Clinicopathologic characteristics and genomic profiling of HER2-low advanced gastric or gastroesophageal junction cancer

Abstract

Background: Human epidermal growth factor 2 (HER2)-low expression has recently emerged as a potential therapeutic target with the advent of HER2-directed antibody-drug conjugates. However, the clinicopathologic and molecular features of HER2-low advanced gastric or gastroesophageal junction (G/GEI) cancer remain inadequately characterized.<br /> Patients and methods: We retrospectively analyzed 2007 patients with stage IV G/GEJ cancer treated between 2015 and 2022 at Yonsei Cancer Center, Korea. HER2 status was classified as HER2-high (immunohistochemistry [IHC] 3+ or IHC 24/in situ hybridization [ISH]), HER2-low (IHC 2+/ISH or IHC 1+) and HER2-null (IHC O). Clinicopathologic features and survival outcomes were assessed in patients receiving first-line doublet chemotherapy with or without immune checkpoint inhibitors (ICs). For molecular analyses, pretreatment tumors from 777 patients underwent in-house next-generation sequencing (NGS), excluding Epstein-Barr virus (EBV)-positive and microsatellite Instability (MSI)-high cases.<br /> Results: Among 2007 patients, 372 (18.5%) were HER2-high, 523 (26.1%) were HER2-low, and 1112 (55.4%) were HER2-Aull. HER2-low tumors closely resembled HER2-null tumors in histopathology, EBV status, MSI, and programmed death-ligand 1 status. In the survival analysis cohort (n = 1417) , first-line progression-free survival was 8.0 months (HER2-high), 6.0 months (HER2-low), and 6.1 months ), while overall survival was 17.2, 13.4, and 14.5 months, respectively. Combination with ICIs conferred greater survival benefit in HER2-low tumors compared with HER2-null tumors. In the NGS cohort (n = 777) , HER2-low tumors were significantly enriched for angiogenesis pathway alterations which were associated with worse survival, a pattern not observed in other subgroups.<br /> 1 Conclusions: HER2-low G/GEJ cancer represents a distinct biological subtype with intermediate survival outcomes and specific angiogenesis-related molecular features. These findings support the need for dedicated therapeutic strategies and further clinical research in HER2-low G/GEJ cancer.