HER2 Positivity as a Prognostic Biomarker and Therapeutic Target in Advanced Biliary Tract Cancer: A Multi-institutional Analysis

PURPOSE: This study aimed to evaluate the prognostic relevance of HER2 positivity and the clinical impact of anti-HER2 therapy in the management of advanced biliary tract cancers using integrated multi-institutional data. EXPERIMENTAL DESIGN: This retrospective analysis included 388 patients with advanced biliary tract cancers and known HER2 status from Yonsei Cancer Center and MD Anderson Cancer Center between 2009 and 2023. HER2 positivity was defined as HER2 IHC 3+, IHC 2+ with in situ hybridization positivity, or ERBB2 amplification by next-generation sequencing. Clinical outcomes, including survival, and genomic profiling with curated oncogenic pathway enrichment were analyzed. RESULTS: HER2 positivity was observed in 25.2% of the epidemiology analysis cohort (n = 309). In the survival analysis (n = 310), HER2-positive biliary tract cancers were associated with shorter overall survival (OS); 13.7 vs. 17.1 months; HR, 1.25; 95% confidence interval (CI), 0.97-1.60 and significantly shorter first-line progression-free survival (5.1 vs. 7.4 months; HR, 1.91; 95% CI, 1.46-2.48) than HER2-negative biliary tract cancers. Anti-HER2 therapy significantly improved OS among HER2-positive patients (18.2 vs. 8.1 months; HR, 0.39; 95% CI, 0.21-0.62). Genomic analysis showed the strongest enrichment of angiogenesis pathway alterations in HER2-positive patients, whereas KRAS mutations were predominant in HER2-negative biliary tract cancers. CONCLUSIONS: HER2 is a clinically meaningful biomarker with prognostic and predictive relevance in advanced biliary tract cancers. Anti-HER2 therapy significantly improves survival in HER2-positive patients. These findings support routine HER2 testing, standardization of HER2 diagnostic criteria, and further prospective evaluation of HER2-targeted strategies for biliary tract cancers. See related commentary by Fitzpatrick and Harding, p. 1603.