C.K. Lee, D.H. Seo, S. Park, T. Yuh, Yong Wook Kim, H. Park, J.S. Shim, H.S. Kim, H.S. Kim, M. Jung, HC Chung, S.Y. Rha
First-line treatment of HER2-positive advanced gastric cancer is entering a second transformation. The central clinical question is shifting from whether HER2 blockade should be combined with chemotherapy to which HER2-targeted platform should anchor first-line therapy, how immune checkpoint inhibition should be integrated, and how HER2 heterogeneity and biomarker evolution should guide treatment sequencing.
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/GEJ) cancer remain inadequately characterized. 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 2+/in situ hybridization [ISH]+), HER2-low (IHC 2+/ISH- or IHC 1+) and HER2-null (IHC 0). Clinicopathologic features and survival outcomes were assessed in patients receiving first-line doublet chemotherapy with or without immune checkpoint inhibitors (ICIs). 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. RESULTS: Among 2007 patients, 372 (18.5%) were HER2-high, 523 (26.1%) were HER2-low, and 1112 (55.4%) were HER2-null. 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 (HER2-null), 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. 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.