ASCO GU 2018: Next Generation Sequencing of Urothelial Bladder Cancer: Memorial Sloan Kettering Cancer Center Experience in 454 Patients

San Francisco, CA (UroToday.com) Genomic characterization of urothelial bladder cancer (UBC) may help to identify alterations associated with tumor stage, novel therapeutic targets and biomarkers to predict outcomes.

Methods:
454 UBC patients were sequenced using next generation sequencing assay (MSK−IMPACT). 264 patients with chemotherapy naïve primary tumors were included. A total of 123 patients had non-muscle invasive bladder cancer [NMIBC], 112 patients had muscle invasive bladder cancer [MIBC] and 29 were metastatic patients.

Results:
Patients whose primary tumors harbored:
  • TP53
  • RB1
  • TP53/MDM2,
  • cell cycle pathway alterations

More frequently presented with advanced disease, whereas those with tumors containing:
  • FGFR3
  • RTK/RAS/RAF pathway alterations
generally presented with NMIBC. TP53, RB1, TP53/MDM2, and cell cycle pathway alterations were associated with worse overall and metastasis free survival, whereas FGFR3 alterations were associated with more favorable overall and metastasis free survival. RTK/RAS/RAF pathway alterations were associated with more favorable metastasis free survival. MIBC with no DNA damage response (DDR) gene alterations, DDR alterations of unknown significance and DDR deleterious alterations had pathologic downstaging rates of 37%, 48% and 81% respectively, with platinum-based neoadjuvant chemotherapy (p = 0.013). Patients with ERCC2 mutations had significantly higher pathologic downstaging with platinum-based neoadjuvant chemotherapy compared to patients without ERCC2 mutations (p = 0.025). MIBC with DDR gene alterations had better overall survival with neoadjuvant chemotherapy compared to MIBC without DDR alterations (p = 0.04). Importantly, MIBC patients with and without DDR alterations had similar overall survival in the absence of neoadjuvant chemotherapy (p = 0.78).

Conclusions:
In summary, TP53, RB1 and FGFR3 alterations as well as TP53/MDM2, cell cycle and RTK/RAS/RAF pathway alterations showed an association with tumor stage and patient outcomes. MIBC with DDR alterations had higher pathological downstaging as well as better overall survival compared to MIBC without DDR alterations after platinum−based neoadjuvant chemotherapy. In absence of neoadjuvant chemotherapy, MIBC with and without DDR alterations have similar patient outcomes.

Speaker: Sumit Isharwal, MSKCC, New-York, USA

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA