ERBB3 driver genomic alterations in intrahepatic cholangiocarcinoma: A genomic landscape and clinical outcome study.

597 Background: HER3, a tyrosine kinase receptor encoded by ERBB3 lacks intrinsic catalytic activity but drives tumorigenesis and drug resistance when heterodimerized with other HER and non-HER receptors. The prevalence, spectrum, and clinical impact of ERBB3 alterations in biliary tract cancers (BTCs) remain poorly defined yet may inform resistance mechanisms and opportunities for HER2/HER3-directed therapies. Methods: We interrogated the following cohorts for intrahepatic cholangiocarcinoma (iCCA) cases: (a) the FoundationCORE database (b) the cBioPortal, and (c) a single-institution retrospective BTC cohort with ERBB3 alterations (IRB-approved). Analyses included alteration frequency, co-mutations, immune biomarkers, treatment outcomes, and survival. Results: 149 (2.02%) cases from the (a) CORE database (n=7380) harbored an ERBB3 alteration of which 48.5% were short variant base substitution mutations (SV) + 54.2% gene amplifications (6 copies or greater). The most commonly occurring co-mutations in the ERBB3 mutated group were TP53 (45.6%), CDKN2A (34.9%), CDK4 (33.6%), and ARID1A (18.1%), ERBB2 (20.8% ) and MDM2 ( 28.9 % ). Classic iCCA drivers were less common ( IDH1 12.7% vs 13.7%; FGFR2 6.7% vs 11.9%). The median TMB was higher (3.6 vs 1.3) and MSI-High status was more common (7.6% vs 1.4%) in ERBB3 altered patients. Similar trends were seen among (b) iCCA in cBioPortal (n=727), with 15 (2.06%) harboring ERBB3 alterations with 53.3% SV and 46.6% gene amplifications. In the institutional BTC cohort (c) (n=21), the median age was 63 years, 57% male. SV predominated (89.5%), with co-alterations in TP53 (38.1%), CDKN2A (21.0%), ARID1A (26.3%), and ERBB2 (15.8%). First-line therapy included gemcitabine/cisplatin (28%), gemcitabine/cisplatin/durvalumab (23%), and capecitabine ± gemcitabine (19%). Median time to progression was 4.7 months (range 1.4–7.7); median overall survival for the cohort was 27.3 months (95% CI, 5.7–90+ months), with 63% alive at last follow-up. The median survival of patients with metastatic disease was 9.5 months (range: 1.7-97.6 months). Conclusions: ERBB3 alterations occur in ~2% of iCCA and are associated with distinct genomic and immune features, including higher TMB, MSI-H, and enrichment of ERBB2 co-mutations. These findings suggest potential therapeutic vulnerability to HER2/HER3-targeted strategies. Prospective studies focusing on structural variants and co-alteration contexts are warranted.