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

Abstract 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 (BTCs), using integrated multi-institutional data. Experimental Design: This retrospective analysis included 388 patients with advanced BTCs and known HER2 status from Yonsei Cancer Center and MD Anderson Cancer Center between 2009 and 2023. HER2-positivity was defined as HER2 immunohistochemistry (IHC) 3+, IHC 2+ with in situ hybridization (ISH)-positivity, or ERBB2 amplification by next-generation sequencing (NGS). 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 BTCs were associated with shorter overall survival (OS) (13.7 vs. 17.1 months; HR, 1.25; 95% 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 BTCs. 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, while KRAS mutations were predominant in HER2-negative BTCs. Conclusion: HER2 is a clinically meaningful biomarker with prognostic and predictive relevance in advanced BTCs. 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 BTCs.