<i>ERBB2</i> mutations and association with molecular phenotype in urothelial carcinoma.
Authors: Marc Machaalani, Talal El Zarif, Paul Stockhammer, Karl Semaan, Marc Eid, Razane El Hajj Chehade, Rashad Nawfal, Emre Yekeduz, Amin Nassar, Gwo-Shu Mary Lee, Sylvan C. Baca, Toni K. CHOUEIRI, Michael J Grant, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2024)

4590 Background: Activating mutations (mut) in ERBB2 are present in up to 11% of urothelial carcinoma (UC). ERBB2 -targeted therapies have demonstrated encouraging results across multiple solid tumors. A better understanding of the mutational landscape of UC tumors harboring ERBB2 mut is warranted to guide treatment selection. Methods: This study included patients (pts) with bladder or upper tract UC who had genomic tumor profiling data in the AACR Project GENIE database. ERBB2 activating mut were confirmed using OncoKB , PolyPhen-2 , or the available literature. The cohort was then stratified into pts with ERBB2 mutant and ERBB2 wild type tumors. Clinical characteristics and genomic data were compared between groups using Chi-squared and Mann–Whitney U tests. FDR-adjusted q-values were determined by the Benjamini–Hochberg method. Results: The cohort included 4,069 pts with UC, and most pts (n=3,475, 85%) had bladder UC. 376 (9.2%) pts had tumors harboring ERBB2 -mutant UC. ERBB2 mut were significantly enriched in pts with bladder vs. upper tract UC (9.6% vs. 6.7%, p=0.04) and in males vs. females (10.2% vs. 6.7%, p&lt;0.001). The most common ERBB2 mut were S310F/Y (51.4%) and I767M (6.6%) missense mut. A higher enrichment with extracellular domain ERBB2 mut was observed in ERBB2 mutant bladder vs. upper tract UC (66.2% vs. 41.5%, p&lt;0.01), particularly for S310F/Y mut (55.5% vs. 36.6%, p=0.03). ERBB2 mutant tumors had a distinct genomic phenotype characterized by a higher median tumor mutation burden (TMB) (15.6 vs 9.1 mut/Mb, p&lt;0.0001), a lower rate of FGFR3 co-mut, and a higher rate of co-mut in several genes (Table). Among ERBB2 mutant tumors, the most common co-occurring amplifications occurred in E2F3 (14.5%) and ERBB2 (12.5%). ERBB2 mutant tumors were more enriched with ERBB2 amplifications vs. ERBB2 wild type tumors (12.5% vs 5.2%, p&lt;0.0001). Among ERBB2 mutant tumors, those with vs. without concomitant ERBB2 amplifications were associated with a higher frequency of co-occurring amplifications in CDK12 (61.5% vs. 0%, p&lt;0.0001), RARA (20% vs. 0%, p&lt;0.0001), and SUZ12 (12.5% vs. 0.72%, p&lt;0.0001). Conclusions: This study provides deeper insights into the biology of UC tumors that harbor activating ERBB2 mut. We demonstrate that tumors with activating ERBB2 mut exhibit distinct molecular phenotypes characterized by higher TMB, lower frequency of FGFR3 co-mutations, and higher frequency of co-occurring genomic alterations. These findings may help elucidate the patterns of response to ERBB2 -targeted therapies and guide future combination therapy studies in UC. Co-Mutation ERBB2 mutant UC% (n=376) ERBB2 wild Type UC% (n=3,693) Q-value FGFR3 8.8% (33) 22.9% (847) &lt;0.0001 ARID1A 38.2% (139) 23.7% (839) &lt;0.0001 KMT2A 21.6% (78) 9.6% (331) &lt;0.0001 ERCC2 19.6% (70) 9% (304) &lt;0.0001 ATM 18.6% (69) 10.5% (384) &lt;0.0001 NF1 15.6% (58) 6.2% (224) &lt;0.0001 BRCA1 11.1% (41) 4.7% (168) &lt;0.0001 CDK12 10.5% (35) 3.9% (126) &lt;0.0001