Purpose: Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer, but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally invasive tool to profile the tumor genome in real-time, but is critically underexplored in bladder cancer.Experimental Design: We applied a combination of wholeexome sequencing and targeted sequencing across 50 bladder cancer driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive bladder cancer, including 37 with metastatic disease.Results: The majority of patients with metastasis, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9%-72.6%). Twelve percent of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic bladder cancer with 95% of patients harboring deleterious alterations to TP53, RB1, or MDM2, and 70% harboring a mutation or disrupting rearrangement affecting chromatin modifiers such as ARID1A. Targetable alterations in MAPK/ERK or PI3K/AKT/ mTOR pathways were robustly detected, including amplification of ERBB2 (20% of patients) and activating hotspot mutations in PIK3CA (20%), with the latter mutually exclusive to truncating mutations in TSC1. A novel FGFR3 gene fusion was identified in consecutive samples from one patient.Conclusions: Our study demonstrates that ctDNA provides a practical and cost-effective snapshot of driver gene status in metastatic bladder cancer. The identification of a wide spectrum of clinically informative somatic alterations nominates ctDNA as a tool to dissect disease pathogenesis and guide therapy selection in patients with metastatic bladder cancer.
Objective To determine whether radiologically defined sarcopenia at the C3 or L3 level as measured by computed tomography or magnetic resonance imaging is prognostic of overall survival (OS) in head and neck cancers (HNCs). Methods Literature searches of PubMed, Embase, and Scopus were conducted on July 12, 2019, to include articles written in the English language with no constraints on publication date. To be included in the analysis, articles had to report the prognostic impact of skeletal muscle mass measured radiologically at the C3 or L3 vertebral level in HNC patients; hazard ratios (HRs) for OS; 95% confidence intervals (CIs); be from a clinical trial, cohort, or case–control study; and have English full‐text availability. Articles were reviewed in consensus by two reviewers, with disagreements reviewed by a third reviewer. Preferred Reporting Items for Systematic Reviews and Meta‐Analyses and Meta‐analysis Of Observational Studies in Epidemiology Checklist guidelines were used for reporting. Study quality assessment was performed using Quality In Prognosis Studies tool. The random‐effects DerSimonian and Laird method was used for meta‐analysis. Results Ten articles, nine retrospective and one prospective, were included in this meta‐analysis (n = 2,181 patients). Significant differences were found in OS for HNC patients with sarcopenia (HR = 1.98; 95% CI: 1.64‐2.39; P < .00001). No heterogeneity was detected in either the overall or subgroup analyses. Conclusions Radiologically defined sarcopenia is a negative predictor of OS in patients with HNC. Early detection of sarcopenia in cancer patients may help guide nutritional and adjuvant support to improve treatment outcomes. Level of Evidence NA Laryngoscope, 131:333–341, 2021
Purpose: Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance. Experimental Design: We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA). Results: Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the AR gene, with an average 50% increase in AR copy number, changes in AR mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements. Conclusions: Our data show that the dominant AR genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.
Purpose: DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features. Experimental Design: We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically. Results: BRCA2, ATM, and CDK12 were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele–specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous BRCA2 deletions. Tumor suppressors TP53, RB1, and PTEN were controlled via disruptive chromosomal rearrangements in BRCA2-defective samples, but via oncogene amplification in context of CDK12 defects. TP53 mutations were rare in cases with ATM defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of BRCA2 and CDK12, but not ATM, was associated with poor clinical outcomes. Conclusions: BRCA2, ATM, and CDK12 defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.
Background: Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting. Patients and methods: This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or !4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response !50%, radiographic response, or stable disease !12 weeks). Results: Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P ¼ 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) ¼ 0.58, P ¼ 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR ¼ 0.87, P ¼ 0.52). The most common first-line treatment-related grade !3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR ¼ 2.38, P < 0.001; HR ¼ 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR ¼ 38.22, P < 0.001). Conclusions: Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.