AUA 2017: Genomic Differences Between “Primary” And “Secondary” Muscle Invasive Bladder Cancer: Implications For Neoadjuvant Chemotherapy

Boston, MA ( Patients with secondary muscle-invasive bladder cancer (MIBC) have substantially worse outcomes with neoadjuvant chemotherapy compared to primary MIBC (Pietzak, et al. AUA 2016). The authors subsequently used next-generation sequencing to investigate genetic differences between primary and secondary MIBC specimens.

MIBC specimens from the Cancer Genome Atlas (TCGA) (n=131), the authors’ institutional genomic research database (n=569), were analyzed. A prospective clinical sequencing protocol (n=214) was used to identify 342 chemotherapy-naive urothelial MIBC specimens (270 primary and 72 secondary) that underwent whole-exome or targeted exon-capture sequencing. Primary and secondary MIBC specimens were compared for genomic alterations in 341 known cancer genes. Primary MIBC was defined as clinical stage ≥T2 on either initial or re-staging TUR on first bladder tumor diagnosis. Patients with a history of NMIBC (Tis, Ta, or T1 with uninvolved detrusor muscle in specimen) confirmed by a second cystoscopy prior to the eventual diagnosis of clinical stage ≥T2 were considered to have secondary MIBC.

270 primary MIBCs were compared to 72 secondary MIBCs specimens for differences in genomic alterations in 341 cancer-associated genes. Significant different rates of ERCC2, APC, and FGFR3 alterations were identified. FGFR3-activating mutations (S249C, Y373C) occurred more frequently in secondary MIBC specimens (18% [13/72] vs. 9% [24/270], p=0.03). APC mutations were only seen in primary MIBC specimens (5% [14/270] vs. 0% [0/72], p=0.047). Surprisingly, ERCC2 missense mutations, which are associated with extreme sensitivity to cisplatin chemotherapy, only occurred in primary MIBC specimens (12% [32/270] vs. 0% [0/72], p<0.001). After adjusting for multiple comparisons, only ERCC2 mutations remained significant (adjusted p =0.016).

In summary, ERCC2 mutations occurred exclusively in primary MIBC patients and may account for their improved outcomes with neoadjuvant chemotherapy compared to secondary MIBC patients.

Presented By: Eugene Pietzak, New York, NY

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre
Twitter: @Goldberghanan

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