Molecular residual disease detection in resected, muscle-invasive urothelial cancer with a tissue-based comprehensive genomic profiling–informed personalized monitoring assay

Frontiers in Oncology

Oncology

Thomas Powles¹  Amanda Young²  Russell W. Madison²  Priti S. Hegde²  Yanmei Huang²  Ole V. Gjoerup²  Chang Xu²  Halla Nimeiri²  Geoffrey Oxnard²  Daniel R. Zollinger²  Alexander Fine²  Alexey Aleshin³  Vasily N. Aushev³  Hsin-Ta Wu³  Viraj Degaonkar⁴  Erica Schleifman⁴  Zoe June Assaf⁴  Corey Carter⁴  Pratyush Gupta⁴  Nicole Davarpanah⁴  Sanjeev Mariathasan⁴ 

[1] Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London ECMC, Barts Health, London, United Kingdom;Foundation Medicine, Cambridge, MA, United States;Natera, Austin, TX, United States;Roche/Genentech, South San Francisco, CA, United States;

关键词: MRD;    CtDNA;    bladder cancer;    immunotherapy;    comprehensive genomic profiling;    next-generation sequencing;    monitoring assay;   

DOI  :  10.3389/fonc.2023.1221718

 received in 2023-05-15, accepted in 2023-07-11,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionCirculating tumor DNA (ctDNA) detection postoperatively may identify patients with urothelial cancer at a high risk of relapse. Pragmatic tools building off clinical tumor next-generation sequencing (NGS) platforms could have the potential to increase assay accessibility.MethodsWe evaluated the widely available Foundation Medicine comprehensive genomic profiling (CGP) platform as a source of variants for tracking of ctDNA when analyzing residual samples from IMvigor010 (ClinicalTrials.gov identifier NCT02450331), a randomized adjuvant study comparing atezolizumab with observation after bladder cancer surgery. Current methods often involve germline sampling, which is not always feasible or practical. Rather than performing white blood cell sequencing to filter germline and clonal hematopoiesis (CH) variants, we applied a bioinformatic approach to select tumor (non-germline/CH) variants for molecular residual disease detection. Tissue-informed personalized multiplex polymerase chain reaction–NGS assay was used to detect ctDNA postsurgically (Natera).ResultsAcross 396 analyzed patients, prevalence of potentially actionable alterations was comparable with the expected prevalence in advanced disease (13% FGFR2/3, 20% PIK3CA, 13% ERBB2, and 37% with elevated tumor mutational burden ≥10 mutations/megabase). In the observation arm, 66 of the 184 (36%) ctDNA-positive patients had shorter disease-free survival [DFS; hazard ratio (HR) = 5.77; 95% confidence interval (CI), 3.84–8.67; P < 0.0001] and overall survival (OS; HR = 5.81; 95% CI, 3.41–9.91; P < 0.0001) compared with ctDNA-negative patients. ctDNA-positive patients had improved DFS and OS with atezolizumab compared with those in observation (DFS HR = 0.56; 95% CI, 0.38–0.83; P = 0.003; OS HR = 0.66; 95% CI, 0.42–1.05). Clinical sensitivity and specificity for detection of postsurgical recurrence were 58% (60/103) and 93% (75/81), respectively.ConclusionWe present a personalized ctDNA monitoring assay utilizing tissue-based FoundationOne® CDx CGP, which is a pragmatic and potentially clinically scalable method that can detect low levels of residual ctDNA in patients with resected, muscle-invasive bladder cancer without germline sampling.

【 授权许可】

Unknown   
Copyright © 2023 Powles, Young, Nimeiri, Madison, Fine, Zollinger, Huang, Xu, Gjoerup, Aushev, Wu, Aleshin, Carter, Davarpanah, Degaonkar, Gupta, Mariathasan, Schleifman, Assaf, Oxnard and Hegde