Genomic concordance between profiling of circulating tumor DNA (ctDNA) and matched tissue in metastatic urothelial carcinoma.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 457-457 ◽  
Author(s):  
Gillian Vandekerkhove ◽  
Jean-Michel Lavoie ◽  
Matti Annala ◽  
Nora Sundahl ◽  
Takeshi Sano ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Somatic Mutations ◽  
Tumor Tissue ◽  
Circulating Tumor Dna ◽  
Driver Gene ◽  
Blood Collection ◽  
Molecular Stratification ◽  
Metastatic Urothelial Carcinoma ◽  
Primary Tissue ◽  
Gene Alterations

457 Background: Biomarkers are urgently needed to facilitate tumor molecular stratification in metastatic urothelial carcinoma (mUC), thus potentially enabling patient selection for targeted- and immuno-therapies. We aimed to assess concordance for clinically-relevant driver gene alterations between same-patient tumor tissue and ctDNA. Methods: Whole blood samples were collected from 90 mUC patients (162 samples in total) for next-generation sequencing of cell-free DNA (cfDNA) and leukocyte DNA. Deep targeted sequencing was performed across a custom 50 bladder cancer gene panel (median cfDNA depth of 986x). Matched archival primary tissue and/or metastatic tissue biopsy was available from 65 patients, and profiled using the same assay. Results: 81% of mUC patients (73/90) had ctDNA fractions above 2% in at least one blood collection (median ctDNA fraction 22%). A high tumor mutation burden (≥25 mutations per Mb) was observed in ctDNA from 20 patients (27%). From ctDNA, TP53 and ARID1A were mutated in 64% and 29% of patients, respectively. Tissue from distant metastatic lesions was available from 17 patients; 82% (62/76) of coding somatic mutations identified were independently detected in the matched ctDNA sample; however, 7/14 discordant calls were attributable to the paired sample having a low ctDNA fraction. Similarly, 89% (88/99) of coding somatic mutations detected in archival primary tissue (cystectomy or nephrectomy) were present in later cfDNA collections. Sequencing multiple sites from archival cystectomies revealed spatially and genomically distinct subclones in 2/4 cases. Conclusions: In mUC, tumor tissue and ctDNA demonstrate remarkably high concordance; our findings support the use of either approach in the characterization of truncal driver gene alterations.

scholarly journals Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Gillian Vandekerkhove ◽  
Jean-Michel Lavoie ◽  
Matti Annala ◽  
Andrew J. Murtha ◽  
Nora Sundahl ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Treatment Options ◽  
Circulating Tumor Dna ◽  
Molecular Stratification ◽  
Clinical Biomarkers ◽  
Surgery Patient ◽  
Metastatic Urothelial Carcinoma ◽  
Ctdna Analysis ◽  
Clinical Genomic ◽  
Tumor Dna

AbstractMolecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.

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

Does escalation results from phase Ib/II Norse study of erdafitinib (ERDA) + PD-1 inhibitor JNJ-63723283 (Cetrelimab [CET]) in patients (pts) with metastatic or locally advanced urothelial carcinoma (mUC) and selected fibroblast growth factor receptor (FGFR) gene alterations.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 511-511 ◽  
Author(s):  
Victor Moreno ◽  
Yohann Loriot ◽  
Begona Pérez Valderrama ◽  
Carmen Beato ◽  
Yann-Alexandre Vano ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Primary Endpoints ◽  
The Us ◽  
Metastatic Urothelial Carcinoma ◽  
Prior Systemic Therapy ◽  
Advanced Urothelial Carcinoma ◽  
Us Fda ◽  
Gene Alterations

511 Background: ERDA, an oral pan-FGFR inhibitor, is approved by the US FDA for pts with metastatic urothelial carcinoma (mUC) with susceptible FGFR3/2 gene alterations and progressed after ≥1 line of prior platinum-containing chemotherapy (PCC).1 CET, an IgG4, binds to anti-programmed cell death proteins (PD-1) and has shown activity in solid tumors.2 ERDA+CET may demonstrate complementary mechanisms as neoantigen release by ERDA may prime the tumor microenvironment for response. NORSE is a phase 1b/2 study to evaluate ERDA+CET in pts with mUC. Methods: Adult mUC pts with specific FGFR alterations who have progressed after ≥1 prior systemic therapy and no prior FGFR or PD-1/PD(L)-1 inhibitors enrolled in 3 dose levels (DL) of ERDA (DL1: 6 mg, DL2A: 8 mg, DL2: 8 mg with uptitration [UPT] to 9 mg) + CET (IV, 240 mg). Cohorts enrolled until dose limiting toxicity (DLT) or RP2D was identified. Primary endpoints: DLT and adverse events (AEs). Results: Of 15 pts (DL1: 4, DL2A: 3, DL2: 8), 11 continued on treatment at the time of the data cut. 14/15 pts experienced AEs; 3 experienced serious unrelated AEs (urinary tract infection, urosepsis, and large intestinal obstruction) all in DL1, 2 led to death; 10 experienced Grade >3 AEs and 2 experienced AEs of special interest, considered related to ERDA (Table). No DLTs were observed in any cohorts, 8 mg with UPT + CET was established as the RP2D. At data cut-off, investigator-assessed best overall response rate (CR+PR+uCR+uPR) in pts treated with the RP2D was 71% and disease control rate was 100% for RECIST 1.1 evaluable pts (n=7). Conclusions: 8 mg ERDA with UPT+240 mg CET was well tolerated and established as the RP2D. The combination of ERDA+CET is being further explored in the ongoing randomized phase 2 study in first-line cisplatin-ineligible mUC pts (NCT03473743). Clinical trial information: 2017-001980-19. [Table: see text]

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

Mutant KRAS and TP53 with high mutation allelic frequency in ctDNA as poor outcome predictors in metastatic pancreatic cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15763-e15763
Author(s):  
Shasha Guan ◽  
Yan Shi ◽  
Quanli Han ◽  
Jie Li ◽  
Yao Lv ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Tissue ◽  
Cox Model ◽  
Mutant Gene ◽  
Circulating Tumor Dna ◽  
Allelic Frequency ◽  
Metastatic Pancreatic Cancer ◽  
Driver Gene ◽  
Kappa Statistics ◽  
Blood Samples

e15763 Background: This study was to investigate the feasibility and the prognostic value of circulating tumor DNA (ctDNA) in metastatic pancreatic cancer (MPC). Methods: From 2015 to 2018 in our center, 40 MPC patients treated with nab-paclitaxel based first-line chemotherapy were prospectively collected both tumor tissue and blood samples, in which the genomic profiling of 425 genes was identified by next-generation sequencing. High mutation allelic frequency (MAF) was defined > 30% and > 5% in tumor tissue and blood, respectively. Kappa statistics were used to compare mutant (mt) genes in tissue and ctDNA. Progression-free and overall survival (PFS, OS) were assessed with Kaplan-Meier and Cox methods. Results: Among 40 MPC patients, tumor tissue and blood samples were available in 34 and 38 patients for somatic and germline alternation test, respectively. The most commonly mutant gene were KRAS (31/34 in tissue with a median MAF of 29.4%, 29/38 in ctDNA with a mMAF of 8.2%), and TP53 (28/34 in tissue with a mMAF of 31.1%, 25/38 in ctDNA with a mMAF of 7.4%). Moderate agreement was seen between ctDNA and tumor tissue (mt KRAS: κ = 0.54, P = 0.001; mt TP53: κ = 0.74, P < 0.001). Mutation in CDNK2A and SMAD4 genes were detected in 8 and 6 patients in tissue and ctDNA, respectively. Germline alternation was found in 7 genes in 9 patients (9/40). High MAF of mt KRAS (r = 0.51, P = 0.005) or mt TP53 (r = 0.50, P = 0.005) in ctDNA was correlated with high CA199 levels (> 5000 u/ml) at baseline. MT KRAS in tissue with high MAF was associated with poor OS (high 7.5m vs low 10.1m, P = 0.001) in univariate and multivariate analyses (HR 3.87, 95%CI 1.47 to 10.19). Univariate analyses showed mt KRAS and mt TP53 in ctDNA with high MAF were associated with poor PFS ( KRAS and TP53: high 3.4m and 3.0m vs low 6.1m and 5.7m, P = 0.001 and P = 0.004, respectively) and OS ( KRAS and TP53: high 5.3m and 5.3m vs low 12.6m and 10.1m, P < 0.001, respectively). The presence of ctDNA in any above four mt driver gene with high MAF was associated with poor PFS (HR 3.79, 95%CI 1.71 to 8.42) and OS (HR 7.21, 95%CI 2.69 to 19.34) in multivariate COX model, when adjusted by age, sex, tumor differentiation, and baseline CA199 level. Conclusions: The presence of mt KRAS and mt TP53 with high MAF in ctDNA was associated with worse PFS and OS in MPC patients. Peripheral ctDNA testing demonstrated an alternative promising prognostic biomarker for MPC patients before treatment.

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

Randomized phase I trial of pembrolizumab with neo-adjuvant versus concomitant stereotactic body radiotherapy in metastatic urothelial carcinoma: Clinical and translational results.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 422-422
Author(s):  
Gillian Vandekerkhove ◽  
Nora Sundahl ◽  
Karel Decaestecker ◽  
Annabel Meireson ◽  
Pieter De Visschere ◽  
...  
Keyword(s):  
Adverse Events ◽  
Urothelial Carcinoma ◽  
Stereotactic Body Radiotherapy ◽  
Phase 1 ◽  
Objective Response ◽  
University Hospital ◽  
Driver Gene ◽  
Disease Evolution ◽  
Biomarker Analysis ◽  
Metastatic Urothelial Carcinoma

422 Background: Preclinical data indicates that stereotactic body radiotherapy (SBRT) works synergistically with pembrolizumab, but the effect and potential toxicity might depend on the timing of SBRT. The current study assessed the safety of two different SBRT schedules in combination with pembrolizumab for metastatic urothelial carcinoma (mUC), and explored correlative biomarkers including circulating tumor DNA (ctDNA). Methods: An open-label phase 1 trial was conducted at Ghent University Hospital in patients with mUC to assess the dose-limiting toxicity (DLT) of the combination of pembrolizumab (200mg intravenously, 3-weekly) and SBRT (3x8Gy to the largest lesion). Patients were randomized (1:1) to receive SBRT either prior to the first (arm A) or the third (arm B) cycle of pembrolizumab. Blood was collected throughout the trial for biomarker analysis. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events version 4.0. Secondary endpoints included best overall response measured per Response Evaluation Criteria in Solid Tumors v1.1 (RECISTv1.1). The trial was approved by the Ethical Committee of Ghent University Hospital and is registered on ClinicalTrials.gov (NCT02826564). Funding was provided by Merck Sharp & Dohme. Results: Eighteen patients were randomized (nine to each arm) and started trial treatment. No DLT occurred. Treatment-related AEs grade 1-2 occurred in 6/9 and 9/9 patients in arm A and B respectively. One patient in arm B experienced lymphopenia grade 3, unrelated to SBRT. No treatment-related AEs grade 4-5 occurred. An objective response rate as per RECISTv1.1 of 0% and 44·4% was noted in arm A and B respectively. Targeted sequencing of tissue DNA and ctDNA revealed high genomic concordance. A decline in ctDNA was observed in responding patients. Conclusions: Neo-adjuvant and concomitant SBRT combined with pembrolizumab is safe, with potentially superior responses in the latter. ctDNA monitoring is feasible during disease evolution and suggests a shared driver gene status throughout disease progression. Clinical trial information: NCT02826564.

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