Molecular biomarkers and treatment outcomes in advanced genitourinary malignancies

Genitourinary malignancies are a diverse group of cancers with an ever expanding array of therapeutic options. This thesis addresses how predictive biomarkers can be derived to help in treatment allocation. First, we survey the challenges around developing predictive biomarkers for checkpoint inhibitors in metastatic urothelial carcinoma through a systematic review. Despite multiple efforts, no single biomarker could be developed. Often, promising biomarkers were developed in single cohorts, and the predictive value of these biomarkers cannot be evaluated without a comparable cohort of patients receiving non-checkpoint inhibitor based treatments. Second, we present a cohort of 103 patients with metastatic urothelial cancer who underwent a liquid biopsy for circulating tumour DNA. This shows that ctDNA can be used to generate clinically relevant genomic data; we correlate specific outcomes to mutations detected in the blood Third, we study the potential role of whole genome and transcriptome analysis (WGTA). In a cohort of patients enrolled in early phase clinical trials, this approach could suggest trial allocation in 50% of cases, which is a 3-fold increase when compared to the data that would be expected from a DNA panel alone. In addition, a cohort of 7 patients with metastatic adrenocortical carcinoma (ACC) has undergone WGTA. We discuss specific genomic findings, and how these may be used to direct treatment. Overall, this thesis provides preliminary data on the application of genomic profiling on diverse cohorts of genitourinary cancers, and suggests future steps for biomarker development in this setting.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat