<i>ERBB3</i> -altered clinically advanced urothelial bladder cancer: Genomic landscape study and therapeutic possibilities.

Abstract

799 Background: ERBB3 is often altered ( ERBB3 -alt) in advanced urothelial bladder cancer (aUBC) and its activation may drive tumor growth and treatment resistance, thus it may serve as a putative biomarker and therapy target. We explored the genomic landscape of ERBB3 -alt and ERBB3 -wild type ( ERBB3 -WT) aUBC. Methods: 9,969 cases of clinically aUBC underwent comprehensive genomic profiling (CGP) using a hybrid-capture based FDA-approved assay (FoundationOneCDx) to assess all classes of genomic alterations (GA). MSI status, TMB, HRD signature, genetic ancestry and COSMIC signature were all calculated from sequencing data for research use-only purposes in the context of this study. PD-L1 expression was determined by IHC using Dako 22C3 TPS assay. PD-L1 IHC was performed on a subset of samples for ERBB3- WT (N=136) and ERRB3 -alt (N=9). Results: 636 (6.4%) aUBC cases featured GA in ERBB3 including 90.2% short variant mutations, 8.8% amplifications and 1% had both. Compared to ERBB3 -WT aUBC, patients with ERBB3 -alt were slightly more often male (78.6% vs 74.7%). Both groups had similar genomic ancestry profiles (European range 84.9% to 86.6%). Median TMB was higher in ERBB3-alt aUBC (12.5 vs 6.3 mutations/Mb) as was TMB ≥10 mut/Mb (61.2% vs 33.0) and ≥20 mut/Mb (28.6% vs 11.1) (Table). APOBEC cosmic genomic signature was more frequent in the ERBB3 -alt aUBC (50.0% vs 30.3%). PD-L1 expression was higher in ERBB3 -WT aUBC with high positive (≥50% TPS) 19.1% vs 11.1% (not significantly different). Individual GA more frequent in the ERBB3 -alt cases included AKT2 (6.8% vs 3.5%), ARID1A (38.4% vs 24.4%), ERBB2 (24.2% vs 18.0%) and TERT (87.1% vs 77.5). GA more frequent in ERBB3-WT aUBC included CDKN2A (38.8% vs 27.2%), CDKN2B (31.2% vs 20.1%), FGFR3 (18.1% vs 14.6%) and MTAP (25.7% vs 16.4%). Conclusions: ERBB3 GA in aUBC identify a subset of cases with relatively distinct genomic characteristics, including higher median TMB and frequency of APOBEC signature as well as potential “targetable” pathways. CGP can help identify putative biomarkers for treatment selection and may inform clinical trial designs. Study limitations include retrospective nature, lack of clinical outcomes data annotation, selection and confounding biases. Genomic and molecular features associated with ERBB3 -altered versus ERBB3 -wildtype tumors. ERBB3-WT ERBB3-alt P-value† N 9333 636 Median TMB 6.3 12.5 &lt;.0001 TMB≥20 mut/Mb 11.10% 28.60% &lt;.0001 APOBEC Signature 30.30% 50.00% &lt;.0001 ARID1A 24.40% 38.40% &lt;.0001 CDKN2A 38.80% 27.20% &lt;.0001 ERBB2 18.00% 24.20% 0.0006 FGFR3 18.10% 14.60% 0.0482 KMT2D 23.60% 16.70% 0.0002 MTAP 25.70% 16.40% &lt;.0001 TERT 77.50% 87.10% &lt;.0001 †FDR corrected using Benjamini/Hochberg adjustment.