Landscape of genomic alterations of circulating tumor DNA in advanced genitourinary cancer patients: SCRUM-Japan MONSTAR SCREEN Project.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 152-152
Author(s):  
Nobuaki Matsubara ◽  
Taigo Kato ◽  
Takao Fujisawa ◽  
Masaki Shiota ◽  
Masatoshi Eto ◽  
...  
Keyword(s):  
Success Rate ◽  
Solid Tumors ◽  
Circulating Tumor Dna ◽  
Advanced Solid Tumors ◽  
Genomic Alterations ◽  
Tumor Mutational Burden ◽  
Somatic Alterations ◽  
Ctdna Analysis ◽  
Tumor Types ◽  
Tumor Dna

152 Background: Circulating tumor DNA in plasma (ctDNA) is an emerging resource for detecting genomic alterations in various cancers. However, the characteristics and clinical utility of ctDNA are not fully elucidated, especially in patients with genitourinary (GU) cancers. Methods: In April 2019, SCRUM-Japan started the MONSTAR-SCREEN project, which evaluates the ctDNA from patients with various advanced solid tumors. We collected plasma and tumor samples from patients with advanced prostate cancer (PC), urothelial carcinoma (UC), and renal cell carcinoma (RCC). Plasma ctDNA and tissue genomic DNA were analyzed using NGS-based cell-free DNA assay, a modified version of FoundationOne Liquid (F1L) including blood tumor mutational burden (TMB) analysis, and tissue-based panel, FoundationOne CDx (F1CDx), respectively. Success rate of ctDNA was defined as the percentage of patients whose sample quality control status was “pass” or “qualified”. Level of ctDNA was defined as the maximum allele fraction (AF) for all known somatic alterations detected. Results: As of June 18, 2020, ctDNA analysis results were available for 470 of 540 patients with advanced solid tumors. Among them, we analyzed 70 advanced GU cancers (35 PC, 17 UC, and 18 RCC) and 400 non-GU cancers. The success rate of ctDNA was significantly lower in GU cancers than in non-GU cancers (81.4% vs. 91.5%, P = 0.016). The levels of ctDNA in PC and UC were similar to those in non-GU cancers. RCC had the second lowest ctDNA level (median 0.13%) after that in malignant melanoma. The median TMB, as estimated by ctDNA, was 4.40, 0.88 and 0.44 mutations/Mb in UC, PC and RCC, respectively. The most frequently altered genes were TP53 (34%), AR (11%), BRCA2 (11%), ATM (8.6%), and CDK12 (8.6%) in PC, TP53 (59%), TERT (41%), and CHEK2 (18%) in UC, and TP53 (22%), ATM (11%), and MTOR (11%) in RCC. The mutation rate in genes related to DNA damage response (DDR) pathways was significantly higher in GU cancers compared to that in non-GU cancers (30.0% vs. 18.0%, P = 0.033). However, other pathways were less frequently altered in GU cancers versus non-GU cancers, including Wnt (5.7% vs. 16.8%, P = 0.017), PI3K (8.6% vs. 19.0%, P = 0.039) and RAS/MAPK (8.6% vs. 29.5%, P < 0.001). Conclusions: Our results reveal the genomic landscape of ctDNA in several advanced solid tumors, and highlight the differences between tumor types. Comprehensive analysis of ctDNA using the F1L assay reveled alterations in DDR-associated genes were significantly more frequent in GU cancers than in non-GU cancers. Clinical trial information: UMIN000036749.

scholarly journals Circulating tumor DNA in advanced solid tumors: Clinical relevance and future directions

2020 ◽  
Author(s):  
Michael L. Cheng ◽  
Eirini Pectasides ◽  
Glenn J. Hanna ◽  
Heather A. Parsons ◽  
Atish D. Choudhury ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Clinical Relevance ◽  
Circulating Tumor Dna ◽  
Advanced Solid Tumors ◽  
Future Directions ◽  
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

scholarly journals Circulating Tumor DNA and Minimal Residual Disease (MRD) in Solid Tumors: Current Horizons and Future Perspectives

2021 ◽  
Vol 11 ◽  
Author(s):  
Yan Peng ◽  
Wuxuan Mei ◽  
Kaidong Ma ◽  
Changchun Zeng
Keyword(s):  
Solid Tumors ◽  
Clinical Decision Making ◽  
Residual Disease ◽  
Malignant Tumors ◽  
Circulating Tumor Dna ◽  
Detection Methods ◽  
Risk Of Recurrence ◽  
Increased Risk ◽  
Ctdna Analysis ◽  
Tumor Dna

Circulating tumor DNA (ctDNA) is cell-free DNA (cfDNA) fragment in the bloodstream that originates from malignant tumors or circulating tumor cells. Recently, ctDNA has emerged as a promising non-invasive biomarker in clinical oncology. Analysis of ctDNA opens up new avenues for individualized cancer diagnosis and therapy in various types of tumors. Evidence suggests that minimum residual disease (MRD) is closely associated with disease recurrence, thus identifying specific genetic and molecular alterations as novel MRD detection targets using ctDNA has been a research focus. MRD is considered a promising prognostic marker to identify individuals at increased risk of recurrence and who may benefit from treatment. This review summarizes the current knowledge of ctDNA and MRD in solid tumors, focusing on the potential clinical applications and challenges. We describe the current state of ctDNA detection methods and the milestones of ctDNA development and discuss how ctDNA analysis may be an alternative for tissue biopsy. Additionally, we evaluate the clinical utility of ctDNA analysis in solid tumors, such as recurrence risk assessment, monitoring response, and resistance mechanism analysis. MRD detection aids in assessing treatment response, patient prognosis, and risk of recurrence. Moreover, this review highlights current advancements in utilizing ctDNA to monitor the MRD of solid tumors such as lung cancer, breast cancer, and colon cancer. Overall, the clinical application of ctDNA-based MRD detection can assist clinical decision-making and improve patient outcomes in malignant tumors.

scholarly journals Early assessment of molecular progression and response by whole-genome circulating tumor DNA in advanced solid tumors

2019 ◽  
Author(s):  
Andrew A. Davis ◽  
Wade T. Iams ◽  
David Chan ◽  
Michael S. Oh ◽  
Robert W. Lentz ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Circulating Tumor Dna ◽  
Molecular Response ◽  
Whole Genome ◽  
Advanced Solid Tumors ◽  
Early Assessment ◽  
Time Required ◽  
Tumor Dna

AbstractTreatment response assessment for patients with advanced solid tumors is complex and existing methods require greater precision. Current guidelines rely on imaging, which has known limitations, including the time required to show a deterministic change in target lesions. Serial changes in whole-genome (WG) circulating tumor DNA (ctDNA) were used to assess response or resistance to treatment early in the treatment course. 96 patients with advanced cancer were prospectively enrolled (91 analyzed and 5 excluded), and blood was collected before and after initiation of a new, systemic treatment. Plasma cell-free DNA libraries were prepared for either WG or WG bisulfite sequencing. Longitudinal changes in the fraction of ctDNA were quantified to retrospectively identify molecular progression (MP) or major molecular response (MMR). Study endpoints were concordance with first follow-up imaging (FFUI) and stratification of progression-free survival (PFS) and overall survival (OS). Patients with MP (n=13) had shorter PFS (median 62d vs. 310d) and OS (255d vs. not reached). Sensitivity for MP to identify clinical progression was 54% and specificity was 100%. MP calls were from samples taken a median of 28d into treatment and 39d before FFUI. Patients with MMR (n=27) had longer PFS and OS compared to those with neither call (n=51). Molecular response assessment can potentially enable early switching to potentially effective therapies, therefore minimizing side effects and costs associated with additional cycles of ineffective treatment. MMR may present a novel endpoint to target to improve long-term patient outcomes.

scholarly journals SL-1 Activity on Nationwide Cancer Genome Screening Project for Advanced Solid Tumors; SCRUM-Japan GI-/MONSTAR-SCREEN

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii1-ii1
Author(s):  
Takayuki Yoshino
Keyword(s):  
Solid Tumors ◽  
Circulating Tumor Dna ◽  
Cancer Genome ◽  
Tumor Evolution ◽  
Precision Oncology ◽  
Advanced Solid Tumors ◽  
Patient Identification ◽  
Tissue Samples ◽  
Genome Screening ◽  
Ctdna Analysis

Abstract Advances in precision oncology have made genotyping mandatory for most advanced solid tumors to ensure proper therapy selection. However, the innovations remains limited by the realities of patient identification-actionable targets are present in only a small fraction of patients. We initiated a nationwide cancer genome screening project, SCRUM-Japan GI- (from 2015 to 19)/MONSTAR-SCREEN (since 2019) with the purpose of matching patients with interventional IND trials. We revealed requirement for tissue samples hampers recruitment, and genotyping using archival tumor samples provides information only at a single spatial and temporal point and fail to detect chronological tumor evolution and intratumoral heterogeneity, both of which are obstacles for proper therapy selection. We also demonstrated circulating tumor DNA (ctDNA) analysis using next-generation sequencing (NGS)-based methods have the potential of ctDNA analysis for genomic profiling as an alternative for tissue genotyping. Recently, gut microbiome has the promise in predictive value of therapy. Serial analyses with ctDNA and microbiome at pre- and post- cancer therapies are ongoing. Updated results will be presented.

scholarly journals Early Assessment of Molecular Progression and Response by Whole-genome Circulating Tumor DNA in Advanced Solid Tumors

2020 ◽  
Vol 19 (7) ◽  
pp. 1486-1496
Author(s):  
Andrew A. Davis ◽  
Wade T. Iams ◽  
David Chan ◽  
Michael S. Oh ◽  
Robert W. Lentz ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Circulating Tumor Dna ◽  
Whole Genome ◽  
Advanced Solid Tumors ◽  
Early Assessment ◽  
Tumor Dna

scholarly journals Assessing tumor heterogeneity: integrating tissue and circulating tumor DNA (ctDNA) analysis in the era of immuno-oncology - blood TMB is not the same as tissue TMB

2021 ◽  
Vol 9 (8) ◽  
pp. e002551
Author(s):  
Stanislav Fridland ◽  
Jaeyoun Choi ◽  
Myungwoo Nam ◽  
Samuel Joseph Schellenberg ◽  
Eugene Kim ◽  
...  
Keyword(s):  
Tumor Heterogeneity ◽  
Predictive Power ◽  
Composite Index ◽  
Circulating Tumor Dna ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Ctdna Analysis ◽  
Tumor Dna ◽  
Predict Treatment Response

Tissue tumor mutational burden (tTMB) is calculated to aid in cancer treatment selection. High tTMB predicts a favorable response to immunotherapy in patients with non-small cell lung cancer. Blood TMB (bTMB) from circulating tumor DNA is reported to have similar predictive power and has been proposed as an alternative to tTMB. Across many studies not only are tTMB and bTMB not concordant but also as reported previously by our group predict conflicting outcomes. This implies that bTMB is not a substitute for tTMB, but rather a composite index that may encompass tumor heterogeneity. Here, we provide a thorough overview of the predictive power of TMB, discuss the use of tumor heterogeneity alongside TMB to predict treatment response and review several methods of tumor heterogeneity assessment. Furthermore, we propose a hypothetical method of estimating tumor heterogeneity and touch on its clinical implications.

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.

scholarly journals 523 Preliminary clinical experience with XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A553-A553
Author(s):  
Elaine Shum ◽  
Matthew Reilley ◽  
Yana Najjar ◽  
Adil Daud ◽  
John Thompson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Bispecific Antibody ◽  
Objective Response ◽  
Checkpoint Blockade ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Tumor Types

BackgroundXmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, dose-escalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options.MethodsA maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST[1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety.ResultsAs of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases ≥ 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade ≥ 3 immunotherapy-related adverse events in ≥ 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%).ConclusionsPreliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer.Trial RegistrationNCT03517488ReferencesShum E, Daud A, Reilley M, et al. Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors. JITC 2020;8(3):A247-8.Ethics ApprovalThe study was approved by each institution’s IRB.

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