Spectrum of FGFR2/3 Alterations in Cell-Free DNA of Patients with Advanced Urothelial Carcinoma

2021 ◽  
pp. 1-6
Author(s):  
Petros Grivas ◽  
Lesli A. Kiedrowski ◽  
Guru P. Sonpavde ◽  
Sumati V. Gupta ◽  
Roby A. Thomas ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Targeted Therapies ◽  
Detection Rate ◽  
Tumor Tissue ◽  
Treatment Options ◽  
Genomic Alterations ◽  
Free Dna ◽  
Activating Mutation ◽  
Platinum Refractory ◽  
Advanced Urothelial Carcinoma

Detecting genomic alterations (GAs) in advanced urothelial carcinoma (aUC) can expand treatment options by identifying candidates for targeted therapies. Erdafitinib is FDA-approved for patients with platinum-refractory aUC with activating mutation or fusion in FGFR2/3. We explored the prevalence and spectrum of FGFR2/3 GAs identified with plasma cfDNA NGS testing (Guardant360) in 997 patients with aUC. FGFR2/3 GAs were detected in 201 patients (20%) with characterized activating GAs in 141 (14%). Our results indicate the Guardant360-based FGFR2/3 GA detection rate is similar to those described from previous studies employing tumor tissue testing, suggesting that plasma-based cfDNA NGS may non-invasively identify candidates for anti-FGFR targeted therapies.

Circulating cell-free DNA profiling of patients with advanced urothelial carcinoma.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 358-358 ◽  
Author(s):  
Guru Sonpavde ◽  
Rebecca J Nagy ◽  
Andrea B. Apolo ◽  
Neeraj Agarwal ◽  
Sumanta K. Pal ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Peripheral Blood ◽  
Tumor Tissue ◽  
Tumor Biology ◽  
Nucleotide Position ◽  
Cell Free Dna ◽  
Free Dna ◽  
Copy Numbers ◽  
Advanced Urothelial Carcinoma ◽  
Circulating Cell Free Dna

358 Background: Urothelial carcinoma (UC) exhibits one of the highest somatic mutation burdens. Circulating cell-free DNA (cfDNA) is obtained non-invasively from peripheral blood and appears detectable in most patients (pts) with advanced UC. We report cfDNA profiling of patients with advanced UC using biopsy-free cfDNA sequencing. Methods: Twenty-nine patients with advanced UC that underwent cfDNA analysis using Guardant360 were identified. A 68-gene cfDNA next generation sequencing (NGS) panel from a CLIA-licensed, CAP-accredited laboratory (Guardant360) offers complete sequencing for all exons in 29 cancer associated genes, as well as the critical exons in 39 other genes, and copy number amplifications (16), fusions (4) and indels (1) in selected genes, harvested from 20 mL of peripheral blood. The mutant allele fraction (MAF) is defined as the number of mutated cfDNA molecules divided by the number wild type cfDNA molecules at a given nucleotide position. Results: Of 29 patients with advanced UC, cfDNA was detectable in 25 patients (86.2%). Twenty-nine patients were available with bladder primary in 27 pts (93.1%), and the median age was 75 years (range 52-91). The most common recurrent somatic mutations in the 25 patients with ≥ 1 alteration were in TP53 (n = 17), BRCA1/2 (n = 6), FGFR2 (n = 5), EGFR (n = 5), PIK3CA (n = 4), APC (n = 4), KRAS (n = 4), RAF1/BRAF (n = 4), and FGFR3, ALK, PDGFRA, NF1, CDKN2A and ARID1A were observed in 3 patients each. The most common genes with ≥ 2 copy numbers in the 25 evaluable patients were ERBB2 (n = 2) and PIK3CA, EGFR, RAF1, and FGFR1 in one patient each. Analysis of additional patients is ongoing in this expanding dataset. MAF data will be presented. Conclusions: cfDNA is frequently detected in patients with advanced UC, and alterations appear similar to those previously reported from UC tumor tissue. The correlation of cfDNA profiling with tumor tissue profiling within patients and ability to predict response requires study. Given that cfDNA offers a non-invasive means of profiling tumor DNA and MAF, further development of this promising modality is warranted to guide therapy with biologic agents and immunotherapy, and serial monitoring may provide insights regarding tumor biology.

Cell-Free DNA Detection of Tumor Mutations in Heterogeneous, Localized Prostate Cancer Via Targeted, Multiregion Sequencing

2021 ◽  
pp. 710-725
Author(s):  
Emmalyn Chen ◽  
Clinton L. Cario ◽  
Lancelote Leong ◽  
Karen Lopez ◽  
César P. Márquez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Tissue ◽  
Somatic Tissue ◽  
Localized Prostate Cancer ◽  
Genomic Alterations ◽  
Cell Free Dna ◽  
Free Dna ◽  
Multiple Regions ◽  
Localized Disease ◽  
Tissue Alterations

PURPOSE Cell-free DNA (cfDNA) may allow for minimally invasive identification of biologically relevant genomic alterations and genetically distinct tumor subclones. Although existing biomarkers may detect localized prostate cancer, additional strategies interrogating genomic heterogeneity are necessary for identifying and monitoring aggressive disease. In this study, we aimed to evaluate whether circulating tumor DNA can detect genomic alterations present in multiple regions of localized prostate tumor tissue. METHODS Low-pass whole-genome and targeted sequencing with a machine-learning guided 2.5-Mb targeted panel were used to identify single nucleotide variants, small insertions and deletions (indels), and copy-number alterations in cfDNA. The majority of this study focuses on the subset of 21 patients with localized disease, although 45 total individuals were evaluated, including 15 healthy controls and nine men with metastatic castration-resistant prostate cancer. Plasma cfDNA was barcoded with duplex unique molecular identifiers. For localized cases, matched tumor tissue was collected from multiple regions (one to nine samples per patient) for comparison. RESULTS Somatic tumor variants present in heterogeneous tumor foci from patients with localized disease were detected in cfDNA, and cfDNA mutational burden was found to track with disease severity. Somatic tissue alterations were identified in cfDNA, including nonsynonymous variants in FOXA1, PTEN, MED12, and ATM. Detection of these overlapping variants was associated with seminal vesicle invasion ( P = .019) and with the number of variants initially found in the matched tumor tissue samples ( P = .0005). CONCLUSION Our findings demonstrate the potential of targeted cfDNA sequencing to detect somatic tissue alterations in heterogeneous, localized prostate cancer, especially in a setting where matched tumor tissue may be unavailable (ie, active surveillance or treatment monitoring).

Circulating cell-free DNA profiling of patients with advanced urothelial carcinoma of the bladder.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 4528-4528 ◽  
Author(s):  
Rebecca J Nagy ◽  
Neeraj Agarwal ◽  
Sumati Gupta ◽  
Sumanta K. Pal ◽  
Petros Grivas ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Dna Profiling ◽  
Cell Free Dna ◽  
Free Dna ◽  
Carcinoma Of The Bladder ◽  
Advanced Urothelial Carcinoma ◽  
Circulating Cell Free Dna

scholarly journals Optimizing management of advanced urothelial carcinoma: A review of emerging therapies and biomarker-driven patient selection

2020 ◽  
Vol 14 (8) ◽  
Author(s):  
Peter C. Black ◽  
Nimira S. Alimohamed ◽  
David Berman ◽  
Normand Blais ◽  
Bernhard Eigl ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Patient Selection ◽  
Treatment Options ◽  
Response Rates ◽  
Fibroblast Growth Factor Receptors ◽  
Term Survival ◽  
Management Algorithm ◽  
Emerging Therapies ◽  
Programmed Death ◽  
Advanced Urothelial Carcinoma

Introduction: Advanced urothelial carcinoma has been challenging to treat due to limited treatment options, poor response rates, and poor long-term survival. New treatment options hold the promise of improved outcomes for these patients. Methods: A multidisciplinary working group drafted a management algorithm for advanced urothelial carcinoma using “consensus development conference” methodology. A targeted literature search identified new and emerging treatments for inclusion in the management algorithm. Published clinical data were considered during the algorithm development process, as well as the risks and benefits of the treatment options. Biomarkers to guide patient selection in clinical trials for new treatments were incorporated into the algorithm. Results: The advanced urothelial carcinoma management algorithm includes newly approved first-line anti- programmed death receptor-1 (PD1)/ programmed death-ligand 1 (PD-L1) therapies, a newly approved anti- fibroblast growth factor receptors (FGFR) therapy, and an emerging anti-Nectin 4 therapy, which have had encouraging results in phase 2 trials for secondline and third-line therapy, respectively. This algorithm also incorporates suggestions for biomarker testing of PD-L1 expression and FGFR gene alterations. Conclusions: Newly approved and emerging therapies are starting to cover an unmet need for more treatment options, better response rates, and improved overall survival in advanced urothelial carcinoma. The management algorithm provides guidance on how to incorporate these new options, and their associated biomarkers, into clinical practice.

scholarly journals Clinical evidence for the first-line treatment of advanced urothelial carcinoma: Current paradigms and emerging treatment options

2020 ◽  
Vol 89 ◽  
pp. 102072 ◽  
Author(s):  
Maria Koufopoulou ◽  
Paulo A.P. Miranda ◽  
Paulina Kazmierska ◽  
Sohan Deshpande ◽  
Priyanka Gaitonde
Keyword(s):  
Urothelial Carcinoma ◽  
Clinical Evidence ◽  
Treatment Options ◽  
Line Treatment ◽  
First Line ◽  
Advanced Urothelial Carcinoma ◽  
First Line Treatment

scholarly journals Genomic profiling of Chinese patients with urothelial carcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bo Yang ◽  
Xiao Zhao ◽  
Chong Wan ◽  
Xin Ma ◽  
Shaoxi Niu ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Tumor Tissue ◽  
Genetic Alterations ◽  
Chinese Patients ◽  
Study Cohort ◽  
Genomic Feature ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Genomic Features ◽  
Somatic Alterations

Abstract Backgrounds Urothelial carcinoma (UC) is the most common genitourinary malignancy in China. In this study, we surveyed the genomic features in Chinese UC patients and investigated the concordance of genetic alterations between circulating tumor DNA (ctDNA) in plasma and matched tumor tissue. Materials and methods A total of 112 UC patients were enrolled, of which 31 were upper tract UC (UTUC) and 81 were UC of bladder (UCB). Genomic alterations in 92 selected genes were analyzed by targeted next-generation sequencing. Results In the study cohort, 94.64, 86.61 and 62.50% of patients were identified as having valid somatic, oncogenic and actionable somatic alterations, respectively. The most frequently altered genes included TP53, KMT2D, KDM6A, FAT4, FAT1, CREBBP and ARID1A. The higher prevalence of HRAS (22.0% vs 3.7%) and KMT2D (59.26% vs 34.57%) was identified in UTUC than in UCB. Comparisons of somatic alterations of UCB and UTUC between the study cohort and western cohorts revealed significant differences in mutant prevalence. Notably, 28.57, 17.86 and 47.32% of the cases harbored alterations in FGFRs, ERBBs and DNA damage repair genes, respectively. Furthermore, 75% of the patients carried non-benign germline variants, but only two (1.79%) were pathogenic. The overall concordance for genomic alterations in ctDNA and matched tumor tissue was 42.97% (0–100%). Notably, 47.25% of alterations detected in ctDNA were not detected in the matched tissue, and 54.14% of which were oncogenic mutations. Conclusions We found a unique genomic feature of Chinese UC patients. A reasonably good concordance of genomic features between ctDNA and tissue samples were identified.

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