Genomic heterogeneity as a barrier to precision oncology in urothelial cancer

Precision oncology relies on the accurate molecular characterization of individual patients with cancer at the time of treatment initiation. However, tumor molecular profiles are not static, and cancers continually evolve because of ongoing mutagenesis and clonal selection. Here, we performed genomic analyses of primary tumors, metastases, and plasma collected from individual patients to define the concordance of actionable genomic alterations and to identify drivers of metastatic disease progression. We observed a high degree of discordance of actionable genomic alterations, with 23% discordant between primary and metastatic disease sites. Among chromatin-modifying genes, ARID1A mutations, when discordant, were exclusive to the metastatic tumor samples. Our findings indicate that the high degree of lesion-to-lesion genomic heterogeneity may be a barrier to precision oncology approaches for bladder cancer and that circulating tumor DNA profiling may be preferred to tumor sequencing for a subset of patients.

Automated summary

Precision oncology relies on accurate molecular characterization of individual cancer patients at the beginning of treatment. However, tumor molecular profiles are not static and can hinder the application of precision oncology approaches. By analyzing the genomes of primary tumors, metastases, and plasma from patients, we found a high degree of inconsistency in actionable genomic alterations, with certain gene mutations exclusive to metastatic samples. Therefore, circulating tumor DNA profiling may be preferred over tumor sequencing for some patients.