Edmund C P Chedgy1, James Douglas2, Jonathan L Wright3, Roland Seiler4, Bas W G van Rhijn5, Joost Boormans6, Tilman Todenhöfer7, Colin P Dinney8, Colin C Collins1, Michiel S Van der Heijden9, Peter C Black10. 1. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. 2. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Urology, University Hospital Southampton, UK. 3. Department of Urology, University of Washington School of Medicine, Seattle, WA. 4. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Urology, Inselspital, University of Bern, Bern, Switzerland. 5. Department of Surgical Oncology (Urology) The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital Amsterdam, The Netherlands. 6. Department of Urology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. 7. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Urology, Eberhard Karls University, Tübingen, Germany. 8. Department of Urology, MD Anderson Cancer Center, Houston, TX. 9. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 10. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: pblack@mail.ubc.ca.
Abstract
BACKGROUND: Bladder cancer is a leading cause of morbidity and mortality. Despite recent advances in understanding its molecular biology, the 5-year survival for muscle-invasive disease (muscle-invasive bladder cancer [MIBC]) remains approximately 50%. Although neoadjuvant chemotherapy (NAC) offers an established 5% absolute survival benefit at 5 years, only the 40% of patients with a major tumor response appear to benefit. There remains, therefore, a critical unmet need for predictive markers to determine which patients are best managed with NAC, as well as for novel targeted therapies to overcome resistance to NAC. METHODS: The NAC paradigm offers the optimal clinical context for developing precision therapy for MIBC. Abundant tissue is available for analysis before NAC in all patients and after NAC in patients with residual MIBC. Technologic advances have enabled next-generation sequencing and gene expression microarray analysis of routinely collected and even archived tissue specimens. These technologies provide a foundation for the identification of markers of chemoresistance and for the development of rational cotargeting strategies. RESULTS: Modern computational methods allow for some measure of target validation, which can be enhanced by the use of patient-derived primary xenografts (PDX). These PDX can be established at the time of radical cystectomy after NAC if there is residual MIBC. By the time a patient recurs clinically, candidate drugs targeting specific molecular changes in the patient tumor and corresponding PDX would have been tested in the PDX model, and only the most efficacious drug(s) would be administered to the patient. Liquid biopsies in the form of circulating tumor DNA and circulating tumor cells allow noninvasive longitudinal monitoring of the molecular landscape of an advanced tumor as it is being treated with successive courses of systemic therapy. CONCLUSIONS: These tools combined form the foundation of an evidence-based precision oncology strategy for MIBC.
BACKGROUND:Bladder cancer is a leading cause of morbidity and mortality. Despite recent advances in understanding its molecular biology, the 5-year survival for muscle-invasive disease (muscle-invasive bladder cancer [MIBC]) remains approximately 50%. Although neoadjuvant chemotherapy (NAC) offers an established 5% absolute survival benefit at 5 years, only the 40% of patients with a major tumor response appear to benefit. There remains, therefore, a critical unmet need for predictive markers to determine which patients are best managed with NAC, as well as for novel targeted therapies to overcome resistance to NAC. METHODS: The NAC paradigm offers the optimal clinical context for developing precision therapy for MIBC. Abundant tissue is available for analysis before NAC in all patients and after NAC in patients with residual MIBC. Technologic advances have enabled next-generation sequencing and gene expression microarray analysis of routinely collected and even archived tissue specimens. These technologies provide a foundation for the identification of markers of chemoresistance and for the development of rational cotargeting strategies. RESULTS: Modern computational methods allow for some measure of target validation, which can be enhanced by the use of patient-derived primary xenografts (PDX). These PDX can be established at the time of radical cystectomy after NAC if there is residual MIBC. By the time a patient recurs clinically, candidate drugs targeting specific molecular changes in the patienttumor and corresponding PDX would have been tested in the PDX model, and only the most efficacious drug(s) would be administered to the patient. Liquid biopsies in the form of circulating tumor DNA and circulating tumor cells allow noninvasive longitudinal monitoring of the molecular landscape of an advanced tumor as it is being treated with successive courses of systemic therapy. CONCLUSIONS: These tools combined form the foundation of an evidence-based precision oncology strategy for MIBC.