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.
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.
Authors: Heather A Parsons; Justin Rhoades; Sarah C Reed; Gregory Gydush; Priyanka Ram; Pedro Exman; Kan Xiong; Christopher C Lo; Tianyu Li; Mark Fleharty; Gregory J Kirkner; Denisse Rotem; Ofir Cohen; Fangyan Yu; Mariana Fitarelli-Kiehl; Ka Wai Leong; Melissa E Hughes; Shoshana M Rosenberg; Laura C Collins; Kathy D Miller; Brendan Blumenstiel; Lorenzo Trippa; Carrie Cibulskis; Donna S Neuberg; Matthew DeFelice; Samuel S Freeman; Niall J Lennon; Nikhil Wagle; Gavin Ha; Daniel G Stover; Atish D Choudhury; Gad Getz; Eric P Winer; Matthew Meyerson; Nancy U Lin; Ian Krop; J Christopher Love; G Mike Makrigiorgos; Ann H Partridge; Erica L Mayer; Todd R Golub; Viktor A Adalsteinsson Journal: Clin Cancer Res Date: 2020-03-13 Impact factor: 12.531
Authors: Kyrillus S Shohdy; Dario M Villamar; Yen Cao; Janson Trieu; Kristin S Price; Rebecca Nagy; Scott T Tagawa; Ana M Molina; Cora N Sternberg; David M Nanus; Juan Miguel Mosquera; Olivier Elemento; Guru P Sonpavde; Petros Grivas; Nicholas J Vogelzang; Bishoy Morris Faltas Journal: Br J Cancer Date: 2022-01-19 Impact factor: 7.640
Authors: Joshua J Meeks; Hikmat Al-Ahmadie; Bishoy M Faltas; John A Taylor; Thomas W Flaig; David J DeGraff; Emil Christensen; Benjamin L Woolbright; David J McConkey; Lars Dyrskjøt Journal: Nat Rev Urol Date: 2020-03-31 Impact factor: 14.432