Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma

作者：Emil Christensen, Karin Birkenkamp‐Demtröder, Himanshu Sethi, Svetlana Shchegrova, Raheleh Salari, Iver Nordentoft, Hsin-Ta Wu, Michael Knudsen, Philippe Lamy, Sia V. Lindskrog, Ann Taber, Mustafa Balcioglu, Søren Vang, Zoe J. Assaf, Shruti Sharma, Antony Tin, Ramya Srinivasan, Dina Hafez, Thomas Reinert, Samantha Navarro, Alexander Olson, Rosalyn Ram, Scott Dashner, Matthew Rabinowitz, Paul R. Billings, Styrmir Sigurjonsson, Claus L. Andersen, Ryan Swenerton, Alexey Aleshin, Bernhard Zimmermann, Mads Agerbæk, Cheng-Ho Jimmy Lin, Jørgen Bjerggaard Jensen, Lars Dyrskjøt · 发表于：Journal of Clinical Oncology · 年份：2019 · DOI：10.1200/jco.18.02052 · 被引用次数：566 · 研究领域：Bladder and Urothelial Cancer Treatments、Cancer Genomics and Diagnostics、Multiple and Secondary Primary Cancers

PURPOSE Novel sensitive methods for early detection of relapse and for monitoring therapeutic efficacy may have a huge impact on risk stratification, treatment, and ultimately outcome for patients with bladder cancer. We addressed the prognostic and predictive impact of ultra-deep sequencing of cell-free DNA in patients before and after cystectomy and during chemotherapy. PATIENTS AND METHODS We included 68 patients with localized advanced bladder cancer. Patient-specific somatic mutations, identified by whole-exome sequencing, were used to assess circulating tumor DNA (ctDNA) by ultra-deep sequencing (median, 105,000×) of plasma DNA. Plasma samples (n = 656) were procured at diagnosis, during chemotherapy, before cystectomy, and during surveillance. Expression profiling was performed for tumor subtype and immune signature analyses. RESULTS Presence of ctDNA was highly prognostic at diagnosis before chemotherapy (hazard ratio, 29.1; P = .001). After cystectomy, ctDNA analysis correctly identified all patients with metastatic relapse during disease monitoring (100% sensitivity, 98% specificity). A median lead time over radiographic imaging of 96 days was observed. In addition, for high-risk patients (ctDNA positive before or during treatment), the dynamics of ctDNA during chemotherapy was associated with disease recurrence ( P = .023), whereas pathologic downstaging was not. Analysis of tumor-centric biomarkers showed that mutational processes (signature 5) were associated wit...