The Clonal evolution of chemotherapy-resistant urothelial carcinoma - Beyond the Abstract

Chemotherapy is the standard of care as the first-line of treatment for advanced bladder cancer. Unfortunately, while initial responses are common, most patients develop resistance within months of the initial treatment. While the recent developments in immunotherapy are promising, there is no consistent cure for this chemotherapy-resistant state of the disease.

We have been investigating this state of the disease in collaboration between Weill Cornell Medicine and the University of Trento to understand how chemotherapy shapes the evolution of these tumors. We recently published our study, in Nature Genetics. We designed our study to capture serial tumor samples at various stages of the disease from 32 patients with advanced urothelial cancer. Additionally, we were able to obtain multiple samples from two rapid autopsies, enabling us researchers to study the full arc of the natural history of the urothelial cancer’s evolution.

We applied the evolutionary perspective to this study and found that chemotherapy acts as a selection pressure favoring the survival of some urothelial cancer cell clones. We identified striking heterogeneity between primary untreated and advanced chemotherapy-resistant tumors. The majority of the mutations were actually not shared between samples from, the same patient. As urothelial cancer progressed, developed new mutations that were different from those in the primary tumor. Surprisingly, this branching evolution was detected very early in the tumor’s lifetime. We also observed an enrichment of the APOBEC-induced mutational signatures in the post-chemotherapy tumors.

Our findings have important clinical implications. Most importantly, they show that tumor’s genetic testing at a single point in the tumor’s lifetime is only but a snapshot of a very complex evolutionary process. This becomes especially important as genomics makes further inroads into the clinical management of bladder cancer patients.

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Author: Bishoy M. Faltas MD


Faltas B, Prandi D, Tagawa ST, Molina AM, Nanus DM, Sternberg C, Rosenberg J, Mosquera JM, Robinson B, Elemento O, Sboner A, Beltran H, Demichelis F, Rubin MA. Clonal Evolution of Chemotherapy-resistant Urothelial Carcinoma. Nat Genet. 2016 Dec;48(12):1490-1499. doi: 10.1038/ng.369

Chemotherapy drives treatment resistance in bladder cancer