sequencing panel (Guardant360). A subset of patients underwent longitudinal analysis of changes in GA associated with systemic therapy. Results: Of the 265 patients, 160 (60.3%) were male; the median age was 66 (range: 21-93 years). The most common GA identified in SBA patients included TP53 [58%], KRAS [44%], and APC [40%]. MSI was detected in 3.4% of SBA patients. When stratified by primary tumor location, APC, KRAS, TP53, PIK3CA, and ARID1A were the most common GA identified in both duodenal and jejunal adenocarcinomas. ERBB2, BRCA2 and CDK6 alterations were enriched in duodenal adenocarcinoma, while NOTCH and BRAF alterations were enriched in jejunal adenocarcinoma. The most common currently-targetable GA identified were ATM [18%], PIK3CA [17%], EGFR [15%], CDK4/6 [11%], BRAF [10%], and ERBB2 [10%]. Unique differences in GA between SBA and CRC were identified: i) the majority of ERBB2 alterations are mutations (89%) in the extracellular domain and kinase domain, not amplifications (11%); ii) the majority of BRAF alterations are non V600E mutations (69%) and amplifications (28%); iii) there is a significantly lower rate of APC mutations (40%). Alterations in DNA damage response pathway proteins, including ATM and BRCA 1/2, were identified in 30% of SBA patients. ATM alterations were more common in patients ³65 years old. The most common mutations predicted to be related to clonal hematopoiesis of indeterminate potential were TP53, KRAS and GNAS. Longitudinal ctDNA analysis in 4 SBA patients revealed loss of mutations associated with therapeutic response (TP53 R342*, MAPK3 R189Q) and acquired mutations associated with therapeutic resistance (NF1 R1968*, MET S170N, RAF1 L613V). Conclusions: This study represents the first large-scale blood-based ctDNA genomic profiling of SBA. SBA represents a unique molecular entity with differences in frequency and types of GA compared to CRC. Variations in GA were noted based on anatomic origin within the small intestine. Longitudinal ctDNA monitoring revealed novel GA associated with therapeutic resistance. Identification of multiple targetable GA may facilitate clinical decision making and improve patient outcomes in SBA, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling.

Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with pancreatic ductal adenocarcinoma (PDA).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4128-4128
Author(s):  
Nathan Bahary ◽  
Jie He ◽  
Mark Bailey ◽  
Shan Zhong ◽  
Gerald Li ◽  
...  
Keyword(s):  
Cancer Biology ◽  
Clinical Care ◽  
Circulating Tumor Dna ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Genomic Profiling ◽  
Tissue Samples ◽  
Comprehensive Genomic Profiling ◽  
Cancer Genome Atlas ◽  
Genomic Characterization

4128 Background: PDA is a lethal and increasingly common malignancy and tissue samples for genomic characterization may be limited. As PDA has a high and consistent frequency of KRAS, p53 and CDKN2A mutations it serves as a robust indication to test the utility of ctDNA in accurately characterizing genomic alterations (GA). A prior study suggested significant differences between ctDNA and tissue base profiling but assays were not conducted on the same platform (PMID27833075). We undertook this study to see whether ctDNA could recapitulate the known genomic hallmarks of tumor based profiling. Methods: Hybrid-capture based genomic profiling of 62 genes (FoundationACT) was performed on ctDNA from 78 pts with advanced PDA with samples received in the course of clinical care. The fraction of ctDNA in the blood was estimated using the maximum somatic allele frequency (MSAF) for each sample. Frequencies of alterations in these common drivers were then compared to those seen in tumors of pts who underwent comprehensive genomic profiling (CGP) tissue testing performed on the same core platform, FoundationOne, and The Cancer Genome Atlas (TCGA). Results: Pt characteristics: Median age 65 (range, 47-88); Female (33) /Male (45). FoundationACT results show that 53/78 (68%) cases had MSAF >0 (56%-78%%, 95% CI). ≥1 GA was reported in 81% of the cases with evidence of ctDNA in the blood. The most common GA detected by FoundationACT (based on cases with evidence of ctDNA in blood) vs FoundationOne were in KRAS (59% vs 89%, p< 0.0001), TP53 (69% vs.74%, p=0.19), and CDKN2A (14% vs.45%). Other detected clinically relevant GA detected by FoundationACT included: BRCA1, ERBB2, NF1, PIK3CA. Conclusions: This study demonstrates significant differences between the established driver oncogenic alterations for PDA, as assessed by ct DNA and tissue based genomic profiling which are unlikely to be explained by differences in assay, but rather novel cancer biology. At present use of ctDNA genomic profiling in PDA should not routinely replace tissue based genomic characterization. [Table: see text]

Noninvasive comprehensive genomic profiling from plasma ctDNA in pancreatic cancer patients.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 753-753
Author(s):  
Danielle Sara Bitterman ◽  
Kristin Sedgwick Price ◽  
Emily E. Van Seventer ◽  
Jeffrey William Clark ◽  
Jill N. Allen ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Circulating Tumor Dna ◽  
Copy Number Variations ◽  
Ductal Adenocarcinoma ◽  
Genomic Profiling ◽  
Single Nucleotide Variants ◽  
Borderline Resectable ◽  
Invasive Approach ◽  
Resectable Disease ◽  
Comprehensive Genomic Profiling

753 Background: The use of comprehensive genomic profiling (CGP) is increasing in pancreatic ductal adenocarcinoma (PDAC) as knowledge improves regarding molecular drivers of tumorigenesis and effective targeted therapies emerge. However, adequate tissue sampling is often limited. Plasma-based CGP offers a non-invasive approach to assess biomarkers that may impact treatment decisions. Methods: We retrospectively evaluated genomic and clinical data from 97 PDAC patients with circulating tumor DNA (ctDNA) testing from 9/2016-8/2019 (Guardant Health, Inc.). ctDNA analysis included single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 74 genes. ctDNA results were assessed across clinical variables. We evaluated for actionable alterations. Results: A total of 114 samples were obtained from 97 patients for ctDNA testing. ctDNA alterations were detected in 82% (93/114) of all samples, including 90% (18/20) at diagnosis, 88% (59/67) at progression, and 56% (10/18) while on stable therapy. ctDNA alterations were found at each stage of PDAC: in 25% (1/4) of samples with resectable disease, 75% (3/4) with borderline resectable disease, 82% (9/11) with locally advanced disease, and 85% (81/95) with metastatic disease. One or more KRAS alterations were detected in 55% (51/93) of patients with alterations present. The median maximum mutant allele frequency was similar between the cohort of patients with KRAS detected (0.55%) versus not detected (0.70%). 8% (8/97) of patients had potentially actionable alterations (2 activating BRAF SNVs, 1 ERBB2 CNV, 1 ERBB2 activating SNV, 1 KRAS G12C, and 3 indels in Homologous Recombination Deficiency genes). Median turnaround time was 8 days. 51% (49/97) of patients had both plasma-based CGP and tissue-based CGP. Of these patients, tissue-based CGP showed ≥ 1 alterations detected in 82% (40/49), test failure in 14% (7/49), and no alterations detected in 4% (2/49). Conclusions: Plasma-based CGP detected ctDNA alterations in 90% of samples tested at diagnosis and 82% of all samples. Potentially actionable mutations were found in 8% of patients, with prompt processing time allowing for rapid decision making.

scholarly journals P1.16-04 Real World Experience of Using Comprehensive Genomic Profiling of Plasma Circulating Tumor DNA

2019 ◽  
Vol 14 (10) ◽  
pp. S586-S587
Author(s):  
Y. Yan ◽  
W. Ma ◽  
M. Molmen ◽  
T. Regalo ◽  
D. Pavlick ◽  
...  
Keyword(s):  
Real World ◽  
Circulating Tumor Dna ◽  
Genomic Profiling ◽  
Comprehensive Genomic Profiling ◽  
Tumor Dna

Prevalence of inferred clonal hematopoiesis (CH) detected on comprehensive genomic profiling (CGP) of solid tumor tissue or circulating tumor DNA (ctDNA).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3009-3009
Author(s):  
Emmanuel S. Antonarakis ◽  
Zheng Kuang ◽  
Hanna Tukachinsky ◽  
Christine Parachoniak ◽  
Andrew David Kelly ◽  
...  
Keyword(s):  
High Risk ◽  
Tumor Tissue ◽  
White Blood Cells ◽  
Pathogenic Mutation ◽  
Circulating Tumor Dna ◽  
Continuous Variable ◽  
Allelic Frequency ◽  
Comprehensive Genomic Profiling ◽  
Clinically Significant ◽  
Solid Tumor Tissue

3009 Background: The increased use of ctDNA CGP has paralleled increased detection and interest in CH, which can confound CGP results from ctDNA or tissue, and can be associated with hematologic and cardiovascular morbidity. However, paired-depth sequencing of white blood cells (WBC) for confirmation of CH is not widely available. We here study the prevalence of inferred CH (iCH), which refers to incidental detection on routine clinical CGP of variants attributable to CH due to their known CH association and their negligible prevalence in solid tumors. Methods: A database of clinical CGP results was reviewed, including two 324-gene NGS panels for tumor tissue (FoundationOne CDx) and plasma ctDNA (FoundationOne Liquid CDx). Analysis was limited to NSCLC, breast, prostate, colorectal, and pancreatic cancers. iCH was defined as any pathogenic mutation in ASXL1, DNMT3A, and TET2, and prespecified mutations in JAK2, SF3B1, U2AF1, MYD88, IDH2, MPL, CBL. Variant allelic frequency (VAF) > 2% was considered clinically significant and VAF > 10% was considered high risk. Results: 100,905 total cases were studied; median age was 65 for tissue CGP and 68 for ctDNA. iCH was more commonly detected in ctDNA (1468/2891, 51%) than in tissue (9416/97993, 10%). Among cases with any iCH detected, multiple iCH mutations were seen more commonly in ctDNA (640/2891, 22%) than in tissue (987/98014, 1%). Focusing on clinically significant iCH ( > 2% VAF), prevalence remained higher in ctDNA (22%, 637) than in tissue (8%, 7878), while the higher sensitivity of ctDNA testing identified more low level iCH (< 2% VAF, 40% in ctDNA, 2% in tissue). Across cancer types, iCH > 2% was consistently more common in ctDNA (Table). As expected, prevalence of iCH > 2% increased with age (continuous variable, p < 0.001). High risk iCH ( > 10% VAF) was seen in 4% of total cases (most commonly ASXL1, TET2, DNMT3A); 1% of all cases had multiple clinically significant iCH variants ( > 2% VAF). Focusing on a subset of 439 cases with both tissue and ctDNA results (median 1.5 months between samples), 290 iCH mutations were detected in ctDNA (median VAF 1%) but only 38 in tissue (median VAF 9%). Conclusions: Inferred CH is common on somatic CGP of cancer patients, with a high prevalence in ctDNA likely due to the deeper sequencing depth and WBC contamination. For the minority of patients with high VAF iCH, further research is needed to understand whether this might be representative of an occult hematologic condition deserving of further evaluation.[Table: see text]

Cell free circulating tumor DNA (ctDNA) landscape in patients with advanced gastroesophageal adenocarcinoma (GEC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 47-47 ◽  
Author(s):  
Daniel V.T. Catenacci ◽  
Rebecca J Nagy ◽  
Fadi S. Braiteh ◽  
Seung Kim ◽  
Eunice Lee Kwak ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Circulating Tumor Dna ◽  
Therapeutic Options ◽  
Genomic Profiling ◽  
Single Nucleotide Variants ◽  
Test Range ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
Gastroesophageal Adenocarcinoma ◽  
Next Generation Sequencing Ngs

47 Background: Esophageal (EC), gastroesophageal junction (GEJ) and gastric cancer (GC), together GEC, have a poor prognosis with few targeted therapeutic options. As genomic profiling is becoming increasingly useful, we queried whether comprehensive genomic profiling of ctDNA would reveal relevant genomic alterations leading to targeted therapies. Methods: Patients (pts) with advanced GEC undergoing next-generation sequencing (NGS) of ctDNA in a CLIA certified lab were identified. ctDNA was analyzed using Guardant360, a digital NGS assay to identify single nucleotide variants, indels, amplifications and fusions in 54-70 genes. Results: 546 pts with GEC had ctDNA testing and 54 pts (10%) had more than one ctDNA test (range 2-6). Pts were similar across the 3 groups, with the exception of an increased male:female ratio (5:1) in the GEJ and EC cohorts. Mean age was 61.5 yrs (range 24-91). ctDNA alterations were detectable in 455 pts (83.3%). Recurrent alterations and therapeutic options for each cohort are shown in Table 1. Serial monitoring of ctDNA correlated with tumor markers, imaging and clinical response. Multiple antitumor responses to targeted therapy will be presented. Conclusions: ctDNA was detected in 83.3% of pts with advanced GEC with a frequency similar to TCGA. The diverse genomic landscape of GEC, obtained noninvasively, along with matched therapies have potential to improve outcomes for this aggressive disease. [Table: see text]

scholarly journals Comprehensive genomic profiling of 30,000 consecutive solid tumors

2020 ◽  
Author(s):  
Scott A. Tomlins ◽  
Daniel H. Hovelson ◽  
Jennifer M. Suga ◽  
Daniel M. Anderson ◽  
Han A. Koh ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Real World ◽  
Tumor Tissue ◽  
Tissue Sample ◽  
Treatment Selection ◽  
Genomic Profiling ◽  
Tissue Samples ◽  
Comprehensive Genomic Profiling ◽  
Prostate Carcinomas ◽  
The Impact

AbstractPurposeTissue-based comprehensive genomic profiling (CGP) is increasingly utilized for treatment selection in patients with advanced solid tumors, however real-world tissue availability may limit widespread implementation. Here we established real-world CGP tissue availability and assessed CGP performance on consecutively received samples.Patients and MethodPost-hoc, non-prespecified analysis of 32,048 consecutive tumor tissue samples received for StrataNGS, a multiplex PCR based-CGP (PCR-CGP) test, as part of an ongoing observational trial (NCT03061305). Tumor tissue sample characteristics and PCR-CGP performance were assessed across all tested tumor samples, including exception samples not meeting minimum input requirements (<20% tumor content [TC], <2mm2 tumor surface area [TSA], DNA or RNA yield <1ng/ul, or specimen age >5yrs). Tests reporting at least one prioritized alteration or meeting all sequencing QC metrics (and ≥20% TC) were considered successful. For prostate carcinoma and lung adenocarcinoma, tests reporting at least one actionable/informative alteration or those meeting all sequencing QC metrics (and ≥20% TC) were considered actionable.ResultsPCR-CGP was attempted in 31,165 of 32,048 (97.2%) consecutively received solid tumor tissue samples. Among the 31,165 tested samples, 10.7% had low (<20%) tumor content (TC) and 58.4% were small (<25mm2 TSA), highlighting the challenging nature of samples received for CGP. Of the 31,101 samples evaluable for input requirements, 8,079 (26.0%) were exceptions not meeting requirements. However, 94.2% of the 31,101 tested samples were successfully reported, including 80.6% of exception samples. Importantly, 80.6% of 1,344 tested prostate carcinomas and 87.8% of 1,144 tested lung adenocarcinomas yielded results informing treatment selection.ConclusionMost real-world tumor tissue samples from patients with advanced cancer desiring CGP are limited, requiring optimized CGP approaches to produce meaningful results. An optimized PCR-CGP test, coupled with an inclusive exception testing policy, delivered reportable results for >94% of samples, potentially expanding the proportion of CGP-testable patients, and thus the impact of biomarker-guided targeted and immunotherapies.

scholarly journals Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA

Cancer ◽  
2018 ◽  
Vol 124 (10) ◽  
pp. 2115-2124 ◽  
Author(s):  
Neeraj Agarwal ◽  
Sumanta K. Pal ◽  
Andrew W. Hahn ◽  
Roberto H. Nussenzveig ◽  
Gregory R. Pond ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Circulating Tumor Dna ◽  
Genomic Profiling ◽  
Comprehensive Genomic Profiling ◽  
Metastatic Urothelial Carcinoma ◽  
Tumor Dna
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