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

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.

FGFR3 Driven Metastatic Urothelial Carcinoma of the Urinary Bladder (mUCB): A Comprehensive Genomic Profiling Study.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 4531-4531
Author(s):  
Jeffrey S. Ross ◽  
Laurie M. Gay ◽  
Elizabeth Kate Ferry ◽  
Joseph Jacob ◽  
Oleg Shapiro ◽  
...  
Keyword(s):  
Urinary Bladder ◽  
Urothelial Carcinoma ◽  
Genomic Profiling ◽  
Comprehensive Genomic Profiling ◽  
Metastatic Urothelial Carcinoma

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

Circulating tumor DNA analysis of genomic alterations in metastatic urothelial carcinoma from NCT03113266 study.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 486-486
Author(s):  
Haige Chen ◽  
Ruiyun Zhang ◽  
Feng Xie ◽  
Pan Du ◽  
Yue Zhang ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Liquid Biopsy ◽  
Circulating Tumor Dna ◽  
Genomic Alterations ◽  
Invasive Approach ◽  
Synonymous Mutations ◽  
Therapeutic Decisions ◽  
Metastatic Urothelial Carcinoma ◽  
Ctdna Analysis ◽  
Tumor Dna

486 Background: Recent studies have suggested the predictive value of liquid biopsies for immune checkpoint inhibitors. NCT03113266 is a multicenter phase II trial to evaluate the safety and efficacy of toripalimab (anti-PD-1) in metastatic urothelial carcinoma (mUC). Here we report the initial circulating tumor DNA (ctDNA) analysis of genomic alterations from a single-institution biomarker cohort. Methods: Twenty-seven mUC patients receiving toripalimab (3 mg/kg Q2W) at Ren Ji Hospital were enrolled and consented to Institutional Review Board-approved protocols permitting biomaterial collection and genetic sequencing. Serial plasma specimens were obtained at baseline and every two cycles. The 600-gene panel (PredicineATLAS) liquid biopsy assay was applied to assess somatic variants and blood tumor mutational burden (bTMB). Results: The ctDNA assays were performed successfully for 100% of baseline samples (n = 27) with average read depth of 24,389 (range 14,000-31,700). A total of 571 non-synonymous mutations were identified, demonstrating prevalent aberrations in TP53 (63%), TERT promoter (30%), KDM2D (26%), PPM1D (26%), and KDM6A (26%). In 5 patients, FGFR3 variants were detected, including 6 missense sites and 4 FGFR3- TACC3 fusion events. Copy number gain ( FGFR1, ERBB2) and loss ( PTEN, BRCA2, CDKN2A) were pinpointed. TMB estimation revealed one case with an exceptionally high bTMB (62.6 mutations/Mb) and genomic features of microsatellite instability (MSI). Concordance with tumor-based genotyping and ctDNA kinetics during toripalimab treatment are being determined. Conclusions: Prospective ctDNA analysis using the PredicineATLAS liquid biopsy assay is feasible and represents a minimally invasive approach to detecting cancer-specific genetic landscape and potentially guiding personalized therapeutic decisions in mUC patients. Clinical trial information: NCT03113266 . Research Sponsor: Shanghai Junshi BioSciences; Huidu Shanghai Medical Sciences Ltd

Characterization of 648 non-small cell lung cancer (NSCLC) cases with 28 unique HER2 exon 20 insertions.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9063-9063 ◽  
Author(s):  
Sai-Hong Ignatius Ou ◽  
Russell Madison ◽  
Jacqulyne Ponville Robichaux ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
...  
Keyword(s):  
Female Gender ◽  
Circulating Tumor Dna ◽  
Her2 Amplification ◽  
Tissue Samples ◽  
Significant Difference ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Exon 20 ◽  
Tumor Dna

9063 Background: EGFR and HER2 ( ERBB2) exon 20 insertion (ex20ins) mutations represent a subset of driver alterations in NSCLC, which historically have largely not responded to available targeted therapies. Recently, inhibitors specifically targeting ex20ins have shown efficacy in the clinic. Previous studies have described the landscape of EGFR ex20ins in NSCLC (PMID: 29981927), but similar descriptions of HER2 ex20ins are lacking. Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on 39,644 tissue and 4,062 blood-based circulating tumor DNA (ctDNA) samples from 43,706 unique patients with advanced NSCLC. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA for tissue samples and reported as mutations/Mb. Results: HER2 ex20ins were detected in 1.5% (648/43,706) of NSCLC cases (614 tissue and 34 ctDNA). HER2 ex20ins represented 35% (648/1,845) of HER2-altered NSCLCs overall, while 46% (843/1,845) of cases had HER2 amplification (≥5 copies), 17% (320/1,845) had a non-ex20ins HER2 short variant (SV; most commonly S310F in 84 cases and V659E in 29 cases), and 1.8% (34/1,845) had HER2 amplification + SV. There were 28 unique ex20ins including most commonly A775_G776insYVMA (69%, 450/648), G776 > VC (12%, 76/648) and P780_Y781insGSP (8.6%, 56/648). Cases with HER2 ex20ins were significantly enriched for adenocarcinoma histology (89% vs 66%), female gender (64% vs 51%) and low TMB (95% vs 65% TMB < 10 mut/Mb) compared to HER2 wild-type cases (all p < 0.0001). HER2 amplification (7 median copies, range 5-39) co-occurred in 16% (103/648) of HER2 ex20ins cases. Co-occurrence of other known NSCLC drivers in HER2 ex20ins cases was rare (0.8%, 5/648). In contrast, non- HER2ex20ins cases with HER2 amplification or other HER2 SVs each had co-occurring known driver alterations in ~30% of cases. There was no significant difference in histology, gender, age, HER2 co-amplification or TMB in cases with YVMA vs non-YVMA ex20ins. Conclusions: HER2 ex20ins are found in 1.5% of NSCLCs and are generally mutually exclusive of other known drivers. Detection of these alterations may be critical to identify matched targeted therapy options for this subset of patients.

Abstract PR08: The genomic landscape of metastatic urothelial carcinoma from circulating tumor DNA

2020 ◽  
Author(s):  
Gillian R. Vandekerkhove ◽  
Matti Annala ◽  
Jean-Michel Lavoie ◽  
Nora Sundahl ◽  
Simon Walz ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Circulating Tumor Dna ◽  
Genomic Landscape ◽  
Metastatic Urothelial Carcinoma ◽  
Tumor Dna
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