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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Emil Christensen
  • Karin Birkenkamp-Demtröder
  • Himanshu Sethi, Natera Inc, San Carlos, California.
  • ,
  • Svetlana Shchegrova, Natera Inc, San Carlos, California.
  • ,
  • Raheleh Salari, Natera Inc, San Carlos, California.
  • ,
  • Iver Nordentoft
  • Hsin-Ta Wu, Natera Inc, San Carlos, California.
  • ,
  • Michael Knudsen
  • Philippe Lamy
  • Sia Viborg Lindskrog
  • Ann Taber
  • Mustafa Balcioglu, Natera Inc, San Carlos, California.
  • ,
  • Søren Vang
  • Zoe Assaf, Natera Inc, San Carlos, California.
  • ,
  • Shruti Sharma, Natera Inc, San Carlos, California.
  • ,
  • Antony S Tin, Natera Inc, San Carlos, California.
  • ,
  • Ramya Srinivasan, Natera Inc, San Carlos, California.
  • ,
  • Dina Hafez, Natera Inc, San Carlos, California.
  • ,
  • Thomas Reinert
  • Samantha Navarro, Natera Inc, San Carlos, California.
  • ,
  • Alexander Olson, Natera Inc, San Carlos, California.
  • ,
  • Rosalyn Ram, Natera Inc, San Carlos, California.
  • ,
  • Scott Dashner, Natera Inc, San Carlos, California.
  • ,
  • Matthew Rabinowitz, Natera Inc, San Carlos, California.
  • ,
  • Paul Billings, Natera Inc, San Carlos, California.
  • ,
  • Styrmir Sigurjonsson, Natera Inc, San Carlos, California.
  • ,
  • Claus Lindbjerg Andersen
  • Ryan Swenerton, Natera Inc, San Carlos, California.
  • ,
  • Alexey Aleshin, Natera Inc, San Carlos, California.
  • ,
  • Bernhard Zimmermann, Natera Inc, San Carlos, California.
  • ,
  • Mads Agerbæk
  • Cheng-Ho Jimmy Lin, Natera Inc, San Carlos, California.
  • ,
  • Jørgen Bjerggaard Jensen
  • Lars Dyrskjøt

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 with pathologic downstaging (P = .024); however, no significant correlation for tumor subtypes, DNA damage response mutations, and other biomarkers was observed. Our results suggest that ctDNA analysis is better associated with treatment efficacy compared with other available methods.

CONCLUSION: ctDNA assessment for early risk stratification, therapy monitoring, and early relapse detection in bladder cancer is feasible and provides a basis for clinical studies that evaluate early therapeutic interventions.

Original languageEnglish
JournalJournal of Clinical Oncology
Volume37
Issue18
Pages (from-to)1547-1557
Number of pages11
ISSN0732-183X
DOIs
Publication statusPublished - 2019

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