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Vandekerkhove, Gillian

University of British Columbia

Targeted agents, antibody-drug conjugates, and immunotherapies are transforming the treatment of metastatic bladder cancer beyond platinum chemotherapy, with molecular stratification poised to optimize therapy selection. Relevant tumour samples are crucial to the success of precision oncology approaches. Blood plasma cell-free DNA (cfDNA) is established in several solid malignancies as a minimally-invasive tool to rapidly profile the tumour genome, but is critically underexplored in bladder cancer. In this thesis, next-generation sequencing assays were applied to cfDNA and tumour tissue from patients with muscle-invasive or metastatic bladder cancer. In the majority of patients with metastasis, but few patients with localized disease, tumour-derived cfDNA (i.e., circulating tumour DNA, ctDNA) was present at levels above 1-2% of total cfDNA. Patient ctDNA abundance was independently prognostic for overall survival in metastatic patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduced known genomic drivers as described from tissue-based cohorts, revealing frequent driver gene alteration and high tumour mutational burden in metastatic bladder cancer; TP53, RB1, and chromatin modifiers such as ARID1A were frequently disrupted. Targetable alterations were robustly detected across several pathways, including in the genes ERBB2, ERCC2, PIK3CA, and FGFR3. Furthermore, mutation concordance between ctDNA and matched tumour tissue was high, enabling benchmarking of proposed clinical biomarkers. Mutations were consistently identified across serial ctDNA samples, however concordance for serial tumour tissue was significantly lower; ctDNA could mitigate against disease undersampling inherent to studying archival primary tumour foci. Analysis of the subset of patients receiving combination immunotherapy and radiotherapy in a clinical trial revealed an association between response and decline in ctDNA abundance, suggesting ctDNA fraction could serve as a surrogate for monitoring disease evolution. Overall, this retrospective body of work demonstrates that genomic profiling of ctDNA is reliable and practical in metastatic bladder cancer; the identification of several proposed clinical biomarkers supports ctDNA as a viable tool for guiding therapy selection. Now, validation will require the prospective incorporation of cfDNA profiling into molecularly guided clinical trials for metastatic bladder cancer.

Text

2022-04-22

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/81294

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/