Developing Precision Medicine for Bladder Cancer

Abstract

The hallmark of precision medicine involves tailoring the treatment to the patient and/or tumor-specific biomarkers. Candidate biomarkers in bladder cancer are abundant, but few have been validated in clinical practice. Significant obstacles to precision medicine in bladder cancer include the limited predictive value of candidate biomarkers, lack of standardization in biomarker assessment, heterogeneity in biomarker expression and function, and limited insight into the biologic factors that influence biomarker expression and predictive capacity. This review summarizes key biomarkers explored in bladder cancer and outlines innovative trial designs to approach these obstacles.

Keywords: Biomarkers; Bladder cancer; Chemotherapy; Immunotherapy; Precision medicine; Targeted therapy; Urothelial carcinoma.

Figure 1.

Oncoprint from The Cancer Genome Atlas (TCGA) depicting the distribution of potentially predictive genomic biomarkers in muscle-invasive bladder cancer.^,, Each column depicts the genomic profile of an individual patient. Y-axis labels include the percentage of muscle-invasive bladder cancers in the TCGA with alterations in each gene. TCGA patients without alterations in one or more of the selected genes are not shown.

Figure 2.

Umbrella trials match patients with a single disease to one of multiple rational targeted therapies based on the presence of informative biomarkers. Basket trials enroll patients with various diseases based on a shared targetable trait to facilitate investigation of a single targeted therapy.

Figure 3.

Example schema for an adaptive platform trial. The schema depicts evolution of a platform trial’s design over time. In this example, patients are screened and matched to a trial stratum based on the presence or absence of targetable biomarkers. Each stratum features one or more investigational therapies personalized to patient biomarker status compared to a standard of care. As evidence from the trial accrues, each stratum or arm within a stratum can be individually stopped early for success or futility, while remaining strata and arms may be left open for continued enrollment. New strata (e.g. Biomarker 3 stratum) and treatment arms (e.g. investigational drug E) can be added as the trial proceeds. If a stratum closes early, patients enrolled in that stratum can be enrolled in another (e.g. transition from Biomarker 1 stratum to the Biomarker-negative stratum). The overall trial does not necessarily feature a fixed stop date.