TY - JOUR
T1 - 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
AU - Christensen, Emil
AU - Birkenkamp-Demtröder, Karin
AU - Sethi, Himanshu
AU - Shchegrova, Svetlana
AU - Salari, Raheleh
AU - Nordentoft, Iver
AU - Wu, Hsin-Ta
AU - Knudsen, Michael
AU - Lamy, Philippe
AU - Lindskrog, Sia Viborg
AU - Taber, Ann
AU - Balcioglu, Mustafa
AU - Vang, Søren
AU - Assaf, Zoe
AU - Sharma, Shruti
AU - Tin, Antony S
AU - Srinivasan, Ramya
AU - Hafez, Dina
AU - Reinert, Thomas
AU - Navarro, Samantha
AU - Olson, Alexander
AU - Ram, Rosalyn
AU - Dashner, Scott
AU - Rabinowitz, Matthew
AU - Billings, Paul
AU - Sigurjonsson, Styrmir
AU - Andersen, Claus Lindbjerg
AU - Swenerton, Ryan
AU - Aleshin, Alexey
AU - Zimmermann, Bernhard
AU - Agerbæk, Mads
AU - Lin, Cheng-Ho Jimmy
AU - Jensen, Jørgen Bjerggaard
AU - Dyrskjøt, Lars
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
KW - CANCER
KW - CIRCULATING TUMOR DNA
KW - CISPLATIN
KW - CLONAL EVOLUTION
KW - LIQUID BIOPSIES
KW - NEOADJUVANT CHEMOTHERAPY
KW - RECURRENCE
KW - SOMATIC ERCC2 MUTATIONS
KW - TREATMENT RESPONSE
UR - http://www.scopus.com/inward/record.url?scp=85068427517&partnerID=8YFLogxK
U2 - 10.1200/JCO.18.02052
DO - 10.1200/JCO.18.02052
M3 - Journal article
C2 - 31059311
SN - 0732-183X
VL - 37
SP - 1547
EP - 1557
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 18
ER -