Analysis Of Her2 Mutant Bladder Urothelial Carcinomas Reveals Unique Mutational Signature.

460 Background: Early work has described the presence of HER2 alterations in metastatic urothelial carcinomas (UC), particularly the micropapillary urothelial carcinoma (MPUC) subtype. We reviewed the genomic profiles of a large set of UC cases to further characterize HER2 altered UCs and how such alterations would suggest benefit from the expanding array of anit-HER2 therapeutics. Methods: Tissue from 2,150 UCs were assayed using hybrid capture-based comprehensive genomic profiling (CGP) of 186 to 315 genes plus introns from 14 to 28 genes commonly arranged in cancer. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA. Results: Within the UC dataset 74.6% of cases were male (1603/2150), with a median TMB of 7 mut/Mb. 383 genomic alterations (GA) of HER2 were identified in 15.5% (334/2150) of cases which exhibited a median TMB of 8.7 mut/Mb (p < 1E-5) vs patients with wildtype HER2, median TMB of 7 mut/Mb. The most frequent HER2 alterations were amplification HER2amp (45.7%, 175/383), S310F (19.8%, 76/383), and S310Y (7/6%, 29/383). Patients harbouring a HER2amp, S310 (n = 105) exhibited a median TMB of 8.7 and 12.2 mut/Mb, respectively. 42 patients presented with multiple ( > 1) HER2 GA and exhibited a median TMB of 11.3 mut/Mb (p < 0.1) vs patients with single HER2 GA, median TMB of 12.3 mut/Mb. Of patients with multiple HER2 alterations, 57% (24/42) harbored a HER2amp. The most common co-occuring HER2 alteration pair was an amplification and extracellular S310X alteration (38.1%, 16/42). Of these 16, the median TMB was 19.5 mut/Mb (average 22.7 mut/Mb). Morphological assessments were performed on the 24 cases harbouring a HER2amp and an additional HER2 GA. 8 cases displayed MPUC features 44.4% (8/18; 6 cases histology unavailable); of these MPUC cases, 75% (6/8), harboured a HER2 amp and S310 extracellular mutation. Conclusions: CGP of bladder urothelial (transitional cell) carcinomas reveals subclasses of HER2 altered cases. Drawing on recent advances in targeting HER2 alterations in breast cancer, dual HER2 blockade (e.g. combinations of mAB/TKI/mAB+ADC) may be needed for HER2amp cases. For cases with both HER2amp and S310 GA, neratinib monotherapy may be the agent of choice and thus may be effective in MPUC.