AUA 2017: Genome Drivers of Response to Existing and Emerging Therapies in Bladder Cancer

Boston, MA (UroToday.com) Dr. Van Allen discussed whether precision medicine can be used to better predict response to platinum based neoadjuvant chemotherapy for MIBC. Generally, NAC has a modest response at 5%, but perhaps better selected patients could improve this rate. His group compared tumor mutational profiles from TURBT specimens in MIBC patients that then went on to cystectomy. He compared mutational profiles in tumors of patients who had a pathologic complete response at cystectomy (pT0 or pTis) vs non responders (pT2 or higher). Not surprisingly, P53, RB1, KDM6A, and ARID1A were all confirmed as mutated in the non-responder group, but there was only one mutated gene that segregated with response: ERCC2. ERCC2 is a protein that facilitates nucleotide excision repair by helping to unwind the DNA double helix. Interestingly, they did not identify any highly conserved mutations, but did find the mutations to cluster around the helicase region of the gene. Furthermore, mutations in ERCC2 were associated with a very defined mutational profile in other genes in the same tumor.

In vitro, ERCC2 null cells were more susceptible to cisplatin and UV stress, and were rescuable by ERCC2 wildtype protein but not the genetic mutants found in cisplatin-responsive tumors. In external validation, ERCC2 mutant patients had better overall survival after NAC/RC. Dr. Van Allen even hypothesized that this cisplatin-sensitive phenotype may be so strong to allow bladder sparing approaches in select patients.

Presented by: Eliezer Van Allen, MD Dana Farber Cancer Institute Boston MA

Contributed by: Jed Ferguson, MD/PhD and Ashish Kamat, MD. MD Anderson Cancer Center, Department of Urology.

at the 2017 AUA Annual Meeting - May 12 - 16, 2017 – Boston, Massachusetts, USA

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